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The HepG2 cells were purchased from the National Center of Cell Sciences, Pune, India. The cells were maintained at 37°C and 5% CO 2 in complete media containing high glucose DMEM supplemented with 10% heat-inactivated (56°C for 30 min) fetal bovine serum (Gibco), 100 U/ml penicillin and streptomycin. For protein analysis, cells were seeded at a density of 0.3 × 10 6 cells per well in 6-well plates in 1.5 ml of complete medium. On day 1, after 24 h of plating, the complete DMEM was replaced with Opti-MEM (Gibco, Thermoscientific, Mumbai, India) and incubated at 37°C; 5% CO 2 for starvation. After the completion of starvation, the cells were incubated with DMEM containing 2% fetal bovine serum, 10 μg/ml cholesterol , and 10 μM ATS for 24 h. For drug intervention studies, cells were pretreated with OICR-9429 and resveratrol for 24 h. After 24 h of inhibitor treatment, cholesterol and ATS were added to the same plate. For RNA extraction, the cells were seeded in 24-well plates with a seeding density of 0.05 × 10 6 per well.
|
39566851_p1
|
39566851
|
Cell culture
| 4.125422 |
biomedical
|
Study
|
[
0.999517560005188,
0.0002759174385573715,
0.0002064766886178404
] |
[
0.9988465309143066,
0.0008202277240343392,
0.00025682226987555623,
0.00007639083924004808
] |
en
| 0.999996 |
The liver harvested from HFD and HFD + statin-treated groups was homogenized using a hand homogenizer with RIPA lysis and extraction buffer and centrifuged at 12,000 rpm for 10 min to pellet the cell debris. The supernatant was collected in fresh tubes, and the protein concentration was quantified using a Pierce BCA protein Assay kit . Briefly, the lysate was mixed with 2× Laemmli buffer and incubated for 10 min at 100°C, and samples were resolved by SDS-PAGE and transferred to nitrocellulose membranes. The membranes were blocked using 5% skimmed milk and were incubated with the primary antibodies ( supplemental Table S1 ) at 4°C overnight. The blots were washed three times with Tris-buffered saline with Tween-20 buffer and incubated with a secondary antibody. The antibody-antigen reactions were detected using the Clarity™ Western ECL Substrates (Bio-Rad, Kolkata, India). The blot images were taken using the ChemiDoc MP Imaging System (Bio-Rad). The optical density of the proteins was expressed as a ratio analysis of the optical density of GAPDH or total histone H3, detected in the same blot after stripping.
|
39566851_p2
|
39566851
|
Immunoblotting
| 4.12737 |
biomedical
|
Study
|
[
0.9995960593223572,
0.000239418339333497,
0.00016451657575089484
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[
0.9991161227226257,
0.00044944428373128176,
0.00036509669735096395,
0.00006933510303497314
] |
en
| 0.999996 |
Total RNA was extracted from the liver and cells using the TRIzol:chloroform:isopropanol method. Briefly, TRIzol was added to chopped liver tissue and homogenized using a hand homogenizer in microcentrifuge tubes incubated at room temperature for 5 min. To this, lysate chloroform was added to each sample and gently mixed by inverting the tubes and using vortex and incubated at room temperature for 5 min. The samples were then centrifuged at 12,000 g for 15 min at 4°C. A clear aqueous layer was formed at the top of the lysate mixture with sediment in the intersection. The upper aqueous layer was collected in a fresh centrifuge tube without disturbing the interphase. Isopropanol was added to the aqueous solution, mixed gently using the vortex mixer, and incubated at room temperature for 10 min. A white pellet was formed at the bottom of the tube. The supernatant was carefully discarded, and the pellet was washed twice with 75% ethanol, followed by centrifugation at 7,500 g at 4°C after each wash. The pellet was air-dried and resuspended in diethylpyrocarbonate-treated water. The purified RNA was quantified, and the quality was measured at an absorbance of 260:280 nm using Multiscan Go. About 2 μg of purified RNA was used for complementary DNA (cDNA) synthesis. cDNA was prepared using a High-Capacity cDNA Reverse Transcription Kit according to the manufacturer’s protocol . The cDNA was subjected to real-time PCR quantification using SYBR Green Master Mix on an Applied Biosystems QuantStudio 5 Real-Time PCR System. Relative amounts of mRNAs were calculated using the comparative ΔΔCT method with 18s as endogenous control.
|
39566851_p3
|
39566851
|
Total RNA extraction, reverse transcription, and RT-PCR
| 4.236623 |
biomedical
|
Study
|
[
0.9994045495986938,
0.00044008661643601954,
0.0001553420879645273
] |
[
0.9959049820899963,
0.0029750096146017313,
0.0009086970239877701,
0.0002113977971021086
] |
en
| 0.999997 |
HepG2 cells were seeded (0.8 × 10 6 ) in 60 mm culture dishes and treated with 10 μg/ml of cholesterol and 10 μM of ATS for 24 h. A chromatin immunoprecipitation (ChIP) assay was carried out according to the user manual provided by EpiQuik ChIP Kit (Farmingdale). In brief, the cells were washed with PBS following incubation in culture media containing 1% formaldehyde and incubated at room temperature for 10 min on a rocking platform (50–100 rpm). About 1.25 M glycine solution was added to the cells and following centrifugation at 1000 rpm for 5 min washed twice with ice-cold PBS. The cell pellet was resuspended using CP3A solution, incubated on ice for 10 min for cell lysis, and centrifuged at 5000 rpm for 5 min. The supernatant was collected, and CP3B solution containing protease inhibitor cocktail was added following incubation on ice for 10 min. DNA was fragmented using the micrococcal nuclear enzyme (NEB, Mumbai, India) digestion and incubated on ice for 20 min (fragment length: 200–1,000 bp) following the addition of EGTA to stop the activity of the enzyme. The fragmented DNA was immunoprecipitated using the ChIP antibody ( supplemental Table S1 ). The samples were washed and reverse crosslinked to obtain purified DNA. The real-time PCR was performed using ChIP primers, and all the reactions were normalized using input DNA and presented as mean ± SD.
|
39566851_p4
|
39566851
|
Chromatin immunoprecipitation and PCR analyses
| 4.136652 |
biomedical
|
Study
|
[
0.9995018243789673,
0.0003085848584305495,
0.0001895131717901677
] |
[
0.9990032315254211,
0.0006234879838302732,
0.000293661403702572,
0.00007957504567457363
] |
en
| 0.999996 |
For histological processing, the animals were anesthetized using isoflurane, and the liver tissue was perfused using PBS solution to 50 ml/10 min. The liver was fixed in a 4% paraformaldehyde solution overnight. Postfixation, the liver was placed in 15% sucrose in PBS until the tissue sank and then transferred to 30% sucrose solution overnight. The tissue was embedded in OCT and frozen immediately using liquid nitrogen, and 7 μm thick sections were cut at a cryotome (Leica), and the section was stored at −20°C until use.
|
39566851_p5
|
39566851
|
Sample preparation and immunofluorescence
| 4.120877 |
biomedical
|
Study
|
[
0.9989702701568604,
0.0007741623558104038,
0.0002555886167101562
] |
[
0.8606378436088562,
0.13578489422798157,
0.0023116120137274265,
0.001265631872229278
] |
en
| 0.999998 |
HepG2 cells were seeded in 24-well plates (seeding density = 0.1 × 10 6 cells/well) and incubated at 37°C in a 5% CO 2 incubator for 24 h. The cells were treated with respective treatments. Cells were fixed with 4% paraformaldehyde for 10 min at room temperature and washed with PBS thrice for 5 min. Cells or tissues were permeabilized with 0.1% Triton X-100 on ice for 5 min, following three 5 min washes with PBS, and subsequently blocked with 2% BSA for 1 h at room temperature. Further, the cells were incubated with primary antibodies ( supplemental Table S1 ) overnight at 4°C. The cells were then stained with a secondary antibody for 1 h and counterstained with 4',6-diamidino-2-phenylindole (1 μg/ml) for 10 min. After three additional 5 min washes, fluorescence imaging was done using the Zeiss ApoTome 2.0 microscope (Carl Zeiss), and images were processed using ImageJ software ( 15 ).
|
39566851_p6
|
39566851
|
Sample preparation and immunofluorescence
| 4.149167 |
biomedical
|
Study
|
[
0.9994679093360901,
0.000345421809470281,
0.00018669827841222286
] |
[
0.9976473450660706,
0.0018350363243371248,
0.0004109167493879795,
0.00010673326323740184
] |
en
| 0.999995 |
PCSK9 serum level in the animals treated with HFD and HFD + STATIN was measured using a commercially available ELISA kit (Quantikine ELISA MPC900; R&D, Bengaluru, India). In brief, the blood collected from the animals was allowed to clot for 2 h at room temperature and then centrifuged for 20 min at 2,000 g . The serum was collected and stored at −80°C for further analysis. Briefly, serum and standards were added to the 96-well plate precoated with a mouse antibody against PCSK9 for 2 h at room temperature. After washing, mouse PCSK9 conjugate was added to the wells and incubated for 2 h at room temperature. In subsequent washing steps, substrate solution was added to the wells for enzymatic reaction followed by stop solution addition to the plates. The optical was determined using a microplate reader set to 450 nm.
|
39566851_p7
|
39566851
|
ELISA
| 4.090904 |
biomedical
|
Study
|
[
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0.00024586671497672796,
0.0001522746024420485
] |
[
0.9990171194076538,
0.0005377974594011903,
0.00037336681270971894,
0.00007173374615376815
] |
en
| 0.999997 |
HepG2 cells attached to coverslips were transfected with siPCSK9 or scrambled RNA using Lipofectamine (Lipofectamine™ RNAiMAX Transfection Reagent). After 24 h of transfection, cells were switched to DMEM supplemented with reduced serum-containing treatment groups, as mentioned earlier. About 48 h later, or 60–62 h post-transfection, cells were incubated with 10 μg/ml of fluorescently labeled LDL (DiI-labeled) for 3 h. The coverslips were washed twice with 3% BSA containing ice-cold PBS. After fixing with 4% paraformaldehyde, cells were counterstained with 4',6-diamidino-2-phenylindole, and the uptake of the LDL was identified using a Zeiss ApoTome 2.0 microscope.
|
39566851_p8
|
39566851
|
LDL uptake assay
| 4.134447 |
biomedical
|
Study
|
[
0.9995328187942505,
0.0002858073858078569,
0.00018129500676877797
] |
[
0.998431384563446,
0.0010729859350249171,
0.0004056566976942122,
0.00008993653318611905
] |
en
| 0.999996 |
Statistical significance was determined by Student’s t -test (a two-tailed distribution with a two-sample equal variance). A P value of less than 0.05 was considered statistically significant. All the values are expressed as the mean ± SD. Statistical differences for more than two groups were determined by a one-way ANOVA for comparisons between groups. Statistical analyses were performed using GraphPad Prism software (GraphPad Software, Inc).
|
39566851_p9
|
39566851
|
Statistics
| 3.293823 |
biomedical
|
Study
|
[
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0.0003097560256719589,
0.0006065451307222247
] |
[
0.9027335047721863,
0.0939352735877037,
0.002773321233689785,
0.0005578247946687043
] |
en
| 0.999997 |
It is proven that statins increase the expression of PCSK9 by regulating the expression of SREBP2. In our study, first, we validated the effects of ATS on the regulation of PCSK9 expression. To mimic the in vivo disease condition, we treated HepG2 with ATS (10 μM) with or without high cholesterol (10 μg/ml). Our data revealed that the addition of ATS significantly upregulated both transcript and protein levels of PCSK9 under high cholesterol . In addition, we also showed that treatment with only ATS causes more than a 2-fold increase in the expression of PCSK9 . Statins are shown to induce post-translational modifications of histones ( 16 ), specifically histone 3; therefore, we began by assessing the enrichment levels of various histone H3 methylation and acetylation marks. In so doing, we evaluated the levels of five different lysine residue trimethylation marks in histone H3, namely H3K4me3, H3K9me3, H3K27me3, H3K36me3, and H3K79me3. Immunoblotting showed a 2-fold elevation in the levels of H3K4me3 in statin-treated cells . However, the other activating methyl marks like H3K36me3 and H3K79me3 remain unchanged . As the addition of methyl group may lead to either activation or repression of the gene, we also checked the modulation of repressive histone methylation marks like H3K9me3 and H3K27me3. Interestingly, we observed a slight decrease in the expression of H3K9me3 ; however, the changes were not significant and the levels of H3K27me3 remained unchanged . Fig. 1 ATS elevates PCSK9 levels and enhances H3K4me3 and H3K9ac by inducing the expression of methyltransferases and acetyltransferases (A) (n = 4). P CSK 9 mRNA levels in HepG2 cells exposed to cholesterol (CHL; 10 μg/ml) with or without ATS (10 μM). C, D: immunoblotting for PCSK9 (n = 6) (B), H3K4me3 (n = 4) (C), and H3K9ac (n = 4) (D) in HepG2 cells treated with ATS (10 μM) and/or CHL (10 μg/ml). E, F: immunofluorescence staining for H3K4me3 (n = 4) (E) and H3K9ac (n = 4) (F) in HepG2 cells treated with ATS (10 μM) and/or CHL (10 μg/ml). 4',6-Diamidino-2-phenylindole staining is shown in blue. Fluorescence intensity (AU) values of individual cells from three independent experiments are indicated. Magnification: 40x, scale represents 50 μm. G–L: immunoblotting for MLL1 N-ter (n = 3) (G), MLL1 C-ter (n = 4) (H), SET1B (n = 4) (I), CBP (n = 3) (J), GCN5L2 (n = 3) (K), and PCAF (n = 4) (L) in HepG2 cells exposed to ATS (10 μM) with or without CHL (10 μg/ml). H3K4me3 and H3K9ac protein levels were normalized to total histone 3, and other protein levels were normalized to GAPDH. Values represent mean ± SD. ∗ P < 0.05, ∗∗∗∗ P < 0.0001, by one-way ANOVA.
|
39566851_p10
|
39566851
|
ATS induces the expression of PCSK9 by modulating histone methylation and acetylation marks
| 4.248342 |
biomedical
|
Study
|
[
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[
0.9993672966957092,
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0.00008716576849110425
] |
en
| 0.999998 |
Next, following the screening of four different acetylation marks, H3K9ac, H3K14ac, H3K18ac, and H3K27ac, by immunoblotting, it showed elevation in the levels of H3K9ac in ATS and cholesterol-treated cells . The other acetylation marks like H3K18ac, H3K14ac, and H3K27ac remained unchanged . Interestingly, the marks that we observed to be significantly elevated, that is, H3K4me3 and H3K9ac, were activating histone marks, and enrichment of these marks to the promoter region leads to the transcriptional activation of genes. In addition, we also performed immunofluorescence that indicated the abundance of H3K4me3 and H3K9ac in statin-treated cells .
|
39566851_p11
|
39566851
|
ATS induces the expression of PCSK9 by modulating histone methylation and acetylation marks
| 4.109627 |
biomedical
|
Study
|
[
0.999541163444519,
0.0002174601686419919,
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[
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0.00005161792432772927
] |
en
| 0.999996 |
Since the addition of ATS elevates the levels of H3K4me3 and H3K9ac, we then examined the alteration in the activity of transferases specific to these histone modifications. SET1/COMPASS family of proteins adds a methyl group to the lysine 4 residue of histone 3. Immunoblotting showed upregulation of MLL1 N and C-terminal and SET1b upon statin treatment; however, the other proteins like MLL2, SET1A, Menin, WDR5, and WDR82 remained unaltered . This confirms that the activation of H3K4me3 upon statin treatment is driven by the MLL1 and SET1 complex of proteins. Similarly, we then investigated the changes in the acetyl transferases complex like CBP, PCAF, and GCN5L2, which are known acetyltransferases. Upon statin treatment, we observed significant upregulation in the expression of CBP and PCAF protein levels . These findings interest us in further exploring whether modulating the expression of PCSK9 would affect the regulation of methyl and acetyltransferases. Silencing the expression of P CSK 9 in HepG2 revealed no significant effect on the expression of methyltransferase proteins like MLL1,2 and acetyltransferases like PCAF and GCN5L2 .
|
39566851_p12
|
39566851
|
ATS induces the expression of PCSK9 by modulating histone methylation and acetylation marks
| 4.244011 |
biomedical
|
Study
|
[
0.9993823766708374,
0.00030878494726493955,
0.0003088423691224307
] |
[
0.9994528889656067,
0.0002023213601205498,
0.0002829351869877428,
0.00006184792437124997
] |
en
| 0.999997 |
Once we ascertained a significant upregulation in the expression of PCSK9 upon statin treatment, we next examined whether activation of PCSK9 expression was associated with changes in the histone H3K4me3 and H3K9ac marks. We performed ChIP-quantitative PCR (qPCR) to confirm the enrichment of H3K4me3 and H3K9ac to the promoter region of PCSK 9 under ATS treatment in HepG2. ChIP assay demonstrated more than 2-fold enrichment of both H3K4me3 and H3K9ac at the gene promoter region of P CSK 9 . These findings confirm the elevation of the methylation and acetylation marks upon statin treatment leads to an increase in the enrichment of K4me3 and K9ac to the promoter of PCSK9 . Furthermore, our data reveal the colocalization of H3K4me3 and H3K9ac to the promoter region of P CSK 9 , which further recruits the transcription machinery for active gene expression. Fig. 2 ATS causes H3K4me3 and H3K9ac enrichment at the P CSK 9 gene promoter (A, B) Chip-qPCR for P CSK 9 gene promoter in the DNA of HepG2 cells treated with cholesterol (10 μg/ml) and ATS (10 μM) immunoprecipitated with H3K4me3 (n = 4) (A) and H3K9ac (n = 4) (B) antibodies. Input samples were used as internal control and represent total chromatin. Data were expressed as fold change of ATS and cholesterol-treated cells with the expression of control samples. Values represent mean ± SD. Data were analyzed using one-way ANOVA. ∗∗ P < 0.01, ∗∗∗ P < 0.001.
|
39566851_p13
|
39566851
|
ATS increases the fold enrichment of activating histone marks to the promoter region of Pcsk9
| 4.1397 |
biomedical
|
Study
|
[
0.9995287656784058,
0.000290369032882154,
0.000180818562512286
] |
[
0.9994271993637085,
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0.0003117197484243661,
0.00007164113048929721
] |
en
| 0.999996 |
In vitro results showed that treatment with high cholesterol and ATS in hepatocytes elevated the H3K4me3 and H3K9ac marks. Similarly, we investigated the change in the regulation of histone marks using an animal model. To this end, we divided WT mice into two groups; both groups of mice were fed HFD for 20 weeks. After 10 weeks of HFD, one of the two groups was administered ATS (10 mg/kg) via drinking water for the remaining 10 weeks. Observations revealed no change in the body weights of the animals in either group . The serum LDL-C levels were significantly lower in the statin group than in the HFD group. However, serum HDL-C levels marginally increased in the statin group. No change was observed in the triglyceride and total cholesterol levels between the groups . First, we checked the PCSK9 levels in the HFD group compared to the chow animals. Interestingly, 20-week-fed HFD animals showed a significant increase in levels of PCSK9 at both transcript and protein levels . We then assessed the SREBP-2 and LDLR mRNA levels and observed reduced SREBP-2 and unchanged LDLR transcripts. In addition, we also checked the levels of methylation and acetylation marks in the HFD-fed mice; the results revealed that modest to no significant changes were observed in H3K4me3 and H3K9ac levels. As our study focuses on the regulation of statin-mediated epigenetic changes, which closely reflect clinical changes, we continued our study with HFD and HFD + ATS groups of mice. Our data revealed a significant increase in the serum PCSK9 levels in the statin-treated HFD-fed group . In addition, we also observed an increase in the liver transcript and protein levels of PCSK9 in statin-treated HFD-fed mice . Data also showed increased transcript levels of SREBP2 and LDLR in the statin group . Furthermore, immunoblotting analysis revealed that ATS significantly elevated the levels of H3K4me3 and H3K9ac in the liver of HFD with the statin group . In addition, immunofluorescence-based histological analysis confirms increased levels of H3K4me3 and H3K9ac in the liver of the two groups . We also assessed the protein level expression of histone methyltransferase in the liver of statin-treated HFD-fed mice. Immunoblotting results showed a significant increase in the MLL-1 expression and WDR5 ; however, the levels of the other proteins like SET1b remain unchanged . We also evaluated the expression of acetyltransferases, which showed a significant increase in the CBP and PCAF protein levels, but other proteins like GCN5L2 remain unchanged . Fig. 3 In vivo ATS administration with HFD increases the serum and liver PCSK9 expression (A–D) serum LDL-C (A), HDL-C (B), total CHL (C), and triglycerides (D) from HFD (n = 6) and HFD + ATS (n = 9) (10 mg/kg) fed mice (E) ELISA for PCSK9 expression in the serum of mice from HFD and HFD + ATS (10 mg/kg) fed groups. F: P csk 9 mRNA levels in the liver of HFD and HFD + ATS (10 mg/kg) fed mice groups. G: immunoblotting for PCSK9 in the liver of mice fed with HFD and HFD + ATS (10 mg/kg). Values represent mean ± SD. ∗ P < 0.05, ∗∗ P < 0.01, by unpaired t -test. Fig. 4 ATS enriches MLL1 and CBP/PCAF-driven H3K4me3 and H3K9ac in HFD-fed mice. Whole liver sections and extracted proteins were analyzed in HFD (n = 6) and HFD + ATS (n = 9). A, B: immunoblotting for H3K4me3 and H3K9ac; immunofluorescence of H3K4me3 (C) and H3K9ac (D). Cells were stained with 4',6-diamidino-2-phenylindole (blue), and merge images show colocalization of H3K4me3 or H3K9ac with 4',6-diamidino-2-phenylindole. Magnification 60X, scale represents 20 μm. Immunoblotting for MLL-1n (E), SET1B (F), WDR5 (G), CBP (H), GCNL52 (I), and (J) PCAF in the treated and untreated mice. H3K4me3 and H3K9ac protein levels were normalized to total histone 3, and other protein levels were normalized to GAPDH. Values represent mean ± SD. Data were analyzed using unpaired t -tests for treatment versus HFD comparisons. ∗ P < 0.05, ∗∗ P < 0.01.
|
39566851_p14
|
39566851
|
ATS administration in HFD-fed mice increases H3K4me3, H3K9ac, and subsequently PCSK9 expression
| 4.264526 |
biomedical
|
Study
|
[
0.999303936958313,
0.00046462350292131305,
0.0002314052835572511
] |
[
0.9992883801460266,
0.0002086122549371794,
0.00040576039464212954,
0.00009734214836498722
] |
en
| 0.999995 |
We speculated whether blocking the methylation of H3K4 would reverse the PCSK9 expression. To determine this, we pretreated cells with OICR-9429 (10 μM and 20 μM), a small-molecule inhibitor (which disrupts WDR-MLL interaction to block the catalysis of H3K4me3), followed by ATS and cholesterol. Immunoblotting analysis revealed a reduction in the levels of H3K4me3 in hepatocytes . We also confirmed the effects of OICR-9429 using immunofluorescence, which showed a significant decrease in the H3K4me3 . Correspondingly, we also determined the expression of PCSK9 upon treatment with OICR-9429. Through such assessment, we observed a significant reduction in the expression of PCSK9 at both protein and transcript levels . This confirmed that statin regulates the expression of PCSK9 via MLL-mediated elevation of H3K4me3 levels, and inhibiting the histone methyl transferase activity reverses the statin-induced upregulation of PCSK9. Fig. 5 Pharmacological inhibition of the activating histone marks reversed the ATS-induced upregulation of PCSK9 immunoblotting for H3K4me3 (n ≥ 4) (A) and PCSK9 (n ≥ 5) (B) in HepG2 pretreated with MLL inhibitor, OICR-9429 (10 μM and 20 μM, 18 h) in combination with ATS (10 μM), with or without cholesterol (10 μg/ml, 24 h). C: PCSK9 mRNA (n = 4) levels in the cells pretreated OICR-9429 and ATS with or without cholesterol with 18s as endogenous control. D: immunofluorescence of H3K4me3 (n = 4) in cell nuclei of HepG2 and the fluorescence intensity AU values were calculated per individual cells and are indicated together with mean and SD. Immunoblotting for H3K9ac (n = 4) (E) and PCSK9 (n = 4) (F) in HepG2 pretreated with RVT (10 μM and 20 μM, 18 h) in combination with ATS (10 μM) with or without cholesterol (10 μg/ml, 24 H). G: PCSK9 mRNA (n ≥ 4) levels in the cells pretreated with RVT and ATS with or without cholesterol (H) H3K9ac (n = 4) expression in HepG2, the fluorescence intensity AU were calculated per individual cell and computed as mean and SD. H3K4me3 and H3K9ac protein levels were normalized to total histone H3 protein levels, and PCSK9 protein levels were normalized to GAPDH levels. Values represent mean ± SD. Data were analyzed using one-way ANOVA for treatment versus control comparisons. ∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗∗ P < 0.0001. RVT, resveratrol.
|
39566851_p15
|
39566851
|
Pharmacological inhibitors against H3K4me and H3K9ac reverse the statin-induced expression of PCSK9
| 4.177508 |
biomedical
|
Study
|
[
0.9994543194770813,
0.0003426215553190559,
0.00020303178462199867
] |
[
0.9993473887443542,
0.00023999995028134435,
0.0003376514359842986,
0.00007497281330870464
] |
en
| 0.999996 |
Our in vitro and in vivo data showed that the administration of statin significantly elevated the acetylation of H3K9. Along similar lines, we asked whether the reversal of histone acetylation by targeting histone deacetylase (HDAC) would reverse the effects of statin. As the literature suggests epigenetic regulation of PCSK9 by SIRT6, we used resveratrol (10 μM and 20 μM), which is a polyphenol compound known to activate SIRT6, an NAD + -dependent HDAC ( 17 ). First, we confirmed the effects of resveratrol on S IRT 6 by qPCR, and we observed a 2-fold increase in the expression of S IRT 6 . Second, upon pretreatment of cells with resveratrol followed by treatment with statin and cholesterol, we observed a significant decrease in the levels of H3K9ac. In addition, immunofluorescence staining confirmed the benefits of resveratrol . Further, we checked the direct effects of resveratrol on the regulation of PCSK9. Our data revealed resveratrol reverses the statin-dependent upregulation of PCSK9 . So, this concludes that resveratrol reduces the acetylation levels by activating HDACs and reverses the statin-induced upregulation of PCSK9.
|
39566851_p16
|
39566851
|
Pharmacological inhibitors against H3K4me and H3K9ac reverse the statin-induced expression of PCSK9
| 4.309461 |
biomedical
|
Study
|
[
0.9995423555374146,
0.00031195880728773773,
0.00014567044854629785
] |
[
0.9989650249481201,
0.00031951942946761847,
0.0005974742234684527,
0.00011794696183642372
] |
en
| 0.999997 |
Treatment with OICR-9429 or resveratrol reversed the statin-induced upregulation of PCSK9. Furthermore, this interests us to check whether these inhibitors, along with statins, would improve the overall LDL uptake by cells by LDLR, a functional examination for their suitability in reducing the free LDL. First, we treated cells with inhibitors in the absence of high cholesterol, followed by the addition of ATS (10 μM) for 24 h. Last, DiI-LDL was added for 3 h before fixing the cells with formaldehyde. The weighted mean intensity revealed a significant increase in the uptake of LDL in OICR-9429 and resveratrol-treated groups compared to the only ATS groups. As a proof of concept, a positive control group, where PCSK9 expression was silenced using siRNA , followed by treatment with ATS. The DiI-LDL uptake in the PCSK9 silenced group was drastically increased compared to only the statin-treated cells . An increase in the uptake of DiI-LDL by the cells in the PCSK9-inhibited group suggests elevation in the number of LDLR expressed on the membrane of hepatocytes. This confirms that inhibition of H3K4me3 and H3K9ac lowers PCSK9 levels and restores the LDLR to the surface of hepatocytes, which helps improve LDL uptake. Fig. 6 Inhibition of PCSK9 in combination with ATS improved the LDL uptake by hepatocytes Representative images are shown for the fluorescent LDL uptake after 3 h of incubation. A: the images of fluorescent dye-labeled LDL endocytosed by the cells (shown in red) and the nuclei (blue) were merged to show LDL uptake by each cell. The LDL influx by cells was calculated by weighted mean Dil-LDL intensities and nuclei count for each cell population. Values represent mean ± SD, and data points are the average weighted mean of three independent experiments. Cells (n ≥ 50) from at least 10 different microscopic frames were analyzed for each independent experiment (n = 3). B: the representative blots for PCSK9 and GAPDH show reduced protein levels normalized to GAPDH. Data were analyzed using one-way ANOVA for treatment versus control comparisons. ∗ P < 0.05, ∗∗ P < 0.01. RVT, resveratrol.
|
39566851_p17
|
39566851
|
Combination of statin and OICR-9429 or resveratrol increases the LDL uptake in hepatocytes
| 4.166183 |
biomedical
|
Study
|
[
0.9994528889656067,
0.0003518385929055512,
0.00019528719712980092
] |
[
0.9993422627449036,
0.00020825555839110166,
0.00037029440863989294,
0.00007915050082374364
] |
en
| 0.999998 |
In this study, we demonstrated that statin regulates the expression of PCSK9 by modulating the levels of H3K4me3 and H3K9ac in hepatocytes. ATS elevates the expression of methyl transferases and acetyltransferases, which facilitates the enrichment of H3K4me3 and H3K9ac in the P CSK 9 gene promoter. Notably, colocalization of H3K4me and H3K9ac leads to the activation of the PCSK9 gene transcription. Mechanistically, inhibiting these activating histone marks using OICR-9429 or resveratrol reversed the statin-induced upregulation of PCSK9. A combination of statins and pharmacological inhibitors significantly improved the LDL uptake in hepatocytes. Thus, we showed the pleiotropic effects of statins at multiple levels, from modulating histone marks to activating methyl and acetyltransferase activity. These findings broaden our understanding of statin-mediated PCSK9 regulation and suggest a possible reason behind statin resistance that limits patient utility.
|
39566851_p18
|
39566851
|
Discussion
| 4.331805 |
biomedical
|
Study
|
[
0.999484658241272,
0.00037964442162774503,
0.00013569377188105136
] |
[
0.9986782670021057,
0.0003630327701102942,
0.0008036924409680068,
0.000154948778799735
] |
en
| 0.999997 |
Statins inhibit the cholesterol de novo synthesis that causes the activation of SREBP-2, further regulating the expression of LDLR ( 11 ). An increase in the surface LDLRs on hepatocytes helps in the clearance of LDL-C from serum. Thus, statins are the most prescribed lipid-lowering drugs for treating hypercholesterolemia ( 2 ). However, activation of SREBP-2 also increases the activity of PCSK9, while statins effectively decrease cholesterol levels; their efficacy is diminished by this increase in PCSK9 ( 10 , 18 ). A recent study on statin naïve coronary artery disease patients showed a relationship between circulating mature PCSK9 and statin hyporesponsiveness in these patients. Post-a-month treatment with statin, 11% of the patients showed baseline mature PCSK9 levels >228 ng/ml associated with hyporesponsiveness to statin ( 19 ). Similar findings suggest that doubling the statin dosage (80 mg) caused a rapid increase in serum PCSK9 levels by 47% within 4 weeks of treatment ( 20 ). Furthermore, a randomized clinical trial treatment of patients with simvastatin, ezetimibe, and a combination of both revealed only simvastatin led to an increase in serum PCSK9 levels. However, only ezetimibe or the combination of both drugs is not associated with the increase in PCSK9 levels ( 21 ). These findings suggest a strong correlation between statins and PCSK9 levels in patients; thus, it is critical to understand the different ways statins modulate the expression of genes. Statins have been shown to alter gene expression by inhibiting HDAC activity and influencing many miRNAs in both in vitro and animal models ( 22 ). Previously, studies have proposed that inhibition of cholesterol biosynthesis diverted the use of acetyl CoA by HATs to elevate the histone acetylation; however, this has not been proven yet ( 23 ). Tao et al. revealed that PCSK9 can also be regulated by epigenetic marks like acetylation of H3K9 and H3K56 ( 13 , 14 ). These indicate that PCSK9 can also be regulated by epigenetic modification, and statins are known for its pleiotropic effects; therefore, we investigated the statin-mediated epigenetic regulation of PCSK9 expression. Initially, we checked the PCSK9 levels in 20-week HFD-fed mice and observed a 2-fold increase in the expression of hepatic PCSK9. Similar observations were reported in other studies, where administration of HFD for more than 8 weeks significantly increased the hepatic PCSK9 levels by more than 2-fold ( 13 , 24 ). In contrast, the hepatic PCSK9 was reduced when the HFD was fed only for 24 h or 1 week ( 25 , 26 ). This shows that chronic exposure to HFD leads to high PCSK9 levels. We also investigated the methylation and acetylation levels in the HFD-fed mice, and these modifications showed limited changes. However, our data revealed that ATS administration, and high cholesterol, significantly induces the levels of activating histone marks H3K4me3 and H3K9ac in both HepG2 and statin-fed mice groups. In addition, we also showed that treatment of hepatocytes only with ATS leads to a significant increase in the levels of H3K4me3 and H3K9ac . Previously, it was reported that colocalization of H3K4me3 and H3K9ac leads to active gene transcription. Gates et al. ( 27 ) demonstrated that H3K4me3 promotes transcription initiation, and H3K9ac is involved in the elongation of the gene by releasing the pol II pause and recruiting the superelongation complex to the chromatin. Our ChIP-qPCR results showed the enrichment of activating marks H3K4me3 and H3K9ac to the promoter, suggesting statins involvement in the active gene transcription of Pcsk9 .
|
39566851_p19
|
39566851
|
Discussion
| 4.445281 |
biomedical
|
Study
|
[
0.9993442893028259,
0.00045316480100154877,
0.00020254704577382654
] |
[
0.9979721903800964,
0.00031489660614170134,
0.001556502771563828,
0.00015644062659703195
] |
en
| 0.999997 |
To date, our understanding of how statins modulate histone methylation is very limited. However, a recent study illustrated that HFD-fed Caenorhabditis elegans showed elevated H3K4me3, which further induced transcription factors like SREBP, DAF-16/FOXO, and nuclear receptors NHR-49 and NHR-80. Among them, only SREBP responded to alteration in H3K4me3 and activated genes involved in lipid metabolism leading to multigenerational obesogenic effects ( 28 ). This shows that H3K4me3 plays a crucial role in cholesterol metabolism. Since we reported that statin increases the levels of H3K4me3, we were interested in looking for the expression of the methyl transferases and their binding partners/associated proteins. The SET1 and MLL1 proteins of the SET1/COMPASS contain the catalytic domain responsible for the monomethylation, dimethylation, and trimethylation of H3K4 ( 29 ). We checked the expression of the SET1/COMPASS family of proteins and observed an increase in the expression of SET1b and MLL1-n in the statin-treated group of hepatocytes and liver of statin-treated mice. This study for the first time reported statin-mediated elevation of H3K4me3, which further increases PCSK9. In addition to this, we also assessed the alteration in the expression of HATs under statin treatment. HATs like p300, CBP, GCNL5, and PCAF are transcriptional coactivators, and localization of these to the promoter causes active gene transcription. Deletion of GCN5/PCAF in mouse embryonic fibroblasts drastically reduces the acetylation of H3K9 ( 30 ). Thus, we evaluated the HAT expression, and our data revealed an increase in the expression of CBP and PCAF in the liver of the statin-treated group of animals. This suggests that statin increases the HAT expression, further elevating H3K9ac. Similarly, a recent study emphasizes that p300 acetyltransferase inhibition using piceatannol reverses the statin-mediated upregulation of PCSK9 ( 14 ). All these findings suggest that increased serum PCSK9 is a result of alterations of histone marks by statins, which further leads to resistance and toxicity.
|
39566851_p20
|
39566851
|
Discussion
| 4.475756 |
biomedical
|
Study
|
[
0.9993640780448914,
0.00043981455382891,
0.00019606905698310584
] |
[
0.9986189603805542,
0.0003949975944124162,
0.0008063054410740733,
0.00017979614494834095
] |
en
| 0.999996 |
To further corroborate these results, we inhibited the alteration of histone marks by using pharmacological inhibitors. One of the well-known small-molecule inhibitors of H3K4me3 is OICR-9429 ( 31 ). OICR-9429 treatment in hepatocytes reduced the methylation of H3K4 and reversed the statin-induced upregulation of PCSK9. As studies have shown, SIRT6 is one of the regulators of PCSK9. We treated cells with resveratrol, which is involved in the direct activation of sirtuins ( 32 , 33 ). Similarly, we observed a significant increase in the expression of S IRT 6 in the presence of resveratrol. Upon treating cells with resveratrol, we observed a significant reduction in the levels of H3K9ac and inhibited the statin-mediated upregulation of PCSK9. As these epigenetic inhibitors successfully decreased the expression of PCSK9, we further checked the overall LDL uptake of hepatocytes. The presence of both inhibitors and statin recuperated the uptake of LDL by hepatocytes. This indicates that the administration of histone methyl transferase or acetyltransferase inhibitors along with statin may help reduce statin resistance and enhance the clearance of LDL-C from the serum.
|
39566851_p21
|
39566851
|
Discussion
| 4.230887 |
biomedical
|
Study
|
[
0.9995458722114563,
0.00030015830998308957,
0.00015395930677186698
] |
[
0.9989435076713562,
0.00026758157764561474,
0.0006922670872882009,
0.0000966622174018994
] |
en
| 0.999996 |
The epigenetic changes are known to be controlled by many external factors, which consecutively regulate the expression of genes in the progression of several diseases ( 31 , 34 , 35 , 36 ). Post-translational modification of histone methylation and acetylation has recently been acknowledged for their involvement in the progression and development of atherosclerotic plaque by regulating the epigenome modification in different cells ( 34 ). Moreover, lately, a methyl transferase inhibitor called tazemetostat has been Food and Drug Administration approved to stop cancer cell dedifferentiation. These findings shed light on epigenetic modifiers as the crucial regulators of various diseases. Similarly, a comprehensive understanding of the epigenetic regulation of PCSK9 will help design potential therapeutic strategies to counter the adverse effects of statins in hyperlipidemia patients.
|
39566851_p22
|
39566851
|
Discussion
| 4.111272 |
biomedical
|
Study
|
[
0.9993515610694885,
0.00032233999809250236,
0.000326009962009266
] |
[
0.7236631512641907,
0.0017749321414157748,
0.2741309106349945,
0.0004309362266212702
] |
en
| 0.999998 |
Together, these findings suggest that statins modulate the expression of PCSK9 by regulating the enrichment levels of H3K4me3 and H3K9ac at the PCSK9 gene promoter. Inhibition of these activating histone modifications repressed statin-dependent PCSK9 expression. Although we reported inhibiting PCSK9 with OICR-9429 or resveratrol improves the LDL uptake in hepatocytes, the lack of pharmacological intervention in animal models limits our understanding of how these inhibitors will help reduce the serum LDL-C and overcome statin resistance. In hepatocytes, statin treatment increases the expression of H3K4me3 by upregulating the expression of SET1B and MLL1; however, specific knockdown of SET1B or MLL1 proteins will provide interesting insights into the involvement of the methyltransferase with PCSK9 regulation. Additional studies are required to investigate the underlying mechanisms involved in statin-mediated epigenomic elevation of PCSK9 in an in vivo setting. In addition, mapping the statin-mediated alterations in the epigenome that regulate PCSK9 expression and other key molecular players would provide important insights into its physiological implications. Despite the above limitations, our study strongly suggests the regulation of PCSK9 by statins via epigenetic pathways. Thus, chromatin remodeling may help negate the adverse effects of statin treatment, primarily of increasing PCSK9 during hypercholesterolemia.
|
39566851_p23
|
39566851
|
Discussion
| 4.512148 |
biomedical
|
Study
|
[
0.9993239641189575,
0.00048359966604039073,
0.00019247156160417944
] |
[
0.9973948001861572,
0.00047607687884010375,
0.001916408189572394,
0.00021268623822834343
] |
en
| 0.999995 |
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
39566851_p24
|
39566851
|
Data availability
| 0.925836 |
other
|
Other
|
[
0.377620130777359,
0.003000538796186447,
0.6193793416023254
] |
[
0.01637202501296997,
0.9823768138885498,
0.0006611060816794634,
0.0005900486721657217
] |
en
| 0.999996 |
This article contains supplemental data .
|
39566851_p25
|
39566851
|
Supplemental data
| 0.978389 |
biomedical
|
Other
|
[
0.8073040246963501,
0.002720913151279092,
0.18997499346733093
] |
[
0.03222294896841049,
0.9639564156532288,
0.0026808236725628376,
0.001139768399298191
] |
fr
| 0.857139 |
Approved by the Institutional Animal Ethics Committee, IIT Kharagpur (protocol no: IE-1/PCS-SMST/2.19).
|
39566851_p26
|
39566851
|
Ethics approval
| 0.733104 |
biomedical
|
Other
|
[
0.5980566740036011,
0.008015420287847519,
0.3939278721809387
] |
[
0.007167065050452948,
0.9904043674468994,
0.0013469484401866794,
0.0010815991554409266
] |
en
| 0.999997 |
The authors declare that they have no conflicts of interest with the contents of this article.
|
39566851_p27
|
39566851
|
Conflict of interest
| 0.954116 |
other
|
Other
|
[
0.010779193602502346,
0.0010554944165050983,
0.9881653785705566
] |
[
0.003445772686973214,
0.9945124387741089,
0.0012665456160902977,
0.0007752737728878856
] |
en
| 0.999997 |
In the absence of disease-modifying therapies for Parkinson's disease (PD), much research focuses on improving quality of life, health, and wellbeing. A new care model, Proactive and Integrated Management and Empowerment in Parkinson's (PRIME) , is a multicomponent intervention being evaluated within a randomized controlled trial (RCT) which is enrolling patients with parkinsonism, and therefore includes those with frailty, multimorbidity and/or cognitive impairment as well as informal caregivers . This intervention aims to improve the experience of living with PD and align care with ‘what matters most’ to individuals . We sought to assess benefit of this innovative care model using an outcome which is aligned to the project aims, captures the hypothesised impact and is meaningful to patients.
|
PMC11699366_p0
|
PMC11699366
|
Background and aims
| 4.072709 |
biomedical
|
Study
|
[
0.9928029179573059,
0.006645858287811279,
0.000551220087800175
] |
[
0.9826997518539429,
0.015465485863387585,
0.0013237933162599802,
0.0005109839257784188
] |
en
| 0.999999 |
Patient-reported outcome measures (PROMs), which collect outcomes directly from the people who experience them are increasingly being used alongside or instead of biomarkers and measures of morbidity, mortality and healthcare use . Many of these are disease-specific which has limitations, particularly in older people, as well as those with multiple long-term conditions, disability or short life expectancy in whom there are often trade-offs when considering multiple interventions/treatments .
|
PMC11699366_p1
|
PMC11699366
|
Background and aims
| 3.689006 |
biomedical
|
Other
|
[
0.9918177127838135,
0.0036586446221917868,
0.004523678217083216
] |
[
0.028640467673540115,
0.7172559499740601,
0.25312915444374084,
0.0009744032868184149
] |
en
| 0.999999 |
Given the complexity and heterogeneity of PD, PROMs focusing on a single domain, such as motor symptoms, are often not appropriate and risk overlooking the spectrum of experience. Conventional outcome measures may not be validated for proxy completion on behalf of someone lacking capacity and, whilst some outcomes have been endorsed for use in PD dementia , floor and ceiling effects may render them unsuitable for use in individuals with intact cognition, precluding their use in a trial recruiting across the disease spectrum. When considering a complex intervention like the PRIME-UK care model, there is a need for PROMs which capture the downstream effects of the multiple components, which are aiming to produce impact across physical, psychological and social domains.
|
PMC11699366_p2
|
PMC11699366
|
Background and aims
| 3.974225 |
biomedical
|
Study
|
[
0.9988079071044922,
0.0007588677108287811,
0.00043329416075721383
] |
[
0.5528044700622559,
0.058701418340206146,
0.3875899910926819,
0.0009041022276505828
] |
en
| 0.999996 |
Given the limitations of traditional PROMs, novel outcomes that can more holistically capture personal experiences and wellbeing have been proposed. Cools et al . suggested happiness as an outcome in PD studies but this also has limitations since wellbeing is a multi-dimensional construct encompassing psychological wellbeing, not simply the pursuit of happiness . Traditional outcomes can be made more patient-centred by reframing them into goal-orientated outcomes: instead of using a pain inventory for arthritis, we may assess pain control sufficient to carry out an activity important to the patient . Instead of disease-free survival, the goal-orientated outcome would be survival until a personal milestone, or there may be no survival outcome if this were not a patient priority . Goal attainment scaling (GAS) requires individuals to set meaningful goals with progress subsequently rated on a standardised scale and a formula applied to calculate an aggregated score . In addition to clinical use as an intervention to motivate behavioural change, goal-orientated approaches have been used to evaluate interventions in research settings, including amongst people with multiple sclerosis , older adults living with frailty and PD patients [ , , , , ]. We aimed to select a suitable primary outcome measure and adapt it for use within the PRIME-UK RCT.
|
PMC11699366_p3
|
PMC11699366
|
Background and aims
| 4.076377 |
biomedical
|
Study
|
[
0.9990113973617554,
0.0006437255069613457,
0.0003449153737165034
] |
[
0.9976000189781189,
0.0008410072769038379,
0.0014659147709608078,
0.00009299939119955525
] |
en
| 0.999998 |
The PRIME RCT, approved by the London-Harrow Research Ethics Committee , aimed to enrol a ‘real-world’ population to make the findings generalisable to clinical practice. The outcome measure therefore needed to be suitable for use in participants across the spectrum of disease stage and phenotype, including those with cognitive impairment and multimorbidity, as well as meaningful to patients and able to capture the effect of a complex intervention acting across multiple domains.
|
PMC11699366_p4
|
PMC11699366
|
Selection of a primary outcome measure
| 3.727238 |
biomedical
|
Study
|
[
0.9614421725273132,
0.03682367131114006,
0.001734080957248807
] |
[
0.8314895033836365,
0.1640128642320633,
0.002370458794757724,
0.00212721130810678
] |
en
| 0.999995 |
Goal-orientated outcomes offered a way to elicit an individual's goals, and generate a numerical score to allow assessment of attainment over time and comparison between patients with multiple personalised goals. From a literature review, we identified four goal-based measures which have been used to evaluate interventions, rather than goal-setting as an intervention itself, each of which we deemed to have pros and cons based on the practicality of use within a trial, prior use in PD and psychometric properties ( Table 1 ). We selected the Bangor Goal-setting Interview (BGSI) as the PRIME RCT primary outcome measure because it was developed for research purposes, rather than for clinical settings with subsequent adaptation, and has advantages for this context ( Table 1 ), including a freely-available manual and the flexibility to adapt it to specific settings . It has also been shown to be feasible for use with people with PD dementia and Dementia with Lewy Bodies . Table 1 Interventional studies, including trials, which included a goal-orientated outcome measure. Table 1 Goal-orientated outcome measure Brief description of measure Examples of uses including study population Pros Cons Goal attainment scaling (GAS) Main problem area/domain is identified during an interview with the patient and goal(s) agreed jointly; the expected outcome defined as achievement level 0 is agreed and descriptors are pre-agreed for level −1/-2 and +1/+2, representing a worse or better outcome than expected respectively. Each goal is rated on the 5-point scale at follow up. - A single blind RCT of cognitive training, transfer training and psychomotor training in people with PD and MCI - A pilot, double-blind RCT of memantine versus placebo for PD dementia - A service evaluation of dance classes for PD - An RCT of comprehensive geriatric assessment as an adjunct to usual care in frail older patients - Goals can be weighted to account for the importance to the patient and/or anticipated difficulty - There is no requirement to record baseline scores (although these are usually rated as −1) - Performance is judged against predefined levels. - Potentially time-consuming to define pre-determined levels for each of the 5 outcome score levels (−2 to +2) - Zero and minus scores can be discouraging for patients - If baseline score is recorded as −1 (which allows for deterioration to −2), it is not possible to record if a goal is partially achieved (but does not warrant the expected outcome level of 0) . Patient-specific functional scale (PSFS) A self-reported measure in which patients list up to five activities they struggle to do because of their condition/problem. For each, they rate from 0 to 10 their ability to perform the activity at baseline and then subsequently at follow-up. - A prospective, observational pre-post study of goal-orientated rehabilitation in individuals with a neurological condition (including PD and MS) - RCTs in populations with COPD , low back pain and cervical radiculopathy . - May be less time-consuming and require fewer resources than a semi-structured interview as the process is patient-directed - Reported to have good reliability, validity and responsiveness in a range of musculoskeletal conditions including mechanical back pain . - Does not involve a semi-structured interview so the patient is not guided/supported through the process which may be challenging for some patient groups including those with cognitive impairment - Lack of evidence for use in neurological disease . Bangor Goal-setting interview (BGSI) The patient sets goals in a collaborative interview with the option for an ‘informant’ to provide input. Goal attainment descriptors are pre-defined to indicate what would constitute e.g. 0, 50, 100 % attainment. Current attainment is rated on a 1 to 10 scale, with option to rate importance and motivation to change. Attainment is rated from 1 to 10 at follow-up. - Primary outcome in a single blind pilot RCT of cognitive rehabilitation versus relaxation therapy for PD dementia/Lewy Body Dementia - Primary outcome in a single-blind RCT of goal-orientated cognitive rehabilitation in early-stage dementia, the’GREAT’ trial - Developed for research purposes and the manual includes specific guidance on use of BGSI in an RCT - The manual and recording sheet are freely available for researchers to use and include resources to guide the interview, written in an accessible format, suitable for individuals with cognitive impairment - Incorporates the option, not only for an informant to support the process, but also for a caregiver to independently rate attainment - The structure allows some flexibility to adapt the measure for use in different settings - Descriptors set at baseline can help with subsequent rating of attainment - Potentially time-consuming to define the descriptors at baseline - Limited information on the psychometric properties Canadian Occupational Performance Measure (COPM) Semi-structured interview in which the patient is guided to consider 3 areas: productivity, self-care and leisure. Patients choose up to 5 problems and rate current performance and satisfaction on a scale of 1–10, where a higher score represents greater performance or satisfaction. Performance and satisfaction are rated again at follow-up. - A case series (pre and post testing) of an 8-week treatment program to train for the use of compensatory external aids to achieve personalised goals - Evidence supports the reliability, construct validity and responsiveness . - Specification of the 3 areas (productivity, self-care and leisure) may not be relevant to all individuals or interventions - The measure and related resources must be purchased GAS: goal attainment scaling; RCT: randomized controlled trial; PD: Parkinson's Disease; PSFS: patient-specific functional scale; MS: Multiple Sclerosis; BGSI: Bangor Goal-setting Interview; COPM: Canadian Occupational Performance Measure.
|
PMC11699366_p5
|
PMC11699366
|
Selection of a primary outcome measure
| 4.115504 |
biomedical
|
Study
|
[
0.9980962872505188,
0.0013129973085597157,
0.0005907501326873899
] |
[
0.8775709867477417,
0.0017997598042711616,
0.12019316852092743,
0.00043601461220532656
] |
en
| 0.999996 |
We adapted the BGSI manual processes for use in our trial. Our sample size calculation was based upon a minimal clinically important difference (MCID) of 2 points on the BGSI, as used in the GREAT trial , based on recommendations for the Canadian Occupational Performance Measure (COPM), a similar rating scale .
|
PMC11699366_p6
|
PMC11699366
|
Selection of a primary outcome measure
| 2.757145 |
biomedical
|
Study
|
[
0.9241679906845093,
0.06715460866689682,
0.00867739599198103
] |
[
0.7680068016052246,
0.22857104241847992,
0.000676542054861784,
0.002745560370385647
] |
en
| 0.999997 |
3.1 Use of the Bangor Goal-setting Interview within the PRIME-RCT Agreement of goals before randomization avoids prior knowledge of intervention status biasing goal selection . During a collaborative interview the participant sets three to five goals with a trained researcher, with input from a family member/caregiver (an ‘informant’), particularly for participants with cognitive impairment . Unlike the original BGSI, we do not pre-specify domains within which participants must identify goals since these are expected to be highly personalised.
|
PMC11699366_p7
|
PMC11699366
|
Operationalizing goals as an outcome measure
| 3.449221 |
biomedical
|
Study
|
[
0.9900521636009216,
0.004674922674894333,
0.005272878333926201
] |
[
0.9192250370979309,
0.07970120757818222,
0.0006050753290764987,
0.0004686515894718468
] |
en
| 0.999996 |
After goal selection, percentage descriptors are specified to indicate what would constitute, for example, 50 % goal attainment. The participant is then asked to rate their current attainment, perceived importance and readiness to change numerically for each goal, with an option for an enrolled caregiver to independently rate attainment. The four steps are summarised in Fig. 1 , described in more detail below and illustrated in Table 2 with an example. Fig. 1 The procedure for using the Bangor Goal-Setting Interview within the PRIME randomized controlled trial prior to randomization. Fig. 1 Table 2 Applying the adapted Bangor Goal-setting interview to set and follow up a goal within the PRIME randomised controlled trial, where text in italics indicates how the researcher would guide the participant through the process. Table 2 STEP 1 Specify the area (domains not pre-specified a ) “Parkinson's can impact on daily life in various ways. There are different things that people may want to change to make their lives more enjoyable. We are asking everyone taking part in this trial to come up with several goals that they would like to achieve. A goal might be something that you currently find difficult to do and wish you could do more easily, or without getting frustrated. Or a goal might be something that you are currently not doing and would like to do more of. Or it might be something that you would like to learn how to do.” Going to the gym STEP 2 SMART goal statement (100 % attainment) I will go to the gym to exercise 3 times per week for 45–60 min Description of current attainment (0 % attainment) I have membership but do not go at all Goal attainment descriptor b (50 %) I will go 1–2 times per week or 3 times for a shorter session (e.g. 20 min s) STEP 3 Rating of attainment Image 1 1 Rating of importance b Image 2 7 Rating of readiness to change b Image 3 6 STEP 4 (e ach 3 monthly follow up conducted by blinded assessor b ) Free text record of current activity in relation to goal “Last time we spoke about going to the gym. Your goal was to go to the gym 3 times per week to exercise for 45–60 min. How are things going with that?” “Due to a recent small fracture of my right ankle I had to wear a boot and rest for 6 weeks, but I'm gradually starting to exercise again. In the last month, I have gone to the gym 4 times for 30–40 min” Participant raw attainment score (without reminder of prior rating in step 3 b ) “What score would you give yourself on a scale of 1-10 for how well you are doing now? 10 would be that you are doing it very successfully, 1 would be that you are not doing it at all or not successfully at all." 3 Calibrated attainments scores a “At your baseline visit, you said you had membership but were not going to the gym and you gave yourself an attainment score of 1. We decided at that time that achieving your goal by 50 % or making it half way to your goal would be going to the gym 1–2 times per week or going 3 times for shorter sessions ( e.g. 20 min). Based on what you have just told me, it sounds like you are more than 50 % of the way to achieving your goal. I wonder whether the new score should be somewhere around 6- would you agree with this?" Interviewer-decided attainment score calibrated from baseline attainment score using % descriptors6 Calibrated score as decided by participant following discussion5 SMART: Specific, Measurable, Achievable, Relevant, Time-bound. a Indicates an aspect of the process which is specific to the operationalisation of BGSI within PRIME-RCT. b Indicates an aspect of the process which was specified as an option within the BGSI manual and which was incorporated into the PRIME-RCT.
|
PMC11699366_p8
|
PMC11699366
|
Operationalizing goals as an outcome measure
| 4.03526 |
biomedical
|
Study
|
[
0.9594242572784424,
0.03821004554629326,
0.0023657314013689756
] |
[
0.9630217552185059,
0.03471372649073601,
0.001053710118867457,
0.0012107744114473462
] |
en
| 0.999997 |
At follow-up, the participant describes their current activity in relation to each goal. They then rate their attainment numerically, without reminder of their prior rating. The researcher uses the percentage descriptors defined at baseline to decide on a researcher-determined calibrated attainment score which reflects the description of current attainment. In dialogue with the participant, the researcher assists them to decide on the participant-determined calibrated score.
|
PMC11699366_p9
|
PMC11699366
|
Follow-up of attainment
| 2.103133 |
biomedical
|
Study
|
[
0.6938722729682922,
0.0057034557685256,
0.3004242479801178
] |
[
0.8101661801338196,
0.1880219280719757,
0.001141844317317009,
0.0006700943340547383
] |
en
| 0.999996 |
Sometimes goals cannot be attained due to factors beyond the participant's control e.g. a dance class not attended because of cancellation; giving a low attainment score would not reflect participant wellbeing, so the goal rating is omitted, and an explanation recorded. However, to avoid overestimation of goal attainment, low attainment is recorded if the reason relates to patient wellbeing; for example, they did not attend the dance class due to an injury. This distinction is an adaptation to the BGSI.
|
PMC11699366_p10
|
PMC11699366
|
Follow-up of attainment
| 1.820552 |
biomedical
|
Other
|
[
0.6242417693138123,
0.08287718147039413,
0.2928810715675354
] |
[
0.15837450325489044,
0.837952733039856,
0.001258316682651639,
0.002414494752883911
] |
en
| 0.999997 |
A key consideration was the frequency of goal follow-up, acknowledging that participants may select goals which are achievable in different timeframes and may subsequently wish to add another goal to replace an event-related goal. In the PRIME RCT, participants specify at baseline the timeframe in which they intend to achieve each goal. Regardless, all goals are followed up 3-monthly by a blinded assessor. Participants are reminded not to reveal their treatment allocation during the call and any unblinding is recorded.
|
PMC11699366_p11
|
PMC11699366
|
Frequency of data collection
| 2.667841 |
clinical
|
Other
|
[
0.4137279987335205,
0.5751250386238098,
0.011146968230605125
] |
[
0.3839157223701477,
0.6031198501586914,
0.0031857071444392204,
0.009778766892850399
] |
en
| 0.999997 |
The primary outcome is change in participant-rated attainment, calculated as shown in Fig. 2 . Whereas for classical measurement instruments a cut-off score may indicate a particular diagnosis and individual scores can be compared to normative data, intervention evaluation using a goal-based outcome relies on comparison of two group means . Follow-up at all 3-monthly timepoints will facilitate a secondary longitudinal analysis to determine whether any improved goal attainment is maintained. Secondary analyses will include change in caregiver-rated attainment and for the three goals rated as most important. Fig. 2 A worked example showing the process for calculating the change in attainment for one participant who had set three goals. Fig. 2
|
PMC11699366_p12
|
PMC11699366
|
Derivation of the score
| 3.66659 |
biomedical
|
Study
|
[
0.9818441271781921,
0.014856823720037937,
0.0032990751788020134
] |
[
0.9806017875671387,
0.018616968765854836,
0.0003076401771977544,
0.00047359755262732506
] |
en
| 0.999998 |
We have described how a goal-orientated outcome measure was adapted for use in a trial involving individuals with complexity, frailty and multimorbidity. As the trial progresses, we will gain crucial real-world experience of applying this in people with parkinsonism, including the time and resources required. We will also gather quantitative data on the numbers of goals set, typical domains chosen, agreement between patient and caregiver scores and the proportion unable to rate attainment (e.g. due to cognitive impairment).
|
PMC11699366_p13
|
PMC11699366
|
Conclusion
| 3.738421 |
biomedical
|
Study
|
[
0.967582106590271,
0.031191058456897736,
0.001226835185661912
] |
[
0.9512658715248108,
0.046605441719293594,
0.0007847617962397635,
0.0013439091853797436
] |
en
| 0.999997 |
The lack of a defined MCID for the BGSI is a limitation; determining this in a parkinsonism population would add to its utility and help to inform whether BGSI is better able to detect a meaningful difference than some other outcomes, as suggested [ , , ]. Whilst the evidence for responsiveness is encouraging , evidence for the validity and reliability of goal-orientated outcome measures is limited and relates mainly to the COPM . Future work could establish whether an improvement in goal attainment is associated with downstream benefits such as reduced unplanned hospitalisation, which would demonstrate predictive validity.
|
PMC11699366_p14
|
PMC11699366
|
Conclusion
| 3.904896 |
biomedical
|
Study
|
[
0.9985997080802917,
0.0006165097584016621,
0.0007838273886591196
] |
[
0.9565759897232056,
0.003682583337649703,
0.0395137220621109,
0.00022768160852137953
] |
en
| 0.999996 |
There are many potential benefits to wider use of goal-orientated outcome measures in clinical trials. They provide a holistic outcome not limited to specific conditions and with universal relevance, important for trials with broad inclusion criteria, enrolling heterogenous populations including adults with frailty and multimorbidity. Above all they aim to provide a meaningful measure of “what matters”. Knowledge gained from use of the adapted BGSI in the PRIME 10.13039/100014144 RCT will help to support its implementation in conditions besides neurodegenerative disease, the focus of its use so far.
|
PMC11699366_p15
|
PMC11699366
|
Conclusion
| 3.827771 |
biomedical
|
Study
|
[
0.9976422190666199,
0.0018082692986354232,
0.0005495059303939342
] |
[
0.7281188368797302,
0.221671000123024,
0.04912511631846428,
0.0010851197876036167
] |
en
| 0.999997 |
Emma Tenison: Writing – original draft, Methodology, Conceptualization. Katherine Lloyd: Writing – review & editing, Project administration, Methodology. Yoav Ben-Shlomo: Writing – review & editing, Supervision, Methodology, Conceptualization. Emily J. Henderson: Writing – review & editing, Supervision, Methodology, Funding acquisition, Conceptualization.
|
PMC11699366_p16
|
PMC11699366
|
CRediT authorship contribution statement
| 0.958863 |
other
|
Other
|
[
0.0911816656589508,
0.002864935202524066,
0.9059533476829529
] |
[
0.0025561454240232706,
0.9967149496078491,
0.00036653332062996924,
0.0003623802331276238
] |
en
| 0.999995 |
NCT05127057.
|
PMC11699366_p17
|
PMC11699366
|
Trial registration number
| 1.028178 |
biomedical
|
Other
|
[
0.6863654255867004,
0.1329202950000763,
0.18071426451206207
] |
[
0.04776123911142349,
0.9393104910850525,
0.006073403637856245,
0.0068548680283129215
] |
vi
| 0.999997 |
10.13039/501100000324 Gatsby Charitable Foundation , GAT3676 .
|
PMC11699366_p18
|
PMC11699366
|
Grant support
| 1.025671 |
other
|
Other
|
[
0.060029469430446625,
0.00214731995947659,
0.9378232955932617
] |
[
0.0028051359113305807,
0.9959069490432739,
0.0007542471867054701,
0.0005336483591236174
] |
en
| 0.999996 |
The PRIME-UK programme is funded by the 10.13039/501100000324 Gatsby Charitable Foundation .
|
PMC11699366_p19
|
PMC11699366
|
Funding sources
| 1.077723 |
other
|
Other
|
[
0.004324675537645817,
0.001334220403805375,
0.9943411350250244
] |
[
0.001163325272500515,
0.997445821762085,
0.000822917849291116,
0.0005680351168848574
] |
en
| 0.999998 |
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ET is funded by a 10.13039/501100000272 National Institute for Health and Care Research Academic Clinical Lectureship and has received a speaker honorarium from the Neurology Academy.
|
PMC11699366_p20
|
PMC11699366
|
Declaration of competing interest
| 1.028398 |
other
|
Other
|
[
0.00603488739579916,
0.0012005938915535808,
0.9927645325660706
] |
[
0.0010076443431898952,
0.9980529546737671,
0.00044134873314760625,
0.0004980527446605265
] |
en
| 0.999998 |
KL is in receipt of PhD fellowship funding from The Gatsby Foundation.
|
PMC11699366_p21
|
PMC11699366
|
Declaration of competing interest
| 0.947088 |
other
|
Other
|
[
0.003465762361884117,
0.0016828624065965414,
0.9948514103889465
] |
[
0.0016145554836839437,
0.9961936473846436,
0.0011584102176129818,
0.0010333647951483727
] |
en
| 0.999998 |
EH is HEFCE funded by University of Bristol for her academic work and has received honoraria from the Neurology Academy and travel support from Bial.
|
PMC11699366_p22
|
PMC11699366
|
Declaration of competing interest
| 0.968433 |
other
|
Other
|
[
0.0033365818671882153,
0.0014113709330558777,
0.9952520132064819
] |
[
0.0013572958996519446,
0.9967982172966003,
0.0009542623301967978,
0.0008903113775886595
] |
en
| 0.999998 |
YBS is partly funded by National Institute for Health and Care Research Applied Research Collaboration West (NIHR ARC West) and University of Bristol and has received funding from Parkinson's UK, Royal Osteoporosis Society, MRC, HQIP, Templeton Foundation, Versus Arthritis, Wellcome Trust, National Institute of Health Research, Gatsby Foundation.
|
PMC11699366_p23
|
PMC11699366
|
Declaration of competing interest
| 1.035476 |
other
|
Other
|
[
0.0034703444689512253,
0.0016394528793171048,
0.9948902130126953
] |
[
0.0009868023917078972,
0.9975747466087341,
0.0007121452363207936,
0.0007263627485372126
] |
en
| 0.999996 |
Medicinal plants have been an essential component of conventional health care around the world for ages since Ayurveda . According to these natural resources provide a wide range of chemicals that are bioactive with a variety of therapeutic potential. Tinospora cordifolia , often called Amrita or Guduchi, holds a great significance in Ayurveda owing to the presence of various secondary metabolites . Giloy leaves have historically been utilized to cure a variety of ailments, such as diabetes, rheumatism, jaundice, and skin diseases . Because of its historical use and the increasing popularity of natural therapies, scientists are looking into the possible therapeutic uses of giloy leaves and the underlying mechanisms behind their medicinal action .
|
PMC11699423_p0
|
PMC11699423
|
Introduction
| 3.331672 |
biomedical
|
Other
|
[
0.997805655002594,
0.0006948478985577822,
0.0014993957011029124
] |
[
0.09200721979141235,
0.560101330280304,
0.34550079703330994,
0.002390699926763773
] |
en
| 0.999995 |
Extract of the giloy leaves helps to alleviate the digestive ailments such as acidosis, gastroenteritis, parasitic infections, lack of appetite, stomach discomfort, extreme thirst, and nausea, as well as liver-related issues like hepatitis .
|
PMC11699423_p1
|
PMC11699423
|
Introduction
| 1.639925 |
biomedical
|
Other
|
[
0.9826533198356628,
0.006507037673145533,
0.01083951536566019
] |
[
0.004701940808445215,
0.9909960627555847,
0.0020880771335214376,
0.0022139602806419134
] |
en
| 0.999996 |
The latest study indicates that giloy leaves immunomodulatory capabilities may be associated with its numerous potential uses. These characteristics may strengthen the immunological response within the body, providing a natural means of promoting general well-being . Despite having a wide range of uses in traditional medicine, the immunomodulatory effects of giloy leaves is less known .
|
PMC11699423_p2
|
PMC11699423
|
Introduction
| 2.157964 |
biomedical
|
Other
|
[
0.9958464503288269,
0.0005911167827434838,
0.003562527010217309
] |
[
0.23964037001132965,
0.7148812413215637,
0.04306402802467346,
0.0024144193157553673
] |
en
| 0.999997 |
This review aims to reduce this gap by thoroughly analyzing immunomodulatory potential of giloy leaves. The research findings about its capacity to regulate the immune system, with particular attention to important pathways such as NF-κB signalling, inflammatory regulation, induction of apoptosis, phagocytosis stimulation, and interleukin modulation. Giloy leaves have been used in the creation of functional food products by comprehending these processes. Through the integration of contemporary scientific findings with traditional wisdom, our goal is to provide insight into the immunomodulatory mechanisms of Giloy leaves and their potential to enhance overall health and well-being. Then, by utilizing this knowledge, innovative giloy leaves-based functional food products can be made, bridging the gap between conventional wisdom and current medical developments.
|
PMC11699423_p3
|
PMC11699423
|
Introduction
| 4.03254 |
biomedical
|
Review
|
[
0.9894071221351624,
0.005345677491277456,
0.005247254390269518
] |
[
0.0036419795360416174,
0.0017480168025940657,
0.9941039681434631,
0.0005061226547695696
] |
en
| 0.999997 |
A systematic search of significant electronic databases such as PubMed, Scopus, and Google Scholar has been done to thoroughly examine the immunomodulatory activities of Giloy ( Tinospora cordifolia ) leaves. The search strategy included various terms that addressed multiple aspects of immune system regulation and prospective uses. Terms such as “ Tinospora cordifolia ” or “Giloy leaves” were used here, along with terms on general immunomodulatory effects, cellular mechanisms of the immune response, and product development, such as “cytokines,” “macrophages,” and “natural killer cells,” as well as terms related to immune system function and anti-inflammatory properties. This comprehensive strategy intended to collect all relevant data on how Tinospora cordifolia affects the immune system and to investigate the potential use of giloy leaves in the development of future functional food products.
|
PMC11699423_p4
|
PMC11699423
|
Identifying relevant research
| 4.036944 |
biomedical
|
Study
|
[
0.9995020627975464,
0.0002055979275610298,
0.0002923264692071825
] |
[
0.9887571930885315,
0.00034589201095514,
0.010795733891427517,
0.00010114839096786454
] |
en
| 0.999997 |
The review process involves a two-tiered selection procedure with a primary focus on research that clarifies the mechanisms of action by which giloy ( Tinospora cordifolia ) leaves affect the immune system. The featured research examines how Tinospora cordifolia affects immune cells or function in animal models or in vitro (lab-based), is published in scholarly journals that undergo peer review, and provides clear evidence of Tinospora cordifolia's action mechanisms on immunological function, including the involvement of specific bioactive chemicals extracted from its leaves.
|
PMC11699423_p5
|
PMC11699423
|
Inclusion and exclusion approach
| 3.955293 |
biomedical
|
Review
|
[
0.9958678483963013,
0.0018975615967065096,
0.002234657993540168
] |
[
0.012798106297850609,
0.004731751512736082,
0.981853187084198,
0.0006168801337480545
] |
en
| 0.999996 |
The research will focus on the utilization of Tinospora cordifolia in value-added products, particularly in functional foods, supplements, and other immunomodulatory products. Only studies that are published in reputable journals focused on product development or peer-reviewed scientific journals were considered. These studies must provide evidence of the product's effectiveness and safety. Research that does not meet these criteria or focuses on different plant species was excluded.
|
PMC11699423_p6
|
PMC11699423
|
Inclusion and exclusion approach
| 2.873206 |
biomedical
|
Study
|
[
0.9974695444107056,
0.0002992326917592436,
0.002231236081570387
] |
[
0.9775371551513672,
0.014872838743031025,
0.007367420941591263,
0.00022253274801187217
] |
en
| 0.999998 |
Tinospora cordifolia is a member of the Menispermaceae family, which is part of the Ranunculales order in the Magnoliopsida class (commonly known as dicots) of the plant world. This classification includes it amid a wide range of blooming plants, while the Menispermaceae family is best recognized for its climbing vines and bushes. Tinospora cordifolia , often known as Guduchi or Gurjo, is an ancient medicinal plant from the Menispermaceae family of moonseeds . The Menispermaceae family is abundant in tropical lowland environments, with 70 genera and 450 species. Tinospora is one of the most common genera in the Menispermaceae family, with around 15 different species . Tinospora cordifolia is extensively widespread in Tropical India and may reach elevations of 1000 feet in South Asia, Indonesia, Philippines, Thailand, Myanmar, China, and Sri Lanka . Ayurvedic and folk medicine systems frequently employ this compound, which may be found in a wide range of soil types (from acidic to alkaline) and only needs a small amount of soil moisture .
|
PMC11699423_p7
|
PMC11699423
|
Taxonomic position of Tinospora cordifolia
| 3.740023 |
biomedical
|
Study
|
[
0.9840421676635742,
0.00035354282590560615,
0.015604239888489246
] |
[
0.697438657283783,
0.2654229700565338,
0.036467403173446655,
0.0006710141315124929
] |
en
| 0.999998 |
Tinospora cordifolia , is a big, glabrous, perennial, deciduous vine with papery bark and juicy branches that spread widely. It is extensively distributed in Sri Lanka, Myanmar, and India . Guduchi is indigenous to India's tropical areas, where it can survive in temperatures between 25 and 45 °C at elevations of up to 500 m. The leaves are heart-shaped, straightforward, and have a deep, vivid green hue. They have a broadly elliptical lamina that is 10–12 cm long and 8–15 cm broad, and they are alternating, stipulate, and whole .
|
PMC11699423_p8
|
PMC11699423
|
Plant description
| 1.663336 |
other
|
Other
|
[
0.2237667292356491,
0.0017892851028591394,
0.774444043636322
] |
[
0.010333145037293434,
0.9886202812194824,
0.0005368466954678297,
0.0005096588865853846
] |
en
| 0.999997 |
The veins of leaves are multicostate and reticulated. The stems' surface has a completely studded appearance of warty tubercles. The skin's surface displays longitudinal fissures, with stems that have a diameter of 3–8 mm and a length of 3–5 cm. Large lenticels that resemble rosettes grow out of the succulent bark, which also includes deep clefts and spots . The bark can be either grey or creamy white in hue. The branches give rise to aerial roots that are long and thread-like branches are either light greyish brown in hue or long and dingy white.
|
PMC11699423_p9
|
PMC11699423
|
Plant description
| 1.659855 |
other
|
Other
|
[
0.2052881419658661,
0.002427814295515418,
0.7922840714454651
] |
[
0.009809340350329876,
0.9892120361328125,
0.00048761838115751743,
0.0004910700372420251
] |
en
| 0.999996 |
Grown on auxiliary and terminal racemes, the tiny, greenish-yellow blooms are unisexual. Female flowers often form single inflorescences, while male flowers are grouped . Six sepals total, arranged freely in two sets of three each on each flower. In addition, six free, oval, membrane petals are smaller than the sepals.: Fruits develop in the winter (November) while flowers blossom in the summer (March to June) . Fruits have a fleshy, orange-red hue and are composed of one to three ovoid, smooth droplets arranged in an aggregate on a stout stalk that has a subterminal-style scar. The moonseed family (Menispermaceae) is characterized by its bent seeds and embryo. Different decorations may be seen on the endocarp, or inner layer of the fruit wall .
|
PMC11699423_p10
|
PMC11699423
|
Plant description
| 1.895641 |
other
|
Other
|
[
0.19377069175243378,
0.0009685865952633321,
0.8052607178688049
] |
[
0.040242064744234085,
0.9580767750740051,
0.001222308725118637,
0.000458751484984532
] |
en
| 0.999997 |
Giloy leaves are a potent source of nutrients and other essential elements. It was found that dehydrated giloy leaves contained high levels of calcium, protein, iron, crude fiber and ash as depicted in Table 1 . All parts of Tinospora cordifolia , including leaves, stems, fruits, and roots, are used as functional foods. Tinospora cordifolia leaves are rich sources of nutrients, essential macronutrients, and micronutrients as shown in Table 1 . Table 1 Nutrient content of Tinospora cordifolia leaves per 100g . Table 1 Nutrients Fresh Dehydrated References Moisture % 31.36 9.64 [ , , ] Ash % 2.3 5.880 Carbohydrates (g) 3.34 7.53 Protein (g) 2.30 5.23 Fat (g) 0.36 1.05 Fibre (g) 11.321 52.295 Iron (g) 5.87 22.55 Calcium (g) 85.247 210 Vitamin C (mg) 56 16 Beta Carotene (μg) 303.7 428.5 Energy (Kcal) 88.64 240
|
PMC11699423_p11
|
PMC11699423
|
Phytochemistry and nutritional composition
| 4.031098 |
biomedical
|
Study
|
[
0.9990099668502808,
0.00012867237091995776,
0.0008613626123405993
] |
[
0.9991426467895508,
0.0005726780509576201,
0.00024422971182502806,
0.00004033598816022277
] |
en
| 0.999994 |
Giloy leaves are a potent source of bioactive compounds such as Alkaloids, Glycosides, Diterpenoids, and steroids as represented in Fig. 1 . Fig. 1 Bioactive components of Tinospora cordifolia (Giloy) leaves. Fig. 1
|
PMC11699423_p12
|
PMC11699423
|
Phytochemistry and nutritional composition
| 2.339502 |
biomedical
|
Other
|
[
0.996390163898468,
0.0004284410970285535,
0.0031813164241611958
] |
[
0.4707320034503937,
0.52199387550354,
0.005390591453760862,
0.0018834462389349937
] |
en
| 0.999996 |
The significant immunomodulatory qualities of Tinospora cordifolia leaves are attributed to a plethora of bioactive substances . These active ingredients include alkaloids (found primarily in the stem) and steroids (beta-sitosterol, d-sitosterol, and g-sitosterol), as well as glycosides (18-norclerodane glycosides, furanoid diterpene glycosides, and tinocordiside) and palmatine D, choline D, tinosporine, magnoflorine, tetrahydropalmatine, and isocolumbin) . Additional components found in its aerial sections include diterpenoid lactones (furanolactone, tinosporon, and columbin) as well as many other substances such cordifolioside A, 11-hydroxymuskatone, N-methyl-2-pyrrolidone, octacosanol, heptacosanol, and nonacosan-15-one . Interestingly, the alkaloid palmatine is also present in the root. RR1, a polysaccharide extracted from the leaves, has been found to possess immune stimulatory properties and has the potential to be used as an adjuvant to boost immunity . Additionally, the various bioactive ingredients present in giloy leaves affect the immune system by increasing cytokine synthesis, enhancing immune cell mitogenicity, and activating specialized immune cells like B cells and macrophages, which can trigger targeted immune responses , . Further research into the exact mechanisms of these active ingredients will help to clarify the immunomodulatory potential of giloy leaves. The various mechanisms through which bioactive compounds of leaves help in boosting the immunomodulatory properties of the body have been illustrated in Fig. 2 . Fig. .2 Immunomodulatory effects of giloy leaves. Fig. .2
|
PMC11699423_p13
|
PMC11699423
|
Immunomodulatory activity of giloy leaves
| 4.242826 |
biomedical
|
Study
|
[
0.9995365142822266,
0.00023270210658665746,
0.00023078180674929172
] |
[
0.9681753516197205,
0.000801028567366302,
0.030845897272229195,
0.0001776736753527075
] |
en
| 0.999998 |
Giloy leaf extract has a high concentration of bioactive components such as alkaloids, glycosides, and terpenoids, contributing to its well-known immunomodulatory activities. The leaf extract constitutes bioactive components that stimulate a variety of immune cells, including natural killer (NK) cells, B cells, and T cells, resulting in the generation of favourable immuno-stimulating cytokines [ , , ]. In addition, among HIV-positive patients, giloy leaves lower total leucocyte, neutrophil, and eosinophil counts . These immuno-stimulating effects are linked to several bioactive chemical compounds found in the leaf, including 11-hydroxymuskatone, N-methyl-2-pyrrolidone, cordifolioside A, magnoflorine, tinocordioside, and Synringin . These compounds specifically target immune cells present inside the human body such as B lymphocytes and macrophages, implying a regulated activation of the immune response . This increases haemoglobin levels and polymorphonuclear leukocytes, indicating an overall increase in immune response . These compounds are well known for their ability to promote a greater immune response by enhancing the proliferation and differentiation of lymphocytes. Thus, it increases total WBC, bone marrow cellularity and alpha esterase-positive cells in the marrow of bone which leads to an increase in humoral immune response. Some of the bioactive components appear to considerably raise IgG antibody levels, which are important components of the immunological response for complimentary inhibition of the pathway .
|
PMC11699423_p14
|
PMC11699423
|
Cellular and molecular mechanism of immunomodulation
| 4.373281 |
biomedical
|
Study
|
[
0.9995311498641968,
0.00021659555204678327,
0.0002521972346585244
] |
[
0.9912042021751404,
0.00055999297183007,
0.0081094428896904,
0.00012633061851374805
] |
en
| 0.999998 |
Inflammation is an immune system response that is necessary for healing, but it can be harmful if it is severe or chronic. Herbal medicines such as giloy leaves have long been utilized to treat inflammation, however, worries about potential side effects have been highlighted . It's important to note that while giloy ( Tinospora cordifolia ) has been used in Ayurvedic medicine for a long time, it should be used with caution due to potential negative effects, especially when taken in large amounts. Research indicates that exceeding the recommended dosage can lead to gastrointestinal issues such as nausea, upset stomach, and constipation . Some studies conducted by researchers exhibits potential hepatotoxic effects due to Giloy's influence on liver enzymes and metabolism . While the blood-sugar-lowering properties of giloy can be beneficial for diabetics, excessive use or concurrent use with blood-sugar-lowering medications can increase the risk of hypoglycemia (low blood sugar) . Finally, allergic reactions are a possibility, particularly for individuals sensitive to plants of the Menispermaceae family . These reactions may include skin rashes and swelling. Giloy leaf extract intake has been associated with the activation of phagocytic cells that aid in wound healing, as well as the acceleration of skin regeneration when applied topically to wounds and bruises. Giloy leaves' immunomodulatory properties, which have been explained by their bioactive chemical constituents such as alkaloids, glycosides, terpenoids, and polysaccharides, which contribute to their capacity to modulate immune responses and decrease inflammation [ , , ].
|
PMC11699423_p15
|
PMC11699423
|
Inflammation and immunity boosting
| 4.076622 |
biomedical
|
Review
|
[
0.9989677667617798,
0.00047523193643428385,
0.0005569924251176417
] |
[
0.3185005187988281,
0.004280074033886194,
0.6766212582588196,
0.0005982255679555237
] |
en
| 0.999997 |
Tinospora cordifolia leaf extract encompasses bioactive chemical compounds that help to reduce inflammation and decrease immunological responses. The leaf extract contains a variety of metabolites, some of which have anti-inflammatory and antioxidant activities . A molecule known as 7,9-Di-tert-butyl-1-oxaspiro (4,5) deca-6,9-diene-2,8dione was discovered as a potential dual inhibitor of COX enzymes, which is critical for treating inflammation. This chemical compound has been demonstrated high binding energies against COX 1 and COX 2, showing its potential as a drug like molecule for inflammatory therapy . In addition, T. cordifolia leaf extract has been studied for in-vitro anti-inflammatory action and shown to decrease protein denaturation, a fundamental process in inflammation. These findings indicate that the chemicals in Tinospora cordifolia leaf extract produce anti-inflammatory actions and modify immunological responses by inhibiting COX and suppressing protein denaturation ,. Compounds in giloy leaves decrease inflammatory mediators, inhibit enzyme activity such as COX and alter immune cell function. Giloy leaves have the potential anti-inflammatory properties through a variety of pathways as shown in Fig. 3 about Inflammation and its action mechanism. More research will be required to determine their clinical benefits in controlling inflammatory diseases. Fig. 3 Lipopolysaccharide-induced inflammation and its attenuation by giloy leaf components through NF-kB pathway. Fig. 3
|
PMC11699423_p16
|
PMC11699423
|
Inflammation and immunity boosting
| 4.200626 |
biomedical
|
Study
|
[
0.9996175765991211,
0.00019105935643892735,
0.00019139073265250772
] |
[
0.9856385588645935,
0.0006447422201745212,
0.013579821214079857,
0.00013686897000297904
] |
en
| 0.999997 |
Giloy leaves anti-inflammatory mechanisms that have been studied. According to studies giloy leaf extract prevented lipopolysaccharide (LPS)-stimulated macrophages from releasing prostaglandin E2 (PGE2) and nitric oxide (NO) . Another study reported that giloy leaf extract reduced the expression of tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), two pro inflammatory cytokines in LPS-stimulated macrophages , . Studies demonstrated by that giloy leaf extract suppressed the activation of the transcription factor-kappa B (NF-κB) signalling pathway, which is crucial for the inflammatory response . Wilkinson showed that giloy leaf extract inhibited the activity of an enzyme produced by the human body cyclooxygenase-2 (COX-2), which plays a role in PGE2 synthesis .
|
PMC11699423_p17
|
PMC11699423
|
Modulation of NF-κB pathway
| 4.144284 |
biomedical
|
Study
|
[
0.9994552731513977,
0.00015404977602884173,
0.0003906518395524472
] |
[
0.9787230491638184,
0.000734232016839087,
0.020423628389835358,
0.00011907099542440847
] |
en
| 0.999997 |
These studies suggest that giloy leaves have multiple anti-inflammatory mechanisms, including the inhibition of NO and PGE2 production, the reduction of pro-inflammatory cytokine expression, and the suppression of NF-κB and COX-2 activity. These mechanisms make giloy leaves a promising natural anti-inflammatory agent with potential uses in the treatment of a variety of inflammatory conditions, which has been illustrated in Fig. 3 .
|
PMC11699423_p18
|
PMC11699423
|
Modulation of NF-κB pathway
| 3.934723 |
biomedical
|
Study
|
[
0.9996923208236694,
0.00015023996820673347,
0.0001574678608449176
] |
[
0.9877583384513855,
0.0013946299441158772,
0.010699977166950703,
0.0001470411370974034
] |
en
| 0.999998 |
Apoptosis is a process which helps in regulating the population of immune cells. For instance, after an immune response, excess immune cells may undergo apoptosis to prevent overactivity of the immune system. Apoptosis is used as a mechanism to eliminate infected cells . When a cell is infected with a virus or bacteria and gets damaged or destroyed beyond repair, it can trigger apoptosis to prevent the spread of the infection , . Some of the bioactive compounds of giloy leaves such as aporphine, magnoflorine, palmatine, tinocordiside, and cordifolioside -A, have demonstrated potential as anti-cancer agents . They induce apoptosis and inhibit the growth of cancer cells, suggesting their significance in cancer therapy. Cancer cells undergo apoptosis, a process of planned cell death, when exposed to giloy leaf extract. It triggers nuclear condensation, the production of apoptotic bodies, and the activation of the essential apoptotic enzyme caspase-3 . It also causes apoptosis in cancer cells by suppressing anti-apoptotic genes like Bcl-2 and upregulating pro-apoptotic genes like Bax (Bcl-2 associated X protein). Giloy leaf extract effectively inhibits cancer cell development by interfering with the G1 phase of the cell cycle , . Cell division and DNA replication depend on this stage. Giloy leaf extract stops the cell cycle at this point, which stops cancer cells from proliferating and growing. Nitric oxide (NO) generation is enhanced by the stimulation of immune cells, specifically macrophages, by giloy leaf extract. NO causes cancer cells to become cytotoxic, leading to their destruction , .
|
PMC11699423_p19
|
PMC11699423
|
Regulation of apoptosis in immune cells
| 4.462732 |
biomedical
|
Study
|
[
0.9995642304420471,
0.00021748158906120807,
0.0002183511242037639
] |
[
0.975796103477478,
0.0021864259615540504,
0.02173064649105072,
0.0002868614683393389
] |
en
| 0.999997 |
Giloy leaves contain several polyphenolic chemicals, including tannins, magnoflorine, jatrorrhizine, tembetarine, tinosporine, isocolumbin, palmatine, and tetrahydropalmatine. These substances are good candidates for antioxidant therapy because of their demonstrated potent antioxidant properties . The giloy leaves extract's antioxidant capacity employs a range of in vitro tests. The extract exhibited noteworthy efficacy against DPPH, hydroxyl, and nitric oxide radicals, as demonstrated by the obtained results. The existence of energy-producing polyphenolic compounds that fight off free radicals and stop oxidative damage is the cause of this waste activity , . The antioxidant activity of giloy leaf extracts in human lymphocytes against oxidative stress - driven through DNA damage. Studies have indicated that these extracts can mitigate DNA damage resulting from exposure to hydrogen peroxide, which is a strong inducer of oxidative stress .
|
PMC11699423_p20
|
PMC11699423
|
Antioxidant
| 4.154385 |
biomedical
|
Study
|
[
0.9995601773262024,
0.00015914581308607012,
0.000280589796602726
] |
[
0.9990088939666748,
0.0002672917617019266,
0.0006707606953568757,
0.000053046183893457055
] |
en
| 0.999997 |
This protection is due to the antioxidant capabilities of giloy leaves polyphenols, which remove free radicals and prevent DNA oxidation . The effect of giloy leaf extract on oxidative stress and antioxidant state in rats with experimental liver injury . Studies indicate that these extracts can enhance Antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase as well as lower oxidative stress markers like malondialdehyde . According to these results, giloy leaf extract may shield the liver from oxidative stress and liver damage . The majority of the research indicates that the polyphenols present in giloy leaves have significant antioxidant properties and can be used to treat a variety of oxidative disorders associated with stress using antioxidant-based therapy.
|
PMC11699423_p21
|
PMC11699423
|
Antioxidant
| 4.003393 |
biomedical
|
Study
|
[
0.9997124075889587,
0.00012843613512814045,
0.00015906186308711767
] |
[
0.9879336953163147,
0.0013865181244909763,
0.010544874705374241,
0.00013498390035238117
] |
en
| 0.999997 |
The immune-modulatory function of Tinospora cordifolia is associated with its bioactive compounds such as terpenes, glycosides, alkaloids, steroids, flavonoids, and polysaccharides . IL-17, Th17 Cells, and the JAK-STAT Pathway interplay is crucial for understanding the potential immunomodulatory activity of Giloy leaf extract ( Tinospora Cordiofolia ). Proinflammatory cytokines like interleukin-17 (IL-17) are released by Th17 cells among other immune cells . It is essential for protecting the body from infections, especially those caused by fungus and extracellular bacteria. Studies have shown that Autoimmune diseases and chronic inflammatory illnesses have been associated with elevated or dysregulated IL-17 generation .
|
PMC11699423_p22
|
PMC11699423
|
Interleukin modulation
| 4.124163 |
biomedical
|
Study
|
[
0.9997100234031677,
0.00014185915642883629,
0.00014818937052041292
] |
[
0.9723461270332336,
0.0020617800764739513,
0.025378702208399773,
0.00021333518088795245
] |
en
| 0.999997 |
T helper 17 (Th17) cells are a subset of CD4 + T lymphocytes that primarily secrete IL-17. Although they may contribute to autoimmune disorders, they are necessary for immune-mediated defence from external infections . The differentiation and activation of diverse immune cells, including Th17 cells, are facilitated by the JAK-STAT pathway, a crucial signalling cascade . It involves the phosphorylation of Janus kinases (JAKs) by cytokines attaching to particular cell surface receptors. Following JAK activation, STAT proteins (Signal Transducers and Activators of Transcription) relocate to the nucleus and regulate the expression of genes required for Th17 development and synthesis of IL17 .
|
PMC11699423_p23
|
PMC11699423
|
Interleukin modulation
| 4.379014 |
biomedical
|
Study
|
[
0.9992836117744446,
0.00043666231795214117,
0.00027972832322120667
] |
[
0.9337256550788879,
0.040580835193395615,
0.024846266955137253,
0.0008472662884742022
] |
en
| 0.999998 |
Studies have shown that Tinospora cordifolia extract can reduce the amount of IL-17 generating cells in CD4 + T cells developed under Th17-polarizing circumstances suggesting an immunomodulatory effect . Another study discovered that the water-soluble extract of Tinospora cordifolia improves macrophage phagocytic capabilities and significantly increases nitric oxide generation by stimulating splenocytes and macrophages at a dose of 1 mg/kg Research found that 100 μg/ml of Tinospora cordifolia extract caused 90 % cytotoxicity in B16F10 murine melanoma cells after 72 h of treatment .
|
PMC11699423_p24
|
PMC11699423
|
Interleukin modulation
| 4.117613 |
biomedical
|
Study
|
[
0.9996287822723389,
0.00016550409782212228,
0.00020572169160004705
] |
[
0.9991680383682251,
0.0002446497092023492,
0.0005319544579833746,
0.000055440606956835836
] |
en
| 0.999997 |
Another research identified a polysaccharide from Tinospora cordifolia, RR1, which has been demonstrated to have innate immune stimulatory capabilities and can offer adjuvant-like action in the formation of a Th1-type immune response to an antigen , . To put it in simple terms, Tinospora cordifolia activates the immune system by influencing cytokine synthesis, mitogenicity, and immune-effector cell activation, as well as enhancing phagocytic power and nitric oxide generation in macrophages . The specific mechanism of interleukin modulation by which Tinospora cordifolia extract produces these benefits is unknown and will require more investigation and study.
|
PMC11699423_p25
|
PMC11699423
|
Interleukin modulation
| 4.070821 |
biomedical
|
Study
|
[
0.9997325539588928,
0.00010826398647623137,
0.00015923810133244842
] |
[
0.9965511560440063,
0.0008322717621922493,
0.00253363698720932,
0.00008292609709315002
] |
en
| 0.999997 |
Research on the uses of giloy ( Tinospora cordifolia) leaf extract in various value-added products has revealed its significant immune-boosting properties and health benefits. Giloy extracts have been incorporated in different forms such as powder, fresh leaves, and stem juice to enhance the nutritional value and taste of the products which has been shown in detail in Table 2 , Table 3 . For instance, a combination of giloy leaf powder, besan, wheat flour, and adusa leaves was utilized to produce biscuits and sev, resulting in nutrient-rich products confirmed through tests like DPPH and Folin-Ciocalteu . The phytochemicals present in giloy have been found to have a positive impact on the immune system, leading to increased consumption of homemade kadha (a herbal concoction) containing fresh giloy leaves and other ingredients during the COVID-19 pandemic . Moreover, products like value-added cookies made with giloy and tulsi powders, herbal squash made with giloy leaf extract and pineapple juice, and herbal lassi made with giloy stem juice have displayed enhanced nutritional properties . Table 2 Immunomodulatory giloy leaves-based value-added products. Table 2 S. No. Objective of study Value added Product Overview of Study Reference 1. Evaluation of Herbal Leaves for the Development of Value-Added Food Product Biscuit and Sev In this study, the giloy leaves were used to make value-added products such as biscuits and sev. The greatest method to add medicinal plants' nutritional advantages to humans' everyday diets to help fight degenerative illnesses is to provide value to food items by including them. It shows that the nutrients in these products can help in the fight against diseases and improve immunity. 2. Consumption of natural products and Ayurvedic decoctions “Kadha” as immunity-boosting measures during the spread of COVID-19 in Delhi Ayurvedic Decoction “Kadha” This study aimed to explore the prevalence of consumption of natural products and Ayurvedic decoctions “kadha” as immunity-boosting measures during the initial phase of the COVID-19 pandemic. Around 540 responses were taken through an online survey which shows the usage of immunity-boosting measures and Ayurvedic decoctions “kadha” among the adult residents of Delhi belonging to different age groups was effective. 3. Development of Giloy leaves-based Herbal Squash incorporated with Pineapple Giloy leaves based Herbal Pineapple Squash This research work was an effort in the direction of producing value-added instant beverages. Due to the functional and nutritional goodness of both plants, it can be further exploited in the development of healthy beverage products to develop giloy leaves-based herbal squash incorporated with pineapple and to determine its physical and biochemical properties. 4. Development of value-added cookies supplemented with giloy leaves and Tulsi powder Cookies with giloy leaves and tulsi powder In this study, giloy leaves powder was utilized in place of whole wheat flour to create herbal biscuits. When preparing herbal cookies, whole wheat flour partially replaces the powdered tulsi leaves and giloy leaves stems. Table 3 Traditional Giloy leaves Based Value-added Products. Table 3 S. No. Objective of study Value-added Product Overview of Study Reference 1. Development of herbal lassi using giloy leaves stem juice Herbal lassi Based on the current study, giloy leaves may be utilized to successfully make herbal lassi. Based on microbiological characteristics, the produced lassi was deemed safe for consumption. Natural antioxidants, such as giloy leaves, effectively lower the risk of heart disease, cancer, and many inflammatory processes, and have a positive impact on cardiovascular illnesses. It also strengthens immunity. 2. Development of Antioxidant-Rich Herbal Tea Bags Herbal Tea Bags with Giloy leaves This study was conducted to develop herbal tea bags using giloy leaves and different herbs which can provide antioxidant properties, boost immunity and also enhance the efficacy of white blood cells which helps in fighting against infections and bacteria-causing diseases. 3. Value Addition and Fortification in NonCentrifugal Sugar (Jaggery): A Potential Source of Functional and Nutraceutical Foods Jaggery fortified with giloy leaves. Jaggery is classified as a nutraceutical since it contains a range of vital amino acids, antioxidants, phenolics, minerals (calcium, phosphorus, iron), and vitamins. Jaggery is a more natural source of nutrients for health benefits and might be utilized as a healthier nutritional option for white sugar. Giloy leaves are incorporated as a health-supporting herb to generate even superior antioxidant, detoxifier, digestive, and immune booster products with potential functional and nutraceutical value. 4. Formulation of Herbal Candies Containing Giloy Leaves Satva: A Nutritious and Palatable Herbal Confectionery Option Herbal Candies Containing Giloy leaves The addition of giloy leaves satva in confections shows potential for improving immunity as it fights free radicals and boosts the body's mechanisms for defence against infections. It offers an intriguing discipline of study and innovation, providing a natural and pleasant method for immunomodulation 5. Sensory Evaluation of Laddu Enriched with Giloy leaves ( Tinospora Cordifolia) - Iron-Rich Powder Laddu Enriched with Giloy leaves The purpose of this study is to formulate and establish a standard giloy leaves laddu for people with anaemia and to determine its level of acceptability. The goal is to make a healthy laddu and put giloy leaves powder into it. 6. A study on incorporation of giloy leaves for the development of shelf-stable goat milk-based functional beverage Goat milk incorporated with giloy leaves By combining debittered giloy leaf juice with goat milk, a study was carried out to develop a shelf-stable giloy leaves goat milk beverage. The product profile was examined in depth, including its proximate composition, bioactive qualities, sensory, rheological, and structural characteristics. The addition of giloy leaves in this creates a functional beverage with a longer shelf life that targets health issues and boosts immunity.
|
PMC11699423_p26
|
PMC11699423
|
Application of value-added products
| 4.177432 |
biomedical
|
Study
|
[
0.9988031387329102,
0.0003509150701574981,
0.0008460070821456611
] |
[
0.9993420243263245,
0.00018016791727859527,
0.0004336148267611861,
0.000044187305320519954
] |
en
| 0.999997 |
The research has shown that giloy can be used in a plethora of products. The sensory qualities of giloy leaves, tulsi, and ginger herbal tea bags were optimised . Additionally, herbal candies made from giloy stems juice and sugar offer a nutritious and nutrient-dense option . Fortified jaggery with giloy leaves powder has shown enhanced nutritional profiles, and shelf-stable goat milk enriched with giloy stem juice has demonstrated extended shelf life and stability . Furthermore, giloy powder has been used in giloy laddus, where it is combined with other components . These diverse uses highlight Giloy's leaf extract potential to improve the nutritional value and health-promoting properties of food items.
|
PMC11699423_p27
|
PMC11699423
|
Application of value-added products
| 2.558491 |
biomedical
|
Other
|
[
0.9593942761421204,
0.0007778271101415157,
0.039827898144721985
] |
[
0.23834073543548584,
0.5494911074638367,
0.21058964729309082,
0.001578554860316217
] |
en
| 0.999998 |
While traditional methods do not allow any combination of other ingredients, modern methods often combine giloy leaves with other herbs to enhance its effect for specific health concerns like stress, skin health, joint pain etc. Quality assurance varies in both traditional and modern value-added products, with modern manufacturing practices there is more focus on quality control and standardized formulations to ensure consistency and quality control in Giloy leaves-based products.
|
PMC11699423_p28
|
PMC11699423
|
Comparison between traditional and modern value-added products
| 2.035864 |
biomedical
|
Other
|
[
0.9541450142860413,
0.002111881272867322,
0.04374309629201889
] |
[
0.010833211243152618,
0.9861235618591309,
0.0025135320611298084,
0.0005297292373143137
] |
en
| 0.999999 |
Different Varieties of modern value-added products are available nowadays, while traditional value-added products are very limited as shown in Table 3 , Table 4 . Table 3 , Table 4 illustrate the contrast between traditional and current applications of giloy leaves. Table 4 displays the Giloy-based products available in the market, while Table 3 outlines traditional uses. There are various value-added products in today’s modern era like capsules, juice, giloy leaves powder, giloy leaves extract and many more while traditional value-added products were limited to most consumers where churan, and kadha (juice blend) are common among all. Modern products are fortified with different vitamins and minerals to enhance the nutritional value of the product while traditional products are not fortified and produced as it is consumed. Modern giloy leaves products are widely available in pharmacies, local stores and online platforms, and are greatly accessible to consumers worldwide, which is not the same in the case of traditional value-added products. Modern giloy leaves products offer a convenient form of consumption, making it easier for individuals to consume and incorporate into their daily routines plus they are less time-consuming. Modern giloy leaves products have a high shelf life as they are preservatives with chemicals like sodium benzoate and potassium sorbate etc. or with various modern preserving methods. Traditional giloy leaves products typically use natural and herbal ingredients plus no chemicals were used resulting in less shelf life of the product. Traditional value-added products are made by methods that are passed down from generation to generation. Which involves manual labour, the use of natural ingredients and traditional equipment, which helps in preparing the perfect desired product. In Modern value-added products, advanced technologies and machines are used for production which works on standardized methods. Automatic machines, standard measurements, and quality control techniques are very common for preparing required products. Table 4 Commercially giloy leaves based on value-added products. Table 4 Product Name Brand Name Health Claims Ingredients Reference Capsules/Tablets rowhead 1. Guduchi Immunity Wellness Himalaya ● Strengthens Immunity ● Fights infections ● Supports detoxification ● Helps in increasing the performance of white blood cells Giloy leaves Stem Extract https://www. amazon. in/HimalayaWellness-Herbs-Guduchi-Immunity/dp/B00B8ROM1M 2. Giloy leaves Immunity Booster Zandu ● Protection Against Infections & Immunity Booster. ● Promotes Liver Health ● Stress Relief ● Anti-oxidant Compounds for Good Skin Health. Giloy leaves Stem Extract https://www. amazon. in/ZanduGuduchi-herbs-immunitywellness/dp/B07V6TPRQ8 3. Guduchi (Giloy leaves) Ghanbati Baidyanath ● Boost Immunity ● Reduces anxiety and improves mental strength. ● Rich in antioxidants and has anti-allergic, antifungal & anti-bacterial benefits. ● Maintain strength and vitality ● Aids pitta disorders & improves digestion. Giloy leaves Stem Extract. Ashwagandha Amla Gorakhmundi https://www. amazon. in/Baidyanath-Guduchi-Giloy leaves-GhanBati/dp/B08CY425YB 4. Divya Giloy leaves Ghanvati Patanjali ● Immune boosting ● Antioxidant properties and anti-inflammatory effects. ● Provide liver support ● Promote respiratory health. Giloy leaves Stem Extract https://www. amazon. com/Patanjali-Giloy leaves-Ghan-Vati-Tablets/dp/B07HWTJ2G3 5. Jiva Giloy leaves Jiva ● Boosts Immunity. ● Helps fight respiratory problems. ● Helps reduce joint pain. ● Improve digestion. ● Helps in detoxification. Giloy leaves Stem Extract https://www. amazon. in/Jiva-Giloy leaves-Capsule-Respiatory-Detoxification/dp/B093KTSXX8 Powder rowhead 1. Organic Giloy leaves/Guduchi Stem Powder CARMEL ORGANICS ● Boosting the immune system. ● Improving digestion. ● Reducing stress and anxiety. ● Controls blood sugar level. Giloy leaves stem powder https://www. amazon. in/CertifiedAmruthavalli-Tinospora-cordifolia-Preservative/dp/B08CHGD429 2. Natural Organic Guduchi Powder/Giloy leaves Powder MY HERB ●Aids in detoxification, increases antibodies, and stimulates vitality. ●Relieves stress and anxiety while also replenishing the body. ●Combats illnesses related to respiration. Demonstrates anti-inflammatory and antiarthritic activities Giloy leaves stem powder https://www. amazon. in/GuduchiPowder-Tinospora-cordifoliaMetabolism/dp/B08MTZPL1C 3. Giloy leaves Satva Baidyanath ●Useful in treating burning sensation in hands & feet, headache, metallic taste in mouth & excessive thirst. ●Enhances immunity of the body. Giloy leaves extract powder https://www. amazon. in/Baidyanath-Giloy leaves-Satwa-Pack-140/dp/B08KT8VB8P Teas Moringa & Giloy leaves Green Tea with Lemongrass Care ●Support to build an Immune system. ●Make bones and joints healthy. ●Help in losing weight. ●Enhance metabolism. Moringa Giloy leaves Licorice Ginger Lemongrass https://www. amazon. in/Moringa-Lemongrass-Immunity-Management-Ayurvedic/dp/B0836MJH7G 2. Giloy leaves Immunity Tea Jiva ●Effective immunity booster. ●Improve skin condition and reduce acne and pimples. ●Helps with seasonal colds and coughs. ●Helps to improve overall health & well-being. Giloy leaves stem powder https://www. amazon. in/Jiva-Giloy leaves-150gm-Pack-Immune-Tea/dp/B085S4ZFZQ 3. Giloy leaves Tea One Herb ●Immunity booster. ●Improves digestion. ●Helps reduce skin infections. ●Relieves chronic fever. ●Help regulate blood sugar levels. ●Boosts metabolism and aids weight management. Giloy leaves stem powder https://www. amazon. in/One-Herb-Ultimate-Immunity-Infections/dp/B08VNLYKTW 4. Ayurvedic Herbs Giloy leaves Green Herbal Tea Rishtpusht ●Immunity booster. ●Helps maintain a healthy heart and nervous system. ●Fight allergies and common infections. ●It improves blood circulation and eliminates harmful substances from the body. Giloy leaves Satva, Dry ginger, Clove, Cardamom, Lemon Basil, Green tea, Cumin seed, Sugar. https://www.amazon.in/Rishtpusht-Ayurvedic-Immunity-Booster-Natural/dp/B091YTDSK8 Juice rowhead 1. Giloy leaves juice Dabur ●Natural immunity booster ●Antioxidant properties ●Good for liver and skin health ●Natural detoxifier Giloy leaves extract https://www. amazon. in/DABUR-Giloy leaves-Neem-JuiceTulsi/dp/B087DJ9L3K 2. Giloy leaves tulsi juice. Vansaar ●Cleans and detox the gut ●Boost immunity & fight against common cough cold ●Antioxidant ●Anti-microbial ●Anti-bacterial ●Anti-inflammatory Giloy leaves stem Tulsi leaves https://www. amazon. in/Enhancing benefits-Handpicked-all-round-Immunity/dp/B07CYYPFFR 3. Giloy leaves juice Baidyanath ●Boost immunity ●Rich source of antioxidant ●Helps maintain a healthy heart and nervous system Giloy leaves extract https://www. amazon. in/Baidyanath-Boost-Immunity-Natural-Giloy leaves/dp/B087LTSC5M 4. Wild tulsi and giloy leaves juice Krishna’s herbal & ayurveda ●Helps regulate blood sugar levels. ●Boost metabolism & improve digestion ●Stimulates insulin secretion ●Helps manage weight Giloy leaves, Jamun, Bel Patra, Amla, Methi, Karela, Kutki, Vijaysar, Tulsi, Gudmaar Neem https://www. amazon. in/Krishnas-Herbal-Ayurveda-GeloyTulsi/dp/B07PLYBMMB 5. Giloy leaves vital AVG health organics ●Immunity booster ●Anti-pyretic ●Reduces inflammation & pain in the body ●Glucose metabolism Giloy leaves Ashwagandha Basil Amla berry https://www. amazon. in/AVGHealth-Organics-Ashwagandha-Premium/dp/B08CYCPTV6
|
PMC11699423_p29
|
PMC11699423
|
Comparison between traditional and modern value-added products
| 3.452991 |
biomedical
|
Study
|
[
0.8141739368438721,
0.0007628746679984033,
0.1850631833076477
] |
[
0.5384619235992432,
0.28507906198501587,
0.17574305832386017,
0.0007158747757785022
] |
en
| 0.999995 |
These methods are often more precise and accurate as compared to traditional techniques which require a large amount of labor work. Traditional value-added products are higher in cost as compared to modern products as they have higher production costs which include labor-intensive processes, limited production scale, and the use of expensive and premium quality ingredients. As a result, they are often highly-priced. Modern products benefit from modern techniques, machines, high-scale production processes, and standardized measurement of ingredients. Which often leads to lower production costs and reasonable pricing.
|
PMC11699423_p30
|
PMC11699423
|
Comparison between traditional and modern value-added products
| 1.815173 |
other
|
Other
|
[
0.14566509425640106,
0.0015999038005247712,
0.8527349829673767
] |
[
0.005409518256783485,
0.9908096790313721,
0.0034864810295403004,
0.0002943928411696106
] |
en
| 0.999997 |
Traditional value-added products also lack innovation as they prioritize traditional or hereditary methods which lack creativity and innovation, resulting in passing down the methods and recipes without any modifications. In the case of modern value-added products modifications are done with time, and new researches are done resulting in new recipes, new flavours, new techniques etc. Traditional production methods have limitations in organizing due to their reliance on manual labour and different techniques. Increasing production volumes is also challenging without compromising quality and effectiveness.
|
PMC11699423_p31
|
PMC11699423
|
Comparison between traditional and modern value-added products
| 1.334957 |
other
|
Other
|
[
0.04264293983578682,
0.0012447858462110162,
0.956112265586853
] |
[
0.0027017646934837103,
0.9960387945175171,
0.0009788550669327378,
0.0002805404074024409
] |
en
| 0.999999 |
While Modern production methods are highly organized due to automation, Standardization and efficient manufacturing processes. Companies can easily adjust production volumes to meet different demands without sacrificing the quality and effectiveness of the product. Traditional products often target markets or consumers seeking authenticity, and local produce. They may be available through speciality stores or directly from the production area. Traditional products use less marketing while Modern products appeal to a broader consumer base due to their convenience, and wider distribution channels. They are often spread in supermarkets, online platforms, and large retail chains.
|
PMC11699423_p32
|
PMC11699423
|
Comparison between traditional and modern value-added products
| 1.206411 |
other
|
Other
|
[
0.00928710587322712,
0.0008597361156716943,
0.9898532032966614
] |
[
0.0012844398152083158,
0.9973760843276978,
0.0009763162233866751,
0.0003632869047578424
] |
en
| 0.999998 |
Tinospora cordifolia , also known as Giloy, is a revered medicinal plant in the Indian Ayurvedic tradition, renowned for its diverse therapeutic applications . However, recent studies have raised concerns about the potential hepatotoxic effects associated with the consumption of giloy leaves powder. The traditional use of giloy in Ayurveda has been well-established, with the plant being recognized for its anti-pyretic, anti-inflammatory, and hepatoprotective properties. However, a growing body of evidence suggests that prolonged or excessive consumption of Giloy leaves powder may lead to liver damage, a phenomenon known as hepatotoxicity.
|
PMC11699423_p33
|
PMC11699423
|
Safety and toxicity
| 3.752698 |
biomedical
|
Review
|
[
0.9988788962364197,
0.00036618064041249454,
0.0007549120928160846
] |
[
0.2763581871986389,
0.10525701940059662,
0.6168724894523621,
0.0015123626217246056
] |
en
| 0.999995 |
Several in vitro and animal studies have investigated the potential hepatotoxic effects of giloy. Researchers have observed that exposure to giloy extracts can result in increased lipid peroxidation, lactate dehydrogenase release, and a decline in glutathione-S-transferase activity, all of which are indicative of cellular stress and potential liver injury . Alkaloids (berberine, palmatine, and jatrorrhizine) and sinapic acid are believed to contribute to its hepatoprotective effects. Berberine, for instance, has been shown to reduce inflammation by inhibiting TNF-α-mediated proinflammatory pathways and nitrosative stress by suppressing iNOS activity . Beyond its hepatoprotective properties, Tinospora cordifolia exhibits a broad spectrum of biological activities, including anticancer, anti-inflammatory, antimicrobial, and antioxidant effects. It is generally considered safe at doses up to 2000 mg/kg. The pharmacological actions of Tinospora cordifolia are attributed to a diverse array of phytochemicals, including polyphenols, alkaloids, steroids, terpenoids, and glycosides . Hepatotoxicity, or liver damage, can be caused by a variety of factors, including the ingestion of toxic substances, overdose of medications, and even certain herbal preparations .
|
PMC11699423_p34
|
PMC11699423
|
Safety and toxicity
| 4.29325 |
biomedical
|
Study
|
[
0.9990208148956299,
0.000511599297169596,
0.0004675954987760633
] |
[
0.6937131881713867,
0.0012654532911255956,
0.3045281171798706,
0.0004932814626954496
] |
en
| 0.999997 |
Although information on the immunomodulatory qualities of giloy leaves is growing, there is still a significant lack of understanding about the precise processes behind these effects. The precise molecular pathways and cellular interactions underlying the observed antioxidant activity, inflammation modulation, Th17 cell regulation, inhibition of the NF-κB pathway, interleukin modulation, and immunosuppressive and white blood cell-enhancing properties remain unclear. To understand the full therapeutic potential of giloy leaves, it is imperative to close this gap between data and intricate processes. Therefore, future research on several areas should be done including important signalling pathways like NF-κB, which have previously been connected to giloy leaves effects, should be the focus of research. These processes have to be clearly understood. Targeted therapies need a clearer comprehension of the molecular interactions that components of giloy leaves have with these pathways. Extensive research is required to determine the particular pathways through which giloy leaves constituents interact with other types of immune modulatory cells, such as Th17 cells, macrophages, and natural killer cells. Having a thorough understanding of how giloy leaves affect these cells' activation, differentiation, and function would help develop therapeutic applications. Investigate the possible benefits that giloy leaves may have when combined with other widely consumed foods that are high in vitamins, minerals, or antioxidants. This can help with dietary suggestions for enhancing immune function and for nutraceutical development. Examine the impacts of food matrices and determine which food ingredients can improve the bioavailability of the bioactive chemicals found in giloy leaves. This information can help formulate products in a way that maximizes health benefits. Contrast the immunomodulatory properties of giloy leaves with known immunomodulatory medications or natural compounds. This analysis can shed light on the distinct processes of giloy leaves and discover potential synergies in combination therapy. Through establishing a connection between current data and comprehensive research, scientists can fully realize the potential of giloy leaves as a medicinal agent. This all-encompassing strategy will open the door for focused therapies and enhanced formulations for particular immune-related ailments. In Future researchers should prioritize the development of standardized protocols for giloy leaves to ensure consistent quality and efficacy. Further research is necessary for negotiating the regulatory environment for giloy-based applications in order to commercialize the product.
|
PMC11699423_p35
|
PMC11699423
|
Future prospective
| 4.384852 |
biomedical
|
Review
|
[
0.9968492388725281,
0.0008413743344135582,
0.0023093915078788996
] |
[
0.11741195619106293,
0.004767000675201416,
0.8773632645606995,
0.00045782237430103123
] |
en
| 0.999996 |
In conclusion, the study we did on the immunomodulatory properties of giloy leaves states that they have many health benefits such as boosting immunity, regulating apoptosis in immune cells and acting as antioxidants. They have active compounds such as alkaloids, polysaccharides, flavonoids, and terpenes present in them that help in immune cell activation which stops cell damage and immune cells like macrophages and B cells which help in inflammation reduction and stop cancer cells from increasing. Giloy leaves modulate interleukins and Th17 cells which helps in protection against infections and increasing immunity.
|
PMC11699423_p36
|
PMC11699423
|
Conclusion
| 3.870665 |
biomedical
|
Study
|
[
0.999642014503479,
0.0000917189972824417,
0.00026623174198903143
] |
[
0.9942986965179443,
0.0022583208046853542,
0.0033228739630430937,
0.00012013036757707596
] |
en
| 0.999997 |
Many modern products are now available in the market that are adapted, formulated and fortified from traditional uses of giloy leaves which can help in treating immunity-related disorders and other diseases. However, for better application and usage of this, further research and studies are required to understand its mechanisms which further helps in understanding its effects, applications and how they work with other compounds and treatments to enhance its use. Giloy leaves contain active ingredients that may be responsible for these benefits. Convenient options to include Giloy into daily routines are provided by modern products. It is crucial to recognize that there may be interactions between giloy leaves and specific drugs. Therefore, we advise speaking with a healthcare professional before incorporating giloy-based products into daily routine to ensure safe and effective use, particularly if you are taking any medications.
|
PMC11699423_p37
|
PMC11699423
|
Conclusion
| 2.649664 |
biomedical
|
Other
|
[
0.9906229376792908,
0.002641084138303995,
0.006735885050147772
] |
[
0.005285486113280058,
0.9876736998558044,
0.006326557137072086,
0.0007142099202610552
] |
en
| 0.999996 |
Overall, giloy leaves are said to be a natural immunomodulatory agent having many other properties such as antioxidant, hepatoprotective, anti-inflammatory and many more which required the researchers to go further to understand its properties fully.
|
PMC11699423_p38
|
PMC11699423
|
Conclusion
| 2.160337 |
biomedical
|
Other
|
[
0.9951686859130859,
0.0009021230507642031,
0.003929307218641043
] |
[
0.03332678601145744,
0.9440601468086243,
0.021300800144672394,
0.0013122492237016559
] |
en
| 0.999997 |
Jyoti Singh: Writing – review & editing, Writing – original draft, Conceptualization. Etika Saxena: Writing – original draft. Anjali Raj Chaudhary: Writing – review & editing. Mandeep Kaur: Writing – review & editing. Molly Salotra: Writing – original draft, Supervision. Prasad Rasane: Writing – review & editing, Writing – original draft. Sawinder Kaur: Writing – review & editing, Supervision. Sezai Ercisli: Writing – review & editing, Methodology, Investigation. Melekber Sulusoglu Durul: Writing – review & editing, Supervision, Formal analysis. Mehmet Ramazan Bozhuyuk: Writing – review & editing, Resources. Ahmet Hakan Urusan: Writing – review & editing, Software. Riaz Ullah: Writing – review & editing, Resources.
|
PMC11699423_p39
|
PMC11699423
|
CRediT authorship contribution statement
| 0.920552 |
other
|
Other
|
[
0.11158619076013565,
0.003033630782738328,
0.8853802680969238
] |
[
0.0028076795861124992,
0.9963500499725342,
0.00041811863775365055,
0.00042409918387420475
] |
en
| 0.999996 |
This study did not require informed consent or review and approval by an ethical committee because it was a literature analysis that solely used data from published studies and did not involve any direct experimentation or studies on living beings.
|
PMC11699423_p40
|
PMC11699423
|
Ethics declaration
| 1.525876 |
biomedical
|
Other
|
[
0.970070481300354,
0.0010725280735641718,
0.02885689213871956
] |
[
0.2718367278575897,
0.7229936122894287,
0.003804934211075306,
0.001364674186334014
] |
en
| 0.999997 |
The research reported in the paper did not involve the utilization of any data. This article's accompanying data has not been added to any publicly accessible databases.
|
PMC11699423_p41
|
PMC11699423
|
Data availability statement
| 0.971851 |
other
|
Other
|
[
0.08723586797714233,
0.0012594889849424362,
0.9115046262741089
] |
[
0.0050551858730614185,
0.9939311742782593,
0.0006349125178530812,
0.00037876126589253545
] |
en
| 0.999996 |
This study received no explicit financing from public, commercial, or non-profit organizations.
|
PMC11699423_p42
|
PMC11699423
|
Funding
| 1.046732 |
other
|
Other
|
[
0.009948003105819225,
0.0007815484423190355,
0.9892704486846924
] |
[
0.003725033951923251,
0.9952953457832336,
0.0005449122982099652,
0.0004347217036411166
] |
en
| 0.999997 |
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
|
PMC11699423_p43
|
PMC11699423
|
Declaration of competing interest
| 0.981821 |
other
|
Other
|
[
0.004888111725449562,
0.0006584165967069566,
0.994453489780426
] |
[
0.001968854106962681,
0.9968124032020569,
0.0006366003071889281,
0.0005821675877086818
] |
en
| 0.999997 |
Oral health has a major impact on overall health, medical costs, and quality of life. Major oral conditions include dental caries, periodontal disease, and tooth loss. Between 1990 and 2017, the global burden of these conditions increased by 38% .
|
39706582_p0
|
39706582
|
Introduction
| 2.071942 |
biomedical
|
Other
|
[
0.992148220539093,
0.0025961603969335556,
0.0052555580623447895
] |
[
0.01847134716808796,
0.9439094066619873,
0.036038365215063095,
0.0015808207681402564
] |
en
| 0.999997 |
There are reports of an increase in the burden of oral diseases in the Kingdom of Saudi Arabia (KSA) over the last few decades . This increase is likely due to transformations in lifestyle, such as changes in dietary habits, particularly an increase in consumption of sugary foods and tobacco products . Thus, oral health conditions constitute one of the major public health concerns in KSA.
|
39706582_p1
|
39706582
|
Introduction
| 1.914213 |
biomedical
|
Other
|
[
0.9846839308738708,
0.0021495302207767963,
0.01316660176962614
] |
[
0.01676797866821289,
0.9776540398597717,
0.004689357243478298,
0.000888669048435986
] |
en
| 0.999995 |
Self-reported oral health status has been used as an important subjective health indicator of oral health care needs and to evaluate the individual’s quality of life . Self-reported information is a cost-effective and time-saving method of data collection. Self-reported oral health can be affected by several factors, such as sociodemographic and socioeconomic factors, cultural values and beliefs, and existing oral health conditions .
|
39706582_p2
|
39706582
|
Introduction
| 2.842982 |
biomedical
|
Other
|
[
0.9955527186393738,
0.000752442458178848,
0.0036948141641914845
] |
[
0.16419056057929993,
0.7381542921066284,
0.09669973701238632,
0.0009554862044751644
] |
en
| 0.999997 |
The Multidimensional Conceptual Model of Oral Health proposed by Gilbert et al states that oral diseases and related tissue damage can result in oral pain (OP) and challenges in daily living that affect self-rated oral health (SROH) status. OP can cause difficulties in chewing and sleep disturbances . In addition, it can affect school and work attendance, causing a loss of a significant number of study and working hours per year . Because of these concerns, OP is frequently incorporated into national health surveys. A 1989 report from the United States reported that 14.5% of adults experienced OP during the past 6 months , while in the United Kingdom, 28% of adults were reported to experience difficulty from OP during the past year in 1998 .
|
39706582_p3
|
39706582
|
Introduction
| 3.921348 |
biomedical
|
Review
|
[
0.9959420561790466,
0.0005282030906528234,
0.0035296787973493338
] |
[
0.26501792669296265,
0.011204119771718979,
0.7233909368515015,
0.00038695387775078416
] |
en
| 0.999997 |
SROH status serves as a valuable indicator of general oral health status . It is considered a comprehensive index reflecting various dimensions of oral health, including functional, psychological, and social impacts on overall well-being . It has been linked to clinical oral health status, such as dental caries, tooth mobility, and tooth loss . Furthermore, SROH has been found to predict future oral health outcomes, as seen in longitudinal studies assessing maternal SROH and their children's caries experience in adulthood .
|
39706582_p4
|
39706582
|
Introduction
| 3.822185 |
biomedical
|
Study
|
[
0.9987071752548218,
0.0002717593451961875,
0.001020974013954401
] |
[
0.7439637780189514,
0.004308648407459259,
0.25142964720726013,
0.00029792083660140634
] |
en
| 0.999998 |
Subsets and Splits
SQL Console for rntc/test-pp-aa
The query retrieves a sample of documents that are clinical cases with an educational score above 3, providing limited analytical value.
Clinical Cases Sample
Returns a sample of 100 clinical case documents, providing a basic overview of the document type's content.