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
OBJECTIVE To determine whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus.METHODS Streptozotocin-induced diabetic mice were introduced,and th...OBJECTIVE To determine whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus.METHODS Streptozotocin-induced diabetic mice were introduced,and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated.RESULTS Berberine combined with canagliflozin(BC)increased reduction of fasting and postprandial blood glucose,diet,and water intake compared with berberine or canagliflozin alone.Interestingly,BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone.In addition,BC showed increased phosphorylated 5′AMP-activated protein kinase(pA MPK)expression and decreased tumor necrosis factor alpha(TNFα)levels in kidneys compared with berberine or canagliflozin alone.CONCLUSION These results indicated that BC is as tronger antidiabetic than berberine or canagliflozin alone with less negative side effectson the kidneys of diabetic mice.The antidiabetic effect is likely mediated by synergically promoting the expression of p AMPK and reducing the expression of TNFαin kidneys.This study first proved that canagliflozin combined withberberine is apromising treatment for diabetes mellitus.However,the exact mechanisms should be further investigated in future studies.展开更多
OBJECTIVE To investigate possible protective effect of berberine,an isoquinoline alkaloid,is the major active constituent of Rhizoma coptidis and Cortex phellodendri,on high-fat diet/streptozotocin-induced early diabe...OBJECTIVE To investigate possible protective effect of berberine,an isoquinoline alkaloid,is the major active constituent of Rhizoma coptidis and Cortex phellodendri,on high-fat diet/streptozotocin-induced early diabetic nephropathy in rats and various mechanisms underlie this effect.METHODS The diabetic rat model was generated by a single intraperitoneal injection of streptozotocin(STZ,50 mg·kg-1).Diabetic rats were randomlyassigned into the following five groups:control,DN,losartan(30 mg·kg-1·d-1),berberine(100,200 mg·kg-1·d-1).Berberine and losartan were given intragastricly for nine weeks.At the end of the experiment,urine of each group was collected in a 24 h period.Rats were weighed and then sacrificed.Plasma and kidneys were collected.The levels of blood glucose,creatinine(Cr),triglycerides(TG),total cholesterol(TCH)and malondialdehyde(MDA)in serum were determined using commercial kits according to the manufacturer′s instructions.Transforming growth factor(TGF)-β1and intracellular adhesion molecule-1(IAM-1)mR NA levels were evaluated by RT-PCR.The renal histopathology was observed by light microscopy.Further biochemical analysis of IKKβ1 and p65(nucleus/cytoplasm)was provided using Western blotting techniques.RESULTS Our study has demonstrated that berberine has various pharmacological activities.The DN rats had significantly higher kidney/body weight ratio(17.4±1.4)mg·g-1,and berberine treatment could reduce this ratio change 13.6±0.6 and(11.6±0.8)mg·g-1,respectively;glucose control still remains the only disease-modifying therapy for diabetic complications,FBG was also recorded in the experiment.The findings reveal that the DN group showed a significantly higher glucose level(28.67±2.78)mmol·L-1.Treatment with8 weeks of berberine improved these parameters except blood glucose〔(18.67±2.59)mmol·L-1and 16.45±1.80 vs(28.67±2.78)mmol·L-1:plasma levels of urea nitrogen(15.67±2.48)mmol·L-1and 14.45±2.40 vs(12.26±2.40)mmol·L-1〕;plasma levels of 24 h urine albuminuria〔30.48±1.56 and 25.72±2.24 vs(15.26±0.12)μg·d-1〕;based on these results,berberine supposed to improve renal functions in diabetic rats.Berberine also ameliorated the inflammatory changes of DN in diabetic animals;levels of TG,TCH and MDA in berberine-treatment rats were significantly lower compared with those in the DN group:TG〔2.78±0.24 and 2.45±0.36 vs(5.20±0.60)mmol·L-1〕;TCH〔4.26±0.46 and 3.74±0.68 vs(6.26±0.50)mmol·L-1〕;MDA〔4.94±1.19 and 4.28±0.64 vs(4.28±0.64)nu·mL-1〕.Chronic inflammation,as is observed in diabetes,is associated with increased production of TGF-β1and IAM-1.Compared with the renal tissues of DN group,TGF-β1and IAM-1 gene expressions in berberine treated groups were reduced at the dose levels(100 and 200 mg·kg-1).And TGF-β1and IAM-1levels in berberine treated groups were reduced in a dosedependent manner:Relative expression of TGF-β1mR NA level(3.56±0.28 and 3.12±0.14 vs 5.12±0.44);Relative expression of IAM-1 mR NA leve(l1.78±0.56 and 1.42±0.24vs 4.36±0.35).Research finds that the NF-κB signaling pathway is activated in the renal tissue of diabetic mice and berberine inhibits activation of the NF-κB pathway:staining score for IKKβ1(4.34±0.26 and 3.82±0.24 vs 6.23±0.76),staining score for p65(2.34±0.26 and 1.74±0.78 vs 6.23±0.24)in nucleus and staining score for p65(7.21±0.13 and8.15±0.45 vs 4.23±0.54)in cytoplasm.CONCLUSION In this field,berberine suppresses the increased expression of p65 in the nucleus and decreases it in cytoplasm,which leads to the inhibition of the NF-κB pathway.These changes will result in decreasing the transcription and translation of many inflammatory mediators,such as TGF-β1and IAM-1.Additionally,these changes decrease the number of inflammatory cells and mononuclear macrophage infiltration into glomeruli and renal interstitium.These results indicated that berberine can protect the kidney of STZ-diabetic rats by reducing the expression of TGF-β1and IAM-1 in the renal tubulointerstitium.And we propose that berberinemayfunction as an effective therapeutic agent for diabetic nephropathy and attenuate the progression of renal injury.展开更多
Aim To investigate the nephroprotective activity of berberine in diabetic nephropathy （DN） mice. Methods Diabetic nephropathy was induced by intraperitoneal injection with 55 mg · kg^-1 streptozotocin（STZ） , ...Aim To investigate the nephroprotective activity of berberine in diabetic nephropathy （DN） mice. Methods Diabetic nephropathy was induced by intraperitoneal injection with 55 mg · kg^-1 streptozotocin（STZ） , Berberine was administered at daily doses of 50, 100 and 200 mg· kg^-1 by gavage for 8 weeks. To detect serum creatinine and blood urea nitrogen （BUN） levels, blood were collected after the last dose of berberine, renal cortex was separated on ice after heart peffusion by precooled normal saline. The specimen was stored in -80℃ for the next experiments, and some of the kidney tissue were immobilized by 4% paraformaldehyde solution and 3% glut- araldehyde solution for the preparation of paraffin tissue slides and electron microscope biopsy respectively. After that, PAS staining and electron microscope were used to observe the glomerular morphology changes; ELISA was used to measure proinflammatory chemokines and cytokines levels in renal cortex. Real time RT-PCR was taken to detect the level of nucleotide binding oligomerzation domain 2 （NOD2） mRNA, Western blot was used to test the ex- pression of NOD2 and autophagy marker light chain 3 （LC3） in renal cortex. Results Histopathological changes and the increase in serum creatinine and BUN in DN mice were significantly ameliorated by berberine in a dose-de- pendent manner. Additionally, The expression of tumor necrosis factor-or （TNF-α）, interleukin-6 （IL-6） and in- tercellular adhesion molecule-1 （ICAM-1） was markedly suppressed by berberine, indicating the inhibition of in- flammatory response. Treatment of DN mice with berberine also significantly reduced the expression of NOD2 and LC3 in the kidneys. Conclusion The current study showed the nephroprotective activity of berberine in DN mice could be attributed to the inhibition of inflammation and展开更多
Acknowledgements This work was supported by Educational Commission of Shanghai of China （2012JW19）; Key Research Innovation Project （13ZZ099）; Key Project from Department of Education of China （20123107130002）; ...Acknowledgements This work was supported by Educational Commission of Shanghai of China （2012JW19）; Key Research Innovation Project （13ZZ099）; Key Project from Department of Education of China （20123107130002）; Shanghai Eastern Scholar Program （2013-59） and Shanghai E-research Institute of Bioactive Constituent in TCM plan. Abstract： Aim This investigation was to identify whether Janus-activated kinase 2 （JAK2） and mitogen-activated protein kinase （MAPK） pathways were involved in the inhibitory effect of berberine hydrochloride （BER） on gastric cancer cell proliferation and IL-8 expression in vitro and in vivo. Methods CCK- 8 assay was used to assess the cell proliferation. IL-8 production was determined by ELISA and qPCR assay. Mo- lecular pathways involved were evaluated by ELISA and western-blotting methods. Results BER time- and dose- dependently inhibited the proliferation of MGC 803 and AGS cells. It also suppressed tumor growth in nude mice xenografted with MGC 803 cells. In addition, BER reduced interleukin-8 （IL-8） secretion of AGS cells as well as MGC 803 cells both in vitro and in vivo. Further study disclosed that inactivation of JAK2, p38 MAPK, ERK1/2 and JNK by BER contributed to the decreased proliferation and tumor growth as well as IL-8 expression in gastric cancer. Although there was no significantly synergistic inhibitory effect between BER and evodiamine on gastric cancer cell proliferation and tumor growth, BER could counteract the up-regulation of IL-8 induced by evodiamine in vitro and vivo. Conclusions Our results suggested that BER might be an efficient and safe drug candidate for treating gastric cancer through JAK2 and MAPK pathways.展开更多
Aim Ulcerative colitis （UC） is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment fuels the search for alternative therapeutic strategies. In the present study, ...Aim Ulcerative colitis （UC） is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment fuels the search for alternative therapeutic strategies. In the present study, we as- sessed the preclinical activity of berberine for the treatment of dextran sodium sulphate （DSS）-induced chronic re- lapsing colitis in C57BL/6 mice. Methods Colitis of mice was induced by three cycles of 2.0% DSS. From day13 onward, colitis mice were orally administered with 20 mg/kg berberine for 30 days. The disease severity was de- termined by daily monitoring the body weight, stool consistency, and stool bleeding of mice. At the end of treat- ment, colons were collected and subjected to histological, RT-qPCR, Western blot, and LC-MS analyses. Lympho- eytes were isolated from spleens and cultured for assessment of eytokine secretion. Results Berberine significantly ameliorated disease severity, colon shortening, histological injuries of colitis mice. Further, berberine treatment consistently and notably regulated DSS-assoeiated increase in mRNAs levels of Thl7-related eytokines （inhibition of IL-17 and ROR-γt） in the colon out of all tested eytokines. Moreover, the increases of TNF-α, IL-6 and IL-23 mRNA, and the phosphorylated STAT3 in colons of DSS - treated mice were significantly reversed by berberine. In addition, berberine directly inhibited TNF-α and IL-17 secretion from cultured lymphoeytes upon PMA/ionomyein -1 re-stimulation. In the meanwhile, a six-time amount of berberine in colon tissue （4.26 ± 2.62 ng · g^-1 colon） was measured when compared that in serum （0.76 ± 0.23 ng · m1^-1） and no detected histological changes was found in major organs of colitis mice. Conclusion We demonstrate for the first time that berberine exerts immuno- modulatory effect in alleviating DSS-indueed chronic relapsing colitis via inhibition of the JAK/STAT signalling acti- vation in the inflamed colon. The demonstration of activity in this model supports the possibility of clinical efficacy of berberine in treating chronic UC.展开更多
OBJECTIVE To investigate berberine(BBR)attenuates arthritis in adjuvant-induced arthritic(AA)rats associated with regulating the energy metabolism and correcting the polarization of macrophages through activation of A...OBJECTIVE To investigate berberine(BBR)attenuates arthritis in adjuvant-induced arthritic(AA)rats associated with regulating the energy metabolism and correcting the polarization of macrophages through activation of AMP-activated protein kinase(AMPK)and inhibition of hypoxia inducible factor 1α(HIF-1α).METHODS AA rats were treated with BBR(40,80,or 160 mg·kg-1)from days 15 to 29 after immunization.The histopathology of ankle joint was examined through hematoxylin-eosin(HE)staining.The concentrations of tumour necrosis factor-α(TNF-α),interleukin-6(IL-6),IL-1β,IL-2,IL-17A,interferon-gamma(IFN-γ),monocyte chemotactic protein 1(MCP-1),IL-4,IL-10,transforming growth factor-β1(TGF-β1),ATP,and lactic acid were measured by using ELISA kits.The percentage of M1 and M2 macro⁃phage cells in joint tissues were evaluated by immune-fluorescence.The expressions of p-AMPK and HIF-1αin joint of AA rats were determined according to immunohistochemistry analysis.The migration of macrophage was detected by Transwell assays.The expression of inducible nitric oxide synthase(iNOS),Arginase-1(Arg1),p-AMPK,AMPK and HIF-1αwere examined by Western blotting.The labeled macrophages were observed with laser confocal microscopy.RESULTS BBR relieved signs and symptoms of AA rats and reversed pathological changes.BBR treatment group exhibited decreases in pro-inflammatory cytokines(TNF-α,IL-1β,IL-6,IL-2,IL-17A,IFN-γ,and MCP-1)coupled with increases anti-inflammatory cytokines(IL-4,IL-10,TGF-β1)in the serum.The number of M1 macrophage was reduced,while the number of M2 macrophage was increased in BBR group joint tissues.Moreover,BBR showed marked up-regu⁃lation the expression of p-AMPK and down-regulation the expression of HIF-1αin joint of AA rats.Next in vitro study,we found BBR up-regulated the expression of p-AMPK,Arg1(M2 marker)and down-regulated the expression of HIF-1α,iNOS(M1 marker)induced by LPS in peritoneal macrophages from normal SD rat.Furthermore,BBR treatment inhibited the migration of macrophages stimulated by LPS.The level of ATP was elevated and lactic acid was reduced in LPSinduced macrophages after treated by BBR.However,Compound C significantly attenuated the effects of BBR on acti⁃vated macrophages.CONCLUSION BBR alleviates inflammation by regulating energy metabolism and correcting the polarization of macrophage through AMPK-HIF-1αpathway.BBR might have great therapeutic value for RA.展开更多
OBJECTIVE To investigate the inhibition and mechanism of berberine on human colorectal cancer HCT116 cells through canonical Hedgehog signaling pathway.METHODS The effect of berberine on cell morphology was observed b...OBJECTIVE To investigate the inhibition and mechanism of berberine on human colorectal cancer HCT116 cells through canonical Hedgehog signaling pathway.METHODS The effect of berberine on cell morphology was observed by microscopy.MTT colorimetric assay,cell scratch experiment,colony formation assay and Hoechest/PI staining were utilized to detect the activities of berberine on cell viability,cell migration and cell apoptosis.Flow cytometry was applied to examine the cell apoptosis.The effects of berberine on caspase-3 and caspase-9 were detected by caspase activity detection kit.The expressions of Hedgehog signaling pathway-related proteins SHH,GLI1,PTCH1,SMO,SUFU,apoptosis-related proteins Bax and Bcl-2 as well as cell cycle-related proteins cyclin D1 were detected by Western blotting.Additionally,quantitative real time RT-PCR was employed to assess the mRNA expression levels of Hedgehog signaling pathway-related genes SHH,GLI1,PTCH1,SMO,SUFU,apoptosis-related genes Bax and Bcl-2 as well as cell cycle-related genes cyclin D1.RESULTS Berberine sharply altered the morphology of human colorectal cancer HCT116 cells,demonstrated by that migration ability of HCT116 cells was reduced significantly and the nuclei were densely stained.Berberine could induce apoptosis in a dose-dependent manner.The activities of caspase-3 and caspase-9 were increased prominently.The expression levels of Hedgehog signaling pathway-related protein SUFU and apoptosis-related protein Bax were augmented substantially.The expression levels of Hedgehog signaling pathway-related proteins SHH,GLI1,PTCH1,SMO,apoptosis-related protein Bcl-2 as well as cell cycle-related genes cyclin D1 were markedly lessened.Besides,the mRNA expression levels of Hedgehog signaling pathway-related gene SUFU and apoptosis-related gene Bax were augmented substantially.The mRNA expression levels of Hedgehog signaling pathway-related genes SHH,GLI1,PTCH1,SMO,apoptosis-related gene Bcl-2 as well as cell cycle-related gene cyclin D1 were markedly lessened.CONCLUSION Berberine,which is the main component of coptidis rhizoma,can remarkably restrain the growth and proliferation,promote apoptosis of human colorectal cancer cells HCT116,and the underlying mechanism may be involved in suppressing the activity of the Hedgehog signaling pathway.展开更多
Increased circulating branched-chain amino acids(BCAAs)have been involved in the pathogenesis of obesity and insulin resistance.However,evidence relating berberine(BBR),gut microbiota,BCAAs,and insulin resis⁃tance is ...Increased circulating branched-chain amino acids(BCAAs)have been involved in the pathogenesis of obesity and insulin resistance.However,evidence relating berberine(BBR),gut microbiota,BCAAs,and insulin resis⁃tance is limited.Here,we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet(HFD)-fed mice.BBR reorganized gut microbiota populations under both the normal chow diet(NCD)and HFD.Particu⁃larly,BBR noticeably decreased the relative abundance of BCAA-producing bacteria,including order Clostridiales;fami⁃lies Streptococcaceae,Clostridiaceae,and Prevotellaceae;and genera Streptococcus and Prevotella.Compared with the HFD group,predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis but the enrichment genes for BCAA degradation and transport by BBR treatment.Accordingly,the elevated serum BCAAs of HFD group were significantly decreased by BBR.Furthermore,the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by acti⁃vation of the multienzyme branched-chain α-ketoacid dehydrogenase complex,whereas by inhibition of the phosphoryla⁃tion state of BCKDHA(E1α subunit)and branched-chain α-ketoacid dehydrogenase kinase.The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes.Finally,data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs.Besides,functional microbiomics integrated high-throughput microbial genomics,metabolomics and molecular biotechnology has also been successfully applied to reveal the anti-obesity mechanism of hydroxysafflor yellow A.展开更多
OBJECTIVE To investigate the antiangiogenic and antitumor effects of berberineα-hydroxy-δ-decanoylethyl sulfonate(HB)in vitro and in vivo.METHODS MTT assay was employed to determine the proliferation of tumor cells....OBJECTIVE To investigate the antiangiogenic and antitumor effects of berberineα-hydroxy-δ-decanoylethyl sulfonate(HB)in vitro and in vivo.METHODS MTT assay was employed to determine the proliferation of tumor cells.Western blot analysis was used to detect the expression of VEGF and MMP-9.Transwell co-culture was used to determine the cell migration at the conditioned medium of Lewis lung carcinoma cells exposed to HB for 24 h.The C57BL/6 mice bearing Lewis lung carcinomas were treated with vehicle,different doses of HB(60,90 and 120mg·kg-1,ig)for 20 d,or cyclophosphamide(50mg·kg-1,ig)at d 1,d 8 and d 15.Afterwards,the xenografted tumors were exercised and weighed,and the lung metastasis was determined by HE stainingof the lung tissues.Tumor angiogenesis was determined by CD34 staining and microvessel density(MVD)by immunohistochemistry.RESULTSHB inhibited the growth of Lewis lung carcinoma cells in a time-dependent manner with IC50 value of 8.87,2.26 and 0.98mg·L-1,respectively when the cells were treated with HB for 24,48 and 72h.Cell migration induced by the conditioned medium of Lewis lung carcinoma cells treated with 2.5,5 and 10mg·L-1 HB was reduced by 37%,54% and 63%respectively(P<0.01).HB suppressed the expression of angiogenesis factors in a concentration-dependent manner.HB was effective in inhibition of MMP-9 expression at 5,10 and 20mg·L-1(P<0.05),whereas HB 20mg·L-1 was minimal effective concentration in inhibition of VEGF expression(P<0.01).On C57BL/6 mice bearing Lewis lung carcinomas,HB significantly reduced the tumor burden and MVD in tumor mass as well as inhibited lung metastasis at doses of 90 and 120mg·kg-1.CONCLUSION HB produces reliable antiangiogenic effect,inhibits the growth and metastasis of Lewis lung carcinoma.These effects may be attributed to its ability of suppressing the expression of VEGF and MMP-9,and reducing MVD.展开更多
Berberine(BBR)is an alkaloid from plants like Coptis chinensis and is for many years an OTC drug in China for bacterial-caused diarrhea.We have identified BBR to be an effective drug in treating hyperlipidemia as well...Berberine(BBR)is an alkaloid from plants like Coptis chinensis and is for many years an OTC drug in China for bacterial-caused diarrhea.We have identified BBR to be an effective drug in treating hyperlipidemia as well as hyperglycemia.Clinical studies showed that oral administration of BBR caused significant reduction of blood cholesterol,triglyceride as well as glucose in patients with hyperlipidemia and T2D,with no obvious side-effect.Mechanism studies have identified several molecular mechanisms involving in the mode of action of BBR.The cholesterol-lowering effect was associated with the extracellular-signalregulated kinase(ERK)mediated LDLR mRNA up-regulation;the glucose-lowering effect mainly resulted from the protein kinase D mediated InsR expression and the activation of AMPK.The observed reduction of triglyceride by BBR might reflect its synergistic effect on both sugar and lipid metabolism.The interaction between gut microbiota and BBR explained the molecular mechanism of BBR′s intestinal absorption.BBR concentrated in liver after oral administration with a level many times more than that in blood.At least three CYP450 subtypes were responsible for BBR phase-Ⅰ metabolism.Structure-activity relationship of BBR was analyzed,and the clinical advantage of BBR was demonstrated.We consider BBR a new medicine for metabolic disorders.展开更多
2025年8月6日,Cell Reports Medicine期刊在线发表了上海交通大学医学院附属仁济医院消化科房静远团队牵头的题为“Berberine for preventing colorectal adenoma recurrence and neoplasm occurrence:6-year follow-up of a randomized...2025年8月6日,Cell Reports Medicine期刊在线发表了上海交通大学医学院附属仁济医院消化科房静远团队牵头的题为“Berberine for preventing colorectal adenoma recurrence and neoplasm occurrence:6-year follow-up of a randomized clinical trial”的研究成果,首次揭示了小檗碱(黄连素)在停药后对结直肠腺瘤复发的长期预防作用。展开更多
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.
基金The project supported by National Natural Science Foundation of China(81373460)by the Natural Science Foundation of Guangdong Province(2014A030313744)
文摘OBJECTIVE To determine whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus.METHODS Streptozotocin-induced diabetic mice were introduced,and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated.RESULTS Berberine combined with canagliflozin(BC)increased reduction of fasting and postprandial blood glucose,diet,and water intake compared with berberine or canagliflozin alone.Interestingly,BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone.In addition,BC showed increased phosphorylated 5′AMP-activated protein kinase(pA MPK)expression and decreased tumor necrosis factor alpha(TNFα)levels in kidneys compared with berberine or canagliflozin alone.CONCLUSION These results indicated that BC is as tronger antidiabetic than berberine or canagliflozin alone with less negative side effectson the kidneys of diabetic mice.The antidiabetic effect is likely mediated by synergically promoting the expression of p AMPK and reducing the expression of TNFαin kidneys.This study first proved that canagliflozin combined withberberine is apromising treatment for diabetes mellitus.However,the exact mechanisms should be further investigated in future studies.
基金The project supported by Fundamental Research Funds for the Central Universities(21615463)
文摘OBJECTIVE To investigate possible protective effect of berberine,an isoquinoline alkaloid,is the major active constituent of Rhizoma coptidis and Cortex phellodendri,on high-fat diet/streptozotocin-induced early diabetic nephropathy in rats and various mechanisms underlie this effect.METHODS The diabetic rat model was generated by a single intraperitoneal injection of streptozotocin(STZ,50 mg·kg-1).Diabetic rats were randomlyassigned into the following five groups:control,DN,losartan(30 mg·kg-1·d-1),berberine(100,200 mg·kg-1·d-1).Berberine and losartan were given intragastricly for nine weeks.At the end of the experiment,urine of each group was collected in a 24 h period.Rats were weighed and then sacrificed.Plasma and kidneys were collected.The levels of blood glucose,creatinine(Cr),triglycerides(TG),total cholesterol(TCH)and malondialdehyde(MDA)in serum were determined using commercial kits according to the manufacturer′s instructions.Transforming growth factor(TGF)-β1and intracellular adhesion molecule-1(IAM-1)mR NA levels were evaluated by RT-PCR.The renal histopathology was observed by light microscopy.Further biochemical analysis of IKKβ1 and p65(nucleus/cytoplasm)was provided using Western blotting techniques.RESULTS Our study has demonstrated that berberine has various pharmacological activities.The DN rats had significantly higher kidney/body weight ratio(17.4±1.4)mg·g-1,and berberine treatment could reduce this ratio change 13.6±0.6 and(11.6±0.8)mg·g-1,respectively;glucose control still remains the only disease-modifying therapy for diabetic complications,FBG was also recorded in the experiment.The findings reveal that the DN group showed a significantly higher glucose level(28.67±2.78)mmol·L-1.Treatment with8 weeks of berberine improved these parameters except blood glucose〔(18.67±2.59)mmol·L-1and 16.45±1.80 vs(28.67±2.78)mmol·L-1:plasma levels of urea nitrogen(15.67±2.48)mmol·L-1and 14.45±2.40 vs(12.26±2.40)mmol·L-1〕;plasma levels of 24 h urine albuminuria〔30.48±1.56 and 25.72±2.24 vs(15.26±0.12)μg·d-1〕;based on these results,berberine supposed to improve renal functions in diabetic rats.Berberine also ameliorated the inflammatory changes of DN in diabetic animals;levels of TG,TCH and MDA in berberine-treatment rats were significantly lower compared with those in the DN group:TG〔2.78±0.24 and 2.45±0.36 vs(5.20±0.60)mmol·L-1〕;TCH〔4.26±0.46 and 3.74±0.68 vs(6.26±0.50)mmol·L-1〕;MDA〔4.94±1.19 and 4.28±0.64 vs(4.28±0.64)nu·mL-1〕.Chronic inflammation,as is observed in diabetes,is associated with increased production of TGF-β1and IAM-1.Compared with the renal tissues of DN group,TGF-β1and IAM-1 gene expressions in berberine treated groups were reduced at the dose levels(100 and 200 mg·kg-1).And TGF-β1and IAM-1levels in berberine treated groups were reduced in a dosedependent manner:Relative expression of TGF-β1mR NA level(3.56±0.28 and 3.12±0.14 vs 5.12±0.44);Relative expression of IAM-1 mR NA leve(l1.78±0.56 and 1.42±0.24vs 4.36±0.35).Research finds that the NF-κB signaling pathway is activated in the renal tissue of diabetic mice and berberine inhibits activation of the NF-κB pathway:staining score for IKKβ1(4.34±0.26 and 3.82±0.24 vs 6.23±0.76),staining score for p65(2.34±0.26 and 1.74±0.78 vs 6.23±0.24)in nucleus and staining score for p65(7.21±0.13 and8.15±0.45 vs 4.23±0.54)in cytoplasm.CONCLUSION In this field,berberine suppresses the increased expression of p65 in the nucleus and decreases it in cytoplasm,which leads to the inhibition of the NF-κB pathway.These changes will result in decreasing the transcription and translation of many inflammatory mediators,such as TGF-β1and IAM-1.Additionally,these changes decrease the number of inflammatory cells and mononuclear macrophage infiltration into glomeruli and renal interstitium.These results indicated that berberine can protect the kidney of STZ-diabetic rats by reducing the expression of TGF-β1and IAM-1 in the renal tubulointerstitium.And we propose that berberinemayfunction as an effective therapeutic agent for diabetic nephropathy and attenuate the progression of renal injury.
文摘Aim To investigate the nephroprotective activity of berberine in diabetic nephropathy （DN） mice. Methods Diabetic nephropathy was induced by intraperitoneal injection with 55 mg · kg^-1 streptozotocin（STZ） , Berberine was administered at daily doses of 50, 100 and 200 mg· kg^-1 by gavage for 8 weeks. To detect serum creatinine and blood urea nitrogen （BUN） levels, blood were collected after the last dose of berberine, renal cortex was separated on ice after heart peffusion by precooled normal saline. The specimen was stored in -80℃ for the next experiments, and some of the kidney tissue were immobilized by 4% paraformaldehyde solution and 3% glut- araldehyde solution for the preparation of paraffin tissue slides and electron microscope biopsy respectively. After that, PAS staining and electron microscope were used to observe the glomerular morphology changes; ELISA was used to measure proinflammatory chemokines and cytokines levels in renal cortex. Real time RT-PCR was taken to detect the level of nucleotide binding oligomerzation domain 2 （NOD2） mRNA, Western blot was used to test the ex- pression of NOD2 and autophagy marker light chain 3 （LC3） in renal cortex. Results Histopathological changes and the increase in serum creatinine and BUN in DN mice were significantly ameliorated by berberine in a dose-de- pendent manner. Additionally, The expression of tumor necrosis factor-or （TNF-α）, interleukin-6 （IL-6） and in- tercellular adhesion molecule-1 （ICAM-1） was markedly suppressed by berberine, indicating the inhibition of in- flammatory response. Treatment of DN mice with berberine also significantly reduced the expression of NOD2 and LC3 in the kidneys. Conclusion The current study showed the nephroprotective activity of berberine in DN mice could be attributed to the inhibition of inflammation and
文摘Acknowledgements This work was supported by Educational Commission of Shanghai of China （2012JW19）; Key Research Innovation Project （13ZZ099）; Key Project from Department of Education of China （20123107130002）; Shanghai Eastern Scholar Program （2013-59） and Shanghai E-research Institute of Bioactive Constituent in TCM plan. Abstract： Aim This investigation was to identify whether Janus-activated kinase 2 （JAK2） and mitogen-activated protein kinase （MAPK） pathways were involved in the inhibitory effect of berberine hydrochloride （BER） on gastric cancer cell proliferation and IL-8 expression in vitro and in vivo. Methods CCK- 8 assay was used to assess the cell proliferation. IL-8 production was determined by ELISA and qPCR assay. Mo- lecular pathways involved were evaluated by ELISA and western-blotting methods. Results BER time- and dose- dependently inhibited the proliferation of MGC 803 and AGS cells. It also suppressed tumor growth in nude mice xenografted with MGC 803 cells. In addition, BER reduced interleukin-8 （IL-8） secretion of AGS cells as well as MGC 803 cells both in vitro and in vivo. Further study disclosed that inactivation of JAK2, p38 MAPK, ERK1/2 and JNK by BER contributed to the decreased proliferation and tumor growth as well as IL-8 expression in gastric cancer. Although there was no significantly synergistic inhibitory effect between BER and evodiamine on gastric cancer cell proliferation and tumor growth, BER could counteract the up-regulation of IL-8 induced by evodiamine in vitro and vivo. Conclusions Our results suggested that BER might be an efficient and safe drug candidate for treating gastric cancer through JAK2 and MAPK pathways.
文摘Aim Ulcerative colitis （UC） is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment fuels the search for alternative therapeutic strategies. In the present study, we as- sessed the preclinical activity of berberine for the treatment of dextran sodium sulphate （DSS）-induced chronic re- lapsing colitis in C57BL/6 mice. Methods Colitis of mice was induced by three cycles of 2.0% DSS. From day13 onward, colitis mice were orally administered with 20 mg/kg berberine for 30 days. The disease severity was de- termined by daily monitoring the body weight, stool consistency, and stool bleeding of mice. At the end of treat- ment, colons were collected and subjected to histological, RT-qPCR, Western blot, and LC-MS analyses. Lympho- eytes were isolated from spleens and cultured for assessment of eytokine secretion. Results Berberine significantly ameliorated disease severity, colon shortening, histological injuries of colitis mice. Further, berberine treatment consistently and notably regulated DSS-assoeiated increase in mRNAs levels of Thl7-related eytokines （inhibition of IL-17 and ROR-γt） in the colon out of all tested eytokines. Moreover, the increases of TNF-α, IL-6 and IL-23 mRNA, and the phosphorylated STAT3 in colons of DSS - treated mice were significantly reversed by berberine. In addition, berberine directly inhibited TNF-α and IL-17 secretion from cultured lymphoeytes upon PMA/ionomyein -1 re-stimulation. In the meanwhile, a six-time amount of berberine in colon tissue （4.26 ± 2.62 ng · g^-1 colon） was measured when compared that in serum （0.76 ± 0.23 ng · m1^-1） and no detected histological changes was found in major organs of colitis mice. Conclusion We demonstrate for the first time that berberine exerts immuno- modulatory effect in alleviating DSS-indueed chronic relapsing colitis via inhibition of the JAK/STAT signalling acti- vation in the inflamed colon. The demonstration of activity in this model supports the possibility of clinical efficacy of berberine in treating chronic UC.
基金National Natural Science Foundation of China(81703529)
文摘OBJECTIVE To investigate berberine(BBR)attenuates arthritis in adjuvant-induced arthritic(AA)rats associated with regulating the energy metabolism and correcting the polarization of macrophages through activation of AMP-activated protein kinase(AMPK)and inhibition of hypoxia inducible factor 1α(HIF-1α).METHODS AA rats were treated with BBR(40,80,or 160 mg·kg-1)from days 15 to 29 after immunization.The histopathology of ankle joint was examined through hematoxylin-eosin(HE)staining.The concentrations of tumour necrosis factor-α(TNF-α),interleukin-6(IL-6),IL-1β,IL-2,IL-17A,interferon-gamma(IFN-γ),monocyte chemotactic protein 1(MCP-1),IL-4,IL-10,transforming growth factor-β1(TGF-β1),ATP,and lactic acid were measured by using ELISA kits.The percentage of M1 and M2 macro⁃phage cells in joint tissues were evaluated by immune-fluorescence.The expressions of p-AMPK and HIF-1αin joint of AA rats were determined according to immunohistochemistry analysis.The migration of macrophage was detected by Transwell assays.The expression of inducible nitric oxide synthase(iNOS),Arginase-1(Arg1),p-AMPK,AMPK and HIF-1αwere examined by Western blotting.The labeled macrophages were observed with laser confocal microscopy.RESULTS BBR relieved signs and symptoms of AA rats and reversed pathological changes.BBR treatment group exhibited decreases in pro-inflammatory cytokines(TNF-α,IL-1β,IL-6,IL-2,IL-17A,IFN-γ,and MCP-1)coupled with increases anti-inflammatory cytokines(IL-4,IL-10,TGF-β1)in the serum.The number of M1 macrophage was reduced,while the number of M2 macrophage was increased in BBR group joint tissues.Moreover,BBR showed marked up-regu⁃lation the expression of p-AMPK and down-regulation the expression of HIF-1αin joint of AA rats.Next in vitro study,we found BBR up-regulated the expression of p-AMPK,Arg1(M2 marker)and down-regulated the expression of HIF-1α,iNOS(M1 marker)induced by LPS in peritoneal macrophages from normal SD rat.Furthermore,BBR treatment inhibited the migration of macrophages stimulated by LPS.The level of ATP was elevated and lactic acid was reduced in LPSinduced macrophages after treated by BBR.However,Compound C significantly attenuated the effects of BBR on acti⁃vated macrophages.CONCLUSION BBR alleviates inflammation by regulating energy metabolism and correcting the polarization of macrophage through AMPK-HIF-1αpathway.BBR might have great therapeutic value for RA.
基金National Natural Science Foundation of China(81573813,81173598)Sichuan Provincial Admin⁃istration of Traditional Chinese Medicine of China(2021MS447)+1 种基金Excellent Talent Program of Chengdu University of Tra⁃ditional Chinese Medicine of China(YXRC2019002,ZRYY1917)and Open Research Fund of State Key Laboratory of Southwestern Chinese Medicine Resources of China(2020XSGG006)。
文摘OBJECTIVE To investigate the inhibition and mechanism of berberine on human colorectal cancer HCT116 cells through canonical Hedgehog signaling pathway.METHODS The effect of berberine on cell morphology was observed by microscopy.MTT colorimetric assay,cell scratch experiment,colony formation assay and Hoechest/PI staining were utilized to detect the activities of berberine on cell viability,cell migration and cell apoptosis.Flow cytometry was applied to examine the cell apoptosis.The effects of berberine on caspase-3 and caspase-9 were detected by caspase activity detection kit.The expressions of Hedgehog signaling pathway-related proteins SHH,GLI1,PTCH1,SMO,SUFU,apoptosis-related proteins Bax and Bcl-2 as well as cell cycle-related proteins cyclin D1 were detected by Western blotting.Additionally,quantitative real time RT-PCR was employed to assess the mRNA expression levels of Hedgehog signaling pathway-related genes SHH,GLI1,PTCH1,SMO,SUFU,apoptosis-related genes Bax and Bcl-2 as well as cell cycle-related genes cyclin D1.RESULTS Berberine sharply altered the morphology of human colorectal cancer HCT116 cells,demonstrated by that migration ability of HCT116 cells was reduced significantly and the nuclei were densely stained.Berberine could induce apoptosis in a dose-dependent manner.The activities of caspase-3 and caspase-9 were increased prominently.The expression levels of Hedgehog signaling pathway-related protein SUFU and apoptosis-related protein Bax were augmented substantially.The expression levels of Hedgehog signaling pathway-related proteins SHH,GLI1,PTCH1,SMO,apoptosis-related protein Bcl-2 as well as cell cycle-related genes cyclin D1 were markedly lessened.Besides,the mRNA expression levels of Hedgehog signaling pathway-related gene SUFU and apoptosis-related gene Bax were augmented substantially.The mRNA expression levels of Hedgehog signaling pathway-related genes SHH,GLI1,PTCH1,SMO,apoptosis-related gene Bcl-2 as well as cell cycle-related gene cyclin D1 were markedly lessened.CONCLUSION Berberine,which is the main component of coptidis rhizoma,can remarkably restrain the growth and proliferation,promote apoptosis of human colorectal cancer cells HCT116,and the underlying mechanism may be involved in suppressing the activity of the Hedgehog signaling pathway.
文摘Increased circulating branched-chain amino acids(BCAAs)have been involved in the pathogenesis of obesity and insulin resistance.However,evidence relating berberine(BBR),gut microbiota,BCAAs,and insulin resis⁃tance is limited.Here,we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet(HFD)-fed mice.BBR reorganized gut microbiota populations under both the normal chow diet(NCD)and HFD.Particu⁃larly,BBR noticeably decreased the relative abundance of BCAA-producing bacteria,including order Clostridiales;fami⁃lies Streptococcaceae,Clostridiaceae,and Prevotellaceae;and genera Streptococcus and Prevotella.Compared with the HFD group,predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis but the enrichment genes for BCAA degradation and transport by BBR treatment.Accordingly,the elevated serum BCAAs of HFD group were significantly decreased by BBR.Furthermore,the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by acti⁃vation of the multienzyme branched-chain α-ketoacid dehydrogenase complex,whereas by inhibition of the phosphoryla⁃tion state of BCKDHA(E1α subunit)and branched-chain α-ketoacid dehydrogenase kinase.The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes.Finally,data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs.Besides,functional microbiomics integrated high-throughput microbial genomics,metabolomics and molecular biotechnology has also been successfully applied to reveal the anti-obesity mechanism of hydroxysafflor yellow A.
文摘OBJECTIVE To investigate the antiangiogenic and antitumor effects of berberineα-hydroxy-δ-decanoylethyl sulfonate(HB)in vitro and in vivo.METHODS MTT assay was employed to determine the proliferation of tumor cells.Western blot analysis was used to detect the expression of VEGF and MMP-9.Transwell co-culture was used to determine the cell migration at the conditioned medium of Lewis lung carcinoma cells exposed to HB for 24 h.The C57BL/6 mice bearing Lewis lung carcinomas were treated with vehicle,different doses of HB(60,90 and 120mg·kg-1,ig)for 20 d,or cyclophosphamide(50mg·kg-1,ig)at d 1,d 8 and d 15.Afterwards,the xenografted tumors were exercised and weighed,and the lung metastasis was determined by HE stainingof the lung tissues.Tumor angiogenesis was determined by CD34 staining and microvessel density(MVD)by immunohistochemistry.RESULTSHB inhibited the growth of Lewis lung carcinoma cells in a time-dependent manner with IC50 value of 8.87,2.26 and 0.98mg·L-1,respectively when the cells were treated with HB for 24,48 and 72h.Cell migration induced by the conditioned medium of Lewis lung carcinoma cells treated with 2.5,5 and 10mg·L-1 HB was reduced by 37%,54% and 63%respectively(P<0.01).HB suppressed the expression of angiogenesis factors in a concentration-dependent manner.HB was effective in inhibition of MMP-9 expression at 5,10 and 20mg·L-1(P<0.05),whereas HB 20mg·L-1 was minimal effective concentration in inhibition of VEGF expression(P<0.01).On C57BL/6 mice bearing Lewis lung carcinomas,HB significantly reduced the tumor burden and MVD in tumor mass as well as inhibited lung metastasis at doses of 90 and 120mg·kg-1.CONCLUSION HB produces reliable antiangiogenic effect,inhibits the growth and metastasis of Lewis lung carcinoma.These effects may be attributed to its ability of suppressing the expression of VEGF and MMP-9,and reducing MVD.
文摘Berberine(BBR)is an alkaloid from plants like Coptis chinensis and is for many years an OTC drug in China for bacterial-caused diarrhea.We have identified BBR to be an effective drug in treating hyperlipidemia as well as hyperglycemia.Clinical studies showed that oral administration of BBR caused significant reduction of blood cholesterol,triglyceride as well as glucose in patients with hyperlipidemia and T2D,with no obvious side-effect.Mechanism studies have identified several molecular mechanisms involving in the mode of action of BBR.The cholesterol-lowering effect was associated with the extracellular-signalregulated kinase(ERK)mediated LDLR mRNA up-regulation;the glucose-lowering effect mainly resulted from the protein kinase D mediated InsR expression and the activation of AMPK.The observed reduction of triglyceride by BBR might reflect its synergistic effect on both sugar and lipid metabolism.The interaction between gut microbiota and BBR explained the molecular mechanism of BBR′s intestinal absorption.BBR concentrated in liver after oral administration with a level many times more than that in blood.At least three CYP450 subtypes were responsible for BBR phase-Ⅰ metabolism.Structure-activity relationship of BBR was analyzed,and the clinical advantage of BBR was demonstrated.We consider BBR a new medicine for metabolic disorders.
文摘2025年8月6日,Cell Reports Medicine期刊在线发表了上海交通大学医学院附属仁济医院消化科房静远团队牵头的题为“Berberine for preventing colorectal adenoma recurrence and neoplasm occurrence:6-year follow-up of a randomized clinical trial”的研究成果,首次揭示了小檗碱(黄连素)在停药后对结直肠腺瘤复发的长期预防作用。
