Berberine Treatment Research Articles

Berberine Suppresses Leukocyte Adherence by Downregulating CX3CL1 Expression and Shedding and ADAM10 in Lipopolysaccharide-Stimulated Vascular Endothelial Cells.

Berberine exerts therapeutic effects in inflammation-associated diseases. In a lipopolysaccharide (LPS)-induced endotoxemic acute lung injury (ALI) rat model, berberine alleviated lung injury through different anti-inflammatory mechanisms; however, treatment effects on CX3CL1 expression and shedding remain to be examined. As these processes play important roles in promoting the binding of leukocytes to the endothelium, the CX3CL1/CX3CR1 axis and its related pathways may serve as potential targets for the clinical treatment of ALI. The anti-inflammatory effects of berberine were investigated in LPS-stimulated rats, human umbilical cord vein endothelial cells (HUVECs), and THP-1 monocytic cells. Cx3cl1 expression in rat pulmonary tissues was examined using immunohistochemistry. CX3CL1, CX3CR1, RELA, STAT3, and ADAM10 levels were examined using Western blotting. CX3CL1 and ADAM10 mRNA levels were examined using quantitative real-time polymerase chain reaction. Soluble fractalkine levels in LPS-stimulated rats and HUVECs were examined using the enzyme-linked immunosorbent assay. Berberine significantly mitigated the LPS-induced upregulation of fractalkine and soluble fractalkine in rats and cultured HUVECs. Berberine mitigated the LPS-induced activation of the NF-κB and STAT3 signaling pathways. In THP-1 cells, berberine mitigated the LPS-induced upregulation of CX3CR1. Furthermore, the membrane expression of ADAM10 in LPS-stimulated HUVECs was suppressed by the berberine treatment. Berberine dose-dependently inhibited the LPS-induced activation of the CX3CL1/CX3CR1 axis and fractalkine shedding through ADAM10. These findings reveal a novel molecular mechanism underlying the inhibitory effect of berberine on monocyte adherence to the endothelium during inflammation.

Alleviation of Diabetic Tendon Injury via Activation of Tendon Fibroblasts Autophagy under Berberine Treatment.

Berberine (BBR) is an isoquinoline alkaloid isolated from Coptis chinensis and possesses valuable pharmacological activities, including anti-inflammatory, anti-tumor, and alleviating several complications of type 2 diabetes mellitus (T2DM). However, the role of BBR in regulating diabetic tendon injury remains poorly understood. In this study, a rat model of T2DM was constructed, and cell apoptosis and autophagy were assessed in tendon tissues after BBR treatment through TdT-Mediated dUTP nick-end labeling (TUNEL) assay and immunohistochemical analysis. Tendon fibroblasts were obtained from the rat Achilles tendon, and the role of BBR in regulating cell apoptosis, the production of inflammatory cytokines, and autophagy activation were assessed using flow cytometry, quantitative real-time PCR (qRT-PCR), and western blot analysis. We demonstrated that BBR treatment significantly increased autophagy activation and decreased cell apoptosis in tendon tissues of T2DM rats. In tendon fibroblasts, BBR repressed High glucose (HG)-induced cell apoptosis and production of proinflammatory cytokines. HG treatment resulted in a decrease of autophagy activation in tendon fibroblasts, whereas BBR restored autophagy activation. More important, pharmacological inhibition of autophagy by 3-MA weakened the protective effects of BBR against HG-induced tendon fibroblasts injury. Taken together, the current results demonstrate that BBR helps relieve diabetic tendon injury by activating autophagy of tendon fibroblasts.

Immunomodulatory effects of berberine on Staphylococcus aureus-induced septic arthritis through down-regulation of Th17 and Treg signaling pathways.

The preseaant study was aimed to investigate the immunomodulatory effects of berberine on Staphylococcus aureus-induced septic arthritis through the downstream signaling mechanism of Th17 and Treg, in the control and prevention of disease progression of Staphylococcus aureus induced septic arthritis of blood, spleen and synovial joints. The study was conducted in mice induced with septic arthritis by S. aureus for 15 days. The infected mice were treated with berberine (50 or 100 or 200 mg/Kg) to evaluate the effects on the isolated cells of Th17 and Treg from synovial joints, blood and spleen against the septic arthritic induced mice followed by JNK, RANKL and NF-κB expressions in the lysates of Th17 and Tregs isolated cells. The evaluation of serum IL-21 and TGF-β levels was also conducted after 15 days post-infection in Th17 and Treg population. Our findings showed that berberine exerted excellent inhibitory effects on the S. aureus (AS-789) strain for inducing sepsis-induced arthritis. The results from the S. aureus testing revealed that at concentrations below 640 μg/mL, the strain was more resistant to berberine, as it had an increased rate of growth. The assessment of S. aureus induced septic arthritis (joint swelling and arthritis index) substantial reduction in the joint swelling and arthritis index (p<0.01) in the berberine-treated groups. The percentage of Th17 cells with CD4 and RORγt; Treg cells with CD4, CD25 and FOXp3 in the synovial joints, blood and spleen was substantially declined in the drug-treated groups (p<0.01) as compared to the S. aureus infected mice. The TGF-β and IL-21 serum levels determinations in S. aureus induced septic arthritis revealed a substantial decrease in serum TGF-β levels (p<0.01) in drug-treated groups compared to the infected animals. The post hoc test revealed a substantial decrease in JNK, NF-κB and RANKL expressions in the lysates of Th17 and Treg isolated cells in the drug-treated animals (p<0.01) when compared to the S. aureus-infected cluster. Our findings demonstrated that a possible strategy for combating disease severity with berberine treatment in Staphylococcus aureus induced septic arthritis in mice, which targets the Th17 and Treg cells have driven the NF-κB/JNK-RANKL axis.

Berberine Inhibits FOXM1 Dependent Transcriptional Regulation of POLE2 and Interferes With the Survival of Lung Adenocarcinoma.

Background: Berberine is one of the most interesting and promising natural anticancer drugs. POLE2 is involved in many cellular functions such as DNA replication and is highly expressed in a variety of cancers. However, the specific molecular mechanism of berberine interfering with POLE2 expression in lung adenocarcinoma (LUAD) is still unknown to a great extent. Method: The KEGG database (Release 91.0) and Gene Ontology (GO) category database were used for functional annotation of differentially expressed genes after berberine treatment. Reproducibility assessment using TCGA dataset. The biological functions of berberine in LUAD were investigated by a series of in vitro and in vivo experiments: MTT, colony formation, mouse xenograft and plasmid transfection. The molecular mechanisms of berberine were demonstrated by plasmid transfection, quantitative RT-PCR and Western blotting. Result: The elevated expression of FOXM1 and the high enrichment of DNA replication pathway were confirmed in LUAD by microarray and TCGA analysis, and were positively correlated with poor prognosis. Functionally, berberine inhibited the proliferation and survival of LUAD cell lines in vitro and in vivo. Mechanistically, berberine treatment down regulated the expression of FOXM1which closely related to survival, survival related genes in Cell cycle and DNA replication pathway, and significantly down regulated the expression of survival related POLE2. Interestingly, we found that the transcription factor FOXM1 could act as a bridge between berberine and POLE2. Conclusion: Berberine significantly inhibited LUAD progression via the FOXM1/POLE2, and FOXM1/POLE2 may act as a clinical prognostic factor and a therapeutic target for LUAD. Berberine may be used as a promising therapeutic candidate for LUAD patients.

Improvement of adjunctive berberine treatment on negative symptoms in patients with schizophrenia.

The upregulation of immune and inflammatory response may play a role in the negative symptoms of schizophrenia. Berberine is an effective drug with anti-inflammatory property, and may be beneficial for the treatment of negative symptoms. The aim of this study is to test this hypothesis through a randomized, double-blind, placebo-controlled, clinical trial. Eligible patients with schizophrenia were randomized to receive placebo or berberine (900mg/day) for 8weeks as adjunctive treatment to single atypical antipsychotic drug. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate clinical symptoms at three time points (baseline, 4th and 8th week). Blood samples were collected at the above three time points to determine the concentrations of inflammatory markers including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP). 59 patients with intention-to-treat were analyzed, 32 in the berberine group and 27 in the placebo group. From the baseline to the 8th week, berberine treatment significantly improved the negative symptom subscale of PANSS (F = 18.981; p < 0.001). From the baseline to the 8th week, the plasma CRP concentration decreased in the berberine group, while increased in the placebo group (F = 5.373; p = 0.024). Furthermore, in the berberine group, the change of CRP concentration was significantly positively correlated with the change of PANSS negative symptom subscale within 8weeks (r = 0.56; p = 0.002). There was no significant difference in adverse events between the two groups (p's > 0.05). Our study suggests that berberine treatment is well tolerated in patients with schizophrenia. Berberine may improve negative symptoms through anti-inflammatory effect.Trial registration: Clinicaltrials.gov identifier: NCT03548155.

Berberine Reduces Lipid Accumulation by Promoting Fatty Acid Oxidation in Renal Tubular Epithelial Cells of the Diabetic Kidney.

Abnormal lipid metabolism in renal tubular epithelial cells contributes to renal lipid accumulation and disturbed mitochondrial bioenergetics which are important in diabetic kidney disease. Berberine, the major active constituent of Rhizoma coptidis and Cortex phellodendri, is involved in regulating glucose and lipid metabolism. The present study aimed to investigate the protective effects of berberine on lipid accumulation in tubular epithelial cells of diabetic kidney disease. We treated type 2 diabetic db/db mice with berberine (300 mg/kg) for 12 weeks. Berberine treatment improved the physical and biochemical parameters of the db/db mice compared with db/m mice. In addition, berberine decreased intracellular lipid accumulation and increased the expression of fatty acid oxidation enzymes CPT1, ACOX1 and PPAR-α in tubular epithelial cells of db/db mice. The mitochondrial morphology, mitochondrial membrane potential, cytochrome c oxidase activity, mitochondrial reactive oxygen species, and mitochondrial ATP production in db/db mice kidneys were significantly improved by berberine. Berberine intervention activated the AMPK pathway and increased the level of PGC-1α. In vitro berberine suppressed high glucose-induced lipid accumulation and reversed high glucose-induced reduction of fatty acid oxidation enzymes in HK-2 cells. Importantly, in HK-2 cells, berberine treatment blocked the change in metabolism from fatty acid oxidation to glycolysis under high glucose condition. Moreover, berberine restored high glucose-induced dysfunctional mitochondria. These data suggested that berberine alleviates diabetic renal tubulointerstitial injury through improving high glucose-induced reduction of fatty acid oxidation, alleviates lipid deposition, and protect mitochondria in tubular epithelial cells.

Therapeutic Effect of Berberine Versus Methotrexate on Histopathology in a Rat Model of Pristane-Induced Arthritis

Introduction: Treatment options for rheumatoid arthritis have potentially fatal adverse effects and failure to achieve complete cure. Alternative medicines are, therefore, being researched for this purpose. Berberine is one of such compounds with high antioxidant activity that may prove beneficial in this disease.&#x0D; Aims &amp; Objectives: To compare effects of berberine with methotrexate on pristane induced arthritis in rats.&#x0D; Place and duration of study: Post Graduate Medical Institute, Lahore; March to May 2014.&#x0D; Material &amp; Methods: Forty female Sprague Dawley rats were allotted to five groups including a berberine control. Arthritis developed in 14 days with a single intradermal injection of pristane in arthritis control and experimental groups. Starting Day 15, berberine and methotrexate were administered as single daily intraperitoneal injection for next 14 days. Arthritis resolution was assessed by measuring body weight, clinical score of arthritis on day 0, 14 and 28 and joint histopathology terminally. Data was analyzed using SPSS version 20, p value &lt;0.05 was considered significant.&#x0D; Results: Arthritis induction reduced body weight in pristane administered groups (142.87 ± 3.56, 146.25 ± 7.49, 112.37 ± 6.23, 114.50 ±3.85, 113.62 ± 7.72 g in Group I, II, III, IV and V respectively) at day 14. Berberine and methotrexate treatment restored body weight in comparison to continuous loss in arthritis control animals on day 28 (155.87 ± 3.72,&#x0D; 162.00 ± 7.96, 105.25 ± 8.04, 133.75 ± 4.89, 133.12 ± 9.24 g in Group I, II, III, IV and V respectively). Berberine and methotrexate both reduced joint inflammation (clinical score 15±1.51, 6.75±1.48, 3.25±1.48 in arthritis control, berberine and methotrexate treated groups). Methotrexate was, however, more effective in reducing clinical arthritis score than berberine on day 28 (p value &lt;0.001). Histopathological changes were reversed similarly by both drugs.&#x0D; Conclusion: Berberine is effective in treating rheumatoid arthritis though less than methotrexate.

Berberine treatment for weight gain in patients with schizophrenia by regulating leptin rather than adiponectin.

Berberine could improve antipsychotic-induced weight gain in obese cell lines and animal models. This study aimed to exam the effect of berberine on weight gain in patients with schizophrenia. Each subject who met DSM-IV-TR criteria for schizophrenia had been on stable dose of a single antipsychotic for at least one month. In an 8-week randomized, double-blind, placebo-controlled study, subjects received either berberine (900mg per day) or placebo. Anthropometric parameters, leptin and adiponectin were measured at baseline, week 4, and week 8. A total of 65 patients were enrolled, 49 of which completed the treatment. At the 8th week, the mean weight of patients in the berberine group (N=27) lost 1.10kg, while in the placebo group (N=22) gained 1.45kg. There were significant differences in body weight (Ftime*group=10.493, P=0.001), BMI (Ftime*group=9.344, P=0.002) and leptin (Ftime*group=6.265, P=0.003). Further, the change of leptin had significant positive correlations with the changes of body weight(r=0.395, P=0.041) and BMI(r=0.389, P=0.045). There was no significant difference in adverse events between the two groups (P>0.05). This study suggests that berberine is a potential weight loss and weight maintenance drug for patients with schizophrenia. The effect of berberine on weight gain may be related to the regulation of leptin, but not adiponectin.

Berberine: Ins and outs of a nature-made PCSK9 inhibitor.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein and a critical regulator of low-density lipoprotein-cholesterol (LDL-C) through inducing degradation of the LDL receptor (LDLR) within the hepatocyte lysosome. PCSK9 deficiency significantly improves the survival rate of cardiovascular disease (CVDs) patients. Up to now, various PCSK9 inhibition approaches have been tested. However, the currently available PCSK9 inhibitors' widespread use is limited due to their inconvenient method of administration and high cost. On the other hand, inhibiting PCSK9 with nutraceuticals is safe and affordable. The plant-derived compound berberine has shown anti-PCSK9 activity in several studies. Berberine is an isoquinoline quaternary alkaloid of phyto origin. Berberine treatment boosts the hepatic expression of LDLRs, while decreasing the expression and secretion of the LDLR modulator PCSK9. The current review presents a collection of in vitro and in vivo studies investigating berberine's effects on PCSK9 mRNA expression, protein level, and function.

Berberine Decreases Intestinal GLUT2 Translocation and Reduces Intestinal Glucose Absorption in Mice.

Postprandial hyperglycemia is an important causative factor of type 2 diabetes mellitus, and permanent localization of intestinal GLUT2 in the brush border membrane is an important reason of postprandial hyperglycemia. Berberine, a small molecule derived from Coptidis rhizome, has been found to be potent at lowering blood glucose, but how berberine lowers postprandial blood glucose is still elusive. Here, we investigated the effect of berberine on intestinal glucose transporter 2 (GLUT2) translocation and intestinal glucose absorption in type 2 diabetes mouse model. Type 2 diabetes was induced by feeding of a high-fat diet and injection of streptozotocin and diabetic mice were treated with berberine for 6 weeks. The effects of berberine on intestinal glucose transport and GLUT2 translocation were accessed in isolated intestines and intestinal epithelial cells (IEC-6), respectively. We found that berberine treatment improved glucose tolerance and systemic insulin sensitivity in diabetic mice. Furthermore, berberine decreased intestinal glucose transport and inhibited GLUT2 translocation from cytoplasm to brush border membrane in intestinal epithelial cells. Mechanistically, berberine inhibited intestinal insulin-like growth factor 1 (IGF-1R) phosphorylation and thus reduced localization of PLC-β2 in the membrane, leading to decreased GLUT2 translocation. These results suggest that berberine reduces intestinal glucose absorption through inhibiting IGF-1R-PLC-β2-GLUT2 signal pathway.

Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study

ABSTRACT Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal Bifidobacterium breve level responding to BBR alone or Prob+BBR treatment. Four fadD genes encoding long-chain acyl-CoA synthetase were identified in the genome of this B. breve strain, and transcriptionally activated by BBR. In vitro BBR treatment further decreased the concentration of FFA in the culture medium of B. breve compared to vehicle. Thus, the activation of fadD by BBR could enhance FFA import and mobilization in B. breve and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (B. breve) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.

Berberine Suppresses Stemness and Tumorigenicity of Colorectal Cancer Stem-Like Cells by Inhibiting m6A Methylation.

BackgroundCancer stem cells (CSCs) are able to survive after cancer therapies, resulting in tumor progression and recurrence, as is seen in colorectal cancer. Therapies targeting CSCs are regarded as novel and promising strategies for efficiently eradicating tumors. Berberine, an isoquinoline alkaloid extracted from the Chinese herbal medicine Coptis chinensis, was found to have antitumor activities against colorectal cancer, without knowing whether it exerts inhibitory effects on colorectal CSCs and the potential mechanisms.MethodsIn this study, we examined the inhibitory roles of Berberine on CSCs derived from HCT116 and HT29 by culturing in serum-free medium. We also examined the effects of Berberine on m6A methylation via regulating fat mass and obesity-associated protein (FTO), by downregulating β-catenin.ResultsWe examined the effects of Berberine on the tumorigenicity, growth, and stemness of colorectal cancer stem-like cells. The regulatory effect of Berberine on N6-methyladenosine (m6A), an abundant mRNA modification, was also examined. Berberine treatment decreased cell proliferation by decreasing cyclin D1 and increasing p27 and p21 and subsequently induced cell cycle arrest at the G1/G0 phase. Berberine treatment also decreased colony formation and induced apoptosis. Berberine treatment transcriptionally increased FTO and thus decreased m6A methylation, which was reversed by both FTO knockdown and the addition of the FTO inhibitor FB23-2. Berberine induced FTO-related decreases in stemness in HCT116 and HT29 CSCs. Berberine treatment also increased chemosensitivity in CSCs and promoted chemotherapy agent-induced apoptosis. Moreover, we also found that Berberine treatment increased FTO by decreasing β-catenin, which is a negative regulator of FTO.ConclusionsOur observation that Berberine effectively decreased m6A methylation by decreasing β-catenin and subsequently increased FTO suggests a role of Berberine in modulating stemness and malignant behaviors in colorectal CSCs.

Blocking HMGB1/RAGE Signaling by Berberine Alleviates A1 Astrocyte and Attenuates Sepsis-Associated Encephalopathy.

As a life-threatening multiple organ dysfunction attributable to maladjusted host immune responses to infection, sepsis is usually the common pathway to serious prognosis and death for numerous infectious diseases all over the world. Sepsis-associated encephalopathy (SAE) is frequently complicated by septic conditions, and is one of the most important reasons for increased mortality and poor outcomes in septic patients which is still an urgent clinical problem need to be solved. In this research, a conspicuously discovery of treatment-related translational use for berberine was elaborated. The results revealed that berberine treatment significantly restored cognitive impairment in sepsis mice. Reduced expression levels of TNF-α, IL-1α, and C1qA were exhibited in the hippocampus of the berberine treatment group, and attenuated effect of declining neo-neuron, activation of microglia and astrocytes in the hippocampus of mice with sepsis were also found. Moreover, berberine inhibits microglia-stressed A1 astrocytes by inhibiting HMGB1 signaling was revealed, then the molecular mechanism of HMGB1/RAGE signaling inhibition leads to the better outcome of SAE was elucidated. To summarize, this research indicated that berberine targets HMGB1/RAGE signaling to inhibit microglia-stressed A1 astrocyte and neo-neuron decline, which consequently alleviates sepsis-induced cognitive impairment. Collectively, berberine may serve as potential therapeutic drug and HMGB1/RAGE signaling would be a novel target for medicine development for treating SAE.

Berberine ameliorates erectile dysfunction in rats with streptozotocin-induced diabetes mellitus through the attenuation of apoptosis by inhibiting the SPHK1/S1P/S1PR2 and MAPK pathways.

The population with diabetes mellitus-induced erectile dysfunction is increasing rapidly, but current drugs are not effective in treating erectile dysfunction. Studies of the traditional Chinese medicine extract berberine on diabetes and its complications provide us with new ideas. To evaluate the therapeutic effect and potential mechanism of berberine on the erectile function of diabetic rats. Fifty male Sprague-Dawley rats were randomly grouped, and 42 rats were injected intraperitoneally with streptozotocin to establish a diabetes model. Erectile dysfunction rats were screened out through the apomorphine test and randomly divided into the diabetes mellitus and berberine groups, and these animals were administered berberine (200mg/kg/day) and normal saline by gavage for 4weeks. Primary corpus cavernous smooth muscle cells from healthy rats were cultured and treated with berberine. Fasting blood glucose in the diabetes mellitus group was significantly increased, while berberine showed no significant effect on glucose. Erectile function was obviously impaired in the diabetes mellitus group, and berberine administration partially rescued this impairment. The expression of sphingosine kinase 1, S1PR2, and sphingosine-1-phosphate in the diabetes mellitus group was increased. Berberine partially inhibited the expression of sphingosine kinase 1 and S1PR2, but the decrease in sphingosine-1-phosphate was not significant. Moreover, mitogen-activated protein kinase pathway factor expression was upregulated and eNOS activity was decreased in the diabetes mellitus group. Berberine treatment could partially reverse these alterations. Severe fibrosis and apoptosis were detected in diabetic rats, accompanied by higher expression of TGFβ1, collagen I/IV, Bax/Bcl-2, and caspase 3 than in the other groups. However, supplementation with berberine inhibited the expression of these proteins and attenuated fibrosis and apoptosis. Berberine ameliorated erectile dysfunction in rats with diabetes mellitus, possibly by improving endothelial function and inhibiting apoptosis and fibrosis by suppressing the sphingosine kinase 1/sphingosine-1-phosphate/S1PR2 and mitogen-activated protein kinase pathways.

Evaluation of Berberine as an Adjunct to TB Treatment.

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect Mtb growth in axenic cultures; however, it showed increased bacterial killing in primary murine bone marrow-derived macrophages and human monocyte-derived macrophages. Ad libitum berberine administration was beneficial to the host in combination with rifampicin and isoniazid. Berberine adjunctive treatment resulted in decreased lung pathology with no additive or synergistic effects on bacterial burdens in mice. Lung immune cell flow cytometry analysis showed that adjunctive berberine treatment decreased neutrophil, CD11b+ dendritic cell and recruited interstitial macrophage numbers. Late onset of adjunctive berberine treatment resulted in a similar phenotype with consistently reduced numbers of neutrophils both in lungs and the spleen. Together, our results suggest that berberine can be supplemented as an immunomodulatory agent depending on the disease stage and inflammatory status of the host.

Berberine affords protection against oxidative stress and apoptotic damage in F1 generation of wistar rats following lactational exposure to chlorpyrifos

Chlorpyrifos (0,0-diethyl 0-(3,5,6-trichloro-2-pyridinyl)-phosphorothioate; (CPF)) is a widely used lipophilic organophosphorus insecticide that primarily manifests into central and peripheral nervous system toxicity. However, it is poorly investigated as a developmental neurotoxicant and thus remains less explored for pharmacological interventions as well. Berberine (BBR) is a benzylisoquinoline alkaloid, primarily found in the plants of Berberidaceae family, and is used for the synthesis of several bioactive derivatives. The goal of this study was to evaluate the CPF-induced neuronal damage through lactational route and analyze the neuroprotective efficacy of berberine (BBR), a potent antioxidant compound in the F1 generation. The environmentally relevant dose of CPF (3 mg/kg b.wt.) was administered via gavage to pregnant dams from postnatal day 1 to day 20 (PND 1–20). BBR (10 mg/kg b.wt.) was administered concurrently with CPF for the same duration as a co-treatment. Levels of reactive oxygen species, lipid peroxidation, membrane bound ATPases (Na+K+ATPase, Ca2+ATPase, and Mg2+ATPase), DNA damage, histomorphological alterations, cellular apoptosis were increased, and activities of glutathione reductase, endogenous antioxidant enzymes (SOD, CAT, GST, and GR) were decreased in cerebellum and cerebrum regions of CPF exposed pups. CPF triggered neuronal apoptosis by upregulating Bax and caspase-3 and downregulating Bcl-2. Co-treatment of BBR significantly attenuated these effects of CPF signifying oxidative stress mediated chlorpyrifos induced neuronal apoptosis. Berberine treatment ameliorated the CPF-induced downregulation of Bcl-2, Bax translocation, and up-regulation of caspase-3 in F1 pups. Therefore, BBR owing to its multiple pharmacological properties can be further explored for its therapeutic potential as an alternative neuroprotective agent against lactational exposure of chlorpyrifos-induced developmental neurotoxicity.

Remodelling of gut microbiota by Berberine attenuates trimethylamine N-oxide-induced platelet hyperreaction and thrombus formation

Berberine is an extract derived from Chinese herbs with pleiotropic cardiovascular protective effects. However, the underlying mechanism remains unclear because of its poor bioavailability. Herin, we aimed to investigate whether berberine affects choline diet-induced arterial thrombosis and explore the potential mechanism. Ultrasound and optical coherence tomography were used to assess the potential risk of artery thrombosis in vivo. The plasma concentrations of trimethylamine N-oxide (TMAO) and trimethylamine (TMA) were quantified with mass spectrometry. Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qPCR) were utilized to detect the levels of microbial TMA-lyase choline utilization C (CutC) in faeces. Gut microbiota analysis was performed with 16S rRNA gene sequencing. For in vitro studies, platelet aggregometry, intracellular Ca2+ measurement, ATP release assay, flow cytometry and Western blot were applied to identify the effects of TMAO on platelets. Berberine treatment significantly decreased the CutC levels in the caecal contents, reduced choline diet-induced TMA and TMAO production, and subsequently, reduced the arterial thrombosis potential risk. Berberine administration remodelled the structure of gut microbiota in rats and increased the levels of the genus Lactobacillus. Finally, TMAO enhanced platelet reactivity to collagen by promoting the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) in platelets. These results demonstrate that berberine attenuates the risk of choline diet-induced arterial thrombosis by changing the gut microbial composition and reducing TMAO generation.

Berberine Alleviates Non-alcoholic Steatohepatitis Through Modulating Gut Microbiota Mediated Intestinal FXR Activation.

Berberine is a natural plant alkaloid isolated from a diverse range of genera, it obtains anti-inflammatory, anti-obesity, and hepatoprotective properties, and is a promising agent for non-alcoholic steatohepatitis (NASH). Farnesoid X receptor (FXR) is a bile acid receptor and a drug target for NASH, however, the underlying mechanisms of berberine on regulating FXR are still unknown. In the present study, we feed mice with a 12-week high-fat diet with interval dextran sulfate sodium (0.5% in drinking water) diet to induce NASH, and treat the mice with berberine (100 mg/kg per day) via oral gavage for additional 4 weeks. We demonstrate that administration of berberine alleviates steatosis and infiltration of inflammatory cells in the liver of NASH mice. We apply 16S ribosomal DNA sequencing to screen the structure of gut microbiota, and ultra-performance liquid chromatography-tandem mass spectrometry analysis to determine the bile acid profiles. The results show that berberine modulates gut dysbiosis, and specifically increases the relative abundance of Clostridiales, Lactobacillaceae, and Bacteroidale. Berberine modulated microbiomes are associated with bile acid de-conjugation and transformation, which are consistent with the altered bile acid species (e.g., deoxycholic acid, ursodeoxycholic acid) upon berberine treatment. BA species that respond to berberine treatment are known FXR agonists, thus we performed quantitative Real Time-PCR and western blot to examine the FXR pathway, and find that berberine up-regulates intestinal FXR and fibroblast growth factor 15 (FGF15) expression, and the secretion of FGF15 further inhibits lipogenesis and nuclear factor-κB activation in the liver. Whereas the beneficial effects of berberine are blunted in FXR knockout mice. Our results reveal that berberine alleviates NASH by modulating the interplay of gut microbiota and bile acid metabolism, as well as the subsequent intestinal FXR activation.

Berberine Attenuates Neonatal Sepsis in Mice By Inhibiting FOXA1 and NF-κB Signal Transduction Via the Induction of MiR-132-3p.

Neonatal sepsis (NS) is a severe syndrome in newborns that is induced by infections, and the initiation and development of NS are closely associated with the function of miRs. In the current study, the effects of berberine, which is a functional component in traditional Chinese medicine (TCM), against NS were assessed by focusing on the interaction of berberine with miR-132-3p-mediated signaling. An NS model was induced using cecal slurry (CS) in vivo and LPS in vitro, and berberine treatment was applies. The changes in survival rate, intestinal structure, and systemic inflammation in mice and the viability, apoptosis, and inflammatory response in intestinal cells were measured. At the molecular level, miR-132-3p levels and the activities of the FOXA1 and NF-κB pathways were analyzed. The data showed that berberine increased the survival rates of CS-induced mice. The intestinal injuries induced by CS were also attenuated by berberine, which was associated with inhibition of the production of systemic IL-6, IL-1β, and TNF-α. At the molecular level, the expression of miR-132-3p was upregulated, suppressing the expression of FOXA1, p-IκBα, and p65 while inducing the expression of IκBα. The effects of berberine on NS-induced impairments were blocked by the injection of the miR-132-3p antagomir, which exacerbated intestinal injuries, induced systemic inflammation, and reactivated the FOXA1 and NF-κB pathways. The findings in the in vivo model were validated with in vitro assays. Collectively, the findings outlined in the current study indicated that berberine had solid protective effects against NS-induced symptoms in newborn mice, and the effects depended on the upregulation of miR-132-3p.

Utilizing Network Pharmacology to Explore the Possible Mechanism of Coptidis Rhizoma in Kawasaki Disease.

Background: The purpose of the research is to identify the main active ingredients in Coptidis Rhizoma (CR) and explore the possible molecular mechanisms in the treatment of Kawasaki disease (KD).Materials and Methods: A total of 58 children with KD were randomly divided into a control group and a Berberine treatment group. The therapeutic indicators of the two groups before and after treatment were compared. Then, compounds and drug targets of CR from the TCMSP, SWISS, SEA, and the STITCH were collected, and targeted KD genes were retrieved from the DisGeNET, DrugBank, and GeneCards databases. The network pharmacology approach involved network construction, target prediction, and module analysis. GO and KEGG enrichment analysis were performed to investigate the possible pathways related to CR for KD treatments. Finally, protein expression was determined to verify the core targets using Western blotting in the cell experiment.Results: In total, nine compounds, 369 relative drug targets, and 624 KD target genes were collected in the above database. The network analysis revealed that 41 targets might be the therapeutic targets of CR on KD. GO and KEGG enrichment analysis revealed that the biological processes, namely, response to hormone, response to inorganic substance, and enzyme-linked receptor protein signaling pathway, and Pathways in cancer, Toll-like receptor signaling pathway, and Pancreatic cancer are the most significant. Protein expression of CASP3, PTGS2, and SRC was upregulated and AKT1 and ERK were downregulated.Conclusion: We provided useful resources to understand the molecular mechanism and the potential targets for novel therapy of KD.