Ellagic Acid

This study investigated whether the daily intake of jaboticaba peel and seed powder (JPSP) for three weeks could modify urolithins metabotype (UM-A, UM-B, or UM-0) and urinary excretion in Brazilian adults (n = 59). Volunteers consumed JPSP or placebo in a crossover design, and urine samples were collected at four time points. Even though most volunteers (66%) maintained their initial metabotype, several exhibited multiple metabotype changes during the trial. These shifts were not associated with JPSP intervention, sex, body mass index, or body fat percentage, and were mainly related to changes in the ability to produce any urolithins (UM-0 to UM-A/UM-B and vice-versa) rather than to shifts between different producers (UM-A to UM-B or vice-versa). Overall, 32.2% of volunteers were UM-A, 52.5% UM-B, and 15.3% UM-0. Normoweight volunteers had a higher frequency of UM-B (71.9%) compared with UM-A (14.6%), whereas overweight/obese individuals showed the opposite distribution. Age also influenced metabotype distribution, with an increased prevalence of UM-B and decreased UM-A in older volunteers. Importantly, JPSP intervention significantly increased total urolithin excretion in normoweight volunteers, but not in overweight/obese. To our knowledge, this is the first clinical study to evaluate urolithin metabotypes at four different time points, underscoring the importance of repeated assessments for accurate stratification in intervention trials.

Background/Objectives: Interindividual variability in polyphenol metabolism may help explain the inconsistent effects of polyphenol intake on health outcomes. This study compared, for the first time, (i) polyphenol-related gut microbiota metabotypes (urolithins: UM0, UMA, UMB; equol: EP, ENP; lunularin: LP, LNP) and their clusters (MCs) in non-medicated premenopausal (Pre-M) and postmenopausal (Post-M) women and (ii) the impact of an 8-week intake of a polyphenol-rich plant extract mixture (PPs) on the quality of life (QoL) of Post-M. Methods: Polyphenol metabotypes were determined in urine via UPLC-QTOF-MS after a 3-day intake of PPs containing resveratrol, pomegranate (ellagitannins and ellagic acid), and red clover (isoflavones) in Pre-M (n = 120) and Post-M (n = 90) women. QoL was assessed with the short-form Cervantes Scale in a randomized, placebo-controlled crossover trial (8-week PPs vs. placebo), completed by 78 Post-M participants. Results: At baseline, Pre-M and Post-M women showed only minor differences in metabotype and MC distributions linked to menopausal status. MC3 (UMA+EP+LP) predominated in Pre-M, while MC7 (UMA+EP+LNP) was most frequent in Post-M. PPs intake in Post-M women led to modest shifts in metabotype and MC distributions toward Pre-M patterns. Quantitative metabolite production was comparable between groups, except for equol, which showed a median 2.8-fold increase after PPs intake in EP Post-M women. Clinically meaningful improvements (score reduction ≥ 6.7 points) in QoL were observed in the Psychic domain in EP women (28%, p = 0.039) and in the Menopause and Health domain, specifically in EP (24.1%, p = 0.004), MC3 (22.5%, p = 0.043), and MC4 (UMB+EP+LP; 41.3%, p = 0.022), were mainly driven by a reduction in hot flashes (p = 0.001). Conclusions: These findings support metabotyping as a tool to guide targeted dietary strategies and enhance QoL through precision health in Post-M women.

Jaboticaba (Plinia jaboticaba) is an underutilized Brazilian berry and a source of dietary fiber, cyanidin-3-O-glucoside, and ellagic acid derivatives. Non-clinical studies have shown the potential of jaboticaba to alleviate insulin resistance, low-grade inflammation, and obesity-related cognitive decline, although clinical evidence remains limited. A clinical study was conducted to investigate whether similar effects could be replicated in human subjects following the intake of jaboticaba peel powder (JPP). Nineteen healthy adults (8 men; 11 women; average age 27.5 years and body mass index 24.6 kg/m2) completed a 4-week randomized, controlled, crossover intervention with a 28-day washout period. Participants consumed either 7 g/day of JPP, providing 225 mg of total polyphenols (including 78 mg of cyanidin-3-O-glucoside and 50 mg of ellagic acid), 2.4 g of dietary fiber, and 1.8 g of insoluble fiber, or a matched control containing equivalent sugar and insoluble fiber, blended in water. A standardized carbohydrate-rich meal was also administered. Fasting and postprandial blood samples were collected on days 1 and 28. The interventions did not show a significant effect on postprandial glucose, insulin, adiponectin, or non-esterified fatty acids (p > 0.05). However, fasting and postprandial levels of the proinflammatory cytokine interleukin-6 were 30-40 % lower following JPP consumption (p < 0.05). Additionally, oxidative species decreased by 9 % postprandially (p < 0.01). Furthermore, JPP significantly improved subjective appetite (∼10 %, p < 0.05) and enhanced postprandial selective attention after 45 min (p < 0.05). These findings suggest that jaboticaba peel may provide anti-inflammatory, antioxidant, and cognitive benefits in healthy individuals, supporting its potential as a functional food ingredient.

BackgroundTraditional Thai herbal medicine represents an alternative and complementary approach for managing hyperlipidemia, according to its low toxicity and advantageous benefits. However, there is limited clinical data for Thai herbal medicine formulations for hyperlipidemia.ObjectivesThe present study aimed to evaluate the biological and clinical efficacy of Thai herbal formulation for lowering blood lipids in patients with borderline hyperlipidemia.Materials and methodsThe chemical profile, in vitro antioxidant activity, pancreatic lipase inhibition, and cytotoxicity tests were evaluated in the aqueous and ethanol extracts of Thai herbal formulation. The clinical efficacy and safety of Thai herbal formulation for reducing blood lipids were assessed in patients with borderline hyperlipidemia during a 12-week period.ResultsThe main chemical constituents of Thai herbal formulation, including (+)-chebulic acid, 4-glucogallic acid, gallic acid, ellagic acid, piscidic acid, and 6-gingerol, demonstrated anti-oxidant and pancreatic lipase inhibitory effects. In cytotoxicity testing, the aqueous extracts exhibited no inhibitory effect on L929 cells and Vero cells (IC50 values above 80 μg/mL), whereas the ethanol extracts presented IC50 values of 18.59 ± 0.58 µg/mL in Vero cells and 39.86 ± 0.02 µg/mL in L929 cells. The clinical investigation revealed that the Thai herbal formulation significantly decreased total cholesterol and low-density lipoprotein levels (P < 0.05), and additionally reduced triglycerides and elevated high-density lipoprotein cholesterol, in comparison to the control group after 12 weeks, thereby demonstrating its efficacy in hyperlipidemia management.ConclusionThe findings indicated that the Thai herbal formulation exhibited potential as a herbal therapeutic approach for borderline hyperlipidemia management.

Background: Dietary polyphenols, particularly flavonoids, have been associated with improved glycemic control and reduced risk of type 2 diabetes. Raspberry leaf (RL) is a rich but underexplored source of such bioactives, including ellagitannins, flavonoids, and phenolic acids. While raspberry fruit has received some attention in nutritional science, the metabolic effects of raspberry leaf-especially its influence on postprandial glucose and insulin responses-remain largely unstudied. Objective: This study is the first to investigate the acute effects of RL tea consumption on postprandial blood glucose and insulin levels in healthy individuals following intake of common dietary carbohydrates (sucrose and glucose). Methods: In a randomized crossover study, 22 healthy adults (12 males, 10 females) consumed 50 g of glucose or sucrose with or without 10 g of RL tea in four separate sessions. Blood glucose and insulin levels were measured at fasting and at 15, 30, 60, 90, and 120 min post-ingestion. A total of 37 polyphenolic compounds were identified in the RL infusion using LC-MS, following a 5-minute hot water extraction. The contents of ellagitannins, flavonoids, and phenolic acids were 38 mg, 7 mg, and 4 mg per 10 g of RL, respectively, contributing to a total polyphenol content of 50 mg per 10 g. Results: When RL tea was consumed with sucrose, postprandial blood glucose levels were significantly reduced at 15 and 30 min by 1.19 ± 0.88 mmol/L (25.59% reduction, p = 0.001) and 2.03 ± 1.05 mmol/L (43.57% reduction, p = 0.0004), respectively. Insulin concentrations were also significantly lower at 15 min (113.90 ± 59.58 pmol/L, p = 0.019), 30 min (161.76 ± 91.96 pmol/L, p = 0.0008), and 60 min (139.44 ± 75.96 pmol/L, p = 0.025). No significant differences were observed with glucose ingestion. Conclusions: This study provides the first clinical evidence that RL tea can blunt early postprandial glycemic and insulinemic responses to sucrose in healthy individuals. The data suggest that these effects are likely mediated by relatively low levels of polyphenols-particularly ellagic acid-through inhibition of carbohydrate-digesting enzymes such as α-glucosidase and β-fruc

BACKGROUND: With few effective therapies, metabolic dysfunction-associated steatotic liver disease (MASLD) is a rising worldwide health problem. Ellagic acid (EA), a polyphenol with antioxidant and anti-inflammatory properties, may address the multifactorial pathogenesis of MASLD. This trial evaluated the efficacy of EA supplementation combined with a hypocaloric diet in reducing hepatic fat and improving metabolic and liver function markers. METHODS: In this double-blind, randomized, placebo-controlled study, 60 persons with MASLD participated. Included patients were randomly assigned to consume either 200 mg of EA once a day or a placebo, alongside a hypocaloric diet for 8 weeks. The primary outcome was the absolute mean change in HRI. Secondary outcomes included liver stiffness (LS), liver function tests, metabolic profile, high-sensitivity C-reactive protein (hs-CRP), and anthropometric indices. RESULTS: EA supplementation significantly reduced HRI compared to the placebo group (mean difference [MD]: -0.23; P < 0.001). Improvements were also observed in LS (MD: - 0.47 kPa; P < 0.001), alanine transaminase (MD: - 27.89 U/L; P < 0.001), aspartate transaminase (MD: - 8.20 U/L; P < 0.001), fasting blood sugar (MD: - 6.78 mg/dL; P < 0.001), triglyceride (MD: - 42.65 mg/dL; P = 0.004), low-density lipoprotein cholesterol (MD: - 14.63 mg/dL; P = 0.026), high-density lipoprotein cholesterol (MD: + 3.38 mg/dL; P = 0.019), and hs-CRP (MD: - 0.81 mg/L; P < 0.001). Anthropometric indices improved significantly by week 8. CONCLUSIONS: EA supplementation, combined with a hypocaloric diet, effectively reduced hepatic fat and improved metabolic and liver function markers in patients with MASLD. EA represents a promising adjunct therapy for MASLD management, warranting further investigation. TRIAL REGISTRATION: The trial was registered in the Iranian Registry of Clinical Trials (Trial identifier: IRCT20180103038199N16). © 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

BACKGROUND: It seems that oxidative stress is involved in the occurrence and progression of non-alcoholic fatty liver disease (NAFLD). Considering the antioxidant features of Ellagic acid (EA), this study was designed to assess the effect of EA on some biochemical factors in patients with NAFLD. METHODS: In this clinical trial, 44 patients were selected based on including criteria and randomly received 180 mg of EA per day (n = 22) or placebo (n = 22) for 8 weeks. At the beginning and end of the study, glycemic indices, lipid profiles, liver enzymes, oxidative stress markers, and inflammatory factors were measured. RESULTS: At the end of the study, the mean of insulin, insulin resistance (IR), triglycerides (TG), low-density lipoprotein (LDL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), malondialdehyde (MDA), and C-reactive protein (CRP) were significantly decreased in the intervention group (P < 0.05). Also, a significant increase in the mean of total antioxidant capacity (TAC) was observed in the EA group (P < 0.05). However, changes in high-density lipoprotein (HDL), total cholesterol (TC), and fasting blood sugar (FBS) were not significant in any of the groups (P > 0.05). CONCLUSIONS: Based on the results, the present study provided evidence that EA can be used as a supplemental therapy alongside current treatment plans to reduce the complications of NAFLD due to its antioxidant and anti-inflammatory properties. TRIAL REGISTRATION: This study was prospectively registered at the Iranian Registry of Clinical Trials on the 23th of January 2022 (ID: IRCT20141025019669N21). © 2025. The Author(s).

BACKGROUND: Mitochondrial dysfunction and impaired mitophagy are integral to myocyte loss and the progression of heart failure. Urolithin A (UA), a microbiota-produced metabolite of ellagitannins and ellagic acid, is a known stimulator of mitophagy and mitochondrial biogenesis that has shown cardioprotective effects in experimental models. METHODS: A randomized, double-blind, placebo-controlled 2×2 crossover trial was conducted on 10 patients with HF with reduced ejection fraction (HFrEF). The trial design involved two 4- week intervention periods of UA (500 mg BID) and placebo, separated by a 2-week washout phase. The patients underwent two-dimensional echocardiogram examination as well as blood sampling at the beginning and end of each period. RESULTS: All patients completed the study. The results failed to reveal any significant effect of UA supplementation on echocardiographic measures (LVEF, LVEDD, LVESV, and TAPSE). Plasma concentrations of pro-BNP, glucose, and CRP (p >0.05) were also not altered. Serum HDL-C levels were increased with UA compared with placebo (+6.46 ± 2.33 mg/dL, p =0.026), whereas other lipid indices (LDL-C, triglycerides, total cholesterol, and VLDL-C) remained unchanged (p >0.05). CONCLUSION: The results of the present study do not support any positive effect of UA supplementation in improving echocardiographic and biochemical indices of HFrEF. Further studies with higher doses of UA and longer supplementation duration are encouraged to be conducted.

BACKGROUND: Depression is one of the most common psychological disorders among multiple sclerosis (MS) patients that characterized as the first symptoms. Ellagic acid is a natural polyphenol that may have neuroprotective properties through antioxidant, anti-inflammatory, and immunomodulatory effects. PURPOSE: The aim of the present study was to investigate the effects of Ellagic acid on circulating levels of brain derived neurotrophic factor (BDNF), interferon-γ (IFN-ƴ), nitric oxide (NO), nuclear factor erythroid-2-related factor 2 (Nrf2), cortisol, serotonergic system, and indoleamine 2, 3-dioxygenase (IDO) gene expression in MS patients with mild to moderate depressive symptoms. STUDY DESIGN: A randomized triple-blind clinical trial. METHODS: The eligible patients according to the inclusion criteria were randomly divided into two groups: either 180 mg Ellagic acid (Axenic company) (n = 25) or 180 mg maltodextrin (n = 25) group for 12 weeks. The Ellagic acid supplement were identical to placebo in shape, color and odor. Serum BDNF, NO, Nrf2, cortisol, serotonin, and IFN-ƴ were measured by ELISA kit in the baseline and end of the study. Also, demographic characteristics, anthropometric measurements, physical activity, food intake, Beck Depression Inventory-II (BDI-II) and expanding disability status scale (EDSS) questionnaires, as well as IDO gene expression were assessed. SPSS software version 24 was used for statistical analysis. RESULTS: Fifty patients were evaluated, and a significant decrease in BDI-II (p = 0.001), IFN-ƴ (p = 0.001), NO (p = 0.004), cortisol (p = 0.015), IDO gene expression (p = 0.001) and as well as increased the level of BDNF (p = 0.006) and serotonin (p = 0.019) was observed among those who received 90 mg Ellagic acid twice a day for 12 weeks versus control group. However, there were no significant differences between groups for Nrf2 levels (p>0.05) at the end of study. CONCLUSION: The current study indicates that Ellagic acid intervention has a favorable effect on depression in MS patients. This is achieved by reducing BDI-II scores, as well as levels of NO, cortisol, IFN-ƴ, and IDO gene expression. Furthermore, we found a significant

BACKGROUND: The quality of sleep in people with irritable bowel syndrome (IBS) is reduced by increased oxidative stress and clinical problems. Assessing the effects of ellagic acid (EA) on sleep quality and gastrointestinal symptoms in patients with IBS was the aim of this study. METHODS: In this research that was conducted as a randomized, double-blind, placebo-controlled clinical trial, 44 patients with IBS were enlisted. Individuals approved by the project clinical counselor were divided into two intervention groups to receive 180 mg of EA per day (n = 22) and a placebo group (n = 22) for 2 months. Petersburg's Sleep Quality (PSQI) questionnaire and IBS severity score system (IBSSS) were assessed at the beginning and end of the study. Statistical analysis was performed using SPSS software. RESULTS: At the end of the study, changes in mean PSQI and scores related to sleep subgroups were significant between the two groups (P < .05). Also, the significant changes were not seen in sleep and sleep subgroups scores in the placebo group at the end of the study (P > .05). EA consumption reduced IBSSS score and IBS symptoms in the intervention group after 2 months (P < .05). DISCUSSION: The results arisen from this study indicated that receiving EA had a beneficial effect on sleep quality and gastrointestinal symptoms in IBS patients. The antioxidant and anti-inflammatory properties of EA may be responsible for these beneficial effects.

The antibiotic resistance crisis has created an urgent need for the development of novel therapeutic strategies to tackle recalcitrant infections. In this study, we identified Tormentil [Potentilla erecta (L.) Raeusch.], a plant that has been used in traditional medicine for centuries, as being capable of effectively inhibiting the growth of carbapenem-resistant Acinetobacter baumannii. We identified agrimoniin and ellagic acid as two bioactive components with antibacterial activity present within Tormentil extracts. Combinatorial RNA-seq analysis revealed that these compounds were able to inhibit the growth of A. baumannii by disrupting intracellular iron homeostasis, an effect that could be reversed through exogenous iron supplementation. We also demonstrated that Tormentil could potentiate the activity of the last-resort antibiotic, colistin. Overall, these findings valorize the centuries-old traditional use of Tormentil to treat infection and highlight how its bioactive constituents could be exploited to prolong the lifespan of our last line of antibiotic defence, colistin.

Terminalia catappa L. (Family: Combretaceae) is used globally to treat various diseases, including bacterial infections. Whilst the antibacterial activity of T. catappa has previously been tested against antibiotic-sensitive bacterial strains, the antimicrobial activity against methicillin and β-lactam-resistant pathogens has been relatively ignored. The antibacterial activity of T. catappa extracts, both alone and combined with selected clinical antibiotics, was evaluated in this study. The inhibition of bacterial growth by the extracts was determined using agar diffusion and broth micro-dilution assays. Combinations of the extracts and several clinical antibiotics were also examined and the ∑FICs were calculated to determine the interaction class. Synergistic combinations were further evaluated by isobologram analysis. The T. catappa leaf extracts were screened for toxicity using Artemia franciscana lethality bioassays (ALA). Orbitrap liquid chromatography-mass spectrometry (LC-MS) profiling analysis was undertaken to identify flavonoid components of the extracts, putatively. The T. catappa methanolic extract inhibited all the tested bacterial strains. It displayed especially good inhibitory activity against E. coli (MIC = 130 µg/mL). Combining the T. catappa extracts with some conventional antibiotics potentiated the inhibitory activity of the combinations compared to the activity of individual components. LC-MS profiling analysis identified multiple flavonoid components, including rutin, quercitin, orientin, the tannin component, and ellagic acid in the extracts. All extracts were non-toxic against Artemia nauplii. The phytochemical constituents present in the T. catappa leaf extracts warrant future investigation as potential antibacterial agents. Synergistic Phenolic Compounds in Medicinal Plant Extracts: Enhanced Furin Protease Inhibition via Solvent-Specific Extraction from Lamiaceae and Asteraceae Families. Üzer FB(1), Helvacı N(1), Elmastaş M(1). Author information: (1)Department of Phytotherapy, University of Health Sciences, Selimiye Complex, Selimiye Neighborhood, Atolyeler Street No: 4, Uskudar, 34668 Istanbul, Turkey. This study aimed to evalua

Background/Objectives: Global warming and concomitant extreme weather events have markedly increased the incidence of heat stroke. Heat stroke (HS) poses a substantial threat to cerebral health by triggering neuroinflammation and accelerating neurodegenerative processes. The activation of the Nod-like receptor protein 3 (NLRP3) inflammasome for interleukin-1β (IL-1β) secretion has been implicated as a critical mechanism underlying HS-related fatalities. However, the potential role of specific dietary factors to counteract heat stroke-induced neurotoxicity remains largely underexplored. We previously reported that eicosapentaenoic acid (EPA) and urolithin A (UroA), a gut metabolite of ellagic acid, effectively suppress NLRP3 inflammasome activation against metabolic or pathogenic insults. This study aimed to assess the impact of eicosapentaenoic acid (EPA), urolithin A (UroA), and their combination on mitigating heatstroke-mediated NLRP3 inflammasome activation in microglial cells. Methods: In vitro heatstroke conditions were replicated by subjecting murine BV2 microglial cells to a high temperature (41 °C) under hypoxic conditions. To achieve nutrient loading, BV2 cells were preincubated with either EPA (50 µM) or UroA (10 µM). NLRP3 inflammasome activation was evaluated by proinflammatory gene expression, caspase-1 cleavage in cells, and IL-1β secretion to the medium. The caspase-1 activation was determined using a luciferase-based inflammasome and protease activity reporter (iGLuc) assay. Results: Exposure to high temperatures under hypoxia successfully mimicked HS conditions and promoted NLRP3 inflammasome activation in BV2 cells. Both EPA and UroA substantially attenuated the heat stroke-induced priming of proinflammatory genes. More importantly, EPA and UroA demonstrated a synergistic effect in mitigating HS-induced active caspase-1 production, leading to a dramatic decrease in IL-1β secretion. This synergistic effect between EPA and UroA was further confirmed by the iGLuc reporter assay. Conclusions: Dietary enrichment with EPA and UroA precursors may constitute an efficacious strategy for mitigating heat stroke-mediated neuroinflammation and neurodegenera

Background: The restoration of collagen and elastin in human dermal fibroblasts plays a crucial role in anti-aging and skin rejuvenation therapies. Numerous studies have examined the effects of various antioxidants on skin health, but there is limited research comparing their combined effects on collagen and elastin synthesis in human dermal fibroblasts. Objective: The objective of this study was to evaluate the individual and combined effects of N-acetylcysteine (NAC), Coenzyme Q10 (CoQ10), Niacinamide (NIAC), Gamma Cyclodextrin (GAMMA), Retinol (RET), Epigallocatechin Gallate (EGCG), and Ellagic Acid (ELA) on collagen type I and elastin synthesis in human dermal fibroblasts (HDFs). Methods: Human dermal fibroblasts were treated with individual and combined antioxidants. The expression of collagen type I and elastin was measured using mRNA analysis, immunofluorescence staining, and matrix protein assays. The study focused on the effects of EGCG in combination with other antioxidants like RET, CoQ10, and NAC to identify synergistic effects. Results: The combination of EGCG + RET and EGCG + CoQ10 showed the most significant increase in both elastin and collagen type I synthesis, surpassing the effects of individual antioxidants. EGCG demonstrated the highest fold change in elastin mRNA expression, while the combination treatments notably enhanced the extracellular matrix restoration in HDFs. Conclusion: The combination of EGCG with CoQ10, Retinol, or NAC presents a promising strategy for enhancing skin elasticity and firmness by promoting both elastin and collagen synthesis. These findings suggest that antioxidant combinations can be developed for effective anti-aging skincare formulations.

Emicizumab shortens activated partial thromboplastin time (aPTT) greater than Factor (F)VIII. Clot waveform analysis triggered by ellagic acid and tissue factor trigger (Elg/TF) provided a useful means of assessing emicizumab activity. Thrombin generation assays (TGA) using this trigger reagent might also overcome the difficulties associated with aPTT by emicizumab. To compare TGA triggered by Elg/TF and other reagents (FXIa, TF) for evaluating emicizumab activity. Emicizumab, FVIII, or FVIII-bypassing agents (BPAs) were incubated with FVIII-deficient plasmas prior to TGA initiated by Elg/TF (0.2 μM/0.5 pM), FXIa (5.21 pM), or TF (PPP-Reagent LOW®). Emicizumab, FVIII, or BPAs increased peak thrombin generation (peak-Th) dose-dependently using Elg/TF-trigger and the other triggers. Low responses were evident with FXIa-trigger and the enhanced effects remained below normal levels with Elg/TF-trigger. Experiments using FVIII with emicizumab demonstrated an additive effect on peak-Th using Elg/TF-trigger, and this effect appeared to be less at FVIII ≥ 40 IU/dl. BPAs with emicizumab appeared to mediate additive effects, although its effects were variable. Parameters of thrombin generation from BPAs and emicizumab with Elg/TF-trigger were improved to normal level compared to low TF-trigger. Elg/TF-TGA could evaluate global coagulation potential during emicizumab prophylaxis including concomitant therapy with FVIII or BPAs.

Radix Glycyrrhizae (RG)-Radix Euphorbiae Pekinensis (REP) is a representative incompatible herbal pair of Eighteen Incompatible Medicaments (EIM) and has been disputed in clinical application for a long time. The present study was performed with the Madin-Darby canine kidney (MDCK) cell line using cell cytotoxicity assay, apoptosis detection, cell cycle measurement, reactive oxygen species (ROS) determination, and high content analysis (HCA) in combination with high-performance liquid chromatography (HPLC) fingerprint comparison to clarify whether RG and REP can be concomitantly used from the perspective of cytotoxicity, investigate the major correlated compounds, and elucidate the underlying mechanisms. The results showed that the toxicity of REP could be significantly enhanced through its concomitant use with RG in the ratio of 1 : 1, and this increased toxicity could be weakened with the further increased proportion of RG. 3,3'-di-O-methylellagic acid-4'-O-β-D-xylopyranoside (DEAX) and 3,3'-di-O-methylellagic acid (DEA) were shown to be mainly responsible for the toxicity induced by concomitant use of REP and RG. Both RG-REP decoctions and the above two compounds boosted cell apoptosis, cellular morphological change, ROS accumulation, and mitochondrial membrane potential (MMP) disruption. In conclusion, the incompatible use of RG and REP is conditionally established because of the bidirectional regulatory effect of RG, and the major compounds responsible for RG-REP incompatibility are DEAX and DEA, which result in toxicity through activation of mitochondria-dependent apoptosis induced by increased ROS production. This study provided a basis for understanding the incompatible use of RG and REP and the EIM theory.

BACKGROUND: The anticarcinogenic effect of ellagic acid (EA), a natural phenol of fruits and vegetables, has been investigated in several types of tumors. The combined effect of EA with bevacizumab (BEV), a common drug used in treatment of recurrent glioma, on glioblastoma has not been reported. This study observed the combined effect of EA with BEV on the expression profile of the C6 glioma cell line. METHODS: Rat C6 glioma cells were treated with EA at 100 μmol/L concentration in combination with BEV at 100 ng/mL concentration for 24, 48, and 72 hours. Cell proliferation was detected by 5-bromo-2'-deoxyuridine immunohistochemistry, and p53 and caspase-3 protein levels were determined by immunohistochemistry and assessed by the H-Score. Expression profiles for P-glycoprotein (MDR1), O6-methylguanine DNA methyltransferase (MGMT), caspase-3, and p53 related proteins were detected by reverse transcriptase polymerase chain reaction after EA treatment with or without BEV. RESULTS: EA combined with BEV conspicuously reduced the cell viability of C6 glioma cells for all incubation times. EA significantly downregulated expression of MGMT regardless of combination with BEV even in the early hours after treatment. Combined EA and BEV reduced MDR1 expression only at 72 hours. EA affected the apoptotic proteins of p53 and caspase-3 at protein level in a time-dependent manner, but not at gene level. CONCLUSIONS: This study suggests successful antiproliferative efficacy of EA combined with BEV, probably through inhibition of MGMT expression and time-dependent inhibition of MDR1. EA combined with BEV may be an alternative treatment for drug-resistant gliomas.

The rise of diabetes incidence in Nigeria enhances the use of popular remedies that may interact with conventional therapies. The aqueous extracts of 27 popular Nigerian "antidiabetic" plants were tested for their in vitro effects on glutathione levels within HepG2 cells, P-glycoprotein (P-gp)-mediated Rh-123 efflux activity in Caco-2 vincristine-resistant cells, and modulation of glibenclamide transport in Caco-2 monolayers. The extract from Ximenia americana significantly depleted intracellular glutathione at 100 µg/mL similarly to the reference buthionine sulphoximine (p < 0.05). Other 10 extracts raised glutathione levels. Eight extracts inhibiting P-gp efflux in a concentration-dependent manner (p < 0.01) were selected for further evaluation in a bi-directional transport model across Caco-2 monolayers: Annona senegalensis, Bridellia ferruginea, Cassytha filiformis, Daniellia ogea, Khaya ivorensis, Syzygium guineense, Terminalia avicennioides, and X. americana. When interferences in paracellular transport were discarded, only 3 of them may be modulating the efflux ratio of glibenclamide (efflux ratio: 2.65 ± 0.13) in the same manner the reference drug verapamil (efflux ratio: 1.14 ± 0.25, p < 0.01) does: Syzygium guineense (efflux ratio: 1.70 ± 0.23, p < 0.01), Terminalia avicennioides (efflux ratio: 1.80 ± 0.25, p < 0.05), and X. americana (efflux ratio: 1.66 ± 0.10, p < 0.01). HPLC-UV analyses for P-gp inhibitors in these extracts revealed several phenolic compounds such as rutin, gallic acid, and ellagic acid reported to decrease P-gp expression and/or directly modify its function. In conclusion, some popular herbal medicines used by Nigerian diabetic patients are here shown to potentially affect glibenclamide absorption at concentrations that could be reached in the intestinal tract. Georg Thieme Verlag KG Stuttgart · New York.

BACKGROUND: In-depth information of potential drug-herb interactions between warfarin and herbal compounds with suspected anticoagulant blood thinning effects is needed to raise caution of concomitant administration. The current study aimed to investigate the impact of co-administration of pomegranate peel and guava leaves extracts, including their quality markers namely; ellagic acid and quercetin, respectively, on warfarin's in vivo dynamic activity and pharmacokinetic actions, in addition to potential in vitro cytochrome P450 enzymes (CYP) inhibition. METHODS: Influence of mentioned extracts and their key constituents on warfarin pharmacodynamic and kinetic actions and CYP activity were evaluated. The pharmacodynamic interactions were studied in Sprague Dawley rats through prothrombin time (PT) and International Normalized Ratio (INR) measurements, while pharmacokinetic interactions were detected in vivo using a validated HPLC method. Furthermore, potential involvement in CYP inhibition was also investigated in vitro on isolated primary rat hepatocytes. RESULTS: Preparations of pomegranate peel guava leaf extract, ellagic acid and quercetin in combination with warfarin were found to exert further significant increase on PT and INR values (p < 0.01) than when used alone (p < 0.05). Pomegranate peel extract showed insignificant effects on warfarin pharmacokinetics (p > 0.05), however, its constituent, namely, ellagic acid significantly increased warfarin Cmax (p < 0.05). Guava leaves extract and quercetin resulted in significant increase in warfarin Cmax when compared to control (p < 0.01). Furthermore, guava leaves extract showed a significant effect on changing the AUC, CL and Vz. Significant reduction in CYP2C8, 2C9, and 3A4 was seen upon concomitant use of warfarin with ellagic acid, guava leaves and quercetin, unlike pomegranate that insignificantly affected CYP activities. CONCLUSION: All combinations enhanced the anticoagulant activity of warfarin as the results of in vivo and in vitro studies were consistent. The current investigation confirmed serious drug herb interactions between warfarin and pomegranate peel or guava leaf extracts. Such results migh

The vascular endothelium is a favorite early target of cardiovascular risk factors, including cigarette smoking. Here, we investigated the synergistic effects of Sanghuang⁻Danshen (SD) bioactives on vascular stiffness in a controlled clinical trial of healthy chronic smokers (n = 72). Relative to placebo, 4-week SD consumption at 900 mg/day improves pulse wave velocity (p = 0.0497), reduces systolic blood pressure (peripheral, p = 0.0008; brachial, p = 0.0046; and ankle, p = 0.0066), and increases endothelial nitric oxide synthase activation (p < 0.0001). We then mapped all differential markers obtained from the clinical data, Affymetrix microarray, and ¹H NMR metabolomics, together with 12 SD bioactives, onto the network platform termed the context-oriented directed associations. The resulting vascular subnetwork demonstrates that ellagic acid, caffeic acid, protocatechuic acid, cryptotanshinone, tanshinone I, and tanshinone IIA are linked to NOS3, ARG2, and EDN1 for vascular dilation, implicated with arginine/proline metabolism. They are also linked to SUCLG1, CYP1A1, and succinate related to the mitochondrial metabolism and detoxification, implicated with various metabolic pathways. These results could explain the synergistic action mechanisms of SD bioactives in the regulation of vascular endothelial dilation and metabolism, confirming the potential of SD in improving vascular stiffness and blood pressure in healthy smokers.

18. Pak J Biol Sci. 2025 Dec;28(12):727-734. doi: 10.3923/pjbs.2025.727.734. Medicinal Applications, Phytochemistry and Pharmacological Properties of Terminalia spinosa Engl.: A Comprehensive Review. Maroyi A. &lt;i&gt;Terminalia spinosa&lt;/i&gt; Engl. is a shrub or small tree widely used as a source of traditional medicines in tropical Africa. This study was aimed at reviewing the medicinal uses, phytochemical and pharmacological properties of &lt;i&gt;T. spinosa&lt;/i&gt;. A search for available information on the medicinal uses, phytochemical and pharmacological properties of &lt;i&gt;T. spinosa &lt;/i&gt;was conducted by searching the electronic databases which included SciELO, ScienceDirect&lt;sup&gt;®&lt;/sup&gt;, Web of Science, PubMed&lt;sup&gt;®&lt;/sup&gt;, SpringerLink&lt;sup&gt;®&lt;/sup&gt;, Scopus&lt;sup&gt;®&lt;/sup&gt; and Google Scholar, as well as pre-electronic literature sources such as books, book chapters and other scientific publications obtained from the university library. This research revealed that the bark, fibres, leaves, roots or stem bark of &lt;i&gt;T. spinosa&lt;/i&gt; are used as traditional medicines for wounds, fever, jaundice, malaria, sore throat and stomach ailments. The phytochemical evaluation of the plant species revealed that it contains flavonoids, fatty acids, anthocyanins, coumarins, ellagic acid, polyphenols, anthraquinone, tannins, polysaccharides, steroids and triterpenoids. The pharmacological evaluations showed that the crude extracts of &lt;i&gt;T. spinosa&lt;/i&gt; have antibacterial, anti-Neisseria gonorrhoeae, antimycobacterial, antifungal, antiplasmodial and antiproliferative activities. To realize the full potential of &lt;i&gt;T. spinosa&lt;/i&gt; as traditional medicine, future studies should focus on conducting detailed phytochemical, pharmacological and toxicological evaluations, &lt;i&gt;in vivo&lt;/i&gt; and clinical research.

Metabolic syndrome comprises a cluster of abnormal metabolic markers, including hyperglycemia, insulin resistance, hypertension, obesity, and dyslipidemia, that increase the risk of diabetes mellitus, cardiovascular diseases, and associated complications. Prolonged hyperglycemia results in microvascular complications such as nephropathy, while other abnormal metabolic markers contribute to progressive kidney dysfunction. Ellagic acid (EA) exhibits antihyperglycemia and nephroprotective effects. This study evaluated the effects of EA on glycemic control markers and kidney function tests in animal and human models with abnormal metabolic markers and preobesity. Comprehensive searches were conducted in Embase, Scopus, PubMed, and the Cochrane Library. Data were synthesized using meta-analysis, and risk of bias was assessed using SYRCLE's tool for animal studies and the Risk of Bias 2 tool for human studies. The certainty of evidence in human studies was evaluated using the GRADE approach. Meta-analysis revealed that EA significantly reduced blood glucose concentration (standardized mean differences = -4.03; 95% confidence intervals = -5.02 to -3.04; P < .0001) and improved insulin resistance by lowering homeostatic model assessment of insulin resistance (standardized mean differences = -2.48, 95% confidence intervals =-3.21 to -1.76, P < .0001) in animal studies. However, EA did not significantly affect glucose concentration, insulin, and homeostatic model assessment of insulin resistance in human studies. EA significantly decreased blood urea nitrogen and creatinine in animal studies. Overall, findings from animal studies suggest that EA may have therapeutic potential for improving glycemic control and mitigating kidney complications in metabolic syndrome. However, the absence of significant effects in humans highlights the need for high-quality clinical trials to determine its translational potential.

CONTEXT: Metabolic syndrome, characterized by dyslipidemia, central obesity, hypertension, hyperglycemia, and insulin resistance, increases the risk of cardiovascular diseases and poses a global health challenge. Ellagic acid (EA), a polyphenol with antioxidant and lipid-lowering properties, shows potential as a therapeutic candidate for modulating metabolic markers. OBJECTIVE: This study aimed to assess the effects of EA on lipid profiles, fat weight, and anthropometric parameters in animals and humans with abnormal metabolic markers or pre-obesity through a systematic review and meta-analysis. DATA SOURCES: Literature searches were conducted using PubMed, Scopus, Embase, and Cochrane Library databases up to October 22, 2024. DATA EXTRACTION: Data were extracted from 78 studies. A random-effects model calculated the standardized mean difference (SMD) with the 95% CI. DATA ANALYSIS: EA significantly reduced triglyceride levels in animals (SMD = -2.93; 95% CI, -3.78 to -2.07; P < .0001) and humans (SMD = -0.58; 95% CI, -0.87 to -0.29; P = .0001) and increased high-density-lipoprotein cholesterol levels in animals (SMD = 1.24; 95% CI, 0.58 to 1.90; P = .0002) and humans (SMD = 0.72; 95% CI, 0.37 to 1.07; P < .0001). Ellagic acid also reduced fat weight in epididymal (SMD = -1.40; 95% CI, -1.81 to -0.99; P < .0001), mesenteric (SMD = -1.21; 95% CI, -1.81 to -0.62; P < .0001), and retroperitoneal (SMD = -1.47; 95% CI, -1.94 to -0.99; P < .0001) regions in animals and waist circumference (SMD = -0.55; 95% CI, -1.06 to -0.44; P = .0336) in humans. CONCLUSION: Ellagic acid improves lipid profiles, reduces fat weight, and optimizes anthropometric parameters in animals and humans with metabolic marker abnormalities or pre-obesity, highlighting its therapeutic potential for managing metabolic syndrome and associated health conditions. Systematic Review Registration: PROSPERO no. CRD42024584248. © The Author(s) 2025. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained th

Urolithin A (UA) is a gut metabolite derived from ellagic acid. This systematic review assesses the potential geroprotective effect of UA in humans. In five studies including 250 healthy individuals, UA (10-1000 mg/day) for a duration ranging from 28 days to 4 months, showed a dose-dependent anti-inflammatory effect and upregulated some mitochondrial genes, markers of autophagy, and fatty acid oxidation. It did not affect mitochondrial maximal adenosine triphosphate production, biogenesis, dynamics, or gut microbiota composition. UA increased muscle strength and endurance, however, had no effect on anthropometrics, cardiovascular outcomes, and physical function. Unrelated adverse events were mild or moderate. Further research across more physiological systems and longer intervention periods is required.

Diabetes mellitus (DM) is a worldwide-concerning disease with a rising prevalence. There are many ongoing studies aimed at finding new and effective treatments. Ellagic acid (EA) is a natural polyphenolic compound abundant in certain fruits and vegetables. It is the objective of this investigation to assess the effectiveness and preventive mechanisms of EA on DM and associated complications. This systematic review used PubMed, Scopus, and Google Scholar as search databases using a predetermined protocol from inception to June 2024. We assessed all related English studies, including in vitro, in vivo, and clinical trials. EA counteracted DM and its complications by diminishing inflammation, oxidative stress, hyperglycemia, apoptosis, insulin resistance, obesity, lipid profile, and histopathological alterations. Several mechanisms contributed to the anti-diabetic effect of EA, the most significant being the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptor gamma (PPAR-γ), protein kinase B, and downregulation of nuclear factor-kappa-B (NF-κB) gene expression. EA also revealed protective effects against diabetes complications, such as diabetic-induced hepatic damage, testicular damage, endothelial dysfunction, muscle dysfunction, retinopathy, nephropathy, cardiomyopathy, neuropathy, and behavioral deficit. Administration of EA could have various protective effects in preventing, treating, and alleviating DM and its complications. Although it could be considered a cost-effective, safe, and accessible treatment, to fully establish the effectiveness of EA as a medication for DM, it is crucial to conduct further well-designed studies. © 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

BACKGROUND: Type 2 diabetes (adult onset diabetes) is the most common type of diabetes, accounting for around 90% of all diabetes cases with insulin resistance and insulin secretion defect. The key goal of anti-diabetic therapy is to increase the development of insulin, immunity and/or decrease the amount of blood glucose. While many synthetic compounds have been produced as antidiabetic agents, due to their side effects and limited effectiveness, their usefulness has been hindered. METHODS: This systematic review investigated the bioactive compounds reported to possess activities against type 2 diabetes. Three (3) databases, PubMed, ScienceDirect and Google Scholar were searched for research articles published between January 2010 and October 2020. A total of 6464 articles were identified out of which 84 articles were identified to be elligible for the study. RESULT AND DISCUSSION: From the data extracted, it was found that quercetin, Kaempferol, Rosmarinic acid, Cyanidin, Rutin, Catechin, Luteolin and Ellagic acid were the most cited bioactive compounds which all falls within the class of polyphenolic compounds. The major sources of these bioactive compounds includes citrus fruits, grapes, onions, berries, cherries, broccoli, honey, apples, green tea, Ginkgo biloba, St. John's wort, green beans, cucumber, spinach, tea, Rosmarinus officinalis, Aloe vera, Moringa oleifera, tomatoes, potatoes, oregano, lemon balm, thyme, peppermint, Ocimum basilicum, red cabbage, pears, olive oil and walnut.

BACKGROUND: Terminalia bellirica (Gaertn.) Roxb. is one of the oldest medicinal herbs of India, Pakistan, Nepal, Bangladesh and Sri Lanka as well as South-East Asia. Its medicinal utility has been described in the different traditional medicinal systems, such as Ayurveda, Unani, Siddha, and traditional Chinese medicine. PURPOSE: The present study is aimed at providing a comprehensive overview on the traditional medicinal use, major phytoconstituents, biological and pharmacological activities and related mechanisms of actions and clinical studies of T. bellirica. Another objective is to describe current limitations and future direction of T. bellirica-related research. METHODS: PubMed, ScienceDirect, Scopus, Cochrane Library, and EBOSCO host databases were selected to explore literature published between 1980 and 2020 (till March). Keywords used in various combinations comprised of Terminalia bellirica, phytoconstituents, health effects, pharmacological activities, molecular targets, in vitro, in vivo, clinical studies, and disease prevention. RESULTS: A broad spectrum in vitro and in vivo studies suggested various biological and pharmacological effects, including antioxidant, anti-inflammatory, immunomodulatory, antimicrobial, hepatoprotective, renoprotective, antidiabetic, anti-hyperlipidemic, and anticancer activities. Diverse bioactivities of T. bellirica have been ascribed to the presence of many bioactive phytochemicals, such as glucoside, tannins, gallic acid, corilagin, ellagic acid, ethyl gallate, galloyl glucose, chebulagic acid, and arjunolic acid. CONCLUSION: Preclinical and clinical studies have suggested that T. bellirica plant and its phytoconstituents have immense potential for prevention and treatment of various diseases. Additional in vivo studies and clinical trials are warranted to realize the complete medicinal attributes of this plant.

Background: Melasma is an acquired skin disease characterized by symmetric hyperpigmentation on sun-exposed areas, particularly on the face. Recently, there has been tremendous scientific interest in novel, safe, and effective topical agents to manage melasma. Objective: To evaluate topical treatments for melasma and provide evidence-based recommendations for clinical use and further research. Methods: We performed a systematic review of randomized controlled trials (RCTs) on topical agents for the treatment of melasma on March 4th, 2019 using PRISMA guidelines. Clinical recommendations were based on the American College of Physicians guidelines. Results: After screening, we identified 35 original RCTs using azelaic acid, cysteamine, epidermal growth factor, hydroquinone (liposomal-delivered), lignin peroxidase, mulberry extract, niacinamide, Rumex occidentalis, triple combination therapy, tranexamic acid, 4-n-butylresorcinol, glycolic acid, kojic acid, aloe vera, ascorbic acid, dioic acid, ellagic acid and arbutin, flutamide, parsley, or zinc sulfate for melasma. Conclusions: Cysteamine, triple combination therapy, and tranexamic acid received strong clinical recommendations for the treatment of melasma. Cysteamine has excellent efficacy and is reported to have anti-cancer properties, but has not been directly compared with hydroquinone. Triple combination agents and tranexamic acid are effective, but carry theoretical risks for ochronosis and thrombosis, respectively. Natural compounds are associated with low risk for adverse events, but more research is needed to determine the efficacy, optimal formulation, and appropriate concentration of novel treatments. J Drugs Dermatol. 2019;18(11):1156-1171.

Much debate has focused on whether antioxidants interfere with the efficacy of cancer chemotherapy. The objective of this study is to systematically review the randomized, controlled clinical trial evidence evaluating the effects of concurrent use of antioxidants with chemotherapy on toxic side effects. We performed a search of literature from 1966-October 2007 using MEDLINE, Cochrane, CinAhl, AMED, AltHealthWatch and EMBASE databases. Randomized, controlled clinical trials reporting antioxidant-based mitigation of chemotherapy toxicity were included in the final tally. Searches were performed following a standardized protocol for systematic reviews. Only 33 of 965 articles considered, including 2,446 subjects, met the inclusion criteria. Antioxidants evaluated were: glutathione (11), melatonin (7), vitamin A (1), an antioxidant mixture (2), N-acetylcysteine (2), vitamin E (5), selenium (2), L-carnitine (1), Co-Q10 (1) and ellagic acid (1). The majority (24) of the 33 studies included reported evidence of decreased toxicities from the concurrent use of antioxidants with chemotherapy. Nine studies reported no difference in toxicities between the 2 groups. Only 1 study (vitamin A) reported a significant increase in toxicity in the antioxidant group. Five studies reported the antioxidant group completed more full doses of chemotherapy or had less-dose reduction than control groups. Statistical power and poor study quality were concerns with some studies. This review provides the first systematically reviewed evidence that antioxidant supplementation during chemotherapy holds potential for reducing dose-limiting toxicities. However, well-designed studies evaluating larger populations of patients given specific antioxidants defined by dose and schedule relative to chemotherapy are warranted. Copyright 2008 Wiley-Liss, Inc.

PURPOSE: Much debate has arisen about whether antioxidant supplementation alters the efficacy of cancer chemotherapy. Some have argued that antioxidants scavenge the reactive oxygen species integral to the activity of certain chemotherapy drugs, thereby diminishing treatment efficacy. Others suggest antioxidants may mitigate toxicity and thus allow for uninterrupted treatment schedules and a reduced need for lowering chemotherapy doses. The objective of this study is to systematically review the literature in order to compile results from randomized trials that evaluate concurrent use of antioxidants with chemotherapy. DESIGN: MEDLINE, Cochrane, CinAhl, AMED, AltHealthWatch and EMBASE databases were searched. Only randomized, controlled clinical trials that reported survival and/or tumor response were included in the final tally. The literature searches were performed in duplicate following a standardized protocol. No meta-analysis was performed due to heterogeneity of tumor types and treatment protocols used in trials that met the inclusion criteria. RESULTS: Of 845 articles considered, 19 trials met the inclusion criteria. Antioxidants evaluated were: glutathione (7), melatonin (4), vitamin A (2), an antioxidant mixture (2), vitamin C (1), N-acetylcysteine (1), vitamin E (1) and ellagic acid (1). Subjects of most studies had advanced or relapsed disease. CONCLUSION: None of the trials reported evidence of significant decreases in efficacy from antioxidant supplementation during chemotherapy. Many of the studies indicated that antioxidant supplementation resulted in either increased survival times, increased tumor responses, or both, as well as fewer toxicities than controls; however, lack of adequate statistical power was a consistent limitation. Large, well-designed studies of antioxidant supplementation concurrent with chemotherapy are warranted.