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[Display omitted] Berberine (Ber), an isoquinoline alkaloid, is a potential drug therapy for ulcerative colitis (UC) because of its anti-inflammatory activity, high biological safety, and few side effects. Nevertheless, its clinical application is hindered by its limited water solubility and low bioavailability. Currently, compared to synthetic nanocarriers, exosomes as carriers possess advantages such as low toxicity, high stability, and high specificity. Human placental mesenchymal stem cell-derived exosomes (HplMSC-Exos) have emerged as a promising drug delivery system, offering intrinsic anti-inflammatory and antioxidant activities. Therefore, we engineered MSC-Exos loaded with Ber (Exos-Ber) to enhance the solubility and bioavailability of Ber and for colon targeting, revealing a novel approach for treating UC with natural compounds. Structurally and functionally, Exos-Ber closely resembled unmodified Exos. Both in vitro and in vivo investigations confirmed the antioxidant and anti-inflammatory properties of Exos-Ber. Notably, Exos-Ber exhibited reparative effects on injured epithelial cells and reduced cellular apoptosis. Furthermore, Exos-Ber concurrently demonstrated anti-inflammatory and antioxidant activities, contributing to the mitigation of UC, possibly through its modulation of the MAPK signaling pathway. Overall, our findings demonstrate the potential of Exos-Ber as a promising therapeutic option for alleviating UC, highlighting its capacity to enhance the clinical applicability of Ber. [ABSTRACT FROM AUTHOR]

Glioma is a clinically heterogeneous disease with a poor prognosis. Berberine (BBR), as a multi-target anti-tumor alkaloid, has the ability to penetrate the blood-brain barrier and shows cytotoxicity to glioma cells. In previous studies, we demonstrated that berberine inhibits glioma cell proliferation by inhibiting mutant p53 protein and promoting mitochondrial damage. In addition, berberine has been shown to reduce collagen accumulation in pulmonary fibrosis, diabetic nephropathy and arthritis. However, its effect on collagen in cancer needs to be further elucidated. In this study, we proved that the collagen XI alpha 1 chain (COL11A1) is highly expressed in glioma cell lines and associated with migration and invasion of glioma cells. Knocking down COL11A1 caused decreased expression of MMPs. Berberine could inhibit the migration and invasion of glioma cells by suppressing the TGF-β1/COL11A1 pathway and changes actin cytoskeleton arrangement. Nude mouse subcutaneous xenografts model also showed that berberine inhibited the expression of COL11A1 in vivo. Collectively, berberine that targets COL11A1 to inhibit glioma migration and invasion, may serve as a promising candidate for the development of anti-glioma drugs in the future. • COL11A1 is highly expressed in glioma. • Knocking down COL11A1 gene inhibits the migration and invasion of glioma cells. • Berberine inhibits the migration and invasion of glioma cells by inhibiting the TGF-β1/COL11A1 pathway. • Berberine is an effective drug targeting COL11A1 for the treatment of glioma. [ABSTRACT FROM AUTHOR]

Cardiovascular disease caused by atherosclerosis is a leading cause of morbidity and mortality worldwide. Diabetes is a major independent risk factor for the development of atherosclerotic cardiovascular diseases. Diabetic atherosclerosis is characterized by hyperglycemia, hyperinsulinemia, and dyslipidemia. These multiple pathological factors can induce oxidative stress, inflammation, and vascular dysfunction, which can initiate and accelerate atherogenesis. Therefore, the strategy to control the development of diabetic atherosclerosis is beneficial to the patients. Berberine is one of the most promising natural products that feature significant beneficial properties on lipid and glucose metabolism, indicating the potential to improve diabetic atherosclerosis. However, the effect and underlying mechanism against diabetic atherosclerosis remain unclear. In this study, HFD and STZ were used to induce diabetic atherosclerosis in apoE−/− mice, which was followed by berberine administration. Subsequently, the degree of atherosclerotic plaque, plaque stability, and lipid and glucose metabolism were determined. In addition, the underlying mechanism was revealed by in vitro and in vivo experiments. We observed that berberine improved the dysfunction of lipid and glucose metabolism, and inhibited vascular inflammation, which reduced atherogenesis and plaque vulnerability. Mechanistically, berberine stimulated KLF16 and PPARα expression in vivo and in vitro , and activation of PPARα by berberine was through enhancing KLF16 expression and nuclear translocation. Collectively, berberine can attenuate diabetic atherosclerosis via enhancing the interplay between KLF16 and PPARα, suggesting that KLF16 is a new target of berberine and enhancing KLF16 by berberine is an efficient strategy for alleviating diabetic atherosclerosis. [Display omitted] • Berberine reduces diabetic atherosclerotic lesion and plaque vulnerability in apoE−/− mice. • Berberine attenuates foam cell formation and endothelium activation by improving lipid and glucose dysfunction. • Berberine enhances the interplay between KLF16 and PPARα. [ABSTRACT FROM AUTHOR]

Berberine (BBR) is a traditional Chinese herb with broad antimicrobial activity. Gut microbiota plays an important role in the metabolism of bile acids and cholesterol. Our study investigated the effects of BBR on alleviating cholesterol and bile acid metabolism disorders induced by high cholesterol diet in mice. Adult male C57BL/6J mice fed with high cholesterol diet (HC) containing 1.25 % cholesterol (HC group) or fed with chow diet containing 0.02 % cholesterol (Chow group) served as controls. BBR50 and BBR100 group mice were fed with HC, and oral BBR daily at doses of 50 or 100 mg/kg respectively for 8 weeks. The results showed that BBR could reshape the homeostasis and composition of gut microbiota. The abundance of Clostridium genera was significantly inhibited by BBR, which resulted in a significant reduction of secondary bile acids within the enterohepatic circulation and a significant lower hydrophobic index of bile acids. The absorption of cholesterol in intestine, the deposition of cholesterol in liver and the excretion of cholesterol in biliary tract were significantly inhibited by BBR, which promoted the unsaturation of cholesterol in bile. These findings suggest the potential utility of BBR as a functional food to alleviate the negative effects of high cholesterol diet. • Berberine rebuilds the homeostasis of gut microbiota in high cholesterol diet fed mice. • Berberine inhibits Clostridium genera, resulting in less secondary bile acids. • Lower bile acid hydrophobicity inhibits intestinal cholesterol absorption. • Reduced cholesterol excretion of liver results in lower cholesterol saturation of bile. [ABSTRACT FROM AUTHOR]

Berberrubine (BRB), a main metabolite of berberine, has stronger hypoglycemic and lipid-lowering activity than its parent form. We previously found that BRB could cause obvious nephrotoxicity, but the molecular mechanism involved remains unknown. In this study, we systematically integrated metabolomics and quantitative proteomics to reveal the potential mechanism of nephrotoxicity caused by BRB. Metabolomic analysis revealed that 103 significant— differentially metabolites were changed. Among the mentioned compounds, significantly upregulated metabolites were observed for phosphorylcholine, sn-glycerol-3-phosphoethanolamine, and phosphatidylcholine. The top three enriched KEGG pathways were the mTOR signaling pathway, central carbon metabolism in cancer, and choline metabolism in cancer. ERK1/2 plays key roles in all three metabolic pathways. To further confirm the main signaling pathways involved, a proteomic analysis was conducted to screen for key proteins (such as Mapk1, Mapk14, and Caspase), indicating the potential involvement of cellular growth and apoptosis. Moreover, combined metabolomics and proteomics analyses revealed the participation of ERK1/2 in multiple metabolic pathways. These findings indicated that ERK1/2 regulated the significant— differentially abundant metabolites determined via metabolomics analysis. Notably, through a cellular thermal shift assay (CETSA) and molecular docking, ERK1/2 were revealed to be the direct binding target involved in BRB-induced nephrotoxicity. To summarize, this study sheds light on the understanding of severe nephrotoxicity caused by BRB and provides scientific basis for its safe use and rational development. [Display omitted] • Berberrubine caused severe nephrotoxicity. • Integrated metabolomics and proteomics revealed main pathways of nephrotoxicity. • ERK1/2 may be a direct binding protein of berberrubine. [ABSTRACT FROM AUTHOR]

Singapore grouper iridovirus (SGIV) is one of the major infectious diseases responsible for high mortality and huge economic losses in the grouper aquaculture industry. Berberine (BBR), a naturally occurring plant alkaloid, is a phytochemical having a variety of biological properties, such as antiviral, antioxidant, and anti-inflammatory effects. In this work, we used an in vitro model based on Western blot, ROS fluorescence probe, and real-time quantitative PCR (qRT-PCR) to examine the antiviral qualities of BBR against SGIV. The outcomes demonstrated that varying BBR concentrations could significantly inhibit the replication of SGIV. In addition, BBR greatly inhibited the production of genes associated with pro-inflammatory cytokines in SGIV-infected or SGIV-uninfected GS cells based on qRT-PCR data. Subsequent investigations demonstrated that BBR suppressed the expression of the promoter activity of NF-κB and NF-κB-p65 protein. Additionally, BBR reduced the phosphorylation of ERK 1/2, JNK, and p38. Furthermore, BBR also inhibits SGIV-induced ROS production by upregulating the expression of antioxidant-related genes. In conclusion, BBR is a viable therapy option for SGIV infection due to its antiviral properties. • BBR significantly inhibited SGIV replication in vitro. • BBR inhibits SGIV-induced inflammatory responses by suppressing NF-κB and MAPK signaling pathways. • BBR inhibits SGIV-induced ROS production by upregulating the expression of antioxidant-related genes. [ABSTRACT FROM AUTHOR]

Pirarubicin (THP) is a new generation of cell cycle non-specific anthracycline-based anticancer drug. In the clinic, THP and THP combination therapies have been shown to be effective in hepatocellular carcinoma (HCC) patients with transcatheter arterial chemoembolization (TACE) without serious side effects. However, drug resistance limits its therapeutic efficacy. Berberine (BBR), an isoquinoline alkaloid, has been shown to possess antitumour properties against various malignancies. However, the synergistic effect of BBR and THP in the treatment of HCC is unknown. In the present study, we demonstrated for the first time that BBR sensitized HCC cells to THP, including enhancing THP-induced growth inhibition and apoptosis of HCC cells. Moreover, we found that BBR sensitized THP by reducing the expression of autophagy-related 4B (ATG4B). Mechanistically, the inhibition of HIF1α-mediated ATG4B transcription by BBR ultimately led to attenuation of THP-induced cytoprotective autophagy, accompanied by enhanced growth inhibition and apoptosis in THP-treated HCC cells. Tumor-bearing experiments in nude mice showed that the combination treatment with BBR and THP significantly suppressed the growth of HCC xenografts. These results reveal that BBR is able to strengthen the killing effect of THP on HCC cells by repressing the ATG4B-autophagy pathway, which may provide novel insights into the improvement of chemotherapeutic efficacy of THP, and may be conducive to the further clinical application of THP in HCC treatment. • THP induces protective autophagy in HCC cells by upregulating ATG4B. • BBR attenuates THP-induced ATG4B and autophagy. • BBR sensitizes THP by inhibiting HIF1α-ATG4B-autophagy pathway. • BBR and THP synergistically repress HCC xenograft growth in nude mice. [ABSTRACT FROM AUTHOR]

Citrus sour rot is a common postharvest citrus disease caused by Geotrichum citri-aurantiiti , which has led to enormous economic losses, particularly during rainy seasons. In this study, we aimed to clarify the impact of berberine hydrochloride (BH), the hydrochloride form of an isoquinoline alkaloid, on the control efficiency of citrus sour rot and its antifungal mode against G. citri-aurantii. Results demonstrated that BH markedly impede the propagation of G. citri-aurantii by delaying the spores development from dormant stage into swollen and germinating stages, with the MIC and MFC value of 0.08 and 0.16 g L−1, respectively. When the artificially inoculated citrus fruit in control group were totally rotted, the disease incidence of BH-treated groups decreased by 35.00%–73.30%, which effectively delayed the disease progression and almost did not negatively affect fruit quality. SEM observation, CFW and PI staining images revealed that BH caused significant damage to both the cell membrane and cell wall of G. citri-aurantii spores, whereas only the cell membrane of the mycelium was affected. The impact of cell wall was related to the block of chitin and β-1,3-glucan synthesis. Transcriptome results and further verification proved that 0.5 × MIC BH treatment affected the glycolysis pathway and TCA cycle mainly by inhibiting the production of acetyl-CoA and pyruvate. Subsequently, the activities of key enzymes declined, resulting in a further decrease in ATP levels, ultimately inhibiting the germination of spores. In conlusion, BH delays citrus sour rot mainly by disrupting carbohydrate and energy metabolism of G. citri-aurantii spores. [Display omitted] • BH effectively delayed the occurrence of citrus sour rot. • BH affected the propagation of G. citri-aurantii by delaying the development of dormant spores. • BH displayed distinct targets for the mycelia and spores of G. citri-aurantii. • BH inhibited the cell wall elongation of spores by blocking the synthesis of chitin and β-1,3-glucan. • BH disturbed carbohydrate and energy metabolism of G. citri-aurantii spores. [ABSTRACT FROM AUTHOR]

The incidence of contrast-induced acute kidney injury (CI-AKI) has escalated to become the third most prevalent cause of hospital-acquired AKI, with a lack of efficacious interventions. Berberine (BBR) possesses diverse pharmacological effects and exhibits renoprotective properties; however, limited knowledge exists regarding its impact on CI-AKI. Therefore, our study aimed to investigate the protective effects and underlying mechanisms of BBR on CI-AKI in a mice model, focusing on the nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3) inflammasome and mitophagy. The CI-AKI mice model was established by administering NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg), indomethacin (10 mg/kg), and iohexol (11 g/kg) following water deprivation. A pretreatment of 100 mg/kg of BBR was orally administered to the mice for two weeks. Renal injury markers, damage-associated molecular patterns (DAMPs), renal histopathology, mitochondrial morphology, autophagosomes, and potential mechanisms were investigated. BBR effectively reduced levels of renal injury biomarkers such as serum cystatin C, urea nitrogen, and creatinine, downregulated the protein level of kidney injury molecule 1 (KIM1), and mitigated renal histomorphological damage. Moreover, BBR reduced DAMPs, including high mobility group box-1 (HMGB1), heat shock protein 70 (HSP70), and uric acid (UA). It also alleviated oxidative stress and inflammatory factors such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β). Furthermore, the activation of NLRP3 inflammasome was attenuated in the BBR pretreatment group, as evidenced by both mRNA and protein levels. Electron microscopy and western blotting examination revealed that BBR mitigated mitochondrial damage and enhanced mitophagy. Additionally, BBR increased the P-AMPK/AMPK ratio. These findings indicated that BBR exerted a protective effect against CI-AKI by suppressing NLRP3 inflammasome activation and modulating mitophagy, providing a potential therapeutic strategy for its prevention. [Display omitted] • Berberine alleviated contrast-induced acute kidney injury in mouse. • Berberine reduced DAMPs, oxidative stress and inflammation. • Berberine limited the NLRP3 inflammasome activation by up-regulating mitophagy. [ABSTRACT FROM AUTHOR]

Berberine hydrochloride (BBR) is efficacious in relieving alcoholic liver injury (ALI) in animal models, but its underlying mechanisms remains largely unclear. In the study, the rats were divided into control group, model group, model with BBR group, and control with BBR group, and given corresponding treatment for 4 weeks. RNA-Seq, ELISA and RT-PCR were performed to explore the potential mechanisms of BBR in ALI. Treatment of rats with BBR (200 mg/kg/d, gavage, once daily) over 4 weeks diminished 4 g/kg/d alcohol-induced inflammation and lipid deposition. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in BBR-treated rats. Hepatic gene expression profile detected that BBR suppressed ethanol-stimulated overexpression of thyroid hormone responsive gene-THRSP. And overexpression of THRSP-responsive genes (fatty acid synthase-FASN, adenosine monophosphate activated protein kinase α-AMPK-α, acetyl-CoA carboxylase-ACC, ATP-citrate lyase-ACLY) responsible for fatty acid synthesis was also downregulated by BBR. Additionally, BBR downregulated expression of cluster of differentiation 36-CD36 and upregulated expression of peroxisome proliferator-activated receptor α (PPARα) and its target genes (carnitine palmitoyltransferase 1 α-CPT1α and acyl-CoA oxidase 1-ACOX1). Meanwhile, BBR treatment suppressed systemic inflammation by mediating a reduction in IL-10, TNF-α, LPS, and ET, but elevated IL-6. The results indicated that BBR alleviated alcoholism-induced hepatic injury by suppressing inflammation (IL-10, TNF-α, LPS, ET and IL-6), and regulating fatty acids uptake (CD36), lipid synthesis (THRSP, FASN, AMPK-α, ACC, ACLY) and lipid oxidation (PPARα, CPT1α, ACOX1), and THRSP may be its novel target. • Overexpression of THRSP in ALD was found for the first time. • BBR suppressed THRSP and its related genes expression involved in lipid synthesis. • BBR suppressed expression of lipid metabolism-related genes. • BBR attenuated ALD by regulating inflammation and lipid metabolism disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] Isoquinoline alkaloids are an important class of natural products that are abundant in the plant kingdom and exhibit a wide range of structural diversity and biological activities. With the deepening of research in recent years, more and more isoquinoline alkaloids have been isolated and identified and proved to contain a variety of biological activities and pharmacological effects. In this review, we introduce the research progress of isoquinoline alkaloids from 2019 to 2022, mainly in the part of biological activities, including antitumor, antimicrobial, antidiabetic, antiviral, anti-inflammatory, antioxidant, neuroprotective, hepatoprotective, analgesic, and other activities. This study provides a clear direction for the rational development and utilization of isoquinoline alkaloids, suggesting that these alkaloids have great potential in the field of drug research. [ABSTRACT FROM AUTHOR]

Berberine, isolated from Coptis chinensis and Phellodendron amurense , can attenuate colonic injury and modulate gut microbiota disorders in ulcerative colitis (UC). However, the mechanism and causal relationship between gut microbiota and the efficacy of Berberine on UC are still unclear, which were investigated by pseudo-germ-free (PGF) mice, 16S rRNA gene analysis and transcriptome analysis in this study. The results demonstrated that Berberine improved gut microbiota disorders, colon damage, tight-junction proteins, inflammatory and anti-inflammatory cytokines in DSS-induced colitis mice with intact gut microbiota but not in PGF mice. Besides, immune-related and inflammation-related pathways were closely related to the efficacy that Berberine alleviated colitis by regulating gut microbiota. Furthermore, Berberine reduced PGE2, PLA2, COX-2, Ptges, EP2 and p-Stat3 only in colitis mice with intact gut microbiota. In summary, our study confirms that Berberine inhibits PLA2-COX-2-PGE2-EP2 pathway in UC through gut microbiota, leading to the alleviation of inflammation in colon, which further elucidates the underlying mechanism and promotes the application of Berberine in UC. [Display omitted] • The efficacy of Berberine on UC relies on gut microbiota. • Berberine reduces PGE2 and inflammation in UC through gut microbiota. • Berberine inhibits PLA2-COX-2-PGE2-EP2 pathway in UC via gut microbiota. • Apply 16S rRNA gene and transcriptome analysis and pseudo-germ-free mice. [ABSTRACT FROM AUTHOR]

Photodynamic sterilization has been regarded as a promising alternative to conventional antibacterial approaches. However, the photodynamic efficiency of conventional photosensitizer is often compromised by aggregation-induced quenching effects. Photosensitizers, especially natural products, with aggregation-induced emission (AIE) properties open a new avenue for photodynamic sterilization. Herein, we investigated the photodynamic antibacterial performance and mechanism of the AIE-type natural product of berberine (BBR) against Listeria monocytogenes (L. monocytogenes). The bactericidal effect was assessed through the determination of minimum bactericidal concentration and implementation of anti -biofilm experiments. The results showed that BBR can significantly suppress the proliferation of L. monocytogenes and can efficiently remove the L. monocytogenes -derived biofilm in a concentration-dependent trend. The mechanism of killing L. monocytogenes has been speculated based on bacterial morphology characterization, viability staining results, enzyme activity assays, DNA electrophoresis analysis, and molecular docking. The excellent anti-bacterial activity of BBR mediated photodynamic process may account for its abilities to the irreversibly disruption of bacterial membrane, inhibition of intracellular enzyme activity and decomposition of intracellular DNA molecules. We also demonstrated that BBR embedded sodium alginate/chitosan packaging film is feasible to maintain the freshness of salmon under light illumination by inhibiting the bacterial proliferation. • An AIE-type natural photosensitizer berberine was reported for photodynamic bacteriostasis. • The AIE photosensitizer can inhibit the proliferation of L. monocytogenes and remove biofilms. • The photodynamic antibacterial properties and mechanisms were investigated. • Berberine embedded sodium alginate/chitosan packaging film was developed for improving salmon preservation. [ABSTRACT FROM AUTHOR]

Berberine is a natural isoquinoline alkaloid present in various herbs and is effective against metabolic syndrome in the pre-diabetic stage and high insulin resistance. The present study aimed to determine the effectiveness of WJCPR11, a berberine derivative that is commonly used for diabetes treatment, in ameliorating insulin resistance and diabetes treatment. WJCPR11 promoted adipocyte differentiation to a higher extent than other berberine derivatives and showed no noticeable toxicity in its effective concentration range. It increased the mRNA expression levels and protein abundance of adipogenic markers, including peroxisome proliferator-activated receptor γ (PPARγ), glucose transporter type 4 (GluT4), and fatty acid synthase (FAS), and markedly enhanced the level of adiponectin, a distinct marker of insulin sensitivity. Meanwhile, the mRNA levels of inflammatory markers such as plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6 (IL-6) were reduced after WJCPR11 treatment. Furthermore, the tumor necrosis factor-α (TNF-α)-induced inhibition of adipocyte differentiation and downregulation of glucose uptake were markedly reversed by WJCPR11 treatment. Collectively, the findings of this study indicate that WJCPR11 has great potential for diabetes treatment. • WJCPR11 promotes the adipocyte differentiation of OP9 cells. • WJCPR11 reverses the TNF-α-induced inhibition of adipocyte differentiation. • WJCPR11 upregulates glucose uptake in insulin-stimulated OP9 cells. [ABSTRACT FROM AUTHOR]

Berberine is a natural isoquinoline alkaloid performing wide-spectrum antimicrobial and antiviral effects like antibiotics. Its production generates berberine containing wastewater, and berberine adsorbed on waste activated sludge (WAS) will unavoidably enter the anaerobic digestion (AD) system while its impact on the AD process is unknown. Our research found that berberine of 20 mg/L (BBR20) slightly enhanced the methane yield (4.2 ± 0.6%) under mesophilic condition (35.0 ± 1.0 °C). However, 100 and 500 mg/L (BBR100 and BBR500) depressed methane production by 17.3 ± 4.3% and 83.2 ± 0.4%; meanwhile more soluble chemical oxygen demand (SCOD) including volatile fatty acid (VFA), protein, and polysaccharide were left in the fermentation broth, which led to an increase in sludge reduction. 88.3 ± 0.09%–99.1 ± 0.04% of berberine was distributed in the sludge phase and could be efficiently removed even under a high berberine level of 500 mg/L during the AD process. Exposure to different berberine concentrations promoted sludge dissolution and triggered more sludge extracellular polymeric substances (EPS) being dissolved. Lower berberine concentration (20 mg/L) enhanced acidification and methanogenesis steps, resulting in a final methane generation increase. While hydrolysis, acidification and methanogenesis processes were all inhibited by 100 and 500 mg/L berberine. Microbial analysis revealed that the main acid-producing bacteria genera were changed as Bacteroidetes vadinHA17 dominated in control, BBR20 and BBR100 groups, was replaced by Petrimonas in BBR500. Additionally, Methanosaeta, as a strict acetoclastic methanogen, was suppressed under exposure to 100 and 500 mg/L berberine. Accordingly, the declined abundance of archaea genera consuming acetic acid caused more VFA accumulation and less methane production in BBR100 and BBR500 groups. [Display omitted] • 20 mg/L berberine slightly rose CH 4 yield, while 100 and 500 mg/L inhibited seriously. • AD process was effective in removing berberine even at high concentration of 500 mg/L. • Berberine promoted sludge dissolution and triggered more sludge EPS being dissolved. • High concentration of berberine altered the keystone acid-producing bacteria genus. • Abundance of archaea genera using VFA was suppressed by 100 and 500 mg/L berberine. [ABSTRACT FROM AUTHOR]

[Display omitted] • C-3 and C-9 fluoroalkoxylated analogues of (S)-12-bromo-stepholidine were prepared. • The analogues were assayed for D1R activity in functional assays. • Compound 13a was found to be a new D1R antagonist in both cAMP-based and β-arrestin-based assays. • Compound 13a is selective for D1R over other dopamine receptors. To illuminate the tolerance of fluoroalkoxylated groups at the C-3 and C-9 positions of tetrahydroprotoberberines (THPBs) on D1R activity, C-3 and C-9 fluoroalkoxylated analogues of (S)-12-bromostepholidine were prepared and evaluated. All compounds examined were D1R antagonists as measured by a cAMP assay. Our structure–activity studies herein indicate that the C-3 position tolerates a 1,1-difluoroethoxy substituent for D1R antagonist activity. Compound 13a was the most potent cAMP-based D1R antagonist identified and was also found to antagonize β-arrestin translocation in a TANGO assay. Affinity assessments at other dopamine receptors revealed that 13a is selective for D1R and unlike other naturally-occurring THPBs such as (S)-stepholidine, lacks D2R affinity. In preliminary biopharmaceutical assays, excellent BBB permeation was observed for 13a. Further pharmacological studies are warranted on (S)-stepholidine congeners to harvest their potential as a source of novel, druggable D1R-targeted agents. [ABSTRACT FROM AUTHOR]

Acute pneumonia induced by Pseudomonas aeruginosa is characterized by massive infiltration of inflammatory cell and the production of reactive oxygen species (ROS), which lead to severe and transient pulmonary inflammation and acute lung injury. However, P.aeruginosa infection is resistant to multiple antibiotics and causes high mortality in clinic, the search for alternative prophylactic and therapeutic strategies is imperative. This study was aimed to investigate the anti-inflammatory and antioxidant effects of DMB, a novel derivative of berberine, and explore the role of AIM2 inflammasome in P. aeruginosa -induced acute pneumonia. Acute pneumonia mice were established by tracheal injection of P. aeruginosa suspension. Pathological changes of lung tissue were observed by its appearance and H&E staining. The lung coefficient ratio was measured to evaluate pulmonary edema. Inflammatory factors were detected by qRT-PCR, western blotting and immunohistochemistry. ROS and other indicators of oxidative damage were analyzed by flow cytometry and specific kit. Proteins related to AIM2 inflammasome were detected by western blotting. Compared with the P. aeruginosa -induced group, DMB ameliorated pulmonary edema, hyperemia, and pathological damage based on its appearance and H&E staining in DMB groups. First, DMB attenuated the inflammatory response induced by P.aeruginosa. Compared with the P. aeruginosa -induced group, the lung coefficient ratio was decreased by 31.5%, the MPO activity of lung tissue was decreased by 44.0%, the mRNA expression levels of TNF-α, IL-1β and IL-6 were decreased by 64.8%, 51.2% and 64.0% respectively, and those protein expression levels were decreased by 40.1%, 42.8% and 47.8% respectively, and the number of white blood cells, neutrophils and monocytes were decreased by 53.5%, 29.4% and 13.7% in high dose (200 mg/kg) DMB group. Second, DMB alleviates oxidative stress in the lung tissue during P. aeruginosa -induced acute pneumonia. Compared with the P. aeruginosa -induced group, the level of GSH was increased by 42.5% and MDA was decreased by 49.5% in high dose DMB group. Moreover, the western blotting results showed that DMB markedly suppressed the expression of AIM2, ASC, Cleaved caspase1 and decreased the secretion of IL-1β. Additionally, these results were also confirmed by in vitro experiments using MH-S and BEAS-2B cell lines. Taken together, these results indicated that DMB ameliorates P. aeruginosa -induced acute pneumonia through anti-inflammatory, antioxidant effects, and inhibition of AIM2 inflammasome activation. [ABSTRACT FROM AUTHOR]

Obesity has become a global health issue, which can cause metabolic abnormalities systemically leading to increased morbidity of series diseases. At present, researches have presented obesity is a high-risk factor for colitis, and berberine shows positive therapeutic effect on colitis. Thus, we explored the beneficial effects and potential mechanisms of berberine on obesity-exacerbated colitis in this article. High-fat diet (HFD) exacerbated dextran sulfate sodium (DSS) induced colitis mice model was applied, the results showed that HFD promoted DSS-induced weight loss and inflammatory manifestations in intestine. The results of cytokines in serum and mRNA expression of inflammatory indicators in colon showed that HFD increased all their levels evidently, and the outcomes of Western blot analyses presented that HFD downregulated the MFN2 expression, inhibited the phosphorylation of AMPK as well as upregulated the BIP/Grp78 expression, while berberine could significantly reverse all these situations. In vitro , we stimulated Caco-2 cells with palmitic acid (PA) to replicate the lipotoxicity damage in the intestine, and the results presented that intervention therapy of berberine effectively enhanced the MFN2 expression, inhibited the mRNA levels of inflammatory factors, and reversed the PA induced protein level changes of AMPK and BIP/Grp78. In general, we proposed that berberine could regulate MFN2 to alleviate obesity exacerbated colitis. • High fat diet can promote DSS-induced experimental colitis. • MFN2 is at the crossroad of endoplasmic reticulum stress and energy metabolism. • Berberine can regulate MFN2 to alleviate obesity exacerbated colitis. [ABSTRACT FROM AUTHOR]

We investigated the novel molecular mechanisms of the antitumor effect of berberine. In this study, two different human cell lines (breast cancer MCF7 cells and non-tumorigenic epithelial MCF12A cells) were treated with various concentrations of berberine. Treatment with 1 and 10 μM berberine inhibited proliferation with G 0 /G 1 cell cycle arrest in both cell lines, and treatment with 100 μM berberine triggered a marked level of cell death in MCF7 cells but not in MCF12A cells. Berberine increased the level of p53 protein and of its target p21 both time- and dose-dependently in MCF7 cells. At any concentration of berberine, immediate uptake (within 15 min) followed by predominantly mitochondrial accumulation were observed by confocal microscopy in both cell lines. At high concentrations (10 or 100 μM), accumulation in the nucleolus became prominent after the transition to the nucleoplasm, especially remarkable in MCF7 cells. Therefore, we evaluated the possibility of berberine-induced nucleolar stress and observed the disappearance of ribosomal protein (RP)L5 from the nucleolus and accumulation of p53 protein in the nucleus after treatment with 10 or 100 μM berberine in MCF7 cells. We also detected the accumulation of RPL5 and RPL11 in the nucleoplasm fraction where they bind to Mdm2. Moreover, downregulation of RPL5 inhibited berberine-driven induction of p53 and p21 and cell death in MCF7 cells. Whereas, in MCF12A cells, down-regulation of RPL5 had little effect on the growth inhibitory effect of high concentration of berberine. These results indicated that cell growth inhibition and cell death induced by higher doses (>10 μM) of berberine in MCF7 cells were due to the upregulation of p53 under the nucleolar stress response caused by a significant accumulation of berberine in the nucleoli. • At high doses (>10 μM), berberine accumulates in the nucleolus of MCF7 cells. • High doses of berberine induce upregulation of p53 under nucleolar stress response. • High doses of berberine do not induce nucleolar stress response in MCF12A cells. [ABSTRACT FROM AUTHOR]

The study investigated whether dietary berberine supplementation could improve intestinal barrier against inflammation induced by high-fat and high-carbohydrate diets in blunt snout bream. Fish (average initial weight 44.83 ± 0.06 g) were fed with six kinds of diets (control, high-fat diet (10% lipid) and high-carbohydrate (43% nitrogen-free extract) diet, control/berberine, high-fat/berberine or high-carbohydrate/berberine) for 8 weeks, respectively. Feeding mode of berberine (50 mg/kg diet) was adopted to two-week interval. After feeding trial, fish growth performance and intestinal barrier function were estimated. The result showed that no significant interactions between diet and berberine in growth performance, whole body composition or protein utilization were observed (P > 0.05). Specific growth rate (SGR) and feed conversion ratio (FCR) were significantly affected by berberine (P < 0.05). Protein efficiency ratio (PER), nitrogen retention (NRE), fish whole-body lipid contents increased greatly in high-fat or high-carbohydrate diets (P < 0.05). Significant interactions between diet and berberine were observed in fish intestinal barrier (physical, chemical, immunological and microbiological barriers) (P < 0.05). High-fat and high-carbohydrate diets could increase significantly intestinal permeability and inflammatory response, decrease intestinal mucins gene expression levels, and make the intestinal microbiota out of balance (P < 0.05). Berberine significantly inhibited inflammation response and modulated intestinal microflora profile (P < 0.05). Taken together, berberine could alleviate intestinal barrier damage injured by high-fat or high-carbohydrate diet and improve the growth performance of blunt snout bream. • Dietary berberine supplementation at two-week interval feeding mode could protect intestinal barrier damage induced by high-fat diet and high-carbohydrate diet. [ABSTRACT FROM AUTHOR]

Berberine is an essential phytochemical for the treatment of various diseases; however, when used to treat osteoporosis, it has minor effect as compared with that of the currently available drugs. This study aimed to find a new compound that would have a better anti-osteoporotic effect than that of berberine. Based on structure and activity relationship study, we identified compound 2c, a berberine derivative, to be the most potent compound to affect osteoblast differentiation. Compound 2c was more effective than berberine and exhibited no toxicity within its effective concentration. Compound 2c increased, in a dose-dependent manner, ALP activity during osteoblast differentiation and enhanced the mRNA expression of osteogenic factors including ALP, Runx2, and Osterix. Furthermore, compound 2c increased the transcriptional activity induced by BMP4 on the ALP and BSP promoter. Taken together, compound 2c shows promise as a therapeutic agent for osteoporosis by promoting osteoblast differentiation. • Among the various berberine derivatives, compound 2c has the highest ALP activity during osteoblast differentiation. • Compound 2c dose-dependently enhances ALP activity during osteoblast differentiation and has no cytotoxicity. • Compound 2c stimulates osteogenic genes and transcriptional activity during osteoblast differentiation. [ABSTRACT FROM AUTHOR]

Berberine (BBR), a natural isoquinoline alkaloid, has been shown to be a promising therapeutic agent for colorectal cancer (CRC), but the molecular mechanism remains unclear. Here, we used mass spectrometry-based label-free proteomics to explore the potential targets of BBR in CRC cells. Comprehensive proteomic profiles demonstrated that of 8051 identified proteins, 503 and 277 differentially expressed proteins (DEPs) were screened out of CACO2 and LOVO cells, respectively. 83 DEPs were overlapped and most of these were down-regulated. A pathway enrichment analysis pinpointed mitochondrial translation, respiratory electron transport and the citric acid (TCA) cycle as biological effectors. The data of proteomics was subsequently confirmed by citrate synthase (CS), Tu translation elongation factor (TUFM), pentatricopeptide repeat domain 3 (PTCD3) and mitochondrial ribosomal protein L48 (MRPL 48) protein measurement. CS protein expression in CRC cells and tissues was higher than it was in normal specimens. Additionally, forcible downregulation of CS led to remarkable cell proliferation inhibition. Taken together, we concluded that the anticancer effects of BBR are attributable to mitochondrial protein synthesis, TCA and respiratory electron transport inhibition and that CS might be a useful therapeutic target in CRC treatment. The graphic abstract of the biological effectors targeted by BBR in the CRC cells. Mitochondrial protein synthesis, TCA and respiratory electron transport are three main effectors of BBR. Image 1 • For the first time to explore potential targets of BBR by using label-free proteomics in CRC. • Mitochondrial protein synthesis, TCA and respiratory electron transport are three main effectors. • Complex I rather than other complexes were inhibited by BBR in OXPHOS inhibition. • CS might be a useful therapeutic target in CRC treatment. [ABSTRACT FROM AUTHOR]

With changing lifestyles, non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide. A substantial increase in the incidence, mortality, and associated burden of NAFLD-related advanced liver disease is expected. Currently, the initial diagnosis of NAFLD is still based on ultrasound and there is no approved treatment method. Lipid-lowering drugs, vitamin supplementation, and lifestyle improvement treatments are commonly used in clinical practice. However, most lipid-lowering drugs can produce poor patient compliance and specific adverse effects. Therefore, the exploration of bio-diagnostic markers and active lead compounds for the development of innovative drugs is urgently needed. More and more studies have reported the anti-NAFLD effects and mechanisms of natural products (NPs), which have become an important source for new drug development to treat NAFLD due to their high activity and low side effects. At present, berberine and silymarin have been approved by the US FDA to enter clinical phase IV studies, demonstrating the potential of NPs against NAFLD. Studies have found that the regulation of lipid metabolism, insulin resistance, oxidative stress, and inflammation-related pathways may play important roles in the process. With the continuous updating of technical means and scientific theories, in-depth research on the targets and mechanisms of NPs against NAFLD can provide new possibilities to find bio-diagnostic markers and innovative drugs. As we know, FXR agonists, PPARα agonists, and dual CCR2/5 inhibitors are gradually coming on stage for the treatment of NAFLD. Whether NPs can exert anti-NAFLD effects by regulating these targets or some unknown targets remains to be further studied. Therefore, the study reviewed the potential anti-NAFLD NPs and their targets. Some works on the discovery of new targets and the docking of active lead compounds were also discussed. It is hoped that this review can provide some reference values for the development of non-invasive diagnostic markers and new drugs against NAFLD in the clinic. [Display omitted] [ABSTRACT FROM AUTHOR]

Bergenin (BG) is a polyphenolic substance which has therapeutic potential in the treatment of diabetic nephropathy (DN), a common complication of type II diabetes. However, the mechanisms underlying these effects remain unclear. We studied the protective effects and mechanisms of BG in DN mice, focusing on the TLR4/MyD88/NF-κB signalling pathway. C57BL/6 J mice were used as experiments (n=60), and 10 animals were randomly selected as normal control. The DN model was developed by administering an intraperitoneal injection of streptozotocin (40 mg/kg BW for three days) and a high-fat diet (n=50). BG (20, 40, and 80 mg/kg BW, once a day) was administered orally for four weeks. After BG treatment, the food and water intake of DN mice decreased, blood glucose levels decreased, and insulin resistance reduced. As a result, serum LDL-C, TC, and TG levels decreased; HDL-C levels increased; SOD, CAT, and GSH-Px levels decreased; and MDA levels increased. BG administration reduced AST, ALT, BUN, and CRE levels and inflammatory factors (including TNF-α, MCP-1, IL-1β, and IL-6). Histopathology revealed a significant improvement in pathological damage to the liver, kidney, and spleen of mice treated with BG, and TLR4, MyD88, and NF-κB p65 were down-regulated at both mRNA and protein levels in the BG-treated group. Based on these results, BG therapeutic type II DN by hypoglycaemia, improving liver and kidney function, and anti-oxidative stress; reducing inflammation; and inhibiting the TLR4/MyD88/NF-κB signalling pathway. The results of this study suggest that BG can be used as an effective treatment for type II DN. [Display omitted] • Body weight and blood glucose in DN mice showed a trend towards recovery. • Berberine improves kidney and liver functions and reduces tissue damage in DN mice. • BG ameliorates DN-induced lipid and oxidative imbalances. • BG reduces renal inflammation in DN mice via the TLR4/MyD88/NF-κB pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • A series of novel berberine analogs were synthesized, and evaluated for their p300 inhibitory activity. • Structure-activity relationship studies yielded a more potent compound 5d. • Compound 5d specifically decreases H3K18Ac and interferes with the function of histone acetyltransferase. • Compound 5d exhibited good antitumor effects in MDA-MB-231 cells in vitro and in vivo. The protein p300 is a positive regulator of cancer progression and is related to many human pathological conditions. To find effective p300/CBP HAT inhibitors, we screened an internal compound library and identified berberine as a lead compound. Next, we designed, synthesized, and screened a series of novel berberine analogs, and discovered that analog 5d was a potent and highly selective p300/CBP HAT inhibitor with IC 50 values of 0.070 μM and 1.755 μM for p300 and CBP, respectively. Western blotting further proved that 5d specifically decreased H3K18Ac and interfere with the function of histone acetyltransferase. Although 5d had only a moderate inhibitory effect on the MDA-MB-231 cell line, 5d suppressed the growth of 4T1 tumor growth in mice with a tumor weight inhibition ratio (TWI) of 39.7%. Further, liposomes-encapsulated 5d increased its inhibition of tumor growth to 57.8 % TWI. In addition, 5d has no obvious toxicity to the main organ of mice and the pharmacokinetic study confirmed that 5d has good absorption properties in vivo. [ABSTRACT FROM AUTHOR]

Berberine (BBR) is known for its strong antioxidant, anti-inflammatory, and capacity to preserve intestinal microbiota balance in fish. This study aimed to investigate the protective effects of berberine against copper-induced toxicity in the intestine of freshwater grouper Acrossocheilus fasciatus. The experiment involved four groups: a control group, a Cu group exposed to 0.02 mg/L Cu2+, and two BBR groups fed with 100 or 400 mg/kg of berberine diets and exposed to the same Cu2+ concentration. Three replicates of healthy fish (initial weight 1.56 ± 0.10 g) were subjected to their respective treatments for 30 days. Results showed that none of the treatments significantly affected the survival rate, final weight, weight gain, and feed intake (P > 0.05). However, supplementation with 100 and 400 mg/kg of BBR significantly lowered the antioxidant activities, and glutathione peroxidase (gpx) and superoxide dismutase (sod) expression levels, as well as reduced malondialdehyde (MDA) content caused by Cu2+ exposure (P < 0.05). Berberine inclusion significantly downregulated proinflammatory factors NLR family pyrin domain containing 3 (nlrp3), interleukin 1 beta (il1β), interleukin 6 cytokine family signal transducer (il6st) but upregulated transforming growth factor beta 1 (tgfβ1) and heat shock 70 kDa protein (hsp70) expression. Moreover, berberine at both levels maintained the intestinal structural integrity and significantly improved gap junction gamma-1 (gjc1) mRNA level compared to the Cu group (P < 0.05). Based on 16S rDNA sequencing, the richness and diversity of intestinal microbiota in different groups were not significantly influenced. Berberine reduced the Firmicutes/Bacteroidota ratio and stifled the growth of some specific pathogenic bacteria such as Pseudomonas , Citrobacter , and Acinetobacter , while boosting the richness of potential probiotic bacteria, including Roseomonas and Reyranella compared with the Cu group. In conclusion, berberine showed significant protective effects against Cu2+-induced intestinal oxidative stress, inflammation response, and microbiota disturbance in freshwater grouper. • Cu exposure activated the antioxidative and immune systems and caused pathogenic bacteria growth. • Dietary berberine reduced intestinal antioxidant stress and inflammation caused by Cu exposure. • Dietary berberine inhibited pathogenic bacteria growth but promoted probiotic richness. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a diffuse pulmonary microvascular remodeling disease accompanied by malignant proliferation of pulmonary artery smooth muscle cells (PASMCs), which causes persistent pulmonary artery pressure elevation, right ventricular hypertrophy (RVH) and death. However, current therapies targeting pulmonary vascular remodeling and RVH remain poorly effective in reversing PAH. Overactivation of the protein tyrosine kinase Src plays an important role in tumor cell growth, proliferation and invasion; we thus hypothesized that inhibitors targeting Src activation could reverse experimental PAH. We demonstrated that Src was markedly activated in hypoxia-stimulated PASMCs from donors and PASMCs isolated from PAH patients. We investigated the effects of the Src-selective inhibitor 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4- d ]pyrimidin-4-amine (PP1) and berberine (BBR) on PAH-PASMC proliferation and migration by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-ethynyl-2′-deoxyuridine (EdU) and wound-healing assays. Our in vitro results showed that inhibition of Src (Tyr416) phosphorylation repressed PAH-PASMC proliferation and migration by inhibiting hypoxia-inducible factor-1α (HIF-1α) expression through Akt/mTOR signal pathway. In vivo, PP1 and BBR significantly alleviated distal pulmonary vascular remodeling and decreased right ventricular systolic pressure (RVSP) and RVH in Sugen (SU) 5416/hypoxia (SU-PAH) mice. These findings demonstrate that pharmacological (PP1 or BBR) inhibition of Src activation could be a novel means of treating severe pulmonary vascular remodeling and RVH in PAH patients. [ABSTRACT FROM AUTHOR]

Abstract The objective of this work was to investigate the effect of berberine (BBR) on the Cell viability, lipid accumulation, apoptosis, cytochrome c , caspase-9 and caspase-3 in lipid accumulation-hepatocytes induced by sodium palmitate in vitro. The lipid accumulation-hepatocytes (induced by 0.5 mM sodium palmitate for 24 h) were treated with 5 μM berberine for 12 h. Then, the Cell viability, intracellular triglyceride (TG) content, lipid peroxide (LPO), malonaldehyde (MDA) content, cytochrome c , caspase-9, caspase-3 and apoptosis were detected. Sodium palmitate decreased Cell viability and increased intracellular TG content, lipid droplet accumulation, LPO and MDA concentrations, caused caspase-3 and caspase-9 activation, then led to apoptosis accompanied by cytochrome c release from mitochondria into the cytoplasm. Beberine could improve intracellular lipid droplet accumulation and oxidative stress, while reduce apoptosis induced by sodium palmitate. Highlights • Hepatocytes lipid accumulation. • Berberine improves oxidative stress. • Apoptosis. [ABSTRACT FROM AUTHOR]

Abstract Our previous studies had identified that both crude extracts and total alkaloid from Chelidonium majus exerted a significant antifeeding and larval lethality on Lymantria dispar. Moreover, sanguinarine, chelidonine, berberine hydrochloride and coptisine were the main alkaloid in C. majus exerting toxicity to L. dispar. In this paper, we evaluated the insecticidal and antifeeding activities of each alkaloid on the 3rd instar L. dispar larvae by bioassay. Meanwhile, the effects of alkaloids from C. majus on the activities and mRNA levels of three main digestive enzymes in L. dispar larvae were investigated. The results indicated that sanguinarine possessed the strongest insecticidal activity with a LD 50 value of 4.963 μg/larva, and the coptisine showed little lethality to 3 rd instar L. dispar larvae among four alkaloids from C. majus. The insecticidal capacity of four alkaloids on 3rd instar L. dispar larvae was in the following decreasing order of sanguinarine > chelidonine > berberine hydrochloride > coptisine. Similarly, except coptisine, the other three alkaloids significantly reduced food intakes of third instar L. dispar larvae and suppressed activities of three digestive enzymes (α-amylase, lipase and total protease) simultaneously. Finally, qRT-PCR analysis revealed that the transcriptions of α-amylase, lipase and serine protease were affected by sanguinarine. Especially, at 48 h after treatment, the mRNA expressions of those digestive enzymes were significantly suppressed by sanguinarine. In conclusion, we suggested that alkaloids from C. majus induced antifeeding and larval lethality on L. dispar larvae by suppressing food intake and digestive enzymes in L. dispar. Our findings provide a novel insight into evaluating the antifeeding and insecticidal properties of C. majus, which afford a new strategy for integrated pest management programs as well. Graphical abstract Unlabelled Image Highlights • Sanguinarine possessed the strongest insecticidal activity to 3 rd instar L. dispar larvae among four alkaloids from C. majus. • Sanguinarine, chelidonine and berberine hydrochloride significantly reduced food intakes of 3rd instar L. dispar larvae. • Three alkaloids from C. majus suppressed digestive enzyme activities of 3rd instar L. dispar larvae. • Sanguinarine affected transcriptions of α-amylase, lipase and serine protease in midguts of L. dispar larvae. [ABSTRACT FROM AUTHOR]

Abstract The current study was designed to explore the underlying therapeutic effect of berberine (BBR), an alkaloid compound against LPS (1 μg/ml)/TNFα (10 ng/ml) mediated apoptosis signal-regulating kinase 1 (ASK1) signaling in RAW 264.7 macrophages and adjuvant-induced arthritic synovial macrophages (AA-SM) with relation to miR-23a levels. LPS and TNFα stimulation abrogated the expression of miR-23a resulting in TLR4/TRAF2 mediated ASK1 activation and downstream phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). BBR (25–75 μM) treatment ameliorated the gene expression levels of TLR4, TRAF2, TNFα, IL-6, and IL-23 through the upregulation of miR-23a. Subsequently, BBR suppressed the levels of TLR4/TRAF2 mediated phosphorylation of ASK1/p38 and attenuated the expression of various pro-inflammatory cytokines (TNFα, IL-6 & IL-23) in RAW 264.7 macrophages and AA-SM cells. BBR was able to counteract these factors through activation of miR-23a levels in LPS/TNFα stimulated RAW 264.7 macrophages and AA-SM cells. NQDI1 (30 μM) treatment inhibited ASK1 activation resulting in basal levels of miR-23a, owing to the conclusion that ASK1 activation downregulates miR-23a levels inside the cells. Overall, our current findings predict that BBR is a potential candidate for therapeutic targeting of TLR4/TRAF2 mediated ASK1 activation in inflammatory and in RA pathogenesis possibly through post-transcriptional gene silencing via upregulation of miR-23a. Highlights • LPS/TNFα induces ASK1 signaling in RAW 264.7 macrophages and AA-SM cells. • MiR-23a regulates TLR4/TRAF2 mediated ASK1 activation. • MiR-23a is a competitive inhibitor of ASK1. • BBR suppresses phosphorylation of ASK1 and p38 through miR-23a activation. • BBR ameliorates inflammatory cytokine levels. [ABSTRACT FROM AUTHOR]

Abstract Berberine is a naturally occurring plant secondary metabolite with allelopathic and cytotoxic properties. We investigated the cytotoxic effects of berberine against tobacco Bright Yellow-2 (BY-2) cells. We found that berberine inhibited tobacco BY-2 cell growth in a concentration-dependent manner and the potency of berberine was comparable to the traditional herbicide glyphosate. Meanwhile, the in vivo test revealed that the herbicidal activity of berberine was also comparable to that of glyphosate. Further mechanism studies for the cytotoxicity demonstrated that berberine at concentrations of 40 μg/mL and 80 μg/mL induced cell death by causing mitochondrial membrane depolarization, irregular nuclei and chromatin condensation but not leading to significant apoptosis. Ultra-structure analysis through transmission electron microscopy (TEM) indicated that treatments with 40 μg/mL berberine for 2 d or 80 μg/mL berberine for 1 d induced cell damage, including nuclei morphological changes, cytoplasm and mitochondria degradation and cell wall fibrosis. Treatment at higher concentration of 80 μg/mL for longer period of 2 d, induced plasmolysis and severe damage to basic cell structure, which are indicative of explosive necrosis. Our results suggest that berberine was cytotoxic to tobacco BY-2 cells by inducing necrosis but not apoptosis. Cell wall, mitochondria, nuclei and chromatin were damaged and may be possible primary targets. Therefore, the herbicidal activity of berberine appears to be a complex process associated with multiple mechanisms of action. Graphical abstract Unlabelled Image Highlights • Berberine inhibited tobacco BY-2 cell growth in a dose-dependent manner. • A complex process associated with multiple mechanisms of the action of berberine. • Cell wall, mitochondria, nuclei and chromatin may be possible primary targets. [ABSTRACT FROM AUTHOR]

Abstract Berberine has been implicated to be involved in maintaining bone health due to its anti-oxidative and osteogenic properties. However, low potency and low bioavailability limit the clinical development of the drug. To overcome these obstacles, we previously synthesized a compound, Q8, which is a structural homolog of berberine. The present study examined the pharmacological functions of Q8 to evaluate its potential use in bone regeneration with respect to osteoblast differentiation. Here, we report that Q8 enhanced BMP4-induced alkaline phosphatase (ALP) activity and transcription from the ALP promoter. In addition, Q8 suppressed the expression and activity of PPARγ (a known negative regulator of osteogenesis due to its stimulatory effects on adipogenesis and its role as an adipogenic transcription factor), which in turn increases β-catenin expression in the nucleus, and ultimately promotes osteoblast differentiation. Meanwhile, Q8 reversed the inhibitory effects of the PPARγ agonist, rosiglitazone, on osteoblast differentiation. This study demonstrated that Q8 promotes osteoblast differentiation via inhibition of PPARγ and the enhancement of osteoblast function by Q8 may contribute to the prevention for osteoporosis. Graphical abstract Image 1 Highlights • Q8 increases BMP4-induced osteoblast differentiation of C2C12 cells. • Q8 induced β-catenin nuclear accumulation by enhancing GSK3β phosphorylation via inactivation of PPARγ. • Q8 ameliorated the inhibitory effects of rosiglitazone during osteoblast differentiation. [ABSTRACT FROM AUTHOR]

Add-on therapy with traditional Chinese medicine (TCM) has been extensively researched in the intractable diseases, such as asthma, cancer, and Alzheimer’s disease. As an entirely new concept, add-on therapy of TCM has been also used to prevent and treat hyperlipidemia via lowering cholesterol level. However, the efficacy of add-on therapy with TCM for mediating lipid metabolism disorders remains controversial. In this review, we summarize and provide strong evidence that add-on therapy of TCM as a novel approach is efficacious and safe for hyperlipidemia associated diseases based on the mediation of lipid metabolism disorders. [ABSTRACT FROM AUTHOR]

A potential role of berberine, a benzyl isoquinoline alkaloid, in cancer therapy is apparent. Its underlying mechanisms of berberine against breast carcinoma under hypoxia have not been elucidated. We focused on the doubt how berberine restrains breast carcinoma under hypoxia in vitro and in vivo. A molecular analysis of the microbiome via 16 S rDNA gene sequencing of DNA from mouse faeces confirmed that the abundances and diversity of gut microbiota were significantly altered in 4T1/Luc mice with higher survival rate following berberine treatment. A metabolome analysis liquid chromatography-mass spectrometer/mass spectrometer (LC-MS/MS) revealed that berberine regulated various endogenous metabolites, especially L -palmitoylcarnitine. Furthermore, the cytotoxicity of berberine was investigated in MDA-MB-231, MCF-7, and 4T1 cells. In vitro to simulate under hypoxic environment, MTT assay showed that berberine inhibited the proliferation of MDA-MB-231, MCF-7, and 4T1 cells with IC 50 values of 4.14 ± 0.35 μM, 26.53 ± 3.12 μM and 11.62 ± 1.44 μM, respectively. Wound healing and trans-well invasion studies revealed that berberine inhibited the invasion and migration of breast cancer cells. RT-qPCR analysis shed light that berberine reduced the expression of hypoxia-inducible factor-1α (HIF-1α) gene. Immunofluorescence and western blot demonstrated that berberine decreased the expression of E-cadherin and HIF-1α protein. Taken together, these results provide evidence that berberine efficiently suppresses breast carcinoma growth and metastasis in a hypoxic microenvironment, highlighting the potential of berberine as a promising anti-neoplastic agent to combat breast carcinoma. [Display omitted] • Berberine inhibits breast carcinoma proliferation and metastasis involving gut microbiota and endogenous metabolites. • Berberine inhibits breast carcinoma cells in tumor hypoxia microenvironment better than normoxia. • Berberine prominently restrains breast carcinoma in mouse 4T1/Luc breast tumor model. [ABSTRACT FROM AUTHOR]

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. This article shows significant data duplication and overlap with Liu, Weihua et al., Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury. European Journal of Pharmacology. 2010 Jul 25; 638(1–3):150-5 (https://doi.org/10.1016/j.ejphar.2010.04.033) without adequate referencing. Although there is a slight difference in the methodology section regarding alloxan-induced diabetes models in the two articles, there is a clear overlap between Table 2 of Lan, Tian et al. (2010); and Tables 1 and 2 of Liu, Weihua et al. (2010). The two manuscripts were submitted from the same laboratory in the same year. [ABSTRACT FROM AUTHOR]

Berberine (BBR) is an effective drug against liver fibrosis (LF). Autophagy is involved in the pathogenesis of LF; however, the mechanism linking BBR to autophagy in LF remains unresolved. To explore the underlying mechanism, we assessed the effects of BBR on autophagy and apoptosis of activated hepatic stellate cells (HSCs) in vitro and in a murine model of fibrosis. The decreased expression of the autophagy activation marker ATG5, autophagosome formation, and autophagy flux in the HSC model confirmed that BBR inhibited autophagy in activated HSCs and in mice with liver fibrosis. Moreover, ATG5 was necessary for inducing autophagy and HSC activation. BBR suppressed ATG5 expression by upregulating miR-30a-5p expression, which affected the stability of ATG5 mRNA by binding to its 3′-untranslated region, an effect that was attenuated by treatment with a miR-30a-5p inhibitor. BBR also markedly induced HSC apoptosis, as indicated by the upregulated expression of the pro-apoptosis markers p53, BAX, and cleaved PARP and the downregulated expression of the anti-apoptosis marker BCL-2, effects that were reversed by ATG5 overexpression. In vivo, BBR improved mouse LF by decreasing collagen deposition, inflammatory cell infiltration, and expression of fibrosis markers hydroxyproline, α-smooth muscle actin, and collagen type 1-A1 and the autophagy marker LC3. BBR had a protective effect on mouse fibrotic livers and reduced serum aspartate aminotransferase and alanine aminotransferase levels. Collectively, these results reveal a novel mechanism of BBR-induced autophagy inhibition triggering apoptosis in HSCs, providing a reliable experimental and theoretical basis for developing BBR-based candidate drugs for LF. [ABSTRACT FROM AUTHOR]

Organic/inorganic hydrid nanoparticles (NPs) composed of berberine (BER) and zinc oxide (ZnO) were developed for the therapy of lung cancers. Without the use of pharmaceutical excipients, NPs were fabricated with only dual anticancer agents (BER and ZnO) by facile blending method. The mean weight ratio between BER and ZnO in BER-ZnO NPs was 39:61 in this study. BER-ZnO NPs dispersed in water exhibited 200–300 nm hydrodynamic size under 5 mg/mL concentration. The exposure of both BER and ZnO in the outer layers of BER-ZnO NPs was identified by X-ray photoelectron spectroscopy analysis. The amorphization of BER and the maintenance of ZnO structure were observed in the results of X-ray powder diffractometer analysis. Improved antiproliferation efficacy, based on the chemo-photothermal therapeutic efficacy, of BER-ZnO NPs in A549 (human lung adenocarcinoma) cells was presented. According to the blood tests in rats after intravenous administration, BER-ZnO NPs did not induce severe hepatotoxicity, renal toxicity, and hemotoxicity. Developed BER-ZnO NPs can be used efficiently and safely for the chemo-photothermal therapy of lung cancers. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) is the main organelle for the synthesis, folding, and processing of secretory and transmembrane proteins. Pathological stimuli including hypoxia, ischaemia, inflammation and oxidative stress interrupt the homeostatic function of ER, leading to accumulation of unfolded proteins, a condition referred to as ER stress. ER stress triggers a complex signalling network referred as the unfolded protein response (UPR). Extensive studies have demonstrated that ER stress plays an important role in the pathogenesis of various cardiovascular diseases such as heart failure, ischemic heart disease and atherosclerosis. The importance of natural products in modern medicine are well recognized and continues to be of interests as a source of novel lead compounds. Natural products targeting components of UPR and reducing ER stress offers an innovative strategic approach to treat cardiovascular diseases. In this review, we discussed several therapeutic interventions using natural products with potential cardiovascular protective properties targeting ER stress signalling pathways. [ABSTRACT FROM AUTHOR]

The current study investigated the therapeutic effect of berberine (BBR), an alkaloid derivative against IL-21/IL-21R mediated phosphotidyl inositol 3 kinase/protein kinase B (PI3K/Akt) signaling in adjuvant induced arthritic fibroblast-like synoviocytes (AA-FLS) isolated from rats and IL-21 mediated osteoclastogenesis in bone-marrow derived monocytes (BMMs). BBR (15–45 µM) treatment attenuated the gene and protein levels of IL-21R complex. BBR suppressed the levels of IL-21 (20 ng/ml) mediated production of inflammatory cytokines such as: tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and interleukin 23 (IL-23) in AA-FLS cells. Subsequently, BBR ameliorated the gene and protein expression levels of mechanistic target of rapamycin (mTOR), IL-23 and nuclear factor kappa B (NFκB) p65 through the inhibition of PI3K and upregulation of phosphatase and tensin homolog (PTEN) at the protein level. Furthermore, BBR also inhibited the phosphorylation of Akt and NFκB p65 in a dose dependant manner. LY294002 (20 µM) treatment suppressed the PI3K/Akt signaling and its downstream elements in AA-FLS cells. BBR also modulated IL-21 mediated osteoclastogenesis through the suppression of PI3K dependant nuclear factor of activated T-cells 1 (Nfatc1) induction. Moreover, BBR controlled the osteoclast differentiation via inhibition of various bone resorptive enzymes including: cathepsin K, matrix metalloproteinase 9 (MMP9) and tartarate acid phosphatase (TRAP). LY294002 also inhibited osteoclast formation via suppression of PI3K mediated Nfatc1 induction and other downstream elements. Overall, our findings suggest that BBR is a potential candidate for therapeutic targeting of IL-21/IL-21R mediated RA pathogenesis. [ABSTRACT FROM AUTHOR]

Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) has been known to exert tumor suppressive activity for long without much knowledge about its regulation and implications. Protein kinase B (Akt), Protein kinase C (PKC) and Ribosomal protein S6 Kinase (S6K) are known downtargets of PHLPP2, regulating a plethora of life processes viz. cell growth, survival and evasion from apoptosis. Present study decoded the crucial role of PHLPP2 in inducing apoptosis by its interaction with the newly found binding partner Mammalian sterile 20-like kinase 1 (Mst1) in berberine (BBR)-treated human hepatoma cells. HepG2 cells were exposed to (50 μM, 100 μM) berberine for different time intervals (18 h, 24 h). The results showed enhanced expression of PHLPP2 at transcriptional (2.13 fold, P  < 0.01) and translational level (4 fold, P  < 0.001), but not of PHLPP1, in berberine-treated HepG2 cells. Elevated expression of PHLPP2 was reported to inactivate Akt by dephosphorylating it on Ser473 ( P  < 0.001). As Akt is known to inhibit apoptotic effect of Mst1, we found that PHLPP2 mediated inactivation of Akt releases its repression from Mst1 leading to heightened phosphorylation of Mst1 on its activating site Thr183 (1.5 fold, P  < 0.001). Consequently, coordination between PHLPP2, Akt and Mst1 stimulated downstream targets c-jun N-terminal kinase (JNK), Bim and Bak which are direct activators of pro-apoptotic proteins leading to cell death. Further, PHLPP2/Mst1 knock-down efficiently curtailed anti-proliferative effect of berberine by restoring the basal level of downstream anti-apoptotic proteins. In addition, pre-treatment of NAC (5 mM) showed that ROS generation was a primitive event to initiate activation of stress kinases. Thus, our findings suggest that PHLPP2, Akt and Mst1 constitute an autoinhibitory triangle which may be partly responsible for antiproliferative effect of berberine. [ABSTRACT FROM AUTHOR]

Abnormal lipid metabolism may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). The ATP-binding cassette transporter A1 (ABCA1) protein mediates the transport of cholesterol and phospholipids from cells to apolipoprotein A-I (apoA-I) to generate nascent HDL particles. Previous studies revealed that the overexpression of ABCA1 alleviated hepatic lipid levels by modifying lipid transport. Here, we examined the effect of berberine (BBR) on ABCA1 in QSG-7701 hepatocytes and in mice. BBR decreased hepatic cholesterol and triglyceride levels. It also increased ABCA1 protein levels but not mRNA levels in a time- and dose-dependent manner. The PKCδ inhibitor rottlerin and PKCδ siRNA completely abolished the effect of BBR on ABCA1. BBR also decreased the phosphorylation of ABCA1 serine residues and PKCδ Tyr 311. The inhibition of ABCA1 with its siRNA abolished the reduction in cellular cholesterol levels by BBR. BBR administration to mice fed a methionine choline-deficient diet also significantly increased ABCA1 protein levels and reduced hepatic lipid levels. These results suggest that BBR can reduce steatosis by increasing ABCA1 protein levels through PKCδ to reduce the phosphorylation of serine residues in ABCA1. [ABSTRACT FROM AUTHOR]

Berberine (BBR) is an isoquinnoline derivative alkaloid extracted from Rhizoma Coptidis that has the potential to protect myocardial tissues from ischemia/reperfusion (I/R) injuries. We attempted to evaluate the effect of BBR on the proliferation and apoptosis of a hypoxia/reoxygenation (H/R) cell model and to reveal the mechanism driving the improving function of BBR myocardial tissues. The H/R cell model was established using H9c2 rat cardiac myoblasts. The cell viability, apoptotic rates, and cell cycle distribution were measured with CCK-8 assay and flow cytometry. The expression of Smad7 and caspase-3 were determined both at mRNA and protein levels. In addition, expression of Smad7 was knocked down with specific siRNA and the effect of the interference was assessed. The proliferation ability of H/R cells was enhanced after the administration of BBR, and the apoptosis and cell cycle arrest due to H/R injury were also alleviated by BBR treatment. Moreover, the treatment of BBR on H/R injury functioned through the Smad7-activation-induced attenuating of apoptosis by activating Smad7 pathway which resulted suppression of caspase 3 expression and activity. The knockdown of Smad7 confirmed our conclusion about the key role of Smad7 in the function of BBR administration. However, our results as well as some previous studies also demonstrated that the effect of BBR was tissue and protocol specific, and the underlying mechanism related to the BBR treatment was so complicated that practical application should be carefully investigated based on certain diseases and patients. [ABSTRACT FROM AUTHOR]

Coptis chinensis has been used as a medicinal herb in traditional oriental medicine. In this study, chemical investigation of a water extract of C. chinensis identified two new quaternary protoberberines ( 1 , 2 ), a new tricyclic amide ( 3 ), together with five known compounds. Their chemical structures were elucidated by analysis with 1D and 2D NMR and high-resolution mass spectroscopy, as well as by comparison with those reported in the literature. Compounds 4 , 5 , and 7 showed potent inhibition against acetylcholinesterase (AChE) with IC 50 values of 1.1, 5.6, and 12.9 μM, respectively. Compounds 2 and 4 showed inhibition of butyrylcholinesterase (BChE) with IC 50 values of 11.5 and 27.8 μM, respectively. The kinetic activities were investigated to find out the type of enzyme inhibition involved. The types of AChE inhibition shown by compounds 5 and 7 were noncompetitive; BChE inhibition by compound 2 was also noncompetitive. [ABSTRACT FROM AUTHOR]

Berberine has been demonstrated to alleviate renal interstitial, liver and myocardial fibrosis when administered orally despite its extremely low bioavailability. Here, we inspected effect of berberine on pulmonary fibrosis (PF) and explored underlying mechanisms on the basis of intestinal endocrine. The results showed that either oral or rectal administration of berberine exhibited marked alleviation of bleomycin-induced PF in mice. In contrast, anti-PF activity of berberine disappeared when given by an intravenous injection, implying that it functioned in a gut-dependent manner. Moreover, berberine promoted both mRNA and protein levels of HGF and PTEN in colons, but only their protein levels in lungs of PF mice. In addition, SU11274 but not BPV abolished the anti-PF effect of berberine. In vitro , berberine preferentially induced expression of HGF in fibroblast cells than epithelial, preadipocyte and endothelial cells. Similarly, rosiglitazone and 15dPGJ2 also enhanced expression of HGF in fibroblasts cells, and GW9662 and siPPAR-γ diminished induction of berberine on HGF expression. Berberine could enter into the cytoplasm, activate PPAR-γ directly and synergistically with 15dPGJ2, as shown by an up-regulation of CD36 and aP2 mRNA expression, nuclear translocation and DNA-binding activity of PPAR-γ both in vitro and in vivo . Additionally, GW9662 almost abolished anti-PF effect of berberine and induction of HGF expression in colons. In conclusion, oral administration of berberine displays anti-PF action probably in a colon-dependent manner, and mechanisms involve activation of PPAR-γ and resultant promotion of HGF expression in colonic fibroblasts. The up-regulated HGF arrives in lung tissues via blood circulation to palliate PF. [ABSTRACT FROM AUTHOR]

Carcinogenesis has a multifactorial etiology, and the underlying molecular pathogenesis is still not entirely understood, especially for eye cancers. Primary malignant intraocular neoplasms are relatively rare, but delayed detection and inappropriate management contribute to poor outcomes. Conventional treatment, such as orbital exenteration, chemotherapy, or radiotherapy, alone results in high mortality for many of these malignancies. Recent sequential multimodal therapy with a combination of high-dose chemotherapy, followed by appropriate surgery, radiotherapy, and additional adjuvant chemotherapy has helped dramatically improve management. Transcription factors are proteins that regulate gene expression by modulating the synthesis of mRNA. Since transcription is a dominant control point in the production of many proteins, transcription factors represent key regulators for numerous cellular functions, including proliferation, differentiation, and apoptosis, making them compelling targets for drug development. Natural compounds have been studied for their potential to be potent yet safe chemotherapeutic drugs. Since the ancient times, plant-derived bioactive molecules have been used to treat dreadful diseases like cancer, and several refined pharmaceutics have been developed from these compounds. Understanding targeting mechanisms of oncogenic transcription factors by natural products can add to our oncologic management toolbox. This review summarizes the current findings of natural products in targeting specific oncogenic transcription factors in various types of eye cancer. [ABSTRACT FROM AUTHOR]

The present study reports a meticulous characterization of the interaction of a potent anti-cancer drug, berberine chloride ( BR ) with a series of bile salt aggregates having varying hydrophobicity (sodium deoxycholate (NaDC), sodium cholate (NaC), and sodium taurocholate (NaTC)). The absorption spectrum of BR reveals a complex profile comprised of four distinct peaks. Analysis of the modulations of the absorption spectral properties of BR following interaction with the bile salts raising deeper questions unveils a critical insight into the mode of interaction of the cationic drug ( BR ) with the bile salts; a greater degree of perturbation of the microenvironment of the isoquinolinic part of BR compared to the benzenoid part. The remarkable modulation of the fluorescence profile of BR with added bile salts provides a sensitive indicator for monitoring the interaction scenario. However, an intriguing observation in this context reveals differential fluorescence behavior of BR in various bile salt aggregates, that is, similar observations in NaDC and NaC (which are legitimately interpreted according to the ‘two-step association model’) in comparison to NaTC. Such contrasting behavior of BR in NaTC aggregates has been rationalized on the basis of the possibility of formation of dye aggregate facilitated because of the proximity of the cationic drug molecules to the anionic headgroup of NaTC bile salt. Surprisingly, our spectroscopic results evidence for binding location of the drug at the interfacial region in all the bile salt aggregates. To this end, the time-resolved fluorescence decay behavior of the drug within various bile salt aggregates has been meticulously studied. The fluorescence decay results are found to be highly sensitive to the structure and size of the bile salt aggregates eventually leading to characterization of the interaction of the drug with the bile salts in excellent corroboration with the steady-state data. Furthermore, the time-resolved fluorescence anisotropy decay measurements yielded insight into the modulation of rotational dynamical behavior of the drug within the bile salt aggregates. [ABSTRACT FROM AUTHOR]

Biological oxidations form the basis of life on earth by utilizing organic compounds as electron donors to drive the generation of metabolic energy carriers, such as ATP. Oxidative reactions are also important for the biosynthesis of complex compounds, i.e. natural products such as alkaloids that provide vital benefits for organisms in all kingdoms of life. The vitamin B 2 -derived cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) enable an astonishingly diverse array of oxidative reactions that is based on the versatility of the redox-active isoalloxazine ring. The family of FAD-linked oxidases can be divided into subgroups depending on specific sequence features in an otherwise very similar structural context. The sub-family of berberine bridge enzyme (BBE)-like enzymes has recently attracted a lot of attention due to the challenging chemistry catalyzed by its members and the unique and unusual bi-covalent attachment of the FAD cofactor. This family is the focus of the present review highlighting recent advancements into the structural and functional aspects of members from bacteria, fungi and plants. In view of the unprecedented reaction catalyzed by the family's namesake, BBE from the California poppy, recent studies have provided further insights into nature's treasure chest of oxidative reactions. [ABSTRACT FROM AUTHOR]

A 8-week feeding trial was conducted to evaluate the effect of different berberine-dietary feeding modes on growth, non-specific immune responses and disease resistance of blunt snout bream, Megalobrama amblycephala . Fish (average initial weight 4.70 ± 0.02 g) were fed two fat levels (5% and 10%) diets in three berberine-feeding modes (supplementing 50 mg/kg berberine continuously, two-week or four-week intervals) with four replicates, respectively. Then, fish were challenged by Aeromonas hydrophila and mortality was recorded for the next 96 h after feeding trial. The results showed that different feeding modes of berberine significantly influenced growth, innate immunity and antioxidant capability of fish. Fish fed normal diet with 50 mg/kg berberine at two-week interval mode reflected remarkably ( P < 0.05 ) high weight gain (WG). Plasma TC and TG contents were significantly ( P < 0.05 ) decreased. The lysozyme (LYZ) activities, complement component 3 (C3) and complement component 4 (C4) concentrations were significantly ( P < 0.05 ) increased. Fish not only exhibited relatively low hepatopancreas malondialdehyde (MDA) and lipid peroxide (LPO) contents, but also significantly ( P < 0.05 ) improved superoxide dismutase (SOD) and catalase (CAT) activities. Fish mortality after challenged by Aeromonas hydrophila was decreased. Same results were also presented in fish fed high-fat diet with 50 mg/kg berberine at two-week, four-week intervals or continuous feeding modes. Based on fish healthy improvement and feeding cost saving, blunt snout bream fed normal diet with 50 mg/kg berberine at two-week interval or fed high-fat diet with berberine at two-week or four-week intervals were optimal feeding mode, respectively. [ABSTRACT FROM AUTHOR]

Berberine (BBR) has shown neuroprotective properties. The present study aims to investigate the effects of BBR on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), and SphK1/S1P signaling, which plays a key role in MS. EAE was induced in mice, followed by treatment with BBR at 50, 100, or 300 mg/kg/d. Neurophysiological function was evaluated daily; inflammation, cell infiltration, and the severity of demyelination were also examined. The SphK1, SphK2, and S1P levels in the animals and primary astrocyte culture were measured. We found that treatment with BBR reduced the loss of neurophysiological function and the degree of demyelination. Moreover, BBR was associated with a decrease in SphK1 and S1P levels both in the animals and in culture. These results indicated that BBR suppresses demyelination and loss of neurophysiological function by inhibiting the SphK1/S1P signaling pathway. The use of BBR as a treatment of MS warrant further exploration. [ABSTRACT FROM AUTHOR]