Therapeutic Potential Of Berberine Research Articles

Therapeutic potential of berberine in attenuating cholestatic liver injury: insights from a PSC mouse model

Background and aimsPrimary sclerosing cholangitis (PSC) is a chronic liver disease characterized by progressive biliary inflammation and bile duct injury. Berberine (BBR) is a bioactive isoquinoline alkaloid found in various herbs and has multiple beneficial effects on metabolic and inflammatory diseases, including liver diseases. This study aimed to examine the therapeutic effect of BBR on cholestatic liver injury in a PSC mouse model (Mdr2−/− mice) and elucidate the underlying mechanisms.MethodsMdr2−/−mice (12–14 weeks old, both sexes) received either BBR (50 mg/kg) or control solution daily for eight weeks via oral gavage. Histological and serum biochemical analyses were used to assess fibrotic liver injury severity. Total RNAseq and pathway analyses were used to identify the potential signaling pathways modulated by BBR in the liver. The expression levels of key genes involved in regulating hepatic fibrosis, bile duct proliferation, inflammation, and bile acid metabolism were validated by qRT-PCR or Western blot analysis. The bile acid composition and levels in the serum, liver, small intestine, and feces and tissue distribution of BBR were measured by LC–MS/MS. Intestinal inflammation and injury were assessed by gene expression profiling and histological analysis. The impact on the gut microbiome was assessed using 16S rRNA gene sequencing.ResultsBBR treatment significantly ameliorated cholestatic liver injury, evidenced by decreased serum levels of AST, ALT, and ALP, and reduced bile duct proliferation and hepatic fibrosis, as shown by H&E, Picro-Sirius Red, and CK19 IHC staining. RNAseq and qRT-PCR analyses indicated a substantial inhibition of fibrotic and inflammatory gene expression. BBR also mitigated ER stress by downregulating Chop, Atf4 and Xbp-1 expression. In addition, BBR modulated bile acid metabolism by altering key gene expressions in the liver and small intestine, resulting in restored bile acid homeostasis characterized by reduced total bile acids in serum, liver, and small intestine and increased fecal excretion. Furthermore, BBR significantly improved intestinal barrier function and reduced bacterial translocation by modulating the gut microbiota.ConclusionBBR effectively attenuates cholestatic liver injury, suggesting its potential as a therapeutic agent for PSC and other cholestatic liver diseases.

A novel berberine derivative targeting adipocyte differentiation to alleviate TNF-α-induced inflammatory effects and insulin resistance in OP9 cells

Inflammation and insulin resistance play important roles in the development and progression of type 2 diabetes mellitus. The enhancement of adipocyte differentiation can improve insulin sensitivity by increasing glucose uptake, improving insulin signaling, and reducing inflammation. However, only a few adipogenic agents have shown clinical success in patients with type 2 diabetes mellitus. The therapeutic potential of berberine in type 2 diabetes mellitus was confirmed in terms of the target gene-disease relationship using a network pharmacology database prior to synthesizing the derivatives. Novel berberine derivatives were synthesized, and compound 3b promoted adipocyte differentiation and improvement of insulin resistance in OP9 cells. Compound 3b significantly increased the expression of key adipogenic markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein β (C/EBPβ) and promoted lipid accumulation without cytotoxicity. Furthermore, tumor necrosis factor α (TNF-α)-induced inhibition of adipocyte differentiation and the elevation of inflammatory responses were reversed by compound 3b. Subsequently glucose uptake level through insulin sensitivity improvement was enhanced by compound 3b. Mechanistically, TNF-α activated mitogen-activated protein kinases (MAPKs): ERK, JNK, and p38, whereas compound 3b attenuated phosphorylation of three MAPKs. Finally, in silico molecular docking suggested the possible binding sites of compound 3b on PPARγ. Collectively, the adipogenic and glucose uptake effects of compound 3b were associated with its anti-inflammatory effects and reduced phosphorylation of MAPKs. These findings suggest that the berberine derivative compound 3b may be a potent antidiabetic agent.

Assessment of anti-arthritic activity of lipid matrix encased berberine in rheumatic animal model

The purpose of this study was to evaluate the drug delivery and therapeutic potential of berberine (Br) loaded nanoformulation in rheumatoid arthritis (RA)-induced animal model. The Br-loaded NLCs (nanostructured lipid carriers) were prepared employing melt-emulsification process, and optimised through Box–Behnken design. The prepared NLCs were assessed for in-vitro and in-vivo evaluations. The optimised NLCs exhibited a mean diameter of 180.2 ± 0.31 nm with 88.32 ± 2.43% entrapment efficiency. An enhanced anti-arthritic activity with reduced arthritic scores to 0.66 ± 0.51, reduction in ankle diameter to 5.80 ± 0.27 mm, decline in paw withdrawal timing, and improvements in walking behaviour were observed in the Br-NLCs treated group. The radiographic images revealed a reduction in bone and cartilage deformation. The Br-NLCs showed promising results in the management of RA disease, can be developed as an efficient delivery system at commercial levels, and may be explored for clinical application after suitable experiments in the future.

Berberine inhibits intestinal epithelial barrier dysfunction in colon caused by peritoneal dialysis fluid by improving cell migration

Ethnopharmacological relevanceBerberine is generally extracted from Rhizoma Coptidis (Coptis chinensis Franch), a traditional Chinese medicine, which can be used in the treatment of intestinal diseases, respiratory infections and cardiovascular diseases. Berberine is especially effective for the treatment of gastrointestinal disorders such as diarrhea because of the effect of heat-clearing and detoxifying in traditional Chinese medicine theory. Aim of the studyThis study aimed to examine the protective effect of berberine (BBR) on the damaged colonic epithelial barrier caused by peritoneal dialysis fluid (PDF). MethodsThe damage to intestinal epithelial barrier was examined by intraperitoneally injecting 4.25% dextrose-containing PDF in mice and establishing a long-term PD model in rats with renal failure. Then, the therapeutic potential of berberine on PD-related colonic injuries was examined. T84 colonic epithelial cells were used to test the effect of PDF and berberine in vitro. The damaging effect of PDF and the protective effect of berberine were evaluated by histology staining, histofluorescence and transmission electron microscopy. The migration of colonic epithelial cell and actin-related protein 2 (Arp2) were tested by wound healing assay and Western blot to determine the possible mechanism in vitro. ResultsPD administration induced intestinal epithelial barrier dysfunction in the colon, and berberine alleviated the injury by increasing the tight junction and adhesion junction protein, both in vivo and in vitro. Berberine could also improve the morphology of microvillus. In the wound healing assay, berberine exhibited the ability to promote cell migration, indicating that berberine could probably recover the function of intestinal epithelial cells when the intestinal epithelial barrier was damaged by the PDF. ConclusionsThe present study demonstrates that berberine can ameliorate intestinal epithelial barrier dysfunction in the colon caused by long-term PDF through improving cell migration.

Therapeutic Potential of Berberine in the Treatment of Glioma: Insights into Its Regulatory Mechanisms.

Glioma is known as one of the most common primary intracranial tumors accounting for four-fifths of malignant brain tumors. There are several biological pathways that play a synergistic, pathophysiological role in glioma, including apoptosis, autophagy, oxidative stress, and cell cycle arrest. According to previous rese arches, the drugs used in the treatment of glioma have been associated with significant limitations. Therefore, improved and/or new therapeutic platforms are required. In this regard, multiple flavonoids and alkaloids have been extensively studied in the treatment of glioma. Berberine is a protoberberine alkaloid with wide range of pharmacological activities, applicable to various pathological conditions. Few studies have reported beneficial roles of berberine in glioma. Berberine exerts its pharmacological functions in glioma by controlling different molecular and cellular pathways. We reviewed the existing knowledge supporting the use of berberine in the treatment of glioma and its effects on molecular and cellular mechanisms.

Combating Neurodegenerative Diseases with the Plant Alkaloid Berberine: Molecular Mechanisms and Therapeutic Potential.

: Neurodegenerative diseases are among the most serious health problems affecting millions of people worldwide. Such diseases are characterized by a progressive degeneration and / or death of neurons in the central nervous system. Currently, there are no therapeutic approaches to cure or even halt the progression of neurodegenerative diseases. During the last two decades, much attention has been paid to the neuroprotective and anti-neurodegenerative activities of compounds isolated from natural products with high efficacy and low toxicity. Accumulating evidence indicates that berberine, an isoquinoline alkaloid isolated from traditional Chinese medicinal herbs, may act as a promising anti-neurodegenerative agent by inhibiting the activity of the most important pathogenic enzymes, ameliorating intracellular oxidative stress, attenuating neuroinflammation, triggering autophagy and protecting neurons against apoptotic cell death. This review attempts to summarize the current state of knowledge regarding the therapeutic potential of berberine against neurodegenerative diseases, with a focus on the molecular mechanisms that underlie its effects on Alzheimer’s, Parkinson’s and Huntington’s diseases.

Possible therapeutic potential of berberine in the treatment of STZ plus HFD-induced diabetic osteoporosis.

Diabetic osteoporosis is a complication of diabetes mellitus, and can result in an increased incidence of bone fractures and a delay in fracture healing. Berberine is one of the most widely distributed isoquinoline alkaloid in plants and possesses antioxidant properties. These properties can reduce the high glucose mediated in the dysfunction of human bone marrow stem cells. Therefore, the present study was designed to investigate the apparent beneficial effect of berberine on bone characteristics in streptozotocin plus HFD-induced diabetic rats. Rats were selected at random and divided into four groups: (A) control group (CG) (n = 10); (B) diabetic group (DG) (n = 10); (C) diabetic group with 50 mg kg-1day-1 of berberine (Brb-50) (n = 10); and (D) diabetic group with 100 mg kg-1day-1 of berberine (Brb-100) (n = 10). After 12 weeks of being treated with berberine, the femora from all rats were assessed and other blood biochemistries evaluated. Berberine at 50 mg/kg showed little effect and significance on diabetic osteopenia, while berberine at 100 mg/kg was significantly increased in diabetic rats. The same group also displayed a significantly decreased serum osteocalcin and serum alkaline phosphatase activity in diabetic rats. The impaired micro-architecture of the femurs in diabetic rats could partially be prevented by berberine with 100 mg/kg. In addition, berberine could to an extent restore the decreased bone formation and reabsorption of the femurs in diabetic rats through the histomorphometric analysis. Berberine could not only significantly lower the oxidative level of DNA damage, but also up-regulate the activity of serum antioxidants. According to our investigations and discoveries, we have found, that berberine may be a potential drug for controlling bone loss in diabetic osteoporosis.

Therapeutic Potential and Mechanisms of Berberine in Cardiovascular Disease

Berberine is originally isolated from extracts of the Chinese herb Coptis chinensis. It was initially used to treat diarrhea. Over the past two decades, berberine has been shown to be effective for improving glycemic and lipid profiles. Interest in its protective effects against diabetes and cardiovascular risk is beginning to emerge, and research investigating the pharmacological activity of berberine is developing rapidly and being reported internationally. Some clinical evidence has demonstrated the ability of berberine to prevent endothelial dysfunction, myocardial infarction, and arrhythmia in patients with cardiovascular risks. Numerous molecular targets of berberine have been explored, including adenosine monophosphate-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and NADPH oxidase (NOX). The aim of this review is to focus on the therapeutic potential of berberine in cardiovascular disease and to describe its underlying mechanisms in the pathogenesis of artherosclerosis, hypertension, heart failure, ischemia reperfusion heart injury, stroke, and arrhythmias.

Berberine improves airway inflammation and inhibits NF-κB signaling pathway in an ovalbumin-induced rat model of asthma

Objectives: Berberine has been reported for its various activities including anti-inflammatory effects and has been used in treating many diseases. However, its effects on airway inflammation in asthma have not been investigated. This study mainly aimed to detect its effects on the airway inflammation and the nuclear factor-κB (NF-κB) signaling pathway activity in a rat model of asthma. Methods: Asthma was induced by ovalbumin (OVA) sensitization and challenge. The asthmatic rats were respectively treated with vehicle PBS or berberine (100 mg/kg or 200 mg/kg) for 28 days. The control rats were treated with PBS. Inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted and the lung inflammation was scored. Levels of NF-κB p65 (mRNA and protein), phosphorylated NF-κB p65 (p-NF-κB p65), inhibitory κB alpha (IκBα) (mRNA and protein) and phosphorylated IκBα (p-IκBα), as well as NF-κB p65 DNA-binding activity, were measured to assess the activity of NF-κB signaling pathway. Levels of the downstream inflammatory mediators of NF-κB signaling, IL-1β, IL-4, IL-5, IL-6, IL-13 and IL-17 in BALF, were measured. Besides, the serum levels of OVA-specific immunoglobulin (Ig)E were measured. Results: Results showed that OVA increased the number of inflammatory cells in BALF, elevated lung inflammation scores, enhanced the NF-κB signaling activity and promoted the production of IgE in rats. Berberine dose-dependently reversed the alterations induced by OVA in the asthmatic rats. Conclusions: The findings suggested a therapeutic potential of berberine on OVA- induced airway inflammation. The ameliorative effects on the OVA-induced airway inflammation might be associated with the inhibition of the NF-κB signaling pathway.

Possible role of P-glycoprotein in the neuroprotective mechanism of berberine in intracerebroventricular streptozotocin-induced cognitive dysfunction

The therapeutic potential of berberine has been well documented in various neurological problems. However, the neurological mechanism of berberine remains untapped in the light of its P-glycoprotein (P-gp)-mediated gut efflux properties responsible for reduced bioavailability. Verapamil, a well known L-type calcium channel blocker, has additional inhibitory activity against P-gp efflux pump. Thus, there is a strong scientific rationale to explore the interaction of berberine with verapamil as a possible neuroprotective strategy. The present study was designed to evaluate the effect of berberine, verapamil, and their combination on behavioral alterations, oxidative stress, mitochondrial dysfunction, neuroinflammation, and histopathological modifications in intracerebroventricular streptozocin (ICV-STZ)-induced sporadic dementia of Alzheimer's type in rats. Single bilateral ICV-STZ (3mg/kg) administration was used as an experimental model of sporadic dementia of Alzheimer's type. Berberine (25, 50, and 100mg/kg, oral gavage) or verapamil (2.5 and 5mg/kg, intraperitoneally) were used as treatment drugs, and memantine (5mg/kg, intraperitoneally) was used as a standard. Berberine and verapamil significantly attenuated behavioral, biochemical, cellular, and histological alterations, suggesting their neuroprotective potential. Further, treatment of berberine (25 and 50mg/kg) with verapamil (2.5 and 5.0mg/kg) combinations respectively significantly potentiated their neuroprotective effect which was significant as compared to their effect per se in ICV-STZ-treated animals. The augmentative outcome of verapamil on the neuroprotective effect of berberine can be speculated due to the inhibition of P-gp efflux mechanism and the prevention of calcium homeostasis alteration. Additionally, anti-inflammatory and antioxidant effects of both berberine and verapamil could also contribute in their protective effect.

The therapeutic potential of berberine against the altered intrinsic properties of the CA1 neurons induced by Aβ neurotoxicity

It was demonstrated that treatment with beta amyloid (Aβ) led to extreme alterations in the intrinsic electrophysiological properties of CA1 pyramidal neurons. Also, malfunction of the cholinergic system is correlated to the memory and cognitive impairments. Several new studies have suggested that Berberis vulgaris can act as a cholinesterase inhibitor. The present study aimed to investigate the effects of berberine (BER) on the Aβ-induced impairments in learning and memory. The male Wistar rats were divided into 4 groups of Sham, BER, Aβ and Aβ+BER. The administration of BER or its vehicle started immediately after the injection of Aβ and followed by 13 days. Then, the animals were tested for learning and memory performance using the Morris water maze (MWM) and passive avoidance tests. Then, they were sacrificed for the whole cell patch clamp recording. The results of the MWM and passive avoidance tasks indicated that administration of the BER in the Aβ+BER group prevented the memory impairment induced by Aβ. The results of the whole cell patch clamp also showed that administration of the BER restored the Aβ-induced impairments in the firing frequency, half-width and rebound action potential. These results suggested that administration of the BER could ameliorate neurotoxicity induced by Aβ. However, this neuroprotection impact could be resulted from the balance effect of the Ca2+ entry. The optimal level of Ca2+ entry by BER could be a major factor that modified the function of the Ca2+-activated K+ channels and decreased the half-width in the Aβ treated rats.

Berberine and neurodegeneration: A review of literature.

The excessive production of reactive oxygen species in nervous tissues is considered one of the major risk factors of neurodegenerative diseases. During the last two decades, much attention has been paid to the antioxidant and anti-inflammatory activity of natural products and compounds isolated from natural products which are often characterized by high efficacy and low adverse effects. Berberine is an isoquinoline alkaloid, widely present in different medicinal herbs, especially in the genus Berberis. It is mainly used as antidiarrhoeal, antibacterial, antifungal, and antiprotozoal agent. However, current research has focused on its beneficial role in neurodegenerative diseases, mainly due to its powerful antioxidant effect. The therapeutic potential of Berberine in different neurodegenerative diseases such as Alzheimer, Parkinson and Huntington disease has been brought to evidence by numerous studies. However, a limited number of reviews focus on the beneficial role of Berberine against neurodegeneration. The main objective of this review is to discuss the role of oxidative stress in neurodegeneration and the potential role of antioxidant compounds, in particular Berberine which is analyzed in its chemical structure, source, bioavailability, therapeutic potential, with special attention to its mechanism of action at a molecular level.

Therapeutic potential of berberine against neurodegenerative diseases.

Berberine (BBR) is an organic small molecule isolated from various plants that have been used in traditional Chinese medicine. Isolation of this compound was its induction into modern medicine, and its usefulness became quickly apparent as seen in its ability to combat bacterial diarrhea, type 2 diabetes, hypercholesterolemia, inflammation, heart diseases, and more. However, BBR’s effects on neurodegenerative diseases remained relatively unexplored until its ability to stunt Alzheimer’s disease (AD) progression was characterized. In this review, we will delve into the multi-faceted defensive capabilities and bio-molecular pathways of BBR against AD, Parkinson’s disease (PD), and trauma-induced neurodegeneration. The multiple effects of BBR, some of which enhance neuro-protective factors/pathways and others counteract targets that induce neurodegeneration, suggest that there are many more branches to the diverse capabilities of BBR that have yet to be uncovered. The promising results seen provide a convincing and substantial basis to support further scientific exploration and development of the therapeutic potential of BBR against neurodegenerative diseases.

Possible therapeutic potential of berberine in diabetic osteopathy

Diabetic osteopathy is a complication that leads to decreased bone mineral density, bone formation and having high risk of fractures that heals slowly. Diabetic osteopathy is a result of increase in osteoclastogenesis and decrease in osteoblastogenesis. Various factors viz., oxidative stress, increased inflammatory markers, PPAR-γ activation in osteoblast, activation of apoptotic pathway, increased glucose levels and inhibitory effect on parathyroid hormone etc. are mainly responsible for decreased bone mineral density. Berberine is an isoquinoline alkaloid widely used in Asian countries as a traditional medicine. Berberine is extensively reported to be an antioxidant, anti-inflammatory, antidiabetic, and having potential to treat diabetic complications and glucocorticoid induced osteoporosis. The osteoclastogenesis decreasing property of berberine can be hypothesized for inhibiting diabetic osteopathy. In addition, chronic treatment of berberine will be helpful for increasing the osteoblastic activity and expression of the modulators that affect osteoblastic differentiation. The apoptotic pathways stimulated due to increased inflammatory markers and nucleic acid damages could be reduced due to berberine. Another important consideration that berberine is having stimulatory effect on glucagon like peptide release and insulin sensitization that will be helpful for decreasing glucose levels and therefore, may exerts osteogenesis. Thiazolidinediones show bone loss due to activation of PPAR-γ in osteoblasts, whereas berberine stimulates PPAR-γ only in adipocytes and not in osteoblasts, and therefore the decreased bone loss due to use of thiazolidinediones may not be observed in berberine treatment conditions. Berberine decreases the advanced glycation end-products (AGE) formation in diabetic condition which will be ultimately helpful to decrease the stiffness of collagen fibers due to AGE-induced cross linking. Lastly, it is also reported that berberine has inhibitory effect on parathyroid hormone and enhances marker genes like osteocalcin, which are responsible for the osteoblastic activity. From these evidences, we hypothesized that berberine may have potential in the treatment of diabetic osteopathy.