Background: Type 2 Diabetes Mellitus (T2DM) is a multifactorial disease that is influenced by genetic, metabolic, and environmental factors. Genetic predisposition, obesity, low physical activity, and unhealthy diet are key risk factors for T2DM. Result: Type 2 diabetes is treated with various natural medicines, the most significant of which is berberine (BBR). Berberine, an isoquinoline alkaloid found in various medicinal plants, exhibits a wide range of pharmacological activities and (BBR) has the potential to treat various diseases, such as diabetes, cancer, and metabolic and cardiovascular diseases. Conclusion: It has been found to be effective in AMPK activation, regulation of blood glucose and lipids, stimulation of insulin secretion from pancreatic beta cells, inhibition of cancer cells, and reduction of fat formation.
Maha AldosariNehad Al-ShawiNoorah Saleh Al-Sowayan
Objective:To evaluate if berberine can act on vitamin D receptors(VDR)and thereby regulate the expression of tight junction proteins(TJPs)in irritable bowel syndrome-diarrhea-predominant(IBS-D)rats.Methods:The newborn rats were induced into IBS-D rat model via neonatal maternal separation combined with acetic acid chemical stimulation.After modeling,the model was evaluated and rats were divided into the control group and berberine treatment groups(0.85,1.7 and 3.4 mg/kg,once a day for 2 weeks).The distal colon was obtained and colonic epithelial cells(CECs)were isolated and cultured after IBS-D model evaluation.The vitamin D receptor response element(VDRE)reporter gene was determined in the CECs of IBS-D rats to analyze the effect of berberine on the VDRE promoter.VDR overexpression or silencing technology was used to analyze whether VDR plays a role in promoting intestinal barrier repair,and to determine which region of VDR plays a role in berberine-regulated intestinal TJPs.Results:The IBS-D rat model was successfully constructed and the symptoms were improved by berberine in a dose-dependent manner(P<0.05).The activity of VDRE promoter was also effectively promoted by berberine(P<0.05).Berberine increased the expression of TJPs in IBS-D CECs(P<0.05).VDR expression was significantly increased after transfection of different domains of VDR when compared to normal control and basic plasmid groups(all P<0.05).RT-qPCR and Western blot results showed that compared with the blank group,expressions of occludin and zonula occludens-1 were significantly higher in VDR containing groups(all P<0.05).Berberine plus pCMV-Myc-VDR-N group exerted the highest expression levels of occludin and zonula occludens-1(P<0.05).Conclusion:Berberine enhances intestinal mucosal barrier function of IBS-D rats by promoting VDR activity,and the main site of action is the N-terminal region of VDR.
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.
Ansari Vikhar Danish AhmadQazi YasarSubur W KhanSyed Ayaz AliAnsari AltamashMohd Mukhtar KhanNikhil S Sakle
Helicobacter pylori(H.pylori)is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis,and its high prevalence and resistance make it difficult to tackle.A graph neural network-based deep learning model,employing different training sets of 13,638 molecules for pre-training and fine-tuning,was aided in predicting and exploring novel molecules against H.pylori.A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H.pylori strains with minimum inhibitory concentrations(MICs)of 0.25-0.5μg/mL.Pharmacokinetic studies demonstrated an ideal gastric retention of 8,with the stomach concentration significantly higher than its MIC at 24 h post dose.Oral administration of 8 and omeprazole(OPZ)showed a comparable gastric bacterial reduction(2.2-log reduction)to the triple-therapy,namely OPZ+amoxicillin(AMX)+clarithromycin(CLA)without obvious disturbance on the intestinal flora.A combination of OPZ,AMX,CLA,and 8 could further decrease the bacteria load(2.8-log reduction).More importantly,the mono-therapy of 8 exhibited comparable eradication to both triple-therapy(OPZ+AMX+CLA)and quadrupletherapy(OPZ+AMX+CLA+bismuth citrate)groups.SecA and BamD,playing a major role in outer membrane protein(OMP)transport and assembling,were identified and verified as the direct targets of 8 by employing the chemoproteomics technique.n summary,by targeting the relatively conserved OMPs transport and assembling system,8 has the potential to be developed as a novel anti-H.pylori candidate,especially for the eradication of drug-resistant strains.
Objective:Hepatolenticular degeneration (HLD) is an autosomal recessive disorder that manifests as multiorgan damage due to impaired copper (Cu) metabolism. Female patients with HLD often experience reproductive impairments. This study investigated the protective effect of berberine against ovarian damage in toxic-milk (TX) mice, a murine model for HLD.Methods:Mice were categorized into control group, HLD TX group (HLD group), penicillamine (Cu chelator)-treated TX group and berberine-treated TX group. Body weight, ovary weight and the number of ovulated eggs were recorded. Follicular morphology and cellular ultrastructure were examined. Total iron, ferrous iron (Fe2+) and trivalent iron (Fe3+) levels, as well as malondialdehyde (MDA), glutathione(GSH) and oxidized glutathione (GSSG), were measured in the ovaries. Western blot analysis was used to analyze the expression of proteins related to ferroptosis and endoplasmic reticulum (ER) stress.Results:Ovarian tissue damage was evident in the HLD group, with a significant increase in ferroptosis and ER stress compared to the control group. This damage was inhibited by treatment with penicillamine,a Cu chelator. Compared with the HLD group, berberine increased the number of ovulations, and improved ovarian morphology and ultrastructure. Further, we found that berberine reduced total iron,Fe2+, MDA and GSSG levels, elevated GSH levels, decreased the expression of the ferroptosis marker protein prostaglandin-endoperoxide synthase 2 (PTGS2), and increased glutathione peroxidase 4 (GPX4)expression. Furthermore, berberine inhibited the expression of ER stress-associated proteins mediated by the protein kinase RNA-like ER kinase (PERK) pathway.Conclusion:Ferroptosis and ER stress are involved in Cu-induced ovarian damage in TX mice. Berberine ameliorates ovarian damage in HLD TX mice by inhibiting ferroptosis and ER stress.
The development of resistance against most of the available antibiotics has made Acinetobacter baumannii(A.baumannii)a pathogen of high risk.In this study,thirty novel berberine derivatives are rationally designed,synthesized,and evaluated for their synergistic antibacterial activities against A.baumannii.Among them,compound 2d shows the most potent synergetic effect to aztreonam against A.baumannii,including carbapenem-resistant and extended-spectrumβ-lactamases-producing strains.Moreover,synergistic effects were observed for the combinations of 2d and different antibacterial used in clinical practices,indicating its potent broad-spectrum antibiotic-sensitizing effects against A.baumannii.The combination of 2d and aztreonam significantly improves the survival rates of G.mellonella larvae compared with aztreonam treatment alone.Mechanism studies indicate that 2d inhibits the drug efflux and iron acquisition of the bacteria by targeting the AdeB transporter protein,thus achieving a synergistic antimicrobial efficacy with different antibacterial agents.Therefore,berberine derivatives represent a new family of antimicrobial adjuvants against A.baumannii,with the advantage of dual-function antibacterial effect,and are worthy of further investigation.
Objective:To investigate potential mechanisms of anti-atherosclerosis by berberine(BBR)using ApoE-/-mice.Methods:Eight 8-week-old C57BL/6J mice were used as a blank control group(normal),and 568-week-old AopE-/-mice were fed a high-fat diet for 12 weeks,according to a completely random method,and were divided into the model group,BBR low-dose group(50 mg/kg,BBRL),BBR medium-dose group(100 mg/kg,BBRM),BBR high-dose group(150 mg/kg,BBRH),BBR+nuclear factor erythroid 2-related factor 2(NRF2)inhibitor group(100 mg/kg BBR+30 mg/kg ML385,BBRM+ML385),NRF2 inhibitor group(30 mg/kg,ML385),and positive control group(2.5 mg/kg,atorvastatin),8 in each group.After 4 weeks of intragastric administration,samples were collected and serum,aorta,heart and liver tissues were isolated.Biochemical kits were used to detect serum lipid content and the expression levels of malondialdehyde(MDA)and superoxide dismutase(SOD)in all experimental groups.The pathological changes of atherosclerosis(AS)were observed by aorta gross Oil Red O,aortic sinus hematoxylin-eosin(HE)and Masson staining.Liver lipopathy was observed in mice by HE staining.The morphology of mitochondria in aorta cells was observed under transmission electron microscope.Flow cytometry was used to detect reactive oxygen species(ROS)expression in aorta of mice in each group.The content of ferrous ion Fe^(2+)in serum of mice was detected by biochemical kit.The mRNA and protein relative expression levels of NRF2,glutathione peroxidase 4(GPX4)and recombinant solute carrier family 7 member 11(SLC7A11)were detected by quantitative real time polymerase chain reaction(RT-q PCR)and Western blot,respectively.Results:BBRM and BBRH groups delayed the progression of AS and reduced the plaque area(P<0.01).The characteristic morphological changes of ferroptosis were rarely observed in BBR-treated AS mice,and the content of Fe^(2+)in BBR group was significantly lower than that in the model group(P<0.01).BBR decreased ROS and MDA levels in mouse aorta,increased SOD activity(P<0.01),significan
Objective Berberine(BBR)has emerged as a promising therapeutic agent for nonalcoholic fatty liver disease(NAFLD).This study aims to elucidate the underlying molecular mechanisms.Methods In this study,db/db mice were chosen as an animal model for NAFLD.A total of 10 healthy C57BL/6J mice and 30 db/db mice were randomly allocated to one of 4 groups:the normal control(NC)group,the diabetic control(DC)group,the Metformin(MET)therapy group,and the BBR therapy group.The total cholesterol(TC),triacylglycerol(TG),low-density lipoprotein cholesterol(LDL-c),high-density lipoprotein cholesterol(HDL-c),aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels in the serum were measured.The glutathione peroxidase(GSH-Px),glutathione(GSH),malondialdehyde(MDA),superoxide dismutase(SOD),catalase(CAT),interleukin(IL)-1β,tumor necrosis factor(TNF)-αand monocyte chemotactic protein 1(MCP-1)levels in liver tissue were measured.Hematoxylin and eosin(H&E),acid-Schiff(PAS)and TUNEL stanning was performed for histopathological analysis.Western blotting and immunohistochemistry were conducted to detect the expression levels of key proteins in the AMPK/SIRT1 pathway.Results BBR could improve lipid metabolism,attenuate hepatic steatosis and alleviate liver injury significantly.The excessive oxidative stress,high levels of inflammation and abnormal apoptosis in db/db mice were reversed after BBR intervention.BBR clearly changed the expression of AMP-activated protein kinase(AMPK)/Sirtuin 1(SIRT1),and their downstream proteins.Conclusion BBR could reverse NAFLD-related liver injury,likely by activating the AMPK/SIRT1 signaling pathway to inhibit oxidative stress,inflammation and apoptosis in hepatic tissue.
