Berberine

Findings:

Berberine (BBR), an alkaloid from Coptidis Rhizoma, demonstrates multiple pharmacological actions including anti-inflammation, antioxidant, antibacterial, and antitumor effects relevant to ulcerative colitis (UC) and cancer. In UC models and a phase I trial, BBR reduced inflammation (cytokines like TNF-α, IL-6, IFN-γ), modulated immune responses (Th17/Treg balance, macrophage polarization), improved gut barrier function, and altered gut microbiota. In cancer studies (in vitro/vivo), BBR inhibited tumor growth, proliferation, and metastasis via pathways like PI3K/AKT/mTOR, Wnt/β-catenin, and NF-κB, induced apoptosis/autophagy, modulated tumor-infiltrating immune cells, and showed potential for immunotherapy by affecting PD-L1.

Participants:

Studies involved rodent models (rats, mice including DSS-induced colitis and CLP-induced injury models), various human cancer cell lines in vitro, and human participants (UC patients in a phase I trial, type 2 diabetes patients).

Study Quality Assessment:

Mini-review summarizing studies from the recent 5 years. Reviewed studies include in vivo (rodent models), in vitro (cell lines), referenced GWAS findings, and a phase I clinical trial (UC patients). Funding sources and conflict of interest statement provided. Published in Frontiers in Immunology.

All Effects:

Findings:

Berberine significantly improved fasting blood glucose (FBG), Morris water maze test (MWM) performance (escape latency, platform crossings, time in target quadrant), serum insulin, OGTT results, amyloid β (Aβ), acetylcholinesterase (AChE), oxidative stress, and inflammation levels in animal models of DCI. The analysis suggests berberine lowers blood glucose and improves learning and memory, possibly via mechanisms involving glucose/lipid metabolism, insulin resistance, anti-oxidation, anti-neuroinflammation, ER stress inhibition, and cholinergic system improvement.

Participants:

Animal models of Diabetes-Related Cognitive Impairment (DCI). Twenty studies involving 442 animals.

Study Quality Assessment:

Systematic review and meta-analysis of 20 studies. Methodological quality assessed using SYRCLE's risk of bias tool. Statistical analysis performed using STATA 15.0 (SMD with 95% CI). Databases searched: PubMed, Web of Science, Embase, CNKI, Wanfang, VIP. Limitation acknowledged: significant heterogeneity. Conflict of interest statement provided: authors declare no commercial or financial relationships.

All Effects:

Authors:

Jia-Wen Shou

Findings:

This review summarizes evidence suggesting Berberine (BBR) has therapeutic potential against various neurological disorders including Alzheimer's, Parkinson's, stroke, Huntington's, dementia, psychiatric disorders (schizophrenia, anxiety, depression), epilepsy, TBI, and brain tumors. Key mechanisms involve antioxidant, anti-inflammatory effects, modulation of cell viability (apoptosis, autophagy, angiogenesis), inhibition of Aβ/Tau pathology, regulation of neurotransmitter systems, and interaction with gut microbiota. Clinical trials indicate BBR may improve outcomes in stroke and, as an adjunct, in schizophrenia.

Participants:

Review covers studies using various animal models (mice, rats, hamsters, rabbits, beagle dogs, zebrafish) including transgenic and chemically-induced disease models, as well as human clinical trials involving stroke patients (N=55, 52, 60, 63) and schizophrenia patients (N=31, 43, 34, 27).

Dosage:

Clinical trials reported dosages for stroke patients ranging from 300mg tid (three times daily) to 700mg tid for 7-14 days. For schizophrenia patients, a dosage of 300mg tid for 8-12 weeks was used in combination therapy.

Study Quality Assessment:

The text is a review article citing numerous references (1-180). It describes findings from in vivo, in vitro, and clinical studies. Specific methods mentioned include transgenic mouse models (TgCRND8, APP/PS1, 3xTg AD, N171-82Q), chemical-induced models (streptozotocin, heavy metals, MPTP/P, 6-OHDA, MCAO, doxorubicin, d-galactose, lipopolysaccharide, MK-801, kainate, pentylenetetrazole), and specific measurements (e.g., AChE activity, Aβ/Tau levels, ROS, cytokines, NF-κB, caspase activity, TH expression, infarct volume, MDA, GSH-Px, SOD, CAT, HIF-1α, prolactin, cholesterol). Clinical trials mentioned include sample sizes (N range 27-63) and one is described as 'randomized double blind'. Limitations acknowledged include BBR's low bioavailability, potential inhibition of CYP enzymes (drug interactions), and conflicting in vitro results regarding rotenone models. Funding source for the review authors is mentioned (Hong Kong Ph.D. Fellowship).

All Effects:

Authors:

Xiaopeng Ai

Findings:

This review systematically describes evidence for berberine as a therapeutic agent in diverse vascular diseases, covering its pharmacological effects, molecular mechanisms, and pharmacokinetics. Berberine exhibits anti-inflammatory, antioxidant, antiapoptotic, and antiautophagic activities by regulating multiple signaling pathways (e.g., AMPK, NF-κB, SIRT-1, HIF-1α, PI3K/Akt, JAK-2/STAT-3). Despite promising preclinical results in conditions like cardiovascular disease, atherosclerosis, hypertension, diabetes, and cancer angiogenesis, its clinical use is limited by poor oral bioavailability due to extensive first-pass elimination.

Participants:

The review summarizes studies conducted on various models including rats, mice, rabbits, zebrafish embryos, human cell lines (HUVECs, HASMCs, human coronary artery endothelial cells, human aortic endothelial cells, human PASMCs, HepG2 liver cancer cells), and humans (healthy individuals, patients with nonalcoholic fatty liver disease).

Dosage:

The review cites various dosages from different studies: In humans, 400mg or 500mg orally resulted in low plasma concentrations; 15mg/kg oral berberine chloride daily for 3 months and 300mg orally three times daily for 2 days were used in metabolic studies. In rats, oral doses ranged from 48.2 mg/kg to 560 mg/kg. In mice, doses included 100 mg/L or 1 mmol/L in drinking water, and 100-300 mg/kg orally. In rabbits, 50 mg/kg oral dose was mentioned. In vitro concentrations ranged from 0.5 μM to 100 μM, and 5-10 μg/ml. A common clinical dosage in China for gastrointestinal infections is 0.1g (100mg) pill form, 1-3 times per day.

Study Quality Assessment:

This is a review article that screened publications from 2010–2021 across multiple databases (Web of Science, ScienceDirect, PubMed, Google Scholar, CNKI). It discusses limitations of berberine, notably low oral bioavailability and first-pass metabolism, and acknowledges the need for further research including toxicity studies, human pharmacokinetic studies, standardized dosage, and higher quality clinical trials. Specific methods mentioned from cited studies include various chromatography-mass spectrometry techniques (HPLC–ESIMS/MS, LC–MS/MS), cell culture models (e.g., caco-2), and in vivo animal experiments. Funding sources for the review itself are disclosed.

All Effects:

Authors:

Yu Ye

Findings:

This systematic review and meta-analysis concluded that berberine treatment alone significantly improves metabolic parameters. It was found to reduce triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), fasting plasma glucose (FPG), and homeostasis model assessment-insulin resistance (HOMA-IR), while increasing high-density lipoprotein (HDL) levels in patients with metabolic disorders. Extending the treatment period beyond 3 months significantly increased the therapeutic effect.

Participants:

Patients with metabolic disorders (including nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, impaired glucose tolerance (prediabetes), polycystic ovarian syndrome (PCOS), and hyperlipidemia). The meta-analysis included data from varying numbers of participants across different outcomes: TG (n=1449), TC (n=1425), LDL (n=1361), HDL (n=1193), HOMA-IR (n=539), FPG (n=1180).

Dosage:

Subgroup analysis was conducted based on treatment dose, but the specific doses used in the included trials are not detailed in the provided text. Inclusion criteria required the dose to be greater than the minimum effective dose.

Study Quality Assessment:

Systematic review and meta-analysis of 18 Randomized Clinical Trials (RCTs). Followed 'Cochrane Handbook for Systematic Reviews of Interventions'. Searched PubMed, GeenMedical, Cochrane library, CNKI databases. Inclusion criteria specified RCTs (placebo or parallel controlled), patients with metabolic disorder, same lifestyle intervention in control/trial groups, berberine alone in trial group, dose > minimum effective dose. Used standardized mean difference (SMD) and random-effect models for analysis. Assessed risk of bias using Cochrane tool across six domains (random sequence generation, allocation concealment, blinding of participants/personnel, blinding of outcome assessment, incomplete outcome data, selective reporting); 8/18 trials reported randomization method, 8/18 specified double-blind, 9 were placebo-controlled, 9 were parallel-controlled. Acknowledged limitations: potential random errors in sample inclusion, heterogeneity in RCT sample characteristics (gender, age), co-morbidities, non-identical life interventions across studies, incomplete reporting in source articles (diagnosis status, visit frequency), potential racial differences in drug efficacy/metabolism, study was not registered.

All Effects:

Findings:

The purpose is to summarize clinical trials on berberine to improve its clinical application.

Study Quality Assessment:

Review of clinical trials

Findings:

Berberine (BBR) exhibits substantial neuroprotective potential against various neurological conditions, attributed to multifaceted molecular mechanisms. These include attenuating oxidative stress, mitigating inflammation and necroptosis, inhibiting apoptosis, inducing autophagy, and modulating neurotransmitter levels, CYP450 enzyme activities, and gut microbiota composition. BBR engages numerous signaling pathways (e.g., PI3K/Akt, NF-κB, AMPK, CREB, Nrf2, MAPK) to exert these effects, although clinical application faces challenges like low bioavailability, which nanodelivery systems aim to overcome.

Participants:

Review summarizing data from in vitro studies (various cell types including neuronal, microglia, astrocytes, SH-SY5Y, PC12), animal models (rats, mice, zebrafish for conditions like ischemia, neurotoxicity, PD, AD, HD, TBI, depression), and human clinical trials (patients with type-2 diabetes, acute ischemic stroke, hyperlipidemia).

Dosage:

Review mentions various dosages: In vitro IC50s reported (e.g., ~0.3 mg/mL for DPPH/ABTS radical tests; 0.17 mg/mL for NO radical scavenging; 0.12 mg/mL for Fe2+ chelation; 0.11 mg/mL for OH• radical scavenging). Animal studies: Oral 10 or 20 mg/kg/day for 19 days (rats, ischemia); Oral 10 or 20 mg/kg (mice, antidepressant-like effect); LD50 in mice varies by route (Oral >20.8 g/kg, IV 9.04 mg/kg, IP 57.6 mg/kg). Human trials (oral): 300mg three times daily for 14 days (CYP inhibition study); 1.5 g/day (500mg TID) for 13 weeks (diabetes study, caused GI side effects); 20mg/day (BBR combined with atorvastatin, stroke study); 1 g/day (0.5 g BID) for 16 weeks (gut microbiota study); 0.5 g/day for 8 weeks (hyperlipidemia/PD study).

Study Quality Assessment:

Comprehensive literature review using Scopus, PubMed, and Web of Science databases (search terms provided: 'berberine and neuroprotection', 'berberine and neuroprotective effect', 'berberine and neurodegenerative diseases'). Cites in vitro, animal, preclinical, and randomized clinical trials. Mentions specific methods (e.g., oral/IV/IP/nasal administration, nanocarriers like BBR-CTS-NLCs, biochemical assays like DPPH/ABTS, IC50 determination, specific disease models like MCAO, 6-OHDA, LPS). Acknowledges limitations like poor oral bioavailability (<1%) and potential dose/route-dependent toxicity (e.g., GI effects in humans at 1.5g/day for 13 weeks). Mentions specific trial details (e.g., N=55 stroke patients, 13-week diabetes trial, 16-week gut microbiota trial, 14-day CYP interaction trial). Article is open access (CC BY license).

All Effects:

Findings:

The meta-analysis, based on 19 studies with 360 animals, indicated that berberine significantly improved cognitive function in AD animal models, as measured by the Morris Water Maze (MWM) test: decreased escape latency (SMD = -2.92), increased number of platform crossings (SMD = 4.27), and increased time spent in the target quadrant (SMD = 5.92). Berberine also significantly reduced β-amyloid precursor protein (APP) expression (SMD = -3.28). The mechanism may involve berberine's influence on APP processing.

Participants:

Animal models of Alzheimer's disease (AD), including transgenic (APP/PS1, 3xTg-AD, TgCRND8, B6C3-Tg) and drug-induced (streptozotocin, colchicine, ethanol, heavy metals) models. Species included mice (APP/PS1, 3xTg-AD, TgCRND8, Swiss Albino, B6C3-Tg) and rats (Wistar, Sprague-Dawley). A total of 19 studies involving 360 animals were included (175 treatment, 175 control). Animal sex varied (mostly male, some female, some both, some unspecified). Age ranged from 1 month to 8 months, weights varied (e.g., 20-25g mice, 170-350g rats).

Dosage:

Dosages varied across the 19 included studies. Seventeen studies used doses between 50-100 mg/kg, one used 40 mg/kg, and one used 187.5 mg/kg. Other doses mentioned in specific studies include 25 mg/kg and 260 mg/kg. Administration routes were primarily oral or intragastric. Intervention duration ranged from 14 days to 6 months.

Study Quality Assessment:

Systematic review and meta-analysis of 19 studies identified as randomized controlled trials in animal models. Databases searched: PubMed, MEDLINE, EMBASE, Web of Science, Cochrane Library (up to June 1, 2023). Quality/Risk of bias assessed using SYRCLE RoB Tool (scores ranged 3-6 out of 10). Limitations noted: No studies rated low risk for sequence generation, allocation concealment, blinded intervention, or random outcome assessment; only 6/19 low risk for blinded outcome assessment. High heterogeneity observed across studies (I2 > 50% for all outcomes). Potential publication bias detected via funnel plots and Egger's test (p<0.05 for all outcomes), though trim-and-fill analysis suggested results were robust. Statistical methods: Random-effects models, SMD, 95% CI, I2 test, subgroup analysis, sensitivity analysis, meta-regression.

All Effects:

Findings:

The study suggests potential induction of GI upset and ulceration, immunotoxicity, phototoxicity, neurotoxicity, cardiotoxicity, and jaundice in a dose-dependent manner.

Dosage:

Effects mentioned occur 'in a dose', suggesting dose-dependency, but specific dosage is not stated.

All Effects: