Berberine

The previous meta-analysis showed an advantageous effect of berberine supplementation on interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and serum C-reactive protein (CRP) concentrations; however, it is unknown the dosage that this component influences inflammatory biomarkers. A comprehensive search was done in Scopus, PubMed, and Web of Science until September 2022 to find randomized controlled trials (RCT) that assessed the effects of berberine/barberry on IL-6, TNF-α, and CRP in adults but not trials without a control group. Studies bias was assessed using RoB 2. A random-effects model was performed to calculate the weighted mean difference (WMD). A dose-dependent effect was calculated. Eighteen clinical trials with 1600 participants were included in the current meta-analysis. These interventions significantly mitigate IL-6 levels (-1.18 pg/mL), TNF-α levels (-3.72 pg/mL), and CRP levels (-1.33 mg/L). In addition, the non-linear analysis showed a significant lowering effect of berberine/barberry on IL-6 and TNF-α levels in doses <1000 mg/day and less than 5 weeks of intervention. There are limitations to our findings, including low-quality studies and significant heterogeneity. These interventions might be considered adjunct therapy to managing inflammation status. However, more investigation and high-quality evidence must be conducted to obtain more comprehensive and generalizable results. © 2023 John Wiley & Sons Ltd.

BACKGROUND: Berberine is widely available as a nutraceutical supplement for improving glucose metabolism. Berberine affects sex hormones, raising the possibility that its effects on glycemic traits and insulin sensitivity have sex disparity which has been overlooked. OBJECTIVE: To assess the overall and sex-specific effects of berberine on glycemic- and insulin-related traits. METHODS: We identified randomized trials of berberine versus placebo from Medline, Embase, CNKI, clinical trial registries and previous systematic reviews. Mean differences were estimated using inverse-variance weighting with random effects models. Subgroup analyses were conducted by sex, diabetes diagnosis, trial duration, berberine dose and ethnicity. RESULTS: We identified 20 eligible studies (n = 1761). Berberine lowered fasting glucose (-0.52 mmol/L, 95% CI -0.72 to -0.33; 18 studies, n = 1522), HbA1c (-4.48 mmol/mol, 95% CI -6.53 to -2.44, 7 studies, n = 756), fasting insulin (-2.36 mU/L, 95% CI -3.64 to -1.08, 11 studies, n = 966), HOMA-IR (-0.85, 95% CI -1.16 to -0.53,12 studies, n = 1065), and 2-h postprandial glucose (-1.81 mmol/L, 95% CI -2.37 to -1.24, 4 studies, n = 501). Effects on fasting glucose and HOMA-IR showed potential differences by sex, with larger reductions in women than in men. Comparing 4 studies conducted in women to one study conducted in men, the mean difference was -0.21 mmol/L (95% CI -0.41 to -0.00) for fasting glucose and -0.97 (95% CI -1.84 to -0.10) for HOMA-IR. We also found larger reductions in fasting glucose in participants with diabetes and in Asians. CONCLUSION: Berberine is effective in improving glucose metabolism and may result in larger effects on fasting glucose in women, in people with diabetes and in Asians, but subgroup comparisons remain to be replicated given the limited number of studies. Berberine can be considered as a complementary intervention in individuals who may benefit from modest improvements in glucose metabolism and who prefer taking a nutraceutical. STUDY REGISTRATION: PROSPERO (CRD42022345172).

BACKGROUND: Berberine is a nutraceutical that can improve lipid metabolism. Berberine may also affect sex hormones and exert sex-specific lipid-modifying effects, which have been overlooked. This study aimed to comprehensively review the efficacy and safety of berberine in adults for the treatment of dyslipidemia with consideration of potential sex disparity. Data Sources We searched Medline, Embase, Wanfang, CNKI, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform from inception to 13 December 2022. No language restrictions were applied. This study was registered in PROSPERO (CRD42021293218) prior to completing the literature search. Study Selection Two blinded reviewers assessed studies for inclusion. Eligible studies were randomized controlled trials in adults that compared berberine versus placebo, and measured blood lipids or lipoproteins. Data Extraction and Synthesis Data extraction was performed by two blinded reviewers using a structured form in Covidence. Risk of bias was assessed using the Cochrane risk of bias tool for randomized trials. Mean differences (MD) were estimated using inverse variance weighting with random effects models for lipid outcomes using R. Adverse events (AEs) were described narratively. Main Outcomes Primary outcomes were low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoprotein B. Secondary outcomes were gastrointestinal and muscle-related AEs. RESULTS: Eighteen studies (n = 1788 participants), conducted mainly in mainland China and Hong Kong (15 studies [83%]), were included with treatment durations ranging from 4 to 24 weeks. Berberine reduced LDL cholesterol (- 0.46 mmol/L, 95% CI - 0.62 to - 0.30, 14 studies, n = 1447), total cholesterol (- 0.48 mmol/L, 95% CI - 0.63 to - 0.33, 17 studies, n = 1637), triglycerides (- 0.34 mmol/L, 95% CI - 0.46 to - 0.23, 18 studies, n = 1661) and apolipoprotein B (- 0.25 g/L, 95% CI - 0.40 to - 0.11, 2 studies, n = 127). Berberine increased HDL cholesterol by 0.06 mmol/L (95% CI 0.00 to 0.11, 15 studies, n = 1471). Notably, the effect on HDL cholesterol was different in women (0.11

Atherosclerosis is a major cause of death and disability. The beneficial effects of phytochemicals and probiotics on atherosclerosis have gained significant interest since these functional foods can improve inflammation, oxidative stress, and microbiome dysbiosis. The direct effect of the microbiome in atherosclerosis, however, needs further elucidation. The objective of this work was to investigate the effects of polyphenols, alkaloids, and probiotics on atherosclerosis using a meta-analysis of studies with mouse models of atherosclerosis. Identification of eligible studies was conducted through searches on PubMed, Embase, Web of Science, and Science Direct until November 2022. The results showed that phytochemicals reduced atherosclerosis, which was significant in male mice, but not in females. Probiotics, on the other hand, showed significant reductions in plaque in both sexes. Berries and phytochemicals modulated gut microbial composition by reducing the Firmicutes/Bacteroidetes (F/B) ratio and by upregulating health-promoting bacteria, including Akkermansia muciniphila. This analysis suggests that phytochemicals and probiotics can reduce atherosclerosis in animal models, with a potentially greater effect on male animals. Thus, consumption of functional foods rich in phytochemicals as well as probiotics are viable interventions to improve gut health and reduce plaque burden in patients suffering from cardiovascular disease (CVD).

Coptis Chinensis Franch is widely used in the treatment of diabetes, and berberine is the primary bioactive component in it. Evidence from previous studies has shown that berberine supplementation is effective for treating diabetic nephropathy (DN) in animal models. In this systematic review and meta-analysis, we evaluated the effects and potential mechanisms of action of berberine in animal models of DN. Relevant studies were searched from the English language databases PubMed, Web of Science, and Embase starting from the establishment of the database till June 2022. Twenty-five studies were included, and the risk of bias tool from SYRCLE was used to assess the methodological quality. Statistical analysis was conducted using STATA 15.1. Fasting blood glucose (FBG), blood urea nitrogen (BUN), serum creatinine (SCR), and the kidney index (KI) were the primary outcomes to be analyzed. The overall results showed that berberine improves the indicators of renal function, such as BUN, SCR, proteinuria, and KI. Meanwhile, berberine also improved inflammatory indicators, such as IL-6 and TNF-α, and oxidative stress indicators, such as the superoxide dismutase activity and malondialdehyde content. Additionally, berberine lowered the levels of known risk factors, including triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL). These beneficial effects of berberine in DN may be related to its anti-fibrotic, anti-inflammatory, and anti-oxidative stress properties. However, to assess the anti-diabetic nephropathy effects and safety of berberine in a more accurate manner, additional large-scale, long-term, and high-quality preclinical trials are needed to confirm these findings before clinical application.

It is estimated that 2.6 million deaths worldwide can be attributed to hypercholesterolemia. The main reason for non-adherence to statin therapy are the statin-associated muscle symptoms (including nocebo/drucebo effect). In this case, apart from ezetimibe, nutraceuticals are prescribed. We aimed to assess the comparative efficacy of different nutraceuticals in terms of lowering low density lipoprotein cholesterol (LDL-C) and improving lipid profile. Electronic and hand searches were performed until February 2021. The inclusion criteria were the following: (1) randomized trial with any of the reportedly LDL-C lowering nutraceutical: artichoke, berberine, bergamot, garlic, green tea extract, plant sterols/stanols, policosanols, red yeast rice (RYR), silymarin or spirulina. (2) outcome either LDL-C (primary outcome), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) or serum triglycerides (TG). Random effects network meta-analysis (NMA) was performed to rank the effect of each intervention using frequentist approach. Finally, a total of 131 trials enrolling 13,062 participants were included. All analysed nutraceuticals except for policosanols were more effective in lowering LDL-C (-1.21 [-46.8 mg/dL] to -0.17 [-6.6 mg/dL] mmol/l reduction) and TC (-1.75 [-67.7 mg/dL] to -0.18 [7 mg/dL] mmol/l reduction) than placebo/no intervention. The most effective approaches in terms of LDL-C- and TC-lowering were bergamot and RYR (-1.21 [-46.8 mg/dl] and -0.94 [-36.4 mg/dl] mmol/l) reduction respectively. In conclusion, bergamot and RYR appear to be the most effective nutraceuticals in terms of LDL-C and TC reduction. Evidence for bergamot effect was based on relatively small study group and may require further investigations. Policosanols have no effect on the lipid profile.

BACKGROUND & AIMS: Despite controversies, no study has systematically summarized findings from earlier studies on the effect of berberine (BBR)-silymarin on liver enzymes. Therefore, the current systematic review and meta-analysis aimed to investigate the effect of berberis aristate and Silybum marianum on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in adults. METHODS: Relevant studies, published up to June 2021, were searched through PubMed/Medline, Scopus, ISI Web of Science, EMBASE and Google Scholar. The mean differences and standard deviations were pooled using a random-effects model. The studies' quality was evaluated using the Cochrane Risk of Bias Tool. RESULTS: Out of 80 citations, 5 trials that enrolled 549 participants were included. Berberis aristate and Silybum marianum resulted in no statistically significant change in ALT (weighted mean differences (WMD): -0.39 mg/dl; 95% CI: -1.67 to 0.89, P = 0.55), and AST (WMD: -0.44 mg/dl; 95% CI: -2.02 to 1.14, P = 0.58). CONCLUSION: We did not find any significant reduction in liver enzymes following BBR-silymarin consumption in adults. Further clinical trials with high quality according to the challenges mentioned seem to be helpful to use BBR-silymarin as a supplement for improving liver function.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberine(BBR) is a kind of isoquinoline alkaloids extracted from the rhizomes of Coptis chinensis Franch., which was the main active ingredient. Accumulating evidence has shown that it has potential pharmacological effects in preventing the recurrence of colorectal adenomas. AIM OF THE STUDY: The roles of BBR in the overall recurrence of colorectal adenoma have still not been assessed because of the limitations of the available data and the restriction of a single study. Therefore, we evaluated the effectiveness and safety of BBR in preventing the recurrence of colorectal adenomas through a systematic review and meta-analysis of available data. MATERIALS AND METHODS: We searched four English databases (PubMed (MEDLINE), the Cochrane Central Register of Controlled Trials (CENTRAL), Embase and Web of Science) and four Chinese language databases (Chinese Biomedicine (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP) and the WanFang Database) from their inception through October 2020. Meta-analysis was performed with RevMan5.3 software after data extraction and the quality of studies assessment. RESULTS: Three randomized controlled clinical trials were included with 1076 patients. Our results illustrated that 1-year and 2-year supplementation with BBR was associated with lower recurrence rate of colorectal adenoma (RR 0.69, 95% CI 0.57 to 0.84, p=0.0001; RR 0.75, 95% CI 0.64 to 0.88, p=0.0004). The relative risk of oral BBR for 1 year and 2 years is not comparable, for 2-year efficacy outcomes were assessed in all participants who had at least one colonoscopy with pathological evaluation after baseline (lots of participants completed the first colonoscopy but discontinued during the second follow-up interval.). Moreover, the results also suggest that BBR had more adverse events than placebo (RR 2.91, 95% CI 1.24 to 6.85, p=0.01). Through the full-text reading, no serious adverse events were observed, and constipation was the most common event which disappears once the drug is discontinued. CONCLUSION: Generally, the present study indicated that BBR has a comparable therapeutic effect on

Armolipid Plus® is a multi-constituent nutraceutical that claims to improve lipid profiles. The aim of this PRISMA compliant systematic review and meta-analysis was to globally evaluate the efficacy and safety of Armolipid Plus® on the basis of the available randomized, blinded, controlled clinical trials (RCTs). A systematic literature search in several databases was conducted in order to identify RCTs assessing the efficacy and safety of dietary supplementation with Armolipid Plus®. Two review authors independently identified 12 eligible studies (1050 included subjects overall) and extracted data on study characteristics, methods, and outcomes. Meta-analysis of the data suggested that dietary supplementation with Armolipid Plus® exerted a significant effect on body mass index (mean difference (MD) = -0.25 kg/m2, p = 0.008) and serum levels of total cholesterol (MD = -25.07 mg/dL, p < 0.001), triglycerides (MD = -11.47 mg/dL, p < 0.001), high-density lipoprotein cholesterol (MD = 1.84 mg/dL, p < 0.001), low-density lipoprotein cholesterol (MD = -26.67 mg/dL, p < 0.001), high sensitivity C reactive protein (hs-CRP, MD = -0.61 mg/L, p = 0.022), and fasting glucose (MD = -3.52 mg/dL, p < 0.001). Armolipid Plus® was well tolerated. This meta-analysis demonstrates that dietary supplementation with Armolipid Plus® is associated with clinically meaningful improvements in serum lipids, glucose, and hs-CRP. These changes are consistent with improved cardiometabolic health.

INTRODUCTION: So far, no study has summarized the findings on the effects of berberine intake on anthropometric parameters, C-reactive protein (CRP) and liver enzymes. This systematic review and meta-analysis were done based upon randomized controlled trials (RCTs) to analyze the effects of berberine on anthropometric parameters, CRP and liver enzymes. METHOD: Following databases were searched for eligible studies published from inception to 30 July 2019: MEDLINE, EMBASE, Web of Science, Cochrane Library, PubMed and Google scholar. Necessary data were extracted. Data were pooled by the inverse variance method and expressed as mean difference with 95% Confidence Intervals (95% CI). RESULT: 12 studies were included. Berberine treatment moderately but significantly decreased body weight (WMD = -2.07 kg, 95% CI -3.09, -1.05, P < 0.001), body mass index (BMI) (WMD = -0.47 kg/m2, 95% CI -0.70, -0.23, P < 0.001), waist circumference (WC) (WMD = -1.08 cm, 95% CI -1.97, -0.19, P = 0.018) and C-reactive protein (CRP) concentrations (WMD = -0.42 mg/L, 95% CI -0.82, -0.03, P = 0.034). However, berberine intake did not affect liver enzymes, including alanine aminotransferase (ALT) (WMD = -1.66 I/U, 95% CI -3.98, 0.65, P = 0.160) and aspartate aminotransferase (AST) (WMD = -0.87 I/U, 95% CI -2.56, 0.82, P = 0.311). CONCLUSION: This meta-analysis found a significant reduction of body weight, BMI, WC and CRP levels associated with berberine intake which may have played an indirect role in improved clinical symptoms in diseases with metabolic disorders. Berberine administration had no significant effect on ALT and AST levels.

IMPORTANCE: Berberine is a potential therapy for metabolic disorders, yet its effects on visceral adipose tissue (VAT) and liver fat remain uncertain. OBJECTIVES: To evaluate the efficacy and safety of berberine in reducing VAT area and liver fat content in diabetes-free individuals with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, double-blind randomized clinical trial, diabetes-free individuals with obesity and MASLD were enrolled at 11 hospitals in China between July 6 and December 29, 2023, with a follow-up duration of 6 months. INTERVENTIONS: Participants were randomly assigned to receive either oral berberine, 1 g/d, or a matching placebo. MAIN OUTCOMES AND MEASURES: The primary outcomes were relative percentage change in VAT area and absolute change in liver fat content assessed by computed tomography. Other outcomes included changes in parameters of glucose, lipids, and inflammation. Analyses were conducted according to the intention-to-treat principle. RESULTS: Among 337 randomized participants (mean [SD] age, 41.8 [10.6] years; 221 [65.6%] male), 169 received berberine and 168 placebo. The mean (SD) medication adherence rates were 90.3% (14.7%) for berberine and 90.7% (17.4%) for placebo. No significant differences were observed between study arms for VAT area (1.4% [97.5% CI, -2.4% to 5.2%]) or liver fat content (0.9% [97.5% CI, -0.4% to 2.1%). Berberine was associated with larger reductions in low-density lipoprotein cholesterol (-7.72 [95% CI, -13.13 to -1.93] mg/dL), apolipoprotein B (-3.42 [95% CI, -6.33 to -0.51] mg/dL) and high-sensitivity C-reactive protein (hs-CRP) (-0.072 [95% CI, -0.140 to -0.004] mg/dL) vs placebo, but not other secondary outcomes. The incidence of adverse events was similar between study arms. Post hoc analyses suggested consistent patterns of larger reductions in low-density lipoprotein cholesterol, apolipoprotein B, and hs-CRP levels in participants with higher baseline hs-CRP levels. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of diabetes-free individuals with obesity and MASLD, a 6-month berberine treatment at a da

BACKGROUND: Metabolically Associated Fatty Liver Disease (MAFLD) is a prevalent liver disorder closely tied to metabolic dysfunction, insulin resistance, and chronic low-grade inflammation. Vascular Endothelial Growth Factor (VEGF) may have a dual interesting role in MAFLD pathophysiology-supporting vascular repair in early stages, but potentially contributing to fibrosis in later stages. In this study, berberine (BBR), a plant-derived isoquinoline alkaloid, exhibits multiple beneficial properties, including anti-inflammatory, antioxidant, and endothelial-protective effects, on the study group, perhaps by influencing VEGF concentration. OBJECTIVE: This study aimed to investigate the effectiveness of BBR in addressing vascular function parameters linked to MAFLD, particularly its impact on serum VEGF levels and arterial stiffness. METHODS: This randomized, double-blind, placebo-controlled clinical trial enrolled seventy individuals with MAFLD who were overweight or obese. Participants were randomly assigned in a 1:1 ratio to receive either BBR (1500 mg/day) or a placebo orally for 12 weeks. The following parameters were assessed pre- and post-intervention: VEGF, brachial SBP (Systolic Blood Pressure)/DBP (Diastolic Blood Pressure), MAP (Mean Arterial Pressure), AIx (Augmentation Index), AP (Aortic Pressure), number of waveforms, Pulse Pressure (PP), PWV (Pulse Wave Velocity), and PWA-SP/PWA-DP (Pulse Wave Analysis Systolic/Diastolic Pressure). The results for the metabolic parameters-FLI (Fatty Liver Index)-and anthropometric parameters-BMI (Body Mass Index), fat mass corp-and laboratory parameters, among them, hsCRP (high-sensitivity C-reactive protein), were published by us earlier. RESULTS: In the BBR-treated cohort, VEGF concentrations demonstrated a statistically significant increase following the intervention, rising from a baseline mean of 456.23 ± 307.61 pg/mL to 561.22 ± 389.77 pg/mL (p < 0.0001). In the BBR group, a significant reduction in PWA-SP was observed after 12 weeks of supplementation (134.85 ± 16.26 vs. 124.46 ± 13.47 mmHg, p < 0.0001). No statistically significant differences were observed in the parameters determining arterial stiffness in t

Comment in Clin Mol Hepatol. 2026 Jul;32(3):1397-1399. doi: 10.3350/cmh.2025.1329. BACKGROUND/AIMS: Cholestatic liver disease (CLD) is a pathological condition characterized by impaired bile formation, secretion, and excretion. However, the key pathophysiological mechanisms of CLD remain elusive, and therapeutic efficacy is unsatisfactory. METHODS: We administered berberine (BBR) or dihydroberberine (dhBBR) in bile duct ligation-, ANIT-, and mdr2-/- CLD mouse models to evaluate the anti-CLD effect. We conducted fecal microbiota transplantation to determine the role of gut microbiota in BBR's effect. We conducted a randomized, controlled clinical trial to evaluate the effects of BBR in patients with CLD. RESULTS: Oral BBR alleviates cholestatic liver injury in multiple mouse models. Gut microbes can transform BBR into dhBBR, which suppresses 5-hydroxytryptamine (5-HT) production in gut enterochromaffin cells by antagonizing tryptophan hydroxylase 1 (TPH1) activity and downregulating Tph1 transcription. This further ameliorates CLD by interrupting the 5-HT/5-HTR axis. A clinical study validated that BBR improved blood biochemical indicators in patients with CLD and decreased 5-HT levels. CONCLUSIONS: BBR is transformed by gut microbiota to ameliorate CLD via inhibiting 5-HT, suggesting potential novel strategies for further clinical use.

Berberine has been reported as a safe and effective pharmacological agent to reduce colorectal adenoma recurrence after polypectomy. This retrospective cohort study is an extended follow-up of a previous clinical trial (NCT02226185) during the post-treatment observational phase. We aim to evaluate the long-term protective effects of berberine on adenoma recurrence. Among 895 patients who finished the previous 2-year randomized trial, we recruited 781 patients at 7 clinical centers across 6 provinces in China. The primary outcome is adenoma recurrence. Between December 29, 2018, and October 10, 2024, 648 patients underwent at least one colonoscopy during the follow-up. The protective effects of berberine persist for at least 6 years after treatment cessation, with lower adenoma recurrence rate (34.7% vs. 52.1%) and lower neoplasm occurrence rate (63.4% vs. 71.0%). Berberine may serve as a potential long-term preventive agent against adenoma recurrence after polypectomy.

Comment in Clin Mol Hepatol. 2026 Apr;32(2):e161-e162. doi: 10.3350/cmh.2025.0804. Clin Mol Hepatol. 2026 Apr;32(2):e158-e160. doi: 10.3350/cmh.2025.0868. BACKGROUND/AIMS: Berberine ursodeoxycholate (HTD1801) has been shown to significantly reduce liver fat content (LFC) in an 18-week, placebo-controlled Phase 2 study in patients with metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus. The purpose of this assessment was to establish proof of concept in liver histologic improvement with HTD1801 treatment based on preclinical and clinical evidence. METHODS: The efficacy of HTD1801 was evaluated in a preclinical MASH/dyslipidemia model (golden hamsters fed a high fat diet, eight/group) after six weeks of daily treatment. Additionally, in a secondary analysis of a Phase 2 clinical study, 100 patients with presumed MASH were evaluated by multiple noninvasive markers associated with MASH resolution and/or fibrosis improvement. These include magnetic resonance imaging proton density fat fraction (MRIPDFF; ≥30% LFC reduction), iron-corrected T1 (≥80 ms reduction), alanine aminotransferase (≥17 U/L reduction), weight loss (≥5% reduction), Fibrosis-4 index (shift to <1.3), and MASH resolution index (achieving ≥-0.67). RESULTS: Preclinical findings in the MASH/dyslipidemia hamster model showed that HTD1801 significantly improved histologic fibrosis and the Nonalcoholic Fatty Liver Disease Activity Score to such a degree that improvements approximated the appearance of the normal controls. In the clinical study, 52% of HTD1801-treated patients achieved MRI response criteria compared to 24% of placebo (P<0.05). Dose-dependent improvements were observed across biomarkers, with more HTD1801-treated patients achieving response criteria associated with improvements in the histologic features of MASH. CONCLUSION: These findings suggest that HTD1801 has strong potential to produce histological improvements in patients with MASH.

Comment in doi: 10.1001/jamanetworkopen.2024.62195. IMPORTANCE: Few of the available therapies for type 2 diabetes (T2D) comprehensively address disease burden beyond glycemic control. Examining whether berberine ursodeoxycholate (HTD1801), a first-in-class gut-liver anti-inflammatory metabolic modulator, has the potential to treat the core aspects of metabolic disease is important. OBJECTIVE: To assess the safety and efficacy of HTD1801 in patients with T2D that is inadequately controlled with diet and exercise. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 double-blind, placebo-controlled, 12-week randomized clinical trial, conducted in China between March 2022 and January 2023, included patients with T2D who underwent 8 or more weeks of diet and exercise, had a hemoglobin A1c (HbA1c) level of 7.0% to 10.5%, and had a fasting plasma glucose (FPG) level less than 250.5 mg/dL. INTERVENTIONS: Patients were randomized 1:1:1 to placebo (n = 38), HTD1801 500 mg twice daily (n = 37), and HTD1801 1000 mg twice daily (n = 38). MAIN OUTCOMES AND MEASURES: The primary end point was the HbA1c level change from baseline to week 12. Secondary end points included glycemic, hepatic, and cardiometabolic parameters. The primary end point was analyzed using a mixed-effects model for repeated measures, with the HbA1c level change from baseline as the dependent variable. Treatment group, measurement time point, and interaction between treatment group and measurement time point were independent variables. RESULTS: The study included 113 patients with T2D (mean [SD] age, 54.3 [10.6] years; 72 male [63.7%]) who were randomized. Among these patients, the mean (SD) HbA1c level was 8.2% (0.8%); body mass index, 25.5 (3.7), calculated as weight in kilograms divided by height in meters squared; and FPG level, 160.7 (38.3) mg/dL. Baseline disease severity was balanced across treatment groups. The primary end point was achieved with significant dose-dependent reductions in the HbA1c level in both HTD1801 groups compared with the placebo group. The least-squares mean difference in the HbA1c level at week 12 was -0.4% (95% CI, -0.79% to -0.03%; P = .04) for the 500-mg group and -0.7% (95%

BACKGROUND: Diabetes is a serious global health issue and increases the risk of several chronic diseases. However, if hyperglycemia and other metabolic abnormalities related to diabetes are controlled, fewer micro- and macrovascular complications may occur. OBJECTIVE: To investigate whether daily supplementation with berberine in combination with cinnamon could have effect on cardiometabolic risk factors, such as impaired glucose regulation, dyslipidemia, and hypertension in patients with diabetes. METHODS: Patients with type 2 diabetes were recruited to participate in a parallel, double-blind, placebo-controlled, randomized study. Participants were randomized into berberine in combination with cinnamon supplementation or placebo group. Participants were then asked to take a divided daily dose of 1200 mg berberine and 600 mg cinnamon or placebo for 12 weeks. ANCOVA was then performed to evaluate the differences between the two groups, controlling for the respective baseline values. RESULTS: At the end of study, fasting blood sugar (FBS) (P = 0.031) and hemoglobin A1C (HbA1c) (P = 0.013) were significantly lower in participants taking berberine plus cinnamon than those taking the placebo capsules. The results of the serum lipid profile also indicated a significant difference in the level of low density lipoprotein cholesterol (LDL-C) (P = 0.039), while no difference was observed in the levels of total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides between the study groups. In addition, there was no difference in other measured metabolic and anthropometric parameters between the two groups. CONCLUSION: Twelve weeks of berberine plus cinnamon consumption reduced blood FBS, HbA1c and LDL-C concentration in patients with diabetes. © 2025. Springer-Verlag GmbH Germany, part of Springer Nature.

Pharmacokinetic drug interactions can lead to unexpected changes in plasma concentrations of the object drug, potentially increasing the risk for adverse effects and/or decreasing therapeutic efficacy. The botanical product goldenseal was previously shown to decrease metformin systemic exposure in healthy adults. This three-arm, open-label, crossover clinical study assessed the pharmacokinetic goldenseal-metformin interaction in adults with type 2 diabetes stabilized on therapeutic doses of metformin (500-2550 mg daily). The aggregate pharmacokinetic data indicated no clinically meaningful interaction as determined by the metformin area under the plasma concentration-time curve (AUC) geometric mean ratio [90% confidence interval] of 0.93 [0.86-1.01] laying within the predefined no-effect range (0.80-1.25). However, metformin AUC decreased by ~20%, 14%, and 0% after goldenseal coadministration at low (500-750 mg), moderate (1000-1500 mg), and high (2000-2550 mg) metformin doses, respectively; renal clearance and half-life remained unchanged throughout. The exploratory pharmacodynamic endpoint, HbA1c, decreased on average from 6.8% to 6.5%, regardless of the effects of goldenseal on metformin pharmacokinetics. The decreasing effect of goldenseal on metformin systemic exposure with increasing metformin dose, coupled with no changes in renal excretion and elimination half-life, indicated that both the pharmacokinetic goldenseal-metformin interaction and the nonlinear absorption of metformin are governed by saturable, intestinal transport mechanism(s). The disconnect between changes in metformin systemic exposure and therapeutic effects emphasizes the need to evaluate clinical biomarkers to comprehensively assess drug interaction risks, particularly those involving natural products. Healthcare providers may consider cautioning patients about supplementing metformin pharmacotherapy with goldenseal to avoid risks for undesired changes in glycemic control. Trial Registration: ClinicalTrials.gov identifier: NCT05081583. © 2025 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and

This study compared the capacity of two different models of HIIT [high-(HC) and low-(LC) compression], with or without the use of berberine (BBR), on NOD-like receptor pyrin domain-containing protein-3 (NLRP3), H19, interleukin (IL)-1β, high-sensitivity C-reactive protein (hs-CRP), and insulin resistance markers. Fifty-four middle-aged men with overweight or obesity and prediabetes [fasting blood glucose (FBG) 110-180 mg/dL] were randomly and equally assigned to the HC, LC, HC + BBR, LC + BBR, BBR, and non-exercising control (CON) groups. The HC (2:1 work-to-rest) and LC (1:1 work-to-rest) home-based training programs included 2-4 sets of 8 exercises at 80%-95% HRmax, twice a week for 8 weeks. Participants in the berberine groups received approximately 1000 mg daily. All exercise interventions led to a significant reduction in hs-CRP, IL-1β, insulin, FBG, and insulin resistance index (HOMA-IR) versus CON. Notably, there was a significant reduction in FBG and HOMA-IR with the BBR group compared to the baseline. Both NLRP3 and H19 experienced a significant drop only with LC in comparison to the baseline. While both exercise protocols were beneficial overall, LC uniquely exhibited more anti-inflammatory effects, as indicated by reductions in H19 and NLRP3. However, the addition of berberine to the exercise programs did not demonstrate additional benefits. © 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Gymnema sylvestre (GS) and berberine (BBR) are natural products that have demonstrated therapeutic potential for the management of obesity and its comorbidities, as effective and safe alternatives to synthetic drugs. Although their anti-obesogenic and antidiabetic properties have been widely studied, comparative research on their impact on the gene expression of adipokines, such as resistin (Res), omentin (Ome), visfatin (Vis) and apelin (Ap), has not been reported. METHODOLOGY: We performed a comparative study in 50 adult Mexican patients with obesity treated with GS or BBR for 3 months. The baseline and final biochemical parameters, body composition, blood pressure, gene expression of Res, Ome, Vis, and Ap, and safety parameters were evaluated. RESULTS: BBR significantly decreased (p < 0.05) body weight, blood pressure and Vis and Ap gene expression and increased Ome, while GS decreased fasting glucose and Res gene expression (p < 0.05). A comparative analysis of the final measurements revealed a lower gene expression of Ap and Vis (p < 0.05) in patients treated with BBR than in those treated with GS. The most frequent adverse effects in both groups were gastrointestinal symptoms, which attenuated during the first month of treatment. CONCLUSION: In patients with obesity, BBR has a better effect on body composition, blood pressure, and the gene expression of adipokines related to metabolic risk, while GS has a better effect on fasting glucose and adipokines related to insulin resistance, with minimal side effects.

The inhibition and metabolism kinetics of tetrahydropalmatine (THP), protopine (PRO), and dehydrocorydaline (DHC), three major biologically active components of Corydalis yanhusuo W. T. Wang, which has been used for thousands of years in China, were evaluated in human liver microsomes (HLMs) to determine their potential for drug-drug interactions.THP acted as a mechanism-based inhibitor of cytochrome P450 2D6 (CYP2D6), with a Kinact of 0.053 min⁻1 and a Ki of 0.26 µM. It was metabolised by HLMs with a Km of 7.62 μM, Vmax of 0.071 nmol/min/mg, and intrinsic clearance (CLint) of 9.27 × 10⁻6 L/min/mg. The oxidative metabolism of THP involved CYP2C19, CYP3A4, CYP1A2, and CYP2D6.PRO was a mixed inhibitor (both competitive and non-competitive) of CYP2D6, with Ki of 0.023 µM and Kis of 0.042 µM. HLMs metabolised PRO with a Km of 3.99 μM, Vmax of 0.033 nmol/min/mg protein, and CLint of 8.20 × 10⁻⁶ L/min/mg. Its oxidative metabolism involved CYP2C19, CYP2D6, and CYP3A4.DHC was a weakly competitive inhibitor of CYP2D6 (Ki = 20.1 µM) and was no longer metabolised by HLMs.These findings indicate that CYP2D6 is a potential target for drug-drug interaction involving THP and PRO, whereas DHC exhibits minimal interaction potential.

Breast cancer ranks among the most prevalent malignant tumors globally, underscoring the urgent need for efficient and low-toxicity treatment strategies. In this study, a novel nanomedicine (BBR-SA) was constructed based on the self-assembled of berberine (BBR) and sinapic acid (SA) for synergistic chemotherapy. Firstly, utilizing π-π stacking, hydrogen bonding, and electrostatic forces between BBR and SA, the BBR-SA achieved a well-defined nanostructure with high drug-loading capacity and favorable water dispersibility. Furthermore, BBR-SA nanomedicine effectively inhibited the proliferation of mouse mammary carcinoma cells (4T1), showing a significantly stronger inhibitory effect than either BBR or SA alone. Moreover, the remarkable anti-tumor effect was obtained after treatment with BBR-SA nanomedicine in vivo, further demonstrating a synergistic therapeutic effect. More importantly, no significant systemic toxicity was observed after 28 days of intravenous administration with BBR-SA nanomedicine. In summary, the BBR-SA nanomedicine represents a safe and effective therapeutic strategy for breast cancer, offering new perspectives on the application of the traditional chinese medicine in anti-tumor therapy.

The escalating crisis of antimicrobial resistance (AMR) among Gram-negative pathogens, particularly Klebsiella pneumoniae (KP), necessitates innovative strategies to enhance the efficacy of existing antibiotics. Synergistic drug combinations present a promising approach to improve therapeutic outcomes and delay the emergence of resistance. This study investigates the synergistic interaction between the natural alkaloid berberine chloride and the repurposed antibiotic rifaximin against KP. Integrated in vitro and in silico analyses reveal significant bactericidal synergy between the two agents, mediated through concurrent inhibition of the transcriptional anti-termination factor RfaH, a key regulator of virulence and capsule biosynthesis. Molecular docking and dynamics simulations demonstrate that both compounds cooperatively bind to the RfaH pocket, stabilizing an inactive ternary complex without major structural disruption. Functional assays confirm that the combination effectively suppresses RfaH-dependent capsule production at lower concentrations compared to monotherapy. These findings suggest that RfaH is a viable target for combinatorial inhibition and provide a plausible mechanistic foundation for the berberine-rifaximin synergy. This work supports the rational development of dual-targeting anti-virulence strategies to combat multidrug-resistant KP infections.

Antifungal resistance is growing increasingly more common due to the widespread use of limited number of antifungal compounds classes. Plant extracts have been used and studied for thousands of years as antifungal therapeutics alone or in combination with other natural products. This study investigated the synergistic effects of combining ethanolic extracts from nine plants with documented antifungal activity to identify natural and more powerful antifungal treatments against Candida albicans. Using checkerboard microdilution assays, 11 out of 15 combinations exhibited additive or synergistic interactions (fractional inhibitory concentration index, FICI < 1). The strongest synergy was observed between Alpinia officinarum and Hydrastis canadensis with MIC90 FICI = 0.08 and MIC50 FICI = 0.05. Combinations involving H. canadensis, Eucalyptus globulus, and Punica granatum produced the most synergistic effects with other tested extracts and with each other. Combining putative active compounds from each of these three extracts demonstrated synergistic antifungal activity, with the strongest synergy observed with berberine (from H. canadensis) and punicalagin (from P. granatum) with MIC90 FICI = 0.31 and MIC50 FICI = 0.13. Eucalyptol did not produce any significant antifungal activity so E. globulus extract was fractionated to identify its main antifungal compounds. UPLC-MS analysis determined that the most active fractions were primarily made up of hydrolysable tannins which produced strong synergy when combined to berberine with MIC90 FICI = 0.31 and MIC50 FICI = 0.25. The combinations of berberine with punicalagin and berberine with the E. globulus high tannin fraction F5 displayed antifungal activity against C. albicans with MIC90 concentrations of 2-16 µg/mL, which are comparable to MIC90 concentration for econazole of 0.5-8 µg/mL. These results suggest that phytochemical mixtures containing different classes of antifungal compounds can approach the efficacy of commercial antifungals and may serve as effective alternatives. Copyright: © 2026 Cho et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which pe

ANTIMICROBIAL RESISTANCE: especially via efflux pump-mediated multidrug resistance is a major factor limiting antibacterial therapy efficacy. Antimicrobial photodynamic therapy (aPDT) is a non-antibiotic strategy that overcomes resistance through generation of reactive oxygen species. Plant-derived compounds exhibit efflux pump inhibitory activity and potential photosensitizing capabilities. This study evaluated the use of plant-derived efflux pump inhibitors (EPIs): berberine, capsaicin, coumarin 6, curcumin, palmatine, and piperine in combination with Chlorin e6 and aPDT against Bacillus cereus (Gram-positive) and Escherichia coli (Gram-negative). The aim was to enhance Chlorin e6 accumulation and reduce bacterial dry mass density. Both qualitative and quantitative methods were used in the study. Minimum inhibitory concentrations (MICs) of EPIs were determined to guide treatment concentrations. A modified resazurin assay assessed bacterial viability after 24-h incubation with EPIs. Spectroscopic properties of all compounds were recorded using UV-VIS spectroscopy. Digital holotomography (DHT) was applied to monitor changes in refractive index (RI) of bacterial cells induced by incubation and treatment, and results were validated using confocal fluorescence microscopy. Changes in RI values indicated structural and compositional changes in the bacteria. Naturally derived EPIs effectively potentiated aPDT by promoting photosensitizer uptake and induced a measurable reduction in dry mass density. Treatment efficacy using combination therapy for B.cereus and E.coli improved 273.90 % and 227.72 %, respectively. These findings suggest naturally derived EPIs effectively potentiate Chlorin e6-mediated aPDT and improve bactericidal capacity against bacteria. The study offers mechanistic insight into photodynamic enhancement via plant-based inhibitors and supports potential applications in clinical antimicrobial therapy, food safety, and industrial decontamination.

Wound infections represent a prevalent clinical challenge. Bacterial infections can impede wound healing, potentially resulting in the development of chronic wounds that pose life-threatening risks in severe cases. In this study, a pH-responsive smart hydrogel for the co-delivery of tobramycin (TOB) and the antibiotic adjuvant berberine (BBR) was designed, aiming to reduce side effects and enhance the antibacterial activity of antibiotics. In the simulated inflammatory environment with a pH of 5.0, the release percentages for TOB and BBR after 48 h were 72.12 % and 93.11 %, respectively. Meanwhile, the hydrogel shows marvelous swelling performance, injectability, good biocompatibility, and excellent self-healing characteristics. The antibacterial assays show that BBR potentiated the antibacterial activity of antibiotics, and the synergistic effect of the dual-drug greatly eradicates the majority of bacteria. These findings collectively suggest that pH-responsive smart hydrogels represent a promising strategy for antibiotic delivery.

Yuanhuzhitong prescription (YZP), composed by Corydalis yanhusuo and Angelica dahurica, is mainly used to treat stomach pain, rib pain, headache. However, there is limited information on the effects of YZP on the activity of CYP450 enzymes, and studies on the compatibility mechanism of YZP in view of CYP-mediated herb-herb interactions are rarely conducted. This study, utilizing probe substrates, human liver microsomes, recombinant CYP metabolic enzymes, CYP inhibitors, and molecular docking, focuses on the metabolic stability and inhibitory activity of YZP components on P450 isozymes, and how imperatorin (IPT) and isoimperatorin (IIP) affect the elimination pathway of tetrahydropalmatine (THP) by inhibiting the activity of the CYP450 enzyme to enhance the analgesic efficacy of CYH. The results showed that THP shows weak inhibition of CYP2C9, CYP2D6, and 3A4; while IPT and IIP are potent inhibitors of CYP1A2, moderate inhibitors of CYP2C19, CYP2C9, CYP2D6, and 3A4. In addition, CYP2B6 was strongly inhibited by IPT and moderately inhibited by IIP. THP is primarily metabolized by CYP1A2, CYP2C9, CYP2D6, and CYP3A4. IPT and IIP undergo metabolism mainly through CYP1A2, CYP2B6, CYP2C19, and 3A4. Molecular docking studies confirmed that THP, IPT and IIP occupy the active sites of CYP1A2, CYP2C9, CYP2D6, and CYP3A4. In vitro and in vivo experiments have shown a significant reduction in metabolism of THP in combination with IPT or IIP. IPT and IIP mediate the metabolism of THP in the liver by inhibiting P450 enzymes, thereby enhancing the bioavailability of THP, reducing the elimination rate of THP, and consequently improving the analgesic efficacy.

Sorafenib, one of multi-kinase inhibitors, is a first-line clinical drug for hepatocellular carcinoma (HCC). However, it can only provide limited survival window and high recurrence of advanced HCC. So, to improve its therapeutical application and efficacy, it is urgent to develop a combination strategy. Berberine is a representative of bioactive compounds isolated from some medicinal herbs, and shows great anti-cancer capacity, including liver cancer. Importantly, berberine shows low toxicity to human beings, which makes it an ideal candidate. Therefore, the purpose of this study is to evaluate the possibility of berberine as a sensitizer to improve the efficacy of sorafenib against HCC and investigate the mechanisms involved. As demonstrated from our results, we found berberine greatly enhanced the inhibitory effects of sorafenib on cell proliferation synergistically against mouse and human liver cancer cell lines in vitro, Hepa1-6 xenograft model in C57/B6J mice in vivo and in the 3D culture system of tumor cells. Compared with sorafenib treatment alone, additional berberine treatment induced more severe mitochondrial dysfunction and ROS accumulation, following exacerbation of lipid peroxidation, which were abolished by ferroptosis inhibitors liproxstatin-1 and ferrostatin-1. In HepG2 cells, we validated ferroptosis induction in combined treatment is p53-dependent by RNA sequencing. Herein, we demonstrated p53 signaling activation is due to p53 protein accumulation without its upregulation transcriptionally. Mechanically, we found p53 protein accumulation is not due to ubiquitin-dependent proteasomal degradation but resulting from repression of NQO1-dependent ubiquitin-independent proteasomal degradation. Additionally, we demonstrated NQO1 activation induced by combined treatment was due to SETDB1 inactivation, following ERVs induction and genome instability, which may be another factor for lipid peroxidation and ferroptosis. Collectively, berberine has great potential to be used as a novel chemo-enhancer to improve the efficacy of sorafenib -based therapy.

Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), is approved as a front-line treatment for metastatic colorectal cancers, but limited efficacy is obtained. Combinatory therapy is a potentially promising strategy to enhance anticancer effects, overcome drug resistance and improve overall clinical survival. Here, we show that berberine combined with cetuximab created a synergistic inhibitory effect on cetuximab-resistant CRC cells in vitro and in vivo. Human phospho-kinase assay explored that the phosphorylation of Src and Chk-2 was inhibited by berberine and decreased greatly when combined with cetuximab. Adding KX2-391 (Src inhibitor) rather than BML-277 (Chk-2 inhibitor) with cetuximab resulted in more cell death and apoptosis. Conversely, activation of Src with MLR-1023 mitigated the inhibitory effect of berberine alone or in combination with cetuximab. Additionally, the activities of downstream kinases of Src such as mTOR, STAT3 and the production of ROS were inhibited greatly by berberine plus cetuximab. Taken together, we concluded that the synergistic effects of BBR and cetuximab may be mediated by decreasing the activities of Src/mTOR/STAT3 and the production of ROS, thus inducing greater extent of apoptosis in cancer cells. © 2025. The Author(s).

Retraction in Biochem Biophys Res Commun. 2026 Jun 25;819:153861. doi: 10.1016/j.bbrc.2026.153861. The synergistic effects of natural compounds provide "multi-component, multi-target" advantages by optimizing efficacy-toxicity profiles. This study elucidates the protective mechanisms and optimal combination of sanguinarine (SA) and curcumin (Cur) in mitigating indomethacin-induced small intestinal injury. A rat model of indomethacin-induced intestinal injury was utilized to assess the therapeutic efficacy of various SA/Cur combinations, with the SA1+Cur40 mg/kg combination identified as optimal, using berberine (Ber) as a positive control. The SA1+Cur40 combination significantly alleviated intestinal injury, as evidenced by improved CMDI/TDI scores and reduced levels of key inflammatory markers, including TNF-α, IL-6, IL-1β, and LDH. Mechanistic investigations revealed that SA and Cur act synergistically through dual-pathway regulation: (1) SA enhances Nrf2 signaling, activating HO-1 and thereby augmenting antioxidant capacity; (2) Cur inhibits NF-κB activation, reducing pp65 and mitigating the inflammatory response. This synergy significantly enhances intestinal epithelial tight junction integrity by effectively inhibiting MMP2/9 activity and upregulating the expression of junctional proteins such as ZO-1, Claudin-1, and Occludin. CONCLUSION: The combination of SA and Cur, notably the SA1+Cur40 formulation, demonstrated significant efficacy in mitigating indomethacin-induced small intestinal injury. This effect was achieved through the synergistic activation of the Nrf2 antioxidant pathway and concurrent inhibition of the NF-κB inflammatory pathway.