Background:Global efforts to discover effective therapeutic agents for combating coronavirus disease 19(COVID-19)have intensified the exploration of natural compounds with potential antiviral properties.In this study,...Background:Global efforts to discover effective therapeutic agents for combating coronavirus disease 19(COVID-19)have intensified the exploration of natural compounds with potential antiviral properties.In this study,we utilized network pharmacology and computational analysis to investigate the antiviral effects of Berberine and Kuwanon Z against severe acute respiratory syndrome coronavirus 2,the viruses responsible for COVID-19.Method:Utilizing comprehensive network pharmacology approaches,we elucidated the complex interactions between these compounds and the host biological system,highlighting their multitarget mechanisms.Network pharmacology identifies COVID-19 targets and compounds through integrated protein‒protein interaction and KEGG pathway analyses.Molecular docking simulation studies were performed to assess the binding affinities and structural interactions of Berberine and Kuwanon Z with key viral proteins,shedding light on their potential inhibitory effects on viral replication and entry.Results:Network-based analyses revealed the modulation of crucial pathways involved in the host antiviral response.Compound-target network analysis revealed complex interactions(122 nodes,121 edges),with significant interactions and an average node degree of 1.37.KEGG analysis revealed pathways such as the COVID-19 pathway,chemokines and Jak-sat in COVID-19.Docking studies revealed that Kuwanon Z had binding energies of-10.5 kcal/mol for JAK2 and-8.1 kcal/mol for the main protease.Conclusion:The findings of this study contribute to the understanding of the pharmacological actions of Berberine and Kuwanon Z in the context of COVID-19,providing a basis for further experimental validation.These natural compounds exhibit promise as potential antiviral agents,offering a foundation for the development of novel therapeutic strategies in the ongoing battle against the global pandemic.展开更多
Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease,including antagonizing tau phosphorylation,and inhibiting acetylcholinesterase activity and neural cell apoptosis.How...Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease,including antagonizing tau phosphorylation,and inhibiting acetylcholinesterase activity and neural cell apoptosis.However,its low bioavailability and adverse reactions with conventional administration limit its clinical application.In this study,we prepared berberine nanoliposomes using liposomes characterized by low toxicity,high entrapment efficiency,and biodegradability,and modified them with lactoferrin.Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency.We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimer’s disease established by injection of amyloid-beta 1-42 into the lateral ventricle.Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus,reduced tau over-phosphorylation in the cerebral cortex,and improved mouse behavior.These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimer’s disease.展开更多
AIM: To investigate the molecular mechanisms of berberine inhibition of hepatic gluconeogenesis in a diabetic rat model.METHODS: The 40 rats were randomly divided into five groups. One group was selected as the normal...AIM: To investigate the molecular mechanisms of berberine inhibition of hepatic gluconeogenesis in a diabetic rat model.METHODS: The 40 rats were randomly divided into five groups. One group was selected as the normal group. In the remaining groups(n = 8 each), the rats were fed on a high-fat diet for 1 mo and received intravenous injection of streptozotocin for induction of the diabetic models. Berberine(156 mg/kg per day)(berberine group) or metformin(184 mg/kg per day)(metformin group) was intragastrically administered to the diabetic rats and 5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside(AICAR)(0.5 mg/kg per day)(AICAR group) was subcutaneously injected to the diabetic rats for 12 wk. The remaining eight diabetic rats served as the model group. Fasting plasma glucose and insulin levels as well as lipid profile were tested.The expressions of proteins were examined by western blotting. The nuclear translocation of CREB-regulated transcription co-activator(TORC)2 was observed by immunohistochemical staining. RESULTS: Berberine improved impaired glucose tolerance and decreased plasma hyperlipidemia. Moreover, berberine decreased fasting plasma insulin and homeostasis model assessment of insulin resistance(HOMA-IR). Berberine upregulated protein expression of liver kinase(LK)B1, AMP-activated protein kinase(AMPK) and phosphorylated AMPK(p-AMPK). The level of phophorylated TORC2(p-TORC2) protein in the cytoplasm was higher in the berberine group than in the model group, and no significant difference in total TORC2 protein level was observed. Immunohistochemical staining revealed that more TORC2 was localized in the cytoplasm of the berberine group than in the model group. Moreover, berberine treatment downregulated protein expression of the key gluconeogenic enzymes(phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in the liver tissues. CONCLUSION: Our findings revealed that berberine inhibited hepatic gluconeogenesis via the regulation of the LKB1-AMPK-TORC2 signaling pathway.展开更多
This study aimed to verify the effects of berberine(BBR)on the fat metabolism proteins involved in the sirtuin 3(SIRT3)/adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)/acetyl-CoA carboxylase(ACC)pat...This study aimed to verify the effects of berberine(BBR)on the fat metabolism proteins involved in the sirtuin 3(SIRT3)/adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)/acetyl-CoA carboxylase(ACC)pathway in the liver tissues of rats with high-fat diet(HFD)-induced non-alcoholic fatty liver disease(NAFLD).Forty-eight rats were randomly divided into the normal control(NC)group,HFD group or BBR group,with 16 rats in each group.After 8 and 16 weeks of treatment,serum and liver samples were collected.Subsequently,body parameters,biochemical parameters and liver pathology were examined.The expression levels of proteins involved in the SIRT3/AMPK/ACC pathway in the liver were detected by Western blotting.After 8 and 16 weeks of a HFD,the successful establishment of rat models with different degrees of NAFLD was confirmed by hematoxylin and eosin(H&E)and Oil Red O staining.NAFLD rat models exhibited obesity and hyperlipidemia,and the protein expression levels of SIRT3,p-AMPK.p-ACC,and CPT-1A in the liver were significantly decreased compared to those in the NC group.The concurrent administration of BBR with the HFD effectively improved serum and liver lipid profiles and ameliorated liver injury.Furthermore,the protein expression levels of SIRT3,p-AMPK,p-ACC,and CPT-1 A in the liver were significantly increased in the BBR group as compared with those in the HFD group.In conclusion,our data suggest that the mechanism by which BBR ameliorates HFD-induced hepatic steatosis may be related to the activation of the SIRT3/AMPK/ACC pathway in the liver.展开更多
Objective:To evaluate the antimicrobial efficacy of berberine,a plant alkaloid.Methods:Five multi-drug resistant（MDR） STEC/EPEC and five MDR ETEC isolates from yaks with haemorrhagic diarrhoea were selected for the ...Objective:To evaluate the antimicrobial efficacy of berberine,a plant alkaloid.Methods:Five multi-drug resistant（MDR） STEC/EPEC and five MDR ETEC isolates from yaks with haemorrhagic diarrhoea were selected for the study.Antibacterial activity of berberine was evaluated by broth dilution and disc diffusion methods.The binding kinetics of berberine to DNA and protein was also enumerated.Results:For both categories of enterovirulent Escherichia coli（E.roli） isolates, berberine displayed the antibaclerial effect in a dose dependent manner.The MIC<sub>50</sub> of berberine chloride for STEC/EPEC isolates varied from 2.07μM to 3.6μM with a mean of（2.95±0.33）μM where as for ETEC strains it varied from 1.75 to 1.96μM with a mean of（1.87±0.03）μM. Berberine bind more tightly with double helix DNA with Bmax and Kd of（24.68±2.62） and（357.8±57.8）,respectively.Berberine reacted with protein in comparatively loose manner with Bmax and Kd of（18.9±3.83） and 【286.2±113.6),respectively.Conclusions:The results indicate clearly that berberine may serve as a good antibacterial against multi drug resistant E.coli.展开更多
BACKGROUND Irritable bowel syndrome (IBS) is a common chronic non-organic disease of the digestive system. Berberine (BBR) has been used to treat patients with IBS, but the underlying therapeutic mechanism is little u...BACKGROUND Irritable bowel syndrome (IBS) is a common chronic non-organic disease of the digestive system. Berberine (BBR) has been used to treat patients with IBS, but the underlying therapeutic mechanism is little understood. We believe that BBR achieves its therapeutic effect on IBS by preventing stress intestinal inflammation and visceral hypersensitivity and reducing bowel motility. AIM To test the hypothesis that BBR achieves its therapeutic effect on IBS by preventing subclinical inflammation of the intestinal mucosa and reducing visceral hypersensitivity and intestinal motility. METHODS IBS was induced in rats via water avoidance stress (WAS). qRT-PCR and histological analyses were used to evaluate the levels of cytokines and mucosal inflammation, respectively. Modified ELISA and qRT-PCR were used to evaluate the nuclear factor kappa-B (NF-κB) signal transduction pathway. Colorectal distention test, gastrointestinal transit measurement, Western blot, and qRT-PCR were used to analyze visceral sensitivity, intestinal motility, the expression of Ckit (marker of Cajal mesenchymal cells), and the expression of brain derived neurotrophic factor (BDNF) and its receptor TrkB.RESULTS WAS led to mucosal inflammation, visceral hyperalgesia, and high intestinal motility. Oral administration of BBR inhibited the NF-κB signal transduction pathway, reduced the expression of pro-inflammatory cytokines [interleukin (IL)- 1β, IL-6, interferon-γ, and tumor necrosis factor-α], promoted the expression of anti-inflammatory cytokines (IL-10 and transforming growth factor-β), and improved the terminal ileum tissue inflammation. BBR inhibited the expression of BDNF, TrkB, and C-kit in IBS rats, leading to the reduction of intestinal motility and visceral hypersensitivity. The therapeutic effect of BBR at a high dose (100 mg/kg) was superior to than that of the low-dose (25 mg/kg) group. CONCLUSION BBR reduces intestinal mucosal inflammation by inhibiting the intestinal NF-κB signal pathway in the IBS rats. BBR reduces the expression of BDNF, its receptor TrkB, and C-kit. BBR also reduces intestinal motility and visceral sensitivity to achieve its therapeutic effect on IBS.展开更多
AIM: To assess the protective effect of berberine administration and the role of nitric oxide (NO) in visceral hypersensitivity. METHODS: Fifty male Sprague-Dawley rats were randomly assigned to five groups. An inflam...AIM: To assess the protective effect of berberine administration and the role of nitric oxide (NO) in visceral hypersensitivity. METHODS: Fifty male Sprague-Dawley rats were randomly assigned to five groups. An inflammatory bowel disease model was induced in rats by intracolonic instillation of 1 mL 4% acetic acid at 8 cm proximal to the anus for 30 s and restraint stress. After subsidence of inflammation on day 7 of the experiment, the rats were subjected to rectal distension, performed by a balloon (6-Fr, 2 mm external diameter, disposable silicon balloon-urethral catheter for pediatric use) which was rapidly inflated with increasing volumes of prewarmed (37 ℃) water (0.1, 0.2, 0.3, 0.4, 0.6, 0.8 and 1 mL) for 30 s at four-minute intervals, and then the abdominal withdrawal reflex (AWR) and the level of fecal output were measured, respectively. AWR scores either 0, 1, 2, 3 or 4 were obtained by blinded observers. Rats had been pretreated with berberine or aminoguanidine (NO synthetase inhibitor) or berberine + aminoguanidine before measurement. RESULTS: The rats in the placebo group showed a hypersensitive response to rectal distension (2.69 ± 0.08 vs 1.52 ± 0.08, P = 0.000) and defecated more frequently than those in the control group (5.0 ± 0.16 vs 0.44 ± 0.16, P = 0.000). Comparing the berberine with placebo group, the AWR scores were reduced for all distension volumes and were significant at 0.2-1 mL (1.90 ± 0.08 vs 2.69 ± 0.08, P = 0.000), while the numbers of hard pellets, soft pellets, formless stools, and total fecal output in the placebo group were significantly larger than in the berberine group (5.0 ± 0.16 vs 2.56 ± 0.16, P = 0.000). Administration of aminoguanidine or berberine + aminoguanidine before VH score measurement reversed the antinociceptive effect of berberine (2.52 ± 0.08 vs 1.90 ± 0.08, P = 0.000; 2.50 ± 0.08 vs 1.90 ± 0.08, P = 0.000). The numbers of hard pellets, soft pellets, formless stool, and total of fecal output in aminoguanidine group were significantly larger than the corresponding values in control group, berberine group, and berberine + aminoguanidine group (4.81 ± 0.16 vs 0.44 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 2.56 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 3.75 ± 0.16, P = 0.000). The berberine and berberine + aminoguanidine groups showed reduced defecation, but aminoguanidine alone did not reduce defecation (2.56 ± 0.16 vs 4.81 ± 0.16, P = 0.000; 3.75 ± 0.16 vs 4.81 ± 0.16, P = 0.000). CONCLUSION: Berberine had an antinociceptive effect on visceral hypersensitivity, and NO might play a role in this effect.展开更多
AIM To investigate the effects of berberine on esophageal cancer(EC) cells and its molecular mechanisms.METHODS Human esophageal squamous cell carcinoma cell line KYSE-70 and esophageal adenocarcinoma cell line SKGT4 ...AIM To investigate the effects of berberine on esophageal cancer(EC) cells and its molecular mechanisms.METHODS Human esophageal squamous cell carcinoma cell line KYSE-70 and esophageal adenocarcinoma cell line SKGT4 were used. The effects of berberine on cell proliferation were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. For cell cycle progression, KYSE-70 cells were stained with propidium iodide(PI) staining buffer(10 mg/m L PI and 100 mg/m L RNase A) for 30 min and cell cycle was analyzed using a BD FACSCalibur flow cytometer. For apoptosis assay, cells were stained with an Annexin V-FITC/PI apoptosis detection kit. The rate of apoptotic cells was analyzed using a dual laser flow cytometer and estimated using BD Mod Fit software. Levels of proteins related to cell cycle and apoptosis were examined by western blotting.RESULTS Berberine treatment resulted in growth inhibition of KYSE-70 and SKGT4 cells in a dose-dependent and time-dependent manner. KYSE-70 cells were more susceptible to the inhibitory activities of berberine than SKGT4 cells were. In KYSE-70 cells treated with 50 μmol/L berberine for 48 h, the number of cells in G2/M phase(25.94% ± 5.01%) was significantly higher than that in the control group(9.77% ± 1.28%, P < 0.01), and berberine treatment resulted in p21 upregulation in KYSE-70 cells. Flow cytometric analyses showed that berberine significantly augmented the KYSE-70 apoptotic population at 12 and 24 h posttreatment, when compared with control cells(0.83% vs 43.78% at 12 h, P < 0.05; 0.15% vs 81.86% at 24 h, P < 0.01), and berberine-induced apoptotic effect was stronger at 24 h compared with 12 h. Western blotting showed that berberine inhibited the phosphorylation of Akt, mammalian target of rapamycin and p70S6 K, and enhanced AMP-activated protein kinase phosphorylation in a sustained manner.CONCLUSION Berberine is an inhibitor of human EC cell growth and could be considered as a potential drug for the treatment of EC patients.展开更多
Berberine(BBR) is a natural alkaloid isolated from the Coptis Chinensis.While this plant has been used in Ay-urvedic and Chinese medicine for more than 2500 years,interest in its effects in metabolic and cardiovascula...Berberine(BBR) is a natural alkaloid isolated from the Coptis Chinensis.While this plant has been used in Ay-urvedic and Chinese medicine for more than 2500 years,interest in its effects in metabolic and cardiovascular disease has been growing in the Western world in the last decade.Many papers have been published in these years reporting beneficial effects in carbohydrate and lip-id metabolism,endothelial function and the cardiovascu-lar system.In this review,we report a detailed analysis of the scientific literature regarding this topic,describing the effects and the underlying mechanisms of BBR on carbohydrate and lipid metabolism,endothelial function and the cardiovascular system.展开更多
Although several studies confirmed that berberine may attenuate airway inflammation in mice with chronic obstructive pulmonary disease(COPD),its underlying mechanisms were not clear until now.We aimed to establish an ...Although several studies confirmed that berberine may attenuate airway inflammation in mice with chronic obstructive pulmonary disease(COPD),its underlying mechanisms were not clear until now.We aimed to establish an experiment mouse model for COPD and to investigate the effects of berberine on airway inflammation and its possible mechanism in COPD model mice induced by cigarette smoke extract(CSE).Twenty SPF C57BL/6 mice were randomly divided into PBS control group,COPD model group,low-dose berberine group and high-dose berberine group,5 mice in each group.The neutrophils and macrophages were examined by Wright's staining.The levels of inflammatory cytokines TNF-α and IL-6 in bronchoalveolar lavage fluid(BALF)were detennined by enzyme-linked immunosorbent assay.The expression levels of TGF-β1,Smad2 and Smad3 mRNA and proteins in lung tissues were respectively detected by quantitative real-time polymerase chain reaction and Western blotting.It was found that CSE increased the number of inflammation cells in BALF,elevated lung inflammation scores,and enhanced the TGF-β1/Smads signaling activity in mice.High-dose berberine restrained the alterations in the COPD mice induced by CSE.It was concluded that high-dose berberine ameliorated CSE-induced airway inflammation in COPD mice.TGF-β1/Smads signaling pathway might be involved in the mechanism.These findings suggested a therapeutic potential of high-dose berberine on the CSE-induced airway inflammation.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease,which attacks human joint system and causes lifelong inflammatory condition.To date,no cure is available for RA and even the ratio of achieving remission is very low.He...Rheumatoid arthritis(RA)is an autoimmune disease,which attacks human joint system and causes lifelong inflammatory condition.To date,no cure is available for RA and even the ratio of achieving remission is very low.Hence,to enhance the efficacy of RA treatment,it is essential to develop novel approaches specifically targeting pathological tissues.In this study,we discovered that RA synovial fibroblasts exhibited higher reactive oxygen species(ROS)and mitochondrial superoxide level,which were adopted to develop ROS-responsive nano-medicines in inflammatory microenvironment for enhanced RA treatment.A selenocystamine-based polymer was synthesized as a ROS-responsive carrier nanoplatform,and berberine serves as a tool drug.By assembling,ROS-responsive berberine polymeric micelles were fabricated,which remarkably increased the uptake of berberine in RA fibroblast and improved in vitro and in vivo efficacy ten times higher.Mechanistically,the anti-RA effect of micelles was blocked by the co-treatment of AMPK inhibitor or palmitic acid,indicating that the mechanism of micelles was carried out through targeting mitochondrial,suppressing lipogenesis and finally inhibiting cellular proliferation.Taken together,our ROS-responsive nano-medicines represent an effective way of preferentially releasing prodrug at the inflammatory microenvironment and improving RA therapeutic efficacy.展开更多
The effect and potential molecular mechanisms of berberine on gluconeogenesis in skeletal muscles and adipose tissues were investigated.After adaptive feeding for one week,8 rats were randomly selected as the normal g...The effect and potential molecular mechanisms of berberine on gluconeogenesis in skeletal muscles and adipose tissues were investigated.After adaptive feeding for one week,8 rats were randomly selected as the normal group and fed on a standard diet.The remaining 32 rats were fed on a high-fat diet and given an intravenous injection of streptozotocin(STZ)for 2 weeks to induce the diabetic models.The diabetic rat models were confirmed by oral glucose tolerance test(OGTT)and randomly divided into 4 groups(n=8 each),which were all fed on a high-fat diet.Berberine(3 g/kg per day)or metformin(183 mg/kg per day)was intragastrically administered to the diabetic rats for 12 weeks,serving as berberine group and metformin group respectively.5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside[AICAR,an agonist of AMP-activated protein kinase(AMPK),0.5 mg/kg per day]was subcutaneously injected to the diabetic rats for 12 weeks,serving as AICAR group.The remaining 8 diabetic rats served as the model group,which was given a 0.5%carboxyl methylcellulose solution by oral gavage.Fasting serum insulin(FINS),OGTT as well as lipid parameters were tested by commercial kit.The protein levels of liver kinase B1(LKB1),AMPK,phosphorylated AMP-activated protein kinase(p-AMPK),transducer of regulated CREB activity 2(TORC2),phosphorylated transducer of regulated CREB activity 2(p-TORC2),phosphoenolpyruvate carboxykinase(PEPCK),and glucose-6-phosphatase(G6Pase)in skeletal muscles and adipose tissues were examined by Western blotting.The results showed that berberine significantly decreased the body weight,plasma glucose,insulin levels,and homeostatic model assessment for insulin resistance(HOMA-IR)of diabetic rats compared with those in the model group.Meanwhile,the serum total triglyceride(TG),total cholesterol(TC),and low-density lipoprotein cholesterol(LDL-C)levels were markedly decreased and high-density lipoprotein cholesterol(HDL-C)level was significantly increased after the treatment with berberine.In addition,we found that berberine significantly increased the expression of p-AMPK and LKB1,while decreasing the p-TORC2 levels in skeletal muscles and adipose tissues.Moreover,the expression of PEPCK and G6Pase was significantly down-regulated after the treatment with berberine compared to the model group.It was suggested that the mechanism by which berberine inhibited peripheral tissue gluconeogenesis may be attributed to the activation of the LKB1-AMPK-TORC2 signaling pathway.展开更多
AIM:To study whether the inflammatory bowel disease(IBD)colon which exhibits varying severity and cytokine levels across its mucosa create varying types of transepithelial leak.METHODS:We examined the effects of tumor...AIM:To study whether the inflammatory bowel disease(IBD)colon which exhibits varying severity and cytokine levels across its mucosa create varying types of transepithelial leak.METHODS:We examined the effects of tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ),interleukin-1-β(IL1β)and hydrogen peroxide(H_2O_2)-singly and in combinations-on barrier function of CACO-2 cell layers.Our focus was on the type(not simply the magnitude)of transepithelial leak generated by these agents as measured by transepithelial electrical resistance(TER)and transepithelial flux of ^(14)C-D-mannitol,3H-Lactulose and ^(14)C-Polyethylene glycol as radiolabeled probe molecules.The isoquinoline alkaloid,berberine,was then examined for its ability to reduce specific types of transepithelial leak.RESULTS:Exposure to TNF-α alone(200 ng/mL;48 h)induced a 50% decrease in TER,i.e.,increased leak of Na^+ and Cl--with only a marginal but statistically significant increase in transepithelial leak of ^(14)C-mannitol(Jm).Exposure to TNF-α + IFN-γ(200 ng/mL;48 h)+ IL1β(50 ng/mL;48 h)did not increase the TER change(from TNF-α alone),but there was now a 100% increase in J_m.There however was no increase in transepithelial leak of two larger probe molecules,~3H-lactulose and ^(14)C-polyethylene glycol(PEG).However,exposure to TNF-α + IFN-γ + IL1β followed by a 5 h exposure to2 mmol/L H_2O_2 resulted in a 500% increase in ^(14)C-PEG leak as well as leak to the luminal mitogen,epidermal growth factor.CONCLUSION:This model of graded transepithelial leak is useful in evaluating therapeutic agents reducing IBD morbidity by reducing barrier leak to various luminal substances.展开更多
Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot synd...Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine(BER) and doxorubicin(DOX), which was called Lipo Be Do. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, Lipo Be Do, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The Lipo Be Do significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil(P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.展开更多
The aim of the study was to prepare berberine hydrochloride long-circulating liposomes and optimize the formulation and process parameters,and investigate the influence of different factors on the encapsulation effici...The aim of the study was to prepare berberine hydrochloride long-circulating liposomes and optimize the formulation and process parameters,and investigate the influence of different factors on the encapsulation efficiency.Berberine hydrochloride liposomes were prepared in response to a transmembrane ion gradient that was established by ionophore A23187.Free and liposomal drug were separated by cation exchange resin,and then the amount of intraliposomal berberine hydrochloride was determined by UV spectrophotometry.The optimized encapsulation efficiency of berberine hydrochloride liposomes was 94.3%2.1%when the drug-to-lipid ratio was 1:20,and the mean diameter was 146.9 nm3.2 nm.As a result,the ionophore A23187-mediated ZnSO_(4)gradient method was suitable for the preparation of berberine hydrochloride liposomes that we could get the desired encapsulation efficiency and drug loading.展开更多
Berberine is used in traditional Chinese medicine for the treatment of congestive heart failure, hypertension, diabetes, and dyslipidaemia and has a good safety profile. We report a case of a 53-year-old sportsman ref...Berberine is used in traditional Chinese medicine for the treatment of congestive heart failure, hypertension, diabetes, and dyslipidaemia and has a good safety profile. We report a case of a 53-year-old sportsman referred to our hospital for the onset of fatigue and dyspnoea upon exertion after he started berberine to treat hypercholesterolaemia. An electrocardiogram showed sinus bradycardia (45 bpm), first-degree atrioventricular block, and competitive junctional rhythm. An ergometric stress test showed slightly reduced chronotropic competence and the presence of runs of competitive junctional rhythm, atrial tachycardia, and sinus pauses in the recovery. After 10 d of wash-out from berberine, the patient experienced a complete resolution of symptoms, and an ergometric stress test showed good chronotropic competence. An electrocardiogram Holtershowed a latent hypervagotonic state. This is the first case report that shows that berberine could present certain side effects in hypervagotonic people, even in the absence of a situation that could cause drug accumulation. Therefore, berberine's use should be carefully weighed in hypervagotonic people due to the drug's bradycardic and antiarrhythmic properties, which could became proarrhythmic, exposing patients to potential health risks.展开更多
Drosophila melanogaster mutants with deficient kynurenine (KYN) formation from tryptophan (TRP) have longer life span than wild type flies. Administration of alpha-methyl-TRP and 5-methyl-TRY, the inhibitors of TRP-KY...Drosophila melanogaster mutants with deficient kynurenine (KYN) formation from tryptophan (TRP) have longer life span than wild type flies. Administration of alpha-methyl-TRP and 5-methyl-TRY, the inhibitors of TRP-KYN metabolism, prolonged life span in wild-type flies. Both inhibitors are not available for human use. Berberine, an isoquinoline alkaloid isolated from berberis aristata is known as the herb widely used in traditional Chinese and Indian medicine. Berberin is a strong inhibitor of the enzyme catalyzing TRP conversion into KYN. Considering this particular feature we investigated the effect of berberine on life-and health-span in wild-type Drosophila melanogaster. The results of our study showed that Berberine extended mean, median and maximum life span of female flies. Berberine did not affect the number of pupae of filial generation and decreased their lethality. Berberine increased locomotor activity (vertical climbing). The results of the study suggest that berberine prolongs life- and improves health-span of Drosophila melanogaster. Berberine might be a candidate drug for prevention and treatment of aging and aging-associated medical and psychiatric disorders.展开更多
Berberine(BBR)is an isoquinoline alkaloid extracted from Coptis chinensis that improves diabetes,hyperlipidemia and inflammation.Due to the low oral bioavailability of BBR,its mechanism of action is closely related to...Berberine(BBR)is an isoquinoline alkaloid extracted from Coptis chinensis that improves diabetes,hyperlipidemia and inflammation.Due to the low oral bioavailability of BBR,its mechanism of action is closely related to the gut microbiota.This study focused on the CYP51 enzyme of intestinal bacteria to elucidate a new mechanism of BBR transformation by demethylation in the gut microbiota through multiple analytical techniques.First,the docking of BBR and CYP51 was performed;then,the pharmacokinetics of BBR was determined in ICR mice in vivo,and the metabolism of BBR in the liver,kidney,gut microbiota and single bacterial strains was examined in vitro.Moreover,16S rRNA analysis of ICR mouse feces indicated the relationship between BBR and the gut microbiota.Finally,recombinant E.coli containing cyp51 gene was constructed and the CYP51 enzyme lysate was induced to express.The metabolic characteristics of BBR were analyzed in the CYP51 enzyme lysate system.The results showed that CYP51 in the gut microbiota could bind stably with BBR,and the addition of voriconazole(a specific inhibitor of CYP51)slowed down the metabolism of BBR,which prevented the production of the demethylated metabolites thalifendine and berberrubine.This study demonstrated that CYP51 promoted the demethylation of BBR and enhanced its intestinal absorption,providing a new method for studying the metabolic transformation mechanism of isoquinoline alkaloids in vivo.展开更多
OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in hu...OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in human umbilical vein endothelial cells(HUVECs) and smooth muscle cells(SMCs).METHODS 48 Apo-/-E mice,at 6-8 weeks old,were randomly allocated into 4 groups:normal,model,bbr and atorvastatin(positive control) groups with 12 mice in each group.They were fed with high-fat diet for 4 weeks except those in Normal group and then treated with indicated drugs orsolvent for another 4 weeks.The morphology and inflammation infiltration of aortic were examined with HE staining.The expression of BMP-2 in aortic was examined by immumohistochemical staining.Blood lipid levels were examined by automatic biochemical analyzer.The expression of IL-6,TNF-α and BMP-2 in serum and tissues was detected by ELISA method.The expression of ALP and the content of calcium were detected by commercially-available kits.HUVEC cells were stimulated with TNF-α and incubated with various concentrations of BBR for 24 h.The contents of intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule(VCAM-1),matrix metalloprotein-9(MMP-9) in the culture supernatant were detected by ELISA method.Calcification was induced with β-glycerophosphatein SMC cells and the effect of BBR on the content of calcium was examined.RESULTS 4-week berberine treatment markedly lowered serum TC and LDL-c levels and improved the plaque stability in Apo-/-E mice fed with a high-fat diet(P<0.05 or P<0.01) which was comparable with the effect of atorvastatin.Berberineal so significantly decreased the levels of IL-6 and TNF-α in mice serum and aortic tissues(P<0.05 or P<0.001).Berberine tended to decrease ALP,BMP-2 levels and the content of calcium in mice serum and aortic tissues(P<0.05,P<0.01 or P<0.001) which were not observed in atorvastatin group.Berberine significantly lowered the levels of ICAM-1,VCAM-1,and MMP-9 in TNF-α-stimulated HUVECs.It can also lowered the content of calcium in SMCs.CONCLUSION BBR can profitably regulate the levels of blood lipid in mice fed with a high-fat diet,decrease the injury caused by inflammation,and attenuate vascular calcification.It may improve atherosclerosis and play a role in cardiovascular protection.展开更多
文摘Background:Global efforts to discover effective therapeutic agents for combating coronavirus disease 19(COVID-19)have intensified the exploration of natural compounds with potential antiviral properties.In this study,we utilized network pharmacology and computational analysis to investigate the antiviral effects of Berberine and Kuwanon Z against severe acute respiratory syndrome coronavirus 2,the viruses responsible for COVID-19.Method:Utilizing comprehensive network pharmacology approaches,we elucidated the complex interactions between these compounds and the host biological system,highlighting their multitarget mechanisms.Network pharmacology identifies COVID-19 targets and compounds through integrated protein‒protein interaction and KEGG pathway analyses.Molecular docking simulation studies were performed to assess the binding affinities and structural interactions of Berberine and Kuwanon Z with key viral proteins,shedding light on their potential inhibitory effects on viral replication and entry.Results:Network-based analyses revealed the modulation of crucial pathways involved in the host antiviral response.Compound-target network analysis revealed complex interactions(122 nodes,121 edges),with significant interactions and an average node degree of 1.37.KEGG analysis revealed pathways such as the COVID-19 pathway,chemokines and Jak-sat in COVID-19.Docking studies revealed that Kuwanon Z had binding energies of-10.5 kcal/mol for JAK2 and-8.1 kcal/mol for the main protease.Conclusion:The findings of this study contribute to the understanding of the pharmacological actions of Berberine and Kuwanon Z in the context of COVID-19,providing a basis for further experimental validation.These natural compounds exhibit promise as potential antiviral agents,offering a foundation for the development of novel therapeutic strategies in the ongoing battle against the global pandemic.
基金financially supported by Shenzhen Sanming Project of Medicine and Health, No. SZSM201612049 (to KJC)the Shenzhen Municipal Basic Research Project for Discipline Layout of China, No. JCYJ20170413161352000 (to YHL)Guangdong Basic Research Project, No. 2020A1515011427 (to ZZW)
文摘Previous studies have shown that berberine has neuroprotective effects against Alzheimer’s disease,including antagonizing tau phosphorylation,and inhibiting acetylcholinesterase activity and neural cell apoptosis.However,its low bioavailability and adverse reactions with conventional administration limit its clinical application.In this study,we prepared berberine nanoliposomes using liposomes characterized by low toxicity,high entrapment efficiency,and biodegradability,and modified them with lactoferrin.Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency.We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimer’s disease established by injection of amyloid-beta 1-42 into the lateral ventricle.Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus,reduced tau over-phosphorylation in the cerebral cortex,and improved mouse behavior.These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimer’s disease.
基金Supported by National Natural Science Foundation of China,No.30973836
文摘AIM: To investigate the molecular mechanisms of berberine inhibition of hepatic gluconeogenesis in a diabetic rat model.METHODS: The 40 rats were randomly divided into five groups. One group was selected as the normal group. In the remaining groups(n = 8 each), the rats were fed on a high-fat diet for 1 mo and received intravenous injection of streptozotocin for induction of the diabetic models. Berberine(156 mg/kg per day)(berberine group) or metformin(184 mg/kg per day)(metformin group) was intragastrically administered to the diabetic rats and 5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside(AICAR)(0.5 mg/kg per day)(AICAR group) was subcutaneously injected to the diabetic rats for 12 wk. The remaining eight diabetic rats served as the model group. Fasting plasma glucose and insulin levels as well as lipid profile were tested.The expressions of proteins were examined by western blotting. The nuclear translocation of CREB-regulated transcription co-activator(TORC)2 was observed by immunohistochemical staining. RESULTS: Berberine improved impaired glucose tolerance and decreased plasma hyperlipidemia. Moreover, berberine decreased fasting plasma insulin and homeostasis model assessment of insulin resistance(HOMA-IR). Berberine upregulated protein expression of liver kinase(LK)B1, AMP-activated protein kinase(AMPK) and phosphorylated AMPK(p-AMPK). The level of phophorylated TORC2(p-TORC2) protein in the cytoplasm was higher in the berberine group than in the model group, and no significant difference in total TORC2 protein level was observed. Immunohistochemical staining revealed that more TORC2 was localized in the cytoplasm of the berberine group than in the model group. Moreover, berberine treatment downregulated protein expression of the key gluconeogenic enzymes(phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in the liver tissues. CONCLUSION: Our findings revealed that berberine inhibited hepatic gluconeogenesis via the regulation of the LKB1-AMPK-TORC2 signaling pathway.
基金grants from the National Natural Science Foundation of China(No.81573844 and No.81774165)Medical Research Fund of Guangdong Province(No.A2017363).
文摘This study aimed to verify the effects of berberine(BBR)on the fat metabolism proteins involved in the sirtuin 3(SIRT3)/adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)/acetyl-CoA carboxylase(ACC)pathway in the liver tissues of rats with high-fat diet(HFD)-induced non-alcoholic fatty liver disease(NAFLD).Forty-eight rats were randomly divided into the normal control(NC)group,HFD group or BBR group,with 16 rats in each group.After 8 and 16 weeks of treatment,serum and liver samples were collected.Subsequently,body parameters,biochemical parameters and liver pathology were examined.The expression levels of proteins involved in the SIRT3/AMPK/ACC pathway in the liver were detected by Western blotting.After 8 and 16 weeks of a HFD,the successful establishment of rat models with different degrees of NAFLD was confirmed by hematoxylin and eosin(H&E)and Oil Red O staining.NAFLD rat models exhibited obesity and hyperlipidemia,and the protein expression levels of SIRT3,p-AMPK.p-ACC,and CPT-1A in the liver were significantly decreased compared to those in the NC group.The concurrent administration of BBR with the HFD effectively improved serum and liver lipid profiles and ameliorated liver injury.Furthermore,the protein expression levels of SIRT3,p-AMPK,p-ACC,and CPT-1 A in the liver were significantly increased in the BBR group as compared with those in the HFD group.In conclusion,our data suggest that the mechanism by which BBR ameliorates HFD-induced hepatic steatosis may be related to the activation of the SIRT3/AMPK/ACC pathway in the liver.
文摘Objective:To evaluate the antimicrobial efficacy of berberine,a plant alkaloid.Methods:Five multi-drug resistant（MDR） STEC/EPEC and five MDR ETEC isolates from yaks with haemorrhagic diarrhoea were selected for the study.Antibacterial activity of berberine was evaluated by broth dilution and disc diffusion methods.The binding kinetics of berberine to DNA and protein was also enumerated.Results:For both categories of enterovirulent Escherichia coli（E.roli） isolates, berberine displayed the antibaclerial effect in a dose dependent manner.The MIC<sub>50</sub> of berberine chloride for STEC/EPEC isolates varied from 2.07μM to 3.6μM with a mean of（2.95±0.33）μM where as for ETEC strains it varied from 1.75 to 1.96μM with a mean of（1.87±0.03）μM. Berberine bind more tightly with double helix DNA with Bmax and Kd of（24.68±2.62） and（357.8±57.8）,respectively.Berberine reacted with protein in comparatively loose manner with Bmax and Kd of（18.9±3.83） and 【286.2±113.6),respectively.Conclusions:The results indicate clearly that berberine may serve as a good antibacterial against multi drug resistant E.coli.
基金the National Natural Science Foundation of China,No.81800489Shenzhen Health and Family Planning System Research Project,No.SZXJ2017030Technical Research and Development Project of Shenzhen,Nos.JCYJ20170307100538697 and JCYJ20170307100911479
文摘BACKGROUND Irritable bowel syndrome (IBS) is a common chronic non-organic disease of the digestive system. Berberine (BBR) has been used to treat patients with IBS, but the underlying therapeutic mechanism is little understood. We believe that BBR achieves its therapeutic effect on IBS by preventing stress intestinal inflammation and visceral hypersensitivity and reducing bowel motility. AIM To test the hypothesis that BBR achieves its therapeutic effect on IBS by preventing subclinical inflammation of the intestinal mucosa and reducing visceral hypersensitivity and intestinal motility. METHODS IBS was induced in rats via water avoidance stress (WAS). qRT-PCR and histological analyses were used to evaluate the levels of cytokines and mucosal inflammation, respectively. Modified ELISA and qRT-PCR were used to evaluate the nuclear factor kappa-B (NF-κB) signal transduction pathway. Colorectal distention test, gastrointestinal transit measurement, Western blot, and qRT-PCR were used to analyze visceral sensitivity, intestinal motility, the expression of Ckit (marker of Cajal mesenchymal cells), and the expression of brain derived neurotrophic factor (BDNF) and its receptor TrkB.RESULTS WAS led to mucosal inflammation, visceral hyperalgesia, and high intestinal motility. Oral administration of BBR inhibited the NF-κB signal transduction pathway, reduced the expression of pro-inflammatory cytokines [interleukin (IL)- 1β, IL-6, interferon-γ, and tumor necrosis factor-α], promoted the expression of anti-inflammatory cytokines (IL-10 and transforming growth factor-β), and improved the terminal ileum tissue inflammation. BBR inhibited the expression of BDNF, TrkB, and C-kit in IBS rats, leading to the reduction of intestinal motility and visceral hypersensitivity. The therapeutic effect of BBR at a high dose (100 mg/kg) was superior to than that of the low-dose (25 mg/kg) group. CONCLUSION BBR reduces intestinal mucosal inflammation by inhibiting the intestinal NF-κB signal pathway in the IBS rats. BBR reduces the expression of BDNF, its receptor TrkB, and C-kit. BBR also reduces intestinal motility and visceral sensitivity to achieve its therapeutic effect on IBS.
文摘AIM: To assess the protective effect of berberine administration and the role of nitric oxide (NO) in visceral hypersensitivity. METHODS: Fifty male Sprague-Dawley rats were randomly assigned to five groups. An inflammatory bowel disease model was induced in rats by intracolonic instillation of 1 mL 4% acetic acid at 8 cm proximal to the anus for 30 s and restraint stress. After subsidence of inflammation on day 7 of the experiment, the rats were subjected to rectal distension, performed by a balloon (6-Fr, 2 mm external diameter, disposable silicon balloon-urethral catheter for pediatric use) which was rapidly inflated with increasing volumes of prewarmed (37 ℃) water (0.1, 0.2, 0.3, 0.4, 0.6, 0.8 and 1 mL) for 30 s at four-minute intervals, and then the abdominal withdrawal reflex (AWR) and the level of fecal output were measured, respectively. AWR scores either 0, 1, 2, 3 or 4 were obtained by blinded observers. Rats had been pretreated with berberine or aminoguanidine (NO synthetase inhibitor) or berberine + aminoguanidine before measurement. RESULTS: The rats in the placebo group showed a hypersensitive response to rectal distension (2.69 ± 0.08 vs 1.52 ± 0.08, P = 0.000) and defecated more frequently than those in the control group (5.0 ± 0.16 vs 0.44 ± 0.16, P = 0.000). Comparing the berberine with placebo group, the AWR scores were reduced for all distension volumes and were significant at 0.2-1 mL (1.90 ± 0.08 vs 2.69 ± 0.08, P = 0.000), while the numbers of hard pellets, soft pellets, formless stools, and total fecal output in the placebo group were significantly larger than in the berberine group (5.0 ± 0.16 vs 2.56 ± 0.16, P = 0.000). Administration of aminoguanidine or berberine + aminoguanidine before VH score measurement reversed the antinociceptive effect of berberine (2.52 ± 0.08 vs 1.90 ± 0.08, P = 0.000; 2.50 ± 0.08 vs 1.90 ± 0.08, P = 0.000). The numbers of hard pellets, soft pellets, formless stool, and total of fecal output in aminoguanidine group were significantly larger than the corresponding values in control group, berberine group, and berberine + aminoguanidine group (4.81 ± 0.16 vs 0.44 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 2.56 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 3.75 ± 0.16, P = 0.000). The berberine and berberine + aminoguanidine groups showed reduced defecation, but aminoguanidine alone did not reduce defecation (2.56 ± 0.16 vs 4.81 ± 0.16, P = 0.000; 3.75 ± 0.16 vs 4.81 ± 0.16, P = 0.000). CONCLUSION: Berberine had an antinociceptive effect on visceral hypersensitivity, and NO might play a role in this effect.
基金Supported by Key Technologies R&D Program of Science and Technology Commission of Henan Province,No.52102310110 to Zhao BSKey Science and Technique Fund of Xinxiang,No.ZG15018 to Zhao BS
文摘AIM To investigate the effects of berberine on esophageal cancer(EC) cells and its molecular mechanisms.METHODS Human esophageal squamous cell carcinoma cell line KYSE-70 and esophageal adenocarcinoma cell line SKGT4 were used. The effects of berberine on cell proliferation were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. For cell cycle progression, KYSE-70 cells were stained with propidium iodide(PI) staining buffer(10 mg/m L PI and 100 mg/m L RNase A) for 30 min and cell cycle was analyzed using a BD FACSCalibur flow cytometer. For apoptosis assay, cells were stained with an Annexin V-FITC/PI apoptosis detection kit. The rate of apoptotic cells was analyzed using a dual laser flow cytometer and estimated using BD Mod Fit software. Levels of proteins related to cell cycle and apoptosis were examined by western blotting.RESULTS Berberine treatment resulted in growth inhibition of KYSE-70 and SKGT4 cells in a dose-dependent and time-dependent manner. KYSE-70 cells were more susceptible to the inhibitory activities of berberine than SKGT4 cells were. In KYSE-70 cells treated with 50 μmol/L berberine for 48 h, the number of cells in G2/M phase(25.94% ± 5.01%) was significantly higher than that in the control group(9.77% ± 1.28%, P < 0.01), and berberine treatment resulted in p21 upregulation in KYSE-70 cells. Flow cytometric analyses showed that berberine significantly augmented the KYSE-70 apoptotic population at 12 and 24 h posttreatment, when compared with control cells(0.83% vs 43.78% at 12 h, P < 0.05; 0.15% vs 81.86% at 24 h, P < 0.01), and berberine-induced apoptotic effect was stronger at 24 h compared with 12 h. Western blotting showed that berberine inhibited the phosphorylation of Akt, mammalian target of rapamycin and p70S6 K, and enhanced AMP-activated protein kinase phosphorylation in a sustained manner.CONCLUSION Berberine is an inhibitor of human EC cell growth and could be considered as a potential drug for the treatment of EC patients.
文摘Berberine(BBR) is a natural alkaloid isolated from the Coptis Chinensis.While this plant has been used in Ay-urvedic and Chinese medicine for more than 2500 years,interest in its effects in metabolic and cardiovascular disease has been growing in the Western world in the last decade.Many papers have been published in these years reporting beneficial effects in carbohydrate and lip-id metabolism,endothelial function and the cardiovascu-lar system.In this review,we report a detailed analysis of the scientific literature regarding this topic,describing the effects and the underlying mechanisms of BBR on carbohydrate and lipid metabolism,endothelial function and the cardiovascular system.
基金This work was supported by the National Natural Science Foundation of China(No.81400008).
文摘Although several studies confirmed that berberine may attenuate airway inflammation in mice with chronic obstructive pulmonary disease(COPD),its underlying mechanisms were not clear until now.We aimed to establish an experiment mouse model for COPD and to investigate the effects of berberine on airway inflammation and its possible mechanism in COPD model mice induced by cigarette smoke extract(CSE).Twenty SPF C57BL/6 mice were randomly divided into PBS control group,COPD model group,low-dose berberine group and high-dose berberine group,5 mice in each group.The neutrophils and macrophages were examined by Wright's staining.The levels of inflammatory cytokines TNF-α and IL-6 in bronchoalveolar lavage fluid(BALF)were detennined by enzyme-linked immunosorbent assay.The expression levels of TGF-β1,Smad2 and Smad3 mRNA and proteins in lung tissues were respectively detected by quantitative real-time polymerase chain reaction and Western blotting.It was found that CSE increased the number of inflammation cells in BALF,elevated lung inflammation scores,and enhanced the TGF-β1/Smads signaling activity in mice.High-dose berberine restrained the alterations in the COPD mice induced by CSE.It was concluded that high-dose berberine ameliorated CSE-induced airway inflammation in COPD mice.TGF-β1/Smads signaling pathway might be involved in the mechanism.These findings suggested a therapeutic potential of high-dose berberine on the CSE-induced airway inflammation.
基金FDCT grants from the Science and Technology Development Fund of Macao(Project Code:003/2018/A1 Grant to FXX0011/2018/A1 and 025/2015/A1 Grants to YZ).
文摘Rheumatoid arthritis(RA)is an autoimmune disease,which attacks human joint system and causes lifelong inflammatory condition.To date,no cure is available for RA and even the ratio of achieving remission is very low.Hence,to enhance the efficacy of RA treatment,it is essential to develop novel approaches specifically targeting pathological tissues.In this study,we discovered that RA synovial fibroblasts exhibited higher reactive oxygen species(ROS)and mitochondrial superoxide level,which were adopted to develop ROS-responsive nano-medicines in inflammatory microenvironment for enhanced RA treatment.A selenocystamine-based polymer was synthesized as a ROS-responsive carrier nanoplatform,and berberine serves as a tool drug.By assembling,ROS-responsive berberine polymeric micelles were fabricated,which remarkably increased the uptake of berberine in RA fibroblast and improved in vitro and in vivo efficacy ten times higher.Mechanistically,the anti-RA effect of micelles was blocked by the co-treatment of AMPK inhibitor or palmitic acid,indicating that the mechanism of micelles was carried out through targeting mitochondrial,suppressing lipogenesis and finally inhibiting cellular proliferation.Taken together,our ROS-responsive nano-medicines represent an effective way of preferentially releasing prodrug at the inflammatory microenvironment and improving RA therapeutic efficacy.
基金This project was supported by the National Natural Science Foundation of China(No.81673757 and No.81603652).
文摘The effect and potential molecular mechanisms of berberine on gluconeogenesis in skeletal muscles and adipose tissues were investigated.After adaptive feeding for one week,8 rats were randomly selected as the normal group and fed on a standard diet.The remaining 32 rats were fed on a high-fat diet and given an intravenous injection of streptozotocin(STZ)for 2 weeks to induce the diabetic models.The diabetic rat models were confirmed by oral glucose tolerance test(OGTT)and randomly divided into 4 groups(n=8 each),which were all fed on a high-fat diet.Berberine(3 g/kg per day)or metformin(183 mg/kg per day)was intragastrically administered to the diabetic rats for 12 weeks,serving as berberine group and metformin group respectively.5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside[AICAR,an agonist of AMP-activated protein kinase(AMPK),0.5 mg/kg per day]was subcutaneously injected to the diabetic rats for 12 weeks,serving as AICAR group.The remaining 8 diabetic rats served as the model group,which was given a 0.5%carboxyl methylcellulose solution by oral gavage.Fasting serum insulin(FINS),OGTT as well as lipid parameters were tested by commercial kit.The protein levels of liver kinase B1(LKB1),AMPK,phosphorylated AMP-activated protein kinase(p-AMPK),transducer of regulated CREB activity 2(TORC2),phosphorylated transducer of regulated CREB activity 2(p-TORC2),phosphoenolpyruvate carboxykinase(PEPCK),and glucose-6-phosphatase(G6Pase)in skeletal muscles and adipose tissues were examined by Western blotting.The results showed that berberine significantly decreased the body weight,plasma glucose,insulin levels,and homeostatic model assessment for insulin resistance(HOMA-IR)of diabetic rats compared with those in the model group.Meanwhile,the serum total triglyceride(TG),total cholesterol(TC),and low-density lipoprotein cholesterol(LDL-C)levels were markedly decreased and high-density lipoprotein cholesterol(HDL-C)level was significantly increased after the treatment with berberine.In addition,we found that berberine significantly increased the expression of p-AMPK and LKB1,while decreasing the p-TORC2 levels in skeletal muscles and adipose tissues.Moreover,the expression of PEPCK and G6Pase was significantly down-regulated after the treatment with berberine compared to the model group.It was suggested that the mechanism by which berberine inhibited peripheral tissue gluconeogenesis may be attributed to the activation of the LKB1-AMPK-TORC2 signaling pathway.
文摘AIM:To study whether the inflammatory bowel disease(IBD)colon which exhibits varying severity and cytokine levels across its mucosa create varying types of transepithelial leak.METHODS:We examined the effects of tumor necrosis factor-α(TNF-α),interferon-γ(IFN-γ),interleukin-1-β(IL1β)and hydrogen peroxide(H_2O_2)-singly and in combinations-on barrier function of CACO-2 cell layers.Our focus was on the type(not simply the magnitude)of transepithelial leak generated by these agents as measured by transepithelial electrical resistance(TER)and transepithelial flux of ^(14)C-D-mannitol,3H-Lactulose and ^(14)C-Polyethylene glycol as radiolabeled probe molecules.The isoquinoline alkaloid,berberine,was then examined for its ability to reduce specific types of transepithelial leak.RESULTS:Exposure to TNF-α alone(200 ng/mL;48 h)induced a 50% decrease in TER,i.e.,increased leak of Na^+ and Cl--with only a marginal but statistically significant increase in transepithelial leak of ^(14)C-mannitol(Jm).Exposure to TNF-α + IFN-γ(200 ng/mL;48 h)+ IL1β(50 ng/mL;48 h)did not increase the TER change(from TNF-α alone),but there was now a 100% increase in J_m.There however was no increase in transepithelial leak of two larger probe molecules,~3H-lactulose and ^(14)C-polyethylene glycol(PEG).However,exposure to TNF-α + IFN-γ + IL1β followed by a 5 h exposure to2 mmol/L H_2O_2 resulted in a 500% increase in ^(14)C-PEG leak as well as leak to the luminal mitogen,epidermal growth factor.CONCLUSION:This model of graded transepithelial leak is useful in evaluating therapeutic agents reducing IBD morbidity by reducing barrier leak to various luminal substances.
基金the Career Development Program for Yong and Middle-aged Teachers in Shenyang Pharmaceutical University。
文摘Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine(BER) and doxorubicin(DOX), which was called Lipo Be Do. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, Lipo Be Do, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The Lipo Be Do significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil(P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.
文摘The aim of the study was to prepare berberine hydrochloride long-circulating liposomes and optimize the formulation and process parameters,and investigate the influence of different factors on the encapsulation efficiency.Berberine hydrochloride liposomes were prepared in response to a transmembrane ion gradient that was established by ionophore A23187.Free and liposomal drug were separated by cation exchange resin,and then the amount of intraliposomal berberine hydrochloride was determined by UV spectrophotometry.The optimized encapsulation efficiency of berberine hydrochloride liposomes was 94.3%2.1%when the drug-to-lipid ratio was 1:20,and the mean diameter was 146.9 nm3.2 nm.As a result,the ionophore A23187-mediated ZnSO_(4)gradient method was suitable for the preparation of berberine hydrochloride liposomes that we could get the desired encapsulation efficiency and drug loading.
文摘Berberine is used in traditional Chinese medicine for the treatment of congestive heart failure, hypertension, diabetes, and dyslipidaemia and has a good safety profile. We report a case of a 53-year-old sportsman referred to our hospital for the onset of fatigue and dyspnoea upon exertion after he started berberine to treat hypercholesterolaemia. An electrocardiogram showed sinus bradycardia (45 bpm), first-degree atrioventricular block, and competitive junctional rhythm. An ergometric stress test showed slightly reduced chronotropic competence and the presence of runs of competitive junctional rhythm, atrial tachycardia, and sinus pauses in the recovery. After 10 d of wash-out from berberine, the patient experienced a complete resolution of symptoms, and an ergometric stress test showed good chronotropic competence. An electrocardiogram Holtershowed a latent hypervagotonic state. This is the first case report that shows that berberine could present certain side effects in hypervagotonic people, even in the absence of a situation that could cause drug accumulation. Therefore, berberine's use should be carefully weighed in hypervagotonic people due to the drug's bradycardic and antiarrhythmic properties, which could became proarrhythmic, exposing patients to potential health risks.
文摘Drosophila melanogaster mutants with deficient kynurenine (KYN) formation from tryptophan (TRP) have longer life span than wild type flies. Administration of alpha-methyl-TRP and 5-methyl-TRY, the inhibitors of TRP-KYN metabolism, prolonged life span in wild-type flies. Both inhibitors are not available for human use. Berberine, an isoquinoline alkaloid isolated from berberis aristata is known as the herb widely used in traditional Chinese and Indian medicine. Berberin is a strong inhibitor of the enzyme catalyzing TRP conversion into KYN. Considering this particular feature we investigated the effect of berberine on life-and health-span in wild-type Drosophila melanogaster. The results of our study showed that Berberine extended mean, median and maximum life span of female flies. Berberine did not affect the number of pupae of filial generation and decreased their lethality. Berberine increased locomotor activity (vertical climbing). The results of the study suggest that berberine prolongs life- and improves health-span of Drosophila melanogaster. Berberine might be a candidate drug for prevention and treatment of aging and aging-associated medical and psychiatric disorders.
基金The project was supported by CAMS Innovation Fund for Medical Sciences(CIFMS,Grant No.:2016-I2M-3-011,China)the National Natural Science Foundation of China(Grant Nos.:81803613 and 81973290)+2 种基金Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study(Grant No.:Z141102004414062,China)Beijing Natural Sciences Fund Key Projects(Grant No.:7181007)the National Megaproject for Innovative Drugs(Grant No.:2018ZX09711001-002-002).
文摘Berberine(BBR)is an isoquinoline alkaloid extracted from Coptis chinensis that improves diabetes,hyperlipidemia and inflammation.Due to the low oral bioavailability of BBR,its mechanism of action is closely related to the gut microbiota.This study focused on the CYP51 enzyme of intestinal bacteria to elucidate a new mechanism of BBR transformation by demethylation in the gut microbiota through multiple analytical techniques.First,the docking of BBR and CYP51 was performed;then,the pharmacokinetics of BBR was determined in ICR mice in vivo,and the metabolism of BBR in the liver,kidney,gut microbiota and single bacterial strains was examined in vitro.Moreover,16S rRNA analysis of ICR mouse feces indicated the relationship between BBR and the gut microbiota.Finally,recombinant E.coli containing cyp51 gene was constructed and the CYP51 enzyme lysate was induced to express.The metabolic characteristics of BBR were analyzed in the CYP51 enzyme lysate system.The results showed that CYP51 in the gut microbiota could bind stably with BBR,and the addition of voriconazole(a specific inhibitor of CYP51)slowed down the metabolism of BBR,which prevented the production of the demethylated metabolites thalifendine and berberrubine.This study demonstrated that CYP51 promoted the demethylation of BBR and enhanced its intestinal absorption,providing a new method for studying the metabolic transformation mechanism of isoquinoline alkaloids in vivo.
基金supported by National Science Foundation of China(81402943)CAMS Major Collaborative Innovation Project(2016-I2M-1-011)PUMC Youth Fund(3332015168)
文摘OBJECTIVE To investigate the beneficial effect of berberine(BBR)on atherosclerosisin Apo^(-/-) E mice and explore the underlying mechanisms based on attenuating vascular inflammation and modulating calcification in human umbilical vein endothelial cells(HUVECs) and smooth muscle cells(SMCs).METHODS 48 Apo-/-E mice,at 6-8 weeks old,were randomly allocated into 4 groups:normal,model,bbr and atorvastatin(positive control) groups with 12 mice in each group.They were fed with high-fat diet for 4 weeks except those in Normal group and then treated with indicated drugs orsolvent for another 4 weeks.The morphology and inflammation infiltration of aortic were examined with HE staining.The expression of BMP-2 in aortic was examined by immumohistochemical staining.Blood lipid levels were examined by automatic biochemical analyzer.The expression of IL-6,TNF-α and BMP-2 in serum and tissues was detected by ELISA method.The expression of ALP and the content of calcium were detected by commercially-available kits.HUVEC cells were stimulated with TNF-α and incubated with various concentrations of BBR for 24 h.The contents of intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule(VCAM-1),matrix metalloprotein-9(MMP-9) in the culture supernatant were detected by ELISA method.Calcification was induced with β-glycerophosphatein SMC cells and the effect of BBR on the content of calcium was examined.RESULTS 4-week berberine treatment markedly lowered serum TC and LDL-c levels and improved the plaque stability in Apo-/-E mice fed with a high-fat diet(P<0.05 or P<0.01) which was comparable with the effect of atorvastatin.Berberineal so significantly decreased the levels of IL-6 and TNF-α in mice serum and aortic tissues(P<0.05 or P<0.001).Berberine tended to decrease ALP,BMP-2 levels and the content of calcium in mice serum and aortic tissues(P<0.05,P<0.01 or P<0.001) which were not observed in atorvastatin group.Berberine significantly lowered the levels of ICAM-1,VCAM-1,and MMP-9 in TNF-α-stimulated HUVECs.It can also lowered the content of calcium in SMCs.CONCLUSION BBR can profitably regulate the levels of blood lipid in mice fed with a high-fat diet,decrease the injury caused by inflammation,and attenuate vascular calcification.It may improve atherosclerosis and play a role in cardiovascular protection.
