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A randomized, parallel controlled, open-label clinical trial was conducted to evaluate the effect of a botanic compound berberine (BBR) on NAFLD. A randomized, parallel controlled, open-label clinical trial was conducted in three medical centers (NIH Registration number: NCT00633282). A total of 184 eligible patients with NAFLD were enrolled and randomly received (i) lifestyle intervention (LSI), (ii) LSI plus pioglitazone (PGZ) 15mg qd, and (iii) LSI plus BBR 0.5g tid, respectively, for 16 weeks. Hepatic fat content (HFC), serum glucose and lipid profiles, liver enzymes and serum and urine BBR concentrations were assessed before and after treatment. We also analyzed hepatic BBR content and expression of genes related to glucose and lipid metabolism in an animal model of NAFLD treated with BBR. As compared with LSI, BBR treatment plus LSI resulted in a significant reduction of HFC (52.7% vs 36.4%, p = 0.008), paralleled with better improvement in body weight, HOMA-IR, and serum lipid profiles (all p<0.05). BBR was more effective than PGZ 15mg qd in reducing body weight and improving lipid profile. BBR-related adverse events were mild and mainly occurred in digestive system. Serum and urine BBR concentrations were 6.99ng/ml and 79.2ng/ml, respectively, in the BBR-treated subjects. Animal experiments showed that BBR located favorably in the liver and altered hepatic metabolism-related gene expression. BBR ameliorates NAFLD and related metabolic disorders. The therapeutic effect of BBR on NAFLD may involve a direct regulation of hepatic lipid metabolism. ClinicalTrials.gov NCT00633282.

Non-alcoholic steatohepatitis is frequently associated with diabetes and may cause progressive liver disease. Current treatment options are limited. Here we report on a prospective, randomised, double-blind, placebo-controlled trial of two doses of HTD1801 (berberine ursodeoxycholate, an ionic salt of berberine and ursodeoxycholic acid), versus placebo that was conducted in 100 subjects with fatty liver disease and diabetes (NCT03656744). Treatment was for 18 weeks with a primary endpoint of reduction in liver fat content measured by magnetic resonance imaging proton density fat fraction. Key secondary endpoints included improvement in glycemic control, liver-associated enzymes and safety. The pre-specified primary endpoint was met. Thus, subjects receiving 1000 mg twice a day of berberine ursodeoxycholate had significantly greater reduction in liver fat content than in placebo recipients (mean absolute decrease −4.8% vs. −2.0% ( p  = 0.011). Compared to placebo, subjects receiving this dose also experienced significant improvement in glycemic control as well as reductions in liver-associated enzymes and significant weight loss. Diarrhea and abdominal discomfort were the most frequently reported adverse events. We conclude that berberine ursodeoxycholate has a broad spectrum of metabolic activity in patients with presumed NASH and diabetes. It is relatively well tolerated and merits further development as a treatment for NASH with diabetes. Berberine ursodeoxycholate has been studied for its serum lipid and lipoprotein lowering effects. Here the authors report an 18-week phase 2, randomised, double-blind, placebo-controlled clinical trial that tested the effect of berberine ursodeoxycholate in patients with fatty liver disease and diabetes, and showed that the group taking the higher dose of the drug had reduced liver fat content.

Berberis darwinii, known for its bioactive alkaloids like berberine and palmatine, has gained attention for its medicinal properties. However, comprehensive studies on the specific bioactive molecules of Michay are lacking, as previous research has primarily focused on wild plants. Therefore, this study proposes to evaluate the alkaloid content in various tissues of B. darwinii collected from different locations, aiming to identify high-yielding accessions suitable for consistent bioactive alkaloid production. This research focuses on plants from a cultivated Michay orchard established five years ago. Leaves, stems, roots, and fruits from 96 accessions of Michay were collected to obtain an alkaloidal extract used for the characterization and comprehensive analysis of bioactive alkaloids through high-performance liquid chromatography. Based on these results, a search for the main outliers was conducted to identify the accessions with the highest alkaloid production. The results showed that roots had the highest concentrations of both berberine and palmatine, followed by stems, while leaves and seeds had lower levels, and the pulp from fruits had no detectable alkaloids. Notably, alkaloid concentrations reached up to 30,806 µg/g in roots, with accession C2P18 standing out for its combined total of 20,827.74 µg/g of berberine and 9978.27 µg/g of palmatine. Accession C3P26 showed the highest berberine concentration at 26,482.20 µg/g. These values underscore the wide variation in alkaloid accumulation and highlight the potential for selecting elite accessions with exceptionally high yields. These findings highlight the importance of plant selection for optimal alkaloid extraction. Choosing high-yielding accessions and standardizing cultivation practices will ensure a stable supply of berberine and palmatine for pharmaceutical, nutraceutical, and food industry applications.

Berberine (BBR), a benzylisoquinoline alkaloid obtained from natural medicines such as coptidis rhizoma , has a wide range of pharmacological activities such as protecting the nervous system, protecting the cardiovascular system, anti-inflammatory, antidiabetic, antihyperlipidemic, antitumor, antibacterial, and antidiarrheal. However, factors such as poor solubility, low permeability, P-glycoprotein (P-gp) efflux, and hepatic-intestinal metabolism result in BBR having a low bioavailability (< 1%), which restricts its application in clinical settings. Therefore, improving its bioavailability is a prerequisite for its clinical applications. This review summarizes the various pharmacological effects of BBR and analyzes the main reasons for its poor bioavailability. It introduces methods to improve the bioavailability of BBR through the use of absorption enhancers and P-gp inhibitors, structural modification of BBR, and preparation of BBR salts and cocrystals as well as the development of new formulations and focuses on the bioavailability study of the new formulations of BBR. The research of BBR was also prospected in order to provide reference for the further research of BBR. Graphical Abstract

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.

Coptisine is a natural small‐molecular compound extracted from Coptis chinensis (CC) with a history of using for thousands of years. This work aimed at summarizing coptisine's activity and providing advice for its clinical use. We analysed the online papers in the database of SciFinder, Web of Science, PubMed, Google scholar and CNKI by setting keywords as ‘coptisine’ in combination of ‘each pivotal pathway target’. Based on the existing literatures, we find (a) coptisine exerted potential to be an anti‐cancer, anti‐inflammatory, CAD ameliorating or anti‐bacterial drug through regulating the signalling transduction of pathways such as NF‐κB, MAPK, PI3K/Akt, NLRP3 inflammasome, RANKL/RANK and Beclin 1/Sirt1. However, we also (b) observe that the plasma concentration of coptisine demonstrates obvious non‐liner relationship with dosage, and even the highest dosage used in animal study actually cannot reach the minimum concentration level used in cell experiments owing to the poor absorption and low availability of coptisine. We conclude (a) further investigations can focus on coptisine's effect on caspase‐1‐involved inflammasome assembling and pyroptosis activation, as well as autophagy. (b) Under circumstance of promoting coptisine availability by pursuing nano‐ or microrods strategies or applying salt‐forming process to coptisine, can it be introduced to clinical trial.

Berberine (BBR) has been confirmed to have multiple bioactivities in clinic, such as cholesterol-lowering, anti-diabetes, cardiovascular protection and anti- inflammation. However, BBR's plasma level is very low; it cannot explain its pharmacological effects in patients. We consider that the in vivo distribution of BBR as well as of its bioactive metabolites might provide part of the explanation for this question. In this study, liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LC/MS(n)-IT-TOF) as well as liquid chromatography that coupled with tandem mass spectrometry (LC-MS/MS) was used for the study of tissue distribution and pharmacokinetics of BBR in rats after oral administration (200 mg/kg). The results indicated that BBR was quickly distributed in the liver, kidneys, muscle, lungs, brain, heart, pancreas and fat in a descending order of its amount. The pharmacokinetic profile indicated that BBR's level in most of studied tissues was higher (or much higher) than that in plasma 4 h after administration. BBR remained relatively stable in the tissues like liver, heart, brain, muscle, pancreas etc. Organ distribution of BBR's metabolites was also investigated paralleled with that of BBR. Thalifendine (M1), berberrubine (M2) and jatrorrhizine (M4), which the metabolites with moderate bioactivity, were easily detected in organs like the liver and kidney. For instance, M1, M2 and M4 were the major metabolites in the liver, among which the percentage of M2 was up to 65.1%; the level of AUC (0-t) (area under the concentration-time curve) for BBR or the metabolites in the liver was 10-fold or 30-fold higher than that in plasma, respectively. In summary, the organ concentration of BBR (as well as its bioactive metabolites) was higher than its concentration in the blood after oral administration. It might explain BBR's pharmacological effects on human diseases in clinic.

Berberine is a natural alkaloid used to improve glycemia but displays poor bioavailability and increased rates of gastrointestinal distress at higher doses. Recently, dihydroberberine has been developed to combat these challenges. This study was designed to determine the rate and extent to which berberine appeared in human plasma after oral ingestion of a 500 mg dose of berberine (B500) or 100 mg and 200 mg doses of dihydroberberine (D100 and D200). In a randomized, double-blind, crossover fashion, five males (26 ± 2.6 years; 184.2 ± 11.6 cm; 91.8 ± 10.1 kg; 17.1 ± 3.5% fat) completed a four-dose supplementation protocol of placebo (PLA), B500, D100, and D200. The day prior to their scheduled visit, participants ingested three separate doses with breakfast, lunch, and dinner. Participants fasted overnight (8–10 h) and consumed their fourth dose with a standardized test meal (30 g glucose solution, 3 slices white bread) after arrival. Venous blood samples were collected 0, 20, 40, 60, 90, and 120 minutes (min) after ingestion and analyzed for BBR, glucose, and insulin. Peak concentration (CMax) and area under the curve (AUC) were calculated for all variables. Baseline berberine levels were different between groups (p = 0.006), with pairwise comparisons indicating that baseline levels of PLA and B500 were different than D100. Berberine CMax tended to be different (p = 0.06) between all conditions. Specifically, the observed CMax for D100 (3.76 ± 1.4 ng/mL) was different than PLA (0.22 ± 0.18 ng/mL, p = 0.005) and B500 (0.4 ± 0.17 ng/mL, p = 0.005). CMax for D200 (12.0 ± 10.1 ng/mL) tended (p = 0.06) to be different than B500. No difference in CMax was found between D100 and D200 (p = 0.11). Significant differences in berberine AUC were found between D100 (284.4 ± 115.9 ng/mL × 120 min) and PLA (20.2 ± 16.2 ng/mL × 120 min, p = 0.007) and between D100 and B500 (42.3 ± 17.6 ng/mL × 120 min, p = 0.04). Significant differences in D100 BBR AUC (284.4 ± 115.9 ng/mL×120 min) were found between PLA (20.2 ± 16.2 ng/mL × 120 min, p = 0.042) and B500 (42.3 ± 17.6 ng/mL × 120 min, p = 0.045). Berberine AUC values between D100 and D200 tended (p = 0.073) to be different. No significant differences in the levels of glucose (p = 0.97) and insulin (p = 0.24) were observed across the study protocol. These results provide preliminary evidence that four doses of a 100 mg dose of dihydroberberine and 200 mg dose of dihydroberberine produce significantly greater concentrations of plasma berberine across of two-hour measurement window when compared to a 500 mg dose of berberine or a placebo. The lack of observed changes in glucose and insulin were likely due to the short duration of supplementation and insulin responsive nature of study participants. Follow-up efficacy studies on glucose and insulin changes should be completed to assess the impact of berberine and dihydroberberine supplementation in overweight, glucose intolerant populations.

In this paper, the selective interactions of synthetic derivatives of two natural compounds, berberine and palmatine, with DNA G-quadruplex structures were reported. In particular, the previous works on this subject concerning berberine were further presented and discussed, whereas the results concerning palmatine are presented here for the first time. In detail, these palmatine derivatives were developed by inserting seven different small peptide basic chains, giving several new compounds that have never been reported before. The preliminary studies of the interactions of these compounds with various G-quadruplex-forming sequences were carried out by means of various structural and biochemical techniques, which showed that the presence of suitable side chains is very useful for improving the interaction of the ligands with G-quadruplex structures. Thus, these new palmatine derivatives might act as potential anticancer drugs.

The magnetization strategy of isoquinoline alkaloids has been successfully used in the extraction and isolation, but the effect of the magnetization on biological activities of those alkaloids still deserves further investigation. Therefore, the antibacterial, lipid-lowering and antioxidant activities of five isoquinoline alkaloids (berberine, tetrahydroberberine, palmatine, tetrahydropalmatine and tetrahydropapavine) before and after magnetization were compared in this study, and the results showed that the relevant activities were enhanced after magnetization. Additionally, among the five magnetic derivatives studied, berberine magnetic derivative ([Ber·H] + [FeCl 4 ] − ) had the best antibacterial effect on S. aureus and E. coli with MIC of 200 and 800 µM, respectively; palmatine magnetic derivative ([Pal·H] + [FeCl 4 ] − ) showed the strongest lipid-lowering activity with IC50 of 429 mM, and the inhibitory effect and type on lipase was reversible and mixed inhibition of competition and non-competition type; tetrahydroberberine magnetic derivative ([THBer·H] + [FeCl 4 ] − ) had the strongest antioxidant activity. This study provides new ideas and references for the further application of magnetization strategy.