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Berberine Inhibits Inflammatory Response and Ameliorates Insulin Resistance in Hepatocytes
Abstract
Berberine, a major isoquinoline alkaloid present in Chinese herb Rhizoma coptidis, is a potent inhibitor of inflammation and has anti-diabetic activity. This study aims to investigate effects of berberine on ameliorating insulin resistance and molecular mechanisms involved in HepG2 cells. Inflammatory responses and insulin resistance were induced by palmitate (PA) stimulation for 24 h. Treatment of berberine enhanced insulin-mediated glycogen synthesis and restored insulin inhibition of triglyceride secretion. Stimulation of PA resulted in IL-6 and TNF-α production in HepG2 cells, and antibody-neutralizing assay further confirmed that IL-6 and TNF-α were involved in the development of insulin resistance. Berberine effectively inhibited IL-6 and TNF-α production in a concentration-dependent manner, demonstrating its anti-inflammatory activity in hepatocytes. Meanwhile, PA-evoked inflammation impaired insulin signaling cascade and berberine improved insulin signaling cascade by modification of Ser/Thr phosphorylation of insulin receptor substrate-1(IRS-1) and downstream Akt (T308). Above results suggest that berberine improved insulin sensitivity in PA-stimulated hepatocytes and this regulation might relative with its anti-inflammatory activity.
... 65 In HepG2 cells, berberine increases insulin sensitivity by increasing glycogen synthesis and reducing proinflammatory cytokine levels. 66 It induces glycolysis by activating the AMP-activated protein kinase (AMPK) pathway and suppresses gluconeogenesis. Berberine reduces inflammation by decreasing pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β), toll-like receptor 4 (TLR4) and tumor necrosis factor-α (TNF-α). ...
... Berberine reduces inflammation by decreasing pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β), toll-like receptor 4 (TLR4) and tumor necrosis factor-α (TNF-α). [66][67][68][69] Increased levels of these cytokines are linked to Type 2 Diabetes and Alzheimer's disease. 70 IL-1β and TLR4 contribute to insulin resistance. ...
... Diabetes, CVD, cancer, and Alzheimer's disease share a common pathology of chronic inflammation. 86,127,128 Berberine has been shown to attenuate these inflammatory pathways by reducing the expression of the inflammatory cytokines TLR4, IL-1β, IL-1, and TNF-α, 18, 65,66,129 which are elevated in all three diseases. TLR4 is activated by NF-κB, which berberine is known to decrease. ...
... In addition, BBR decreased interleukin (IL)-17A production by regulating mitogen-activated protein kinase activity (Cui et al., 2009). Furthermore, a study of palmitate-stimulated HepG2 cells, a human liver cell line, showed that BBR reduced release of inflammatory factors IL-6 and tumor necrosis factor alpha (TNF-a) from these cells, which significantly increased under palmitate stimulation (Lou et al., 2011). In addition, it has been reported that exposure of the liver to toxins causes oxidative stress that can lead to release of TNF-a from Kupffer cells and damaged hepatocytes, thereby enhancing inflammation and liver damage. ...
... Histopathological examination of the liver tissue showed that application of 600 mg/kg BBR to PCACT-fed birds reduced apoptosis in hepatocytes. Research on hepatocytes has shown that BBR decreases release of IL-6 and TNF-a from palmitate-stimulated HepG2 cells (Lou et al., 2011). Therefore, it can be speculated that the antiinflammatory activity of BBR was able to reduce lesions caused by aflatoxin by reducing inflammatory cytokine production. ...
Many types of mycotoxins are found in food sources contaminated with fungi, and if these are ingested in large quantities or over a long period, they can affect the health of humans and domestic animals. Berberine (BBR) is a plant alkaloid with multiple pharmacological functions. This study aimed to investigate the effect of different levels of the plant alkaloid BBR on reducing toxic effects of aflatoxin B1 (AFB) and ochra-toxin A (OTA) in broilers by examining performance characteristics, blood biochemistry, antioxidant systems, ileum morphology, and histopathology of the liver. The experiment was performed with 288 Ross 308 broilers reared in floor pens for 42 d in a randomized design with 9 treatments. Each treatment was replicated 4 times, and each replicate contained 8 chicks. Experimental treatments included (1) negative control diet with no additives (NC); (2) NC 1 2 ppm AFB (positive control AFB; PCAFB); (3) NC 1 2 ppm OTA (positive control OTA; PCOTA); (4) PCAFB 1 200 mg/kg BBR; (5) PCAFB 1 400 mg/kg BBR; (6) PCAFB 1 600 mg/kg BBR; (7) PCOTA 1 200 mg/kg BBR; (8) PCOTA 1 400 mg/kg BBR; and (9) PCOTA 1 600 mg/ kg BBR. Compared with NC, feeding PCAFB and PCOTA diets reduced average daily feed intake, weight gain, serum concentrations of superoxide dismutase, glutathione peroxidase, and the length and width of ileum villi (P , 0.05). At the same time, these parameters increased in birds fed PCAFB or PCOTA diets supplemented with 600 mg/kg of BBR (P , 0.05). Feeding PCAFB and PCOTA diets increased feed conversion ratio (FCR), serum aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) activities, serum urea, and liver lesions compared with NC. By contrast, compared with PCAFB and PCOTA, adding 600 mg/kg BBR decreased FCR, AST, LDH, ALT, and GGT activities , urea, and liver lesions (P , 0.05). Overall, supple-mentation with 600 mg/kg BBR may improve growth performance, liver function, and antioxidant status of broilers fed diets contaminated with AFB and OTA.
... Berberine (BBR) is the main active component of Coptis chinensis, Berberis, and etc, and is used as a traditional Chinese medicine in clinical treatment of diarrhea and bacterial dysentery [16]. Recently, BBR has been found to have new potential therapeutic effects on metabolic diseases, such as diabetes [17,18], hyperlipidemia [19,20] and cardiovascular diseases [4,21]. Studies of molecular mechanism have shown that BBR activates the extracellular-regulated protein kinase pathway, increases the expression of LDL receptor on the surface of liver cells [19], and attenuates cholesterol accumulation in macrophage foam cells by suppressing AP-1 activity and activating the Nrf2/HO-1 pathway [22]. ...
... Previous studies indicated that the transmembrane glycoprotein LOX-1 serves as the oxLDL receptor that binds to and internalizes oxLDL, which is associated with endothelial dysfunction, VSMC proliferation and migration, and increased collagen synthesis and foam cell formation [31]. In recent years, many clinical research and experimental studies reported that BBR could be used to treat cardiovascular diseases and hyperlipidemia by targeting several intracellular signal pathways and autophagy [17][18][19][20][21][22][25][26][27][28][29][30]. BBR could suppress expression of LOX-1 in HUVECs and monocyte/macrophages [23,24]. ...
Damage to vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) caused by oxidized low-density lipoprotein (oxLDL) contributes to cardiovascular and cerebrovascular diseases. Protection effects of Berberine (BBR) on the cardiovascular system have been reported, however, the molecular mechanism of vascular protection is still unclear. In this study, we established two hyperlipidemia models in zebrafish and VEC-VSMC co-culture using high-cholesterol food (HCF) and oxLDL, respectively. We demonstrated that HCF doubled total cholesterol and total glyceride levels, and BBR decreased these indices in a concentration-dependent manner. Lipid staining and hematoxylin-eosin staining revealed that BBR inhibited oxLDL-induced VSMC bulge-like proliferation and migration toward VECs and prevented the HCF-induced trunk vascular obstruction in zebrafish. Immunoblot analysis, cell immunofluorescence, co-immunoprecipitation assays, and transmission electron microscopy showed that oxLDL/HCF increased lectin-like oxLDL receptor-1 (LOX-1) expression at least 5-fold and significantly inhibited autophagolysosome formation in the blood vessel cells and in zebrafish. These observations were associated with endothelial-to-mesenchymal transition (EMT) in VECs and triggered VE-cadherin ectopic expression in VSMCs, and they were responsible for aberrant VSMC migration and vascular occlusion. However, BBR, by promoting autolysosome formation and degradation of LOX-1, reversed the above events and maintained intracellular homeostasis of vessel cells and vascular integrity. In conclusion, regulation of autophagy may be an effective approach to treating oxLDL-induced cardiovascular diseases by reducing LOX-1 protein level. BBR can protect blood vessels by adjusting the oxLDL-LOX-1-EMT-autophagy axis. This study is a step toward the development of new applications of BBR.
... Berberine is an isoquinoline alkaloid compound extracted from the traditional Chinese medicine Coptis chinensis, and modern research has proven that it has multiple pharmacological activities (Li et al., 2018;Neag et al., 2018;Belwal et al., 2020). Recently, basic research has proven that berberine can be used to lower the blood glucose level , improve insulin resistance (Lou et al., 2011), improve hyperlipidemia , and prevent mild cognitive impairment (Kumar et al., 2016). This feature improves the shortcomings of the combination of statins and metformin and shows potential as a new first-line treatment drug. ...
... In addition, berberinemediated AMPK activation has an anti-inflammatory effect, which improves insulin resistance. Berberine can also stabilize LDLR mRNA and prolong half-life (Lou et al., 2011;Yang et al., 2016). The stable expression of LDLR can increase the clearance rate of plasma LDL through receptor-mediated endocytosis, thereby reducing LDL (Kong et al., 2004). ...
Background: Metabolic activity is the basic life activity of organisms and the fundamental for maintaining body functions. With the improvement of living standards, the incidence of metabolic disorder is also increasing. At present, most of the clinical treatment strategies and meta-analysis for metabolic disorder uncover that combined medicines with berberine ameliorate several metabolic disorders. However, evidence to disclose the therapeutic effect of berberine treatment alone and the possible factors affecting the efficacy is limited. Therefore, we have formulated strict inclusion criteria and selected more reliable data for meta-analysis through more refined screening strategies to provide evidence and guidance for clinical decision-making and understand the effect of berberine treatment alone and the factors affecting its efficacy.
Methods and results: Using meta-analysis of “Cochrane Handbook for Systematic Reviews of Interventions” as guidelines, we searched PubMed, GeenMedical, Cochrane library, and china national knowledge infrastructure (CNKI) for trials reporting clinical treatment data of berberine. Another 417 trials were included through other sources to increase confidence in results. Among the 1,660 related documents retrieved from the four databases, 18 eligible documents were selected for analysis. Given the differences in trial design and measurement units, we used the standardized mean difference (SMD) method to eliminate the differences and then summarize the data for analysis. The main factors are triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), homeostasis model assessment-insulin resistance (HOMA-IR), and fasting plasma glucose (FPG). Random-effect model analysis was performed: TG (SMD: 0.94; 95%CI: 0.49,1.38; p = 0.00), TC (SMD: 1.06; 95%CI: 0.64, 1.48; p = 0.00), LDL (SMD: 1.77; 95%CI: 1.11,2.44; p = 0.00), HDL (SMD: −1.59; 95%CI: −2.32, −0.85; p = 0.00), HOMA-IR (SMD: 1.25; 95%CI: 0.25,2.24; p = 0.01), and FPG (SMD: 0.65; 95%CI: 0.28,1.03; p = 0.00). This study aimed to conduct a systematic review and meta-analysis of the literature to evaluate the therapeutic effect of berberine singly on metabolic diseases.
Conclusion: Berberine can improve obesity and hyperlipidemia by reducing TG, TC, and LDL and increasing HDL; reduce insulin resistance to improve type Ⅱ diabetes; and prevent diabetic encephalopathy.
... In addition, BBR decreased interleukin (IL)-17A production by regulating mitogen-activated protein kinase activity (Cui et al., 2009). Furthermore, a study of palmitate-stimulated HepG2 cells, a human liver cell line, showed that BBR reduced release of inflammatory factors IL-6 and tumor necrosis factor alpha (TNF-a) from these cells, which significantly increased under palmitate stimulation (Lou et al., 2011). In addition, it has been reported that exposure of the liver to toxins causes oxidative stress that can lead to release of TNF-a from Kupffer cells and damaged hepatocytes, thereby enhancing inflammation and liver damage. ...
... Histopathological examination of the liver tissue showed that application of 600 mg/kg BBR to PCACT-fed birds reduced apoptosis in hepatocytes. Research on hepatocytes has shown that BBR decreases release of IL-6 and TNF-a from palmitate-stimulated HepG2 cells (Lou et al., 2011). Therefore, it can be speculated that the antiinflammatory activity of BBR was able to reduce lesions caused by aflatoxin by reducing inflammatory cytokine production. ...
Aflatoxin, Ochratoxin, Berberine, Broiler
... Repurposing of gut-targeting herbal products for treating NPDs 4.6.1. Rhizoma coptidis Berberine, one of the major bioactive isoquinoline alkaloids of Rhizoma coptidis (Yi et al., 2013), is associated with the suppression of proinflammatory cytokine production both in vitro and in vivo (Choi et al., 2006;Chueh & Lin, 2012;Cui et al., 2009;Lou et al., 2011). Besides, it was reported to suppress LPS-induced proinflammatory cytokine gene expressions and secretions in splenocytes (Lin & Lin, 2011), probably through the inhibition of Toll-like receptor 4 associated NF-κB signalling pathway which are correlated to the neuroinflammatory response (Chu et al., 2014;M. ...
... Berberine Suppresses the in vitro and in vivo production of proinflammatory cytokines (Choi et al., 2006;Chueh & Lin, 2012;Cui et al., 2009;Lou et al., 2011). ...
Chronic inflammation of the central nervous system (CNS) is critical to the pathogenesis of neuropsychiatric disorders (NPDs) that affect the global population. Current therapeutics for NPDs are limited to relieving symptoms and induce many adverse effects. Therefore, the discovery of novel therapeutic agents from natural sources is urgently needed. Intriguingly, the immune responses of peripheral organs are closely linked through the molecular communication between resident and blood-borne cellular components, which shape the neuroinflammatory phenotypes of NPDs. Since the gut and spleen are the two largest immunological organs of the body, the brain-gut microbiome and brain-spleen axes have been implicated in the connection between the CNS and the peripheral immune system. Accordingly, it has been proposed that the local CNS inflammation observed in NPDs is regulated via the manipulation of the systemic immune system by targeting the gut and spleen. Additionally, the complexity of the signalling network underlying the communication between the CNS and the systemic immune system suggests a strong potential for treating NPDs through a polypharmacological approach. The close association between systemic immunity and the homeostasis of the CNS points to the concept of repurposing interventions for systemic immune disorders to treat NPDs. Notably, natural products represent a promising source of such effective compounds due to both their pharmacological potency and safety. This review discusses the complex implications of dysregulated systemic immunity mediated by the brain-spleen and brain-gut microbiome axes in NPDs, such as Alzheimer's disease, Parkinson's disease, schizophrenia and major depressive disorder. In addition, the potential of repurposing natural product-based bioactive compounds for treating NPDs via modulating systemic immune disorders is intensively discussed.
... For the purpose of this study, the researchers wanted to determine the effects of administering berberine to individuals who were diagnosed with metabolic syndrome for a period of three months, as well as to preadipocytes that were extracted from human omental fat [61]. By administering 10 μM of berberine, we were able to demonstrate that the growth of human preadipocytes and the secretion of leptin and adiponectin were considerably reduced [62]. This inhibition was accompanied by a decrease in the expression of PPARγ2, C/EBPα, adiponectin, and leptin mRNA [63]. ...
The complex metabolic and endocrine disorder known as polycystic ovarian syndrome (PCOS) is characterised by anovulation, infertility, obesity, insulin resistance, and polycystic ovaries. Factors that predispose women to polycystic ovarian syndrome encompass dietary and lifestyle decisions, environmental pollutants, genetic predisposition, gut dysbiosis, alterations in neuroendocrine function, and excess adiposity. Hyperinsulinemia, oxidative stress, hyperandrogenism, inadequate folliculogenesis, and irregular menstrual periods are symptoms that may arise from these variables, potentially contributing to an escalation of metabolic syndrome. Pathogenic dysbiosis of the gut microbiota may have a role in the aetiology of polycystic ovarian syndrome (PCOS). Immature oocytes, insulin resistance, hyperandrogenism, inflammation, oxidative stress, and resveratrol are pathological features of PCOS that may be ameliorated by supplementation with natural compounds such as polyphenols, quercetin, resveratrol, flavonoids, vitamin C, gamma-linolenic acid, piperine, and omega-3 fatty acids, along with natural and semi-synthetic polymers. This review encapsulates the current understanding of the efficacy of natural chemical supplementation in the treatment of PCOS.
... IRS-1 and its downstream Akt and activate this pathway (Lou et al., 2011). Results indicate that berberine may improve insulin resistance in type 2 diabetes by modulating inflammatory responses and insulin signaling in liver cells. ...
Berberis vulgaris (B. vulgaris or barberry) is a medicinal plant that has been used for various purposes in traditional medicine. Berberine is one of the main alkaloids isolated from B. vulgaris and other plants. Both B. vulgaris and berberine have shown anti‐inflammatory, antioxidant, and immunomodulatory effects in different experimental models and clinical trials. This review aims to summarize the current evidence on the mechanisms and applications of B. vulgaris and berberine in modulating inflammation, oxidative stress, and immune responses. The literature search was performed using PubMed, Scopus, and Google Scholar databases until August 2023. The results indicated that B. vulgaris and berberine could inhibit the production of pro‐inflammatory cytokines, such as tumor necrosis factor‐alpha (TNF‐α), interleukin‐1β (IL‐1β), interleukin 6 (IL‐6), and interleukin‐17 (IL‐17), and enhance the expression of anti‐inflammatory cytokines, such as interleukin 10 (IL‐10) and transforming growth factor‐β (TGF‐β), in various cell types and tissues. B. vulgaris and berberine can also scavenge free radicals, increase antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and reduce lipid peroxidation and DNA damage. B. vulgaris and berberine have been reported to exert beneficial effects in several inflammatory, oxidative, and immune‐related diseases, such as diabetes, obesity, cardiovascular diseases, neurodegenerative diseases, autoimmune diseases, allergic diseases, and infections. However, more studies are needed to elucidate the optimal doses, safety profiles, and potential interactions of B. vulgaris and berberine with other drugs or natural compounds.
... It has been shown that this compound has a variety of biological proprieties, involving antihyperglycaemic, anti-neoplastic, anti-inflammatory, and antioxidant actions (Ang et al., 2010;Polk et al., 2016;Xu et al., 2019). Production of inflammatory mediators is inhibited by BBR according to previous studies (Lou et al., 2011;Fontanella et al., 2014). In addition, BBR appears to improve the antioxidant defense mechanism within the cell, involving the activity of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) while decreasing oxidative stress variables such as malondialdehyde (MDA), NO levels, and protein carbonyl content (Zhou and Zhou, 2011). ...
Background
Paracetamol (PCM) overdosing induces hepatotoxicity, which can result in death if the dose is high enough and the patients are not given N-acetyl cysteine. Berberine (BBR) has a variety of biological proprieties including anti-inflammatory and antioxidant activities.
Aim
Assessment of the potential effect of BBR and selenium when used alone or together on the PCM–induced acute hepatic toxicity in rats.
Methods
This research involved 40 clinically healthy mature adult male albino rats, their weights ranged from 150 to 200 g and housed in standard conditions. Our study involved evaluating the potential effect of BBR and selenium when used alone or together on the PCM–induced acute hepatic toxicity via estimation of the liver function tests, determination of the antioxidant enzyme activities, lipid peroxidation markers, immune-modulatory effects, liver histopathological, and immunohistochemical studies.
Results
Co-treatment of BBR (150 mg/kg BW) with selenium (5 mg/kg BW) showed significant improvement in the liver function parameters, the antioxidant enzyme activities, reduction in the nitric oxide (NO), lysozyme, malondialdehyde (MDA), TNF-α, and TGF-β1 levels, and marked elevation in the IgM levels.
Conclusion
Altogether, BBR, selenium, or both augment antioxidant activity and alleviate PCM-induced hepatic toxicity.
... It was suggested that bioactive compounds such as berberine were able to inhibit AST, ALT, and ALP production via activation of extracellular signal-regulated kinase activity that could inhibit Th17 differentiation. The depression effects on interleukin 17 A (IL-17 A), IL-6, and TNF-α are part of mechanisms plausibly explaining the anti-inflammatory properties of berberine (Cui et al. 2009;Jakovac et al. 2011;Lou et al. 2011;Malekinezhad et al. 2021). ...
Aflatoxin contamination in feed is a common problem in broiler chickens. The present systematic review and meta-analysis examined the impact of aflatoxin-contaminated feed and the efficacy of various feed additives on the production performance of broiler chickens fed aflatoxin-contaminated feed (AF-feed). A total of 35 studies comprising 53 AF-feed experiments were selected following PRISMA guidelines. Feed additives included in the analyses were toxins binder (TB), mannan-oligosaccharides (MOS), organic acid (OA), probiotics (PRO), protein supplementation (PROT), phytobiotics (PHY), and additive mixture (MIX). Random effects model and a frequentist network meta-analysis (NMA) were performed to rank the efficacy of feed additives, reported as standardized means difference (SMD) at 95% confidence intervals (95% CI). Overall, broiler chickens fed AF-feed had significantly lower final body weight (BW) (SMD = 198; 95% CI = 198 to 238) and higher feed conversion ratio (SMD = 0.17; 95% CI = 0.13 to 0.21) than control. Treatments with TB, MOS, and PHY improved the BW of birds fed AF-feed (P < 0.05) to be comparable with non-contaminated feed or control. Predictions on final BW from the broiler-fed aflatoxin-contaminated diet were 15% lower than the control diet. Including feed additives in the aflatoxins diet could ameliorate the depressive effect. Remarkably, our network meta-analysis highlighted that TB was the highest-performing additive (P-score = 0.797) to remedy aflatoxicosis. Altogether, several additives, especially TB, are promising to ameliorate aflatoxicosis in broiler chickens, although the efficacy was low regarding the severity of the aflatoxicosis.
... Consistent with our results, it was reported that the neuroprotective effect of Ber against learning and memory deficits in traumatic brain injury occurs through the suppression of inflammation, oxidative stress and apoptosis [55]. A growing body of evidence supports the potent anti-inflammatory effect of Ber in experimental rats [82,83]. Other researchers have also suggested that Ber is a potential agent for the treatment of liver fibrosis. ...
Background:
Liver cirrhosis (LC) is one of the chronic liver diseases with high disability and mortality accompanying hepatic encephalopathy (HE) followed by cognitive dysfunctions. In this work, the effect of berberine (Ber) on spatial cognition was studied in a rat model of LC induced by thioacetamide (TAA).
Materials and methods:
Male Wistar rats (200-250 g) were divided into six groups: (1) control; (2) TAA, 200 mg/kg/day, i.p.; (3-5) TAA + Ber; received Ber (10, 30, and 60 mg/kg, i.p., daily after last TAA injection); (6) Dizocilpine (MK-801) + TAA, received MK-801 (2 mg/kg/day, i.p.) 30 m before TAA injection. The spatial memory, BBB permeability, brain edema, liver enzymes, urea, serum and brain total bilirubin, oxidative stress and cytokine markers in the hippocampus were measured. Furthermore, a histological examination of the hippocampus was carried out.
Results:
The BBB permeability, brain edema, liver enzymes, urea, total bilirubin levels in serum and hippocampal MDA and TNF-α increased significantly after TAA injection (p < 0.001); the spatial memory was impaired (p < 0.001), and hippocampal IL-10 decreased (p < 0.001). Ber reversed all the above parameters significantly (p < 0.05, p < 0.01 and p < 0.001). MK-801 prevented the development of LC via TAA (p < 0.001).
Conclusion:
Results showed that Ber improves spatial learning and memory in TAA-induced LC by improving the BBB function, oxidative stress and neuroinflammation. Ber might be a promising therapeutic agent for cognitive improvement in LC.
... According to a metaanalysis of randomized controlled trials (RCTs) on Chinese subjects with MetS and associated illnesses, high-sensitivity C-reactive protein (hs-CRP) was strongly connected with IR (r = 0.9929, p < 0.05) (Cao and Su, 2019). BBR efficiently suppressed IL-6 and TNF-α production in palmitate (PA)-stimulated hepatocytes, indicating that BBR may increase insulin sensitivity in conjunction with its anti-inflammatory effects (Lou et al., 2011). BBR inhibited PA-induced NLRP3 inflammasome activation and caspase 1 and interleukin-1 (IL-1) release in HFD-induced IR (Zhou et al., 2017). ...
The prevalence of metabolic syndrome (MetS) is drastically growing worldwide, resulting in MetS-associated kidney disease. According to traditional theories, preventing blood pressure, lipid, glycose, and obesity and improving insulin resistance (IR), a couple of medications are required for MetS. It not only lowers patients’ compliance but also elevates adverse reactions. Accordingly, we attempted to seek answers from complementary and alternative medicine. Ultimately, berberine (BBR) was chosen due to its efficacy and safety on MetS through multi-pathways and multi-targets. The effects and mechanisms of BBR on obesity, IR, diabetic nephropathy, hypertension, hyperlipidemia, and hyperuricemia were elaborated. In addition, the overall properties of BBR and interventions for various kidney diseases were also collected. However, more clinical trials are expected to further identify the beneficial effects of BBR.
... There are studies showing that berberine treatment reduces TNF-and IL-6 in cultures of various cells (49)(50)(51)(52). The antiinflammatory activity of berberine has been also observed in splenocytes, kidneys, and liver of NOD mice (17,18). ...
The protective and/or therapeutic effect of berberine on cyclophosphamide-induced testicular injury was investigated in rats. A total of 40 male Sprague-Dawley rats were divided into 5 groups (n=8 per group). The control group received saline and CP, BER75, BER150 and BER300 groups received single dose of intraperitoneal 200 mg/kg CP on day 8. Berberine (75 mg/kg, 150 mg/kg and 300 mg/kg) was administered orally for 7 days before and after the CP injection. At the end of the protocol, testes were removed for histological examination, immunohistochemical staining, and biochemical assessments. In our study, CP did not cause a significant change in body weight and testis weight, whereas berberine treatment significantly decreased body weight. Although no significant change was observed in terms of oxidative stress markers and cytokine levels, degenerative changes and apoptotic findings were found in the CP group; which were improved significantly with increasing doses of berberine treatment. In conclusion, we found that treatment with berberine may have anti-degenerative and anti-apoptotic potential rather than altering oxidative stress markers and/or inflammatory pathways in CP-induced testicular damage.
... Numerous evidence highlighted that BBR can regulate diverse metabolic aspects and exert favorable therapeutic effects on metabolic diseases, including lowering blood glucose, increasing insulin sensitivity, ameliorating insulin resistance, regulating blood lipids, and reducing inflammation. [23][24][25][26] Recently, the atypical antipsychotics associated metabolic side effects have drawn much clinical attention. [1][2][3][4] Indeed, several studies have revealed that BBR has potential application as a therapeutic drug for antipsychotic-induced MetS. ...
Berberine (BBR), an isoquinoline alkaloid, possesses multiply pharmacological effects as a potential therapeutic drug for antipsychotic-induced metabolic syndrome (MetS). However, the underlying therapeutic mechanisms have not been fully elucidated. In this study, we aim to investigate the possible mechanisms by identifying the key targets and biological pathways through network pharmacology and molecular docking analysis. A total of 23 overlapping targets in the intersection set among BBR, atypical antipsychotic drugs (AADs), and MetS were determined. PPI network analysis showed that 22 out of the 23 overlapping targets closely interacted with the others. The following pathway enrichment analysis and molecular docking indicated a central role of peroxisome proliferator-activated receptor-γ (PPARG) as the key target of BBR against AAD-induced MetS by acting on the PPAR signaling pathway, lipid and atherosclerosis, and AMP activated protein kinase (AMPK) signaling pathway. In addition, cytochrome P-450 2D6 (CYP2D6) could be considered as another target of BBR in ameliorating antipsychotic-induced metabolic side effects. Collectively, this study investigated the central targets and biological pathways of BBR against AAD-induced MetS from a systematic perspective, and thus brings novel insights into further understanding of the protective effects of BBR.
... AMPK activation also increases energy production hence normalizing the imbalance between glucose, lipid, and energy (16). This activation can also impose antiinflammatory effects (112) and can speed up the transport of glucose in the serum by promoting glucose transporter type 4 (GLUT4) translocation (113). It is proposed by Zhang et al. that BBR can also increase the expression of the insulin receptor in a variety of human cells in type 2 diabetic patients (77). ...
Cardiovascular disease (CVD) is a major concern today. Herbal medicine is one helping way to control CVD risks. One conclusive of herbal medicine is Berberine (BBR) and converse about it still exists, to clarify this issue, this meta-analysis was performed. PubMed/Medline, Scopus, and Web of Science were searched for RCTs in adults on the effect of BBR supplementation on CVD risk factors up to July 2022. The pooled results showed BBR significantly reduced triglyceride (WMD = −23.70 mg/dl; 95%CI −30.16, −17.25; P < 0.001), total cholesterol (WMD = −20.64 mg/dl; 95%CI −23.65, −17.63; P < 0.001), low-density lipoprotein WMD = −9.63 mg/dl; 95%CI, −13.87, −5.39; P < 0.001), fasting blood glucose (FBG) (WMD = −7.74 mg/dl; 95%CI −10.79, −4.70; P < 0.001), insulin (WMD = −3.27 mg/dl; 95%CI −4.46,−2.07; P < 0.001), HbA1c (WMD = −0.45%; 95%CI −0.68, −0.23; P < 0.001), HOMA-IR (WMD = −1.04; 95%CI −1.55, −0.52; P < 0.001), systolic blood pressure (WMD = −5.46 mmHg; 95%CI −8.17, −2.76; P < 0.001), weight (WMD = −0.84; 95%CI −1.34,−0.34; P < 0.001), body mass index (WMD = −0.25 kg/m²; 95%CI −0.46, −0.04; P = 0.020), while increased high-density lipoprotein (HDL) (WMD = 1.37 mg/dl; 95%CI 0.41,2.23; P = 0.005). The optimal dose of BBR was 1 g/day for TG, TC, and weight, 1.8 g/day for insulin and HOMA-IR, and 5 g/day for HDL. FBG's most efficient time frame was 40 weeks from the beginning of supplementation, whereas DBP and waist circumference was 50 weeks. In conclusion, the lipid profile, FBG balance, obesity parameters, and SBP were improved with BBR supplementation.
Systematic review registration
CRD42022347004.
... Kung et al. [57] showed that berberine increases the expression of insulin receptor substrates (IRS) gene, which acts as a binding protein for transmitting insulin signals. Lou et al. [58] showed that berberine decreased IR by increasing IRS expression in rodent hepatocytes. A study using diabetic rats showed that BBR supplementation stimulated IRS promoters and increased insulin sensitivity by increasing the expression of IRS gene [59]. ...
Background
Pregnancy, parturition, and the onset of lactation represent an enormous physiological and hormonal challenge to the homeostasis of dairy animals, being a risk for their health and reproduction. Thus, as a part of the homothetic changes in preparturition period, goats undergo a period of IR as well as uncoupled GH/IGF-1 axis. The objective for this study was to determine the effect of berberine (BBR) during the peripartal period on hormonal alteration and somatotropic axis in dairy goats as well as glucose and insulin kinetics during an intravenous glucose tolerance test (IVGTT). At 21 days before the expected kidding date, 24 primiparous Saanen goats were assigned randomly to 4 dietary treatments. Goats were fed a basal diet from wk. 3 antepartum (AP) until wk. 3 postpartum (PP) supplemented with 0 (CTRL), 1 (BBR1), 2 (BBR2), and 4 (BBR4) g/d BBR. Blood samples were collected on days − 21, − 14, − 7, 0, 7, 14, and 21 relative to the expected kidding date. An IVGTT was also performed on day 22 PP.
Results
Compared with CTRL, supplementation with either BBR2 or BBR4 increased DMI at kidding day and PP, as well as body conditional score (BCS) and milk production (p ≤ 0.05). On d 7 and 14 PP plasma glucose was higher in BBR2- and BBR4-treated than in CTRL. The glucagon concentration was not affected by BBR during the experimental period. However, supplemental BBR indicated a tendency to decrease in cortisol concentration on days 7 (p = 0.093) and 14 (p = 0.100) PP. Lower plasma GH was observed in BBR than in non-BBR goats (p ≤ 0.05). Plasma IGF-1 concentration was enhanced in both BBR2 and BBR4 at kidding and day 7 PP (p ≤ 0.05). During the IVGTT, glucose area under the curve (AUC), clearance rate (CR), T1/2, and Tbasal was lower (p ≤ 0.05) in both BBR2 and BBR4 goats as compared with CTRL. Likewise, the insulin CR was higher (p ≤ 0.05) in goats receiving either BBR2 or BBR4 which was accompanied by a lower insulin T1/2 and AUC.
Conclusions
Altogether, our results indicated an improved glucose and insulin status along with the modulation of the somatotropic axis and glucose and insulin response to IVGTT in dairy goats supplemented with 2 and 4 g/d BBR.
... BBR has been demonstrated to have anti-inflammatory functions in a number of animal and human tissues, such as the hepatic, vascular endothelial, intestinal, and adipose tissues [138][139][140][141]. BBR inhibits the expression of several proinflammatory cytokines and acute-phase proteins, including inducible nitric oxide synthase, monocyte chemoattractant protein-1, TNF-α, cyclooxygenase-2 (COX-2), prostaglandins (PGs), IL-1β, matrix metalloprotease 9, IL-6, and C-reaction protein, all of which are essential in the prevention and treatment of inflammation-related disorders [142]. ...
Traditionally, herbal compounds have been the focus of scientific interest for the last several centuries, and continuous research into their medicinal potential is underway. Berberine (BBR) is an isoquinoline alkaloid extracted from plants that possess a broad array of medicinal properties, including anti-diarrheal, anti-fibrotic, antidiabetic, anti-inflammatory, anti-obesity, antihyperlipidemic, antihypertensive, antiarrhythmic, antidepressant, and anxiolytic effects, and is frequently utilized as a traditional Chinese medicine. BBR promotes metabolisms of glucose and lipids by activating adenosine monophosphate-activated protein kinase, stimulating glycolysis and inhibiting functions of mitochondria; all of these ameliorate type 2 diabetes mellitus. BBR has also been shown to have benefits in congestive heart failure, hypercholesterolemia, atherosclerosis, non-alcoholic fatty liver disease, Alzheimer’s disease, and polycystic ovary syndrome. BBR has been investigated as an interesting pharmacophore with the potential to contribute significantly to the research and development of novel therapeutic medicines for a variety of disorders. Despite its enormous therapeutic promise, the clinical application of this alkaloid was severely limited because of its unpleasant pharmacokinetic characteristics. Poor bioavailability, limited absorption, and poor water solubility are some of the obstacles that restricted its use. Nanotechnology has been suggested as a possible solution to these problems. The present review aims at recent updates on important therapeutic activities of BBR and different types of nanocarriers used for the delivery of BBR in different diseases.
... Both berberine and epicatechin can inhibit mucin production in sputum and have been shown to induce a bronchodilator activity which has a relaxant effect on the tracheal muscle. Additionally, epicatechin is well known to have potent antiviral and antibacterial activities [9][10][11][12][13][14][15][16]. ...
UI026 is an expectorant and antitussive agent which is a new combination of Pelargonium sidoides extract and Coptis extract. The bioactive compounds of Pelargonium sidoides and Coptis extracts were identified as epicatechin and berberine, respectively. This study evaluated the effect of food on the pharmacokinetics (PKs) and safety of UI026. A randomized, open-label, single-dose, 2-treatment, parallel study in 12 healthy male subjects was performed. Subjects received a single oral dose of UI026 (27 mL of syrup) under a fed or fasted condition according to their randomly assigned treatment. Blood samples for the PK analysis were obtained up to 24 hours post-dose for berberine and 12 hours post-dose for epicatechin. The PK parameters were calculated by non-compartmental analysis. In the fed condition, the mean maximum plasma concentration (Cmax) and mean area under the plasma concentration-time curve from time zero to the last observed time point (AUClast) for berberine were approximately 33% and 67% lower, respectively, compared with the fasted condition, both showing statistically significant difference. For epicatechin, the mean Cmax and mean AUClast were about 29% and 45% lower, respectively, compared to the fasting condition, neither of which showed a statistically significant difference. There were no drug-related adverse events. This finding suggests that food affects the systemic exposure and bioavailability of berberine and epicatechin.
Trial registration:
Clinical Research Information Service Identifier: KCT0003451.
... [48,82], and L. plantarum [83] increased the expression of proinflammatory cytokines. Berberine has been proven to have anti-inflammatory tendencies and can influence NF-κB pathways [84][85][86]. These results indicate that inactivated L. plantarum alone could increase intestinal proinflammatory response, and berberine inclusion together with L. plantarum can help ameliorate the possibility of excessive inflammation damage to EICs and maintain tissue homeostasis. ...
The interactive effect of dietary inactivated Lactobacillus plantarum and berberine on black sea bream, Acanthopagrus schlegelii, was investigated with three diets designated as D1 (Con: basal diet), D2 (LP: basal diet + 400 mg/kg L. plantarum), and D3 (LPBB: basal diet + 400 mg/kg L. plantarum + 50 mg/kg berberine) and fed to juvenile black sea bream ( 5.67 ± 0.05 g) for 56 days. The growth performance and feed utilization parameters, as well as intestinal trypsin activity, were significantly improved in the LP and LPBB groups ( P < 0.05 ). Fish fed the LPBB diet showed better serum and hepatic antioxidant capacity, whilst the LP group had better hepatic antioxidant capacity, than the control fish ( P < 0.05 ). Intestinal IgM and C3 levels significantly increased in the LPBB fish than the rest of the groups ( P < 0.05 ). NF-κB was significantly upregulated in the LP group ( P < 0.05 ). Nrf2 and IL-10 were significantly upregulated, whilst Keap1b and NF-κB were significantly downregulated in the LPBB group ( P < 0.05 ). These findings show that a combination of inactivated L. plantarum and berberine in the diet of black sea bream can improve the immune response and antioxidant capacity than a diet with only the inactivated probiotic, whilst both diets can equally improve growth performance.
... Berberine shows anti-inflammatory activity by reducing the pro-inflammatory response via the activation of AMP-activated protein kinase (AMPK) in macrophages and suppressing the expression of pro-inflammatory genes such as TNF-α, IL-Iβ, IL-6, monocyte chemoattractant protein-1 (MCP-1), COX-2, and iNOS [95]. Most importantly, berberine also inhibits the production of TNF-α and IL-6 in HepG2 cells, illustrating its anti-inflammatory activity in hepatocytes [96]. e use of berberine has been widely studied in the NDDs model. ...
Alkaloids are a type of natural compound possessing different pharmacological activities. Natural products, including alkaloids, which originate from plants, have emerged as potential protective agents against neurodegenerative disorders (NDDs) and chronic inflammations. A wide array of prescription drugs are used against these conditions, however, not free of limitations of potency, side effects, and intolerability. In the context of personalized medicine, further research on alkaloids to unravel novel therapeutic approaches in reducing complications is critical. In this review, a systematic survey was executed to collect the literature on alkaloids and their health complications, from which we found that majority of alkaloids exhibit anti-inflammatory action via nuclear factor-κB and cyclooxygenase-2 (COX-2), and neuroprotective interaction through acetylcholinesterase (AChE), COX, and β-site amyloid precursor protein activity. In silico ADMET and ProTox-II-related descriptors were calculated to predict the pharmacological properties of 280 alkaloids isolated from traditional medicinal plants towards drug development. Out of which, eight alkaloids such as tetrahydropalmatine, berberine, tetrandrine, aloperine, sinomenine, oxymatrine, harmine, and galantamine are found to be optimal within the categorical range when compared to nicotine. ese alkaloids could be exploited as starting materials for novel drug synthesis or, to a lesser extent, manage inflammation and neurodegenerative-related complications.
... Recently, an increase number of studies have revealed this compound has an extensive spectrum of biological functions such as antioxidant and anti-inflammatory (Li et al. 2014), anticancer (Sun et al. 2009), and anti-hyperglycemic (Mahmoud et al. 2017) effects. Studies have been shown that BBR attenuates the output of inflammatory mediators like TNF-α, IL-1β, IL-6, and IL-8 (Lou et al. 2011;Zhang et al. 2011Zhang et al. , 2016b. In addition, BBR seems to increase the cellular antioxidant defense machinery including increasing the activity of CAT, SOD, and GPx and decrease OS factors like protein carbonyl (PC) content, MDA and NO levels (Zhou and Zhou 2011). ...
PurposeCyclophosphamide is an alkylating agent with nephrotoxicity that constrains its clinical application. Berberine is an isoquinoline derivative alkaloid with biological functions like antioxidant and anti-inflammatory. The current research intended to examine the nephroprotective impacts of berberine against cyclophosphamide-stimulated nephrotoxicity.Methods
Forty animal subjects were randomly separated into five categories of control (Group I), cyclophosphamide (200 mg/kg, i.p., on 7th day) (Group II), and groups III and IV that received berberine 50 and 100 mg/kg orally for seven days and a single injection of cyclophosphamide on 7th day. Group V as berberine (100 mg/kg, alone). On day 8, blood samples were drawn from the retro-orbital sinus to determine serum levels of blood urea nitrogen (BUN), creatinine (Cr), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) as biomarkers for kidney injury. Nitric oxide (NO), malondialdehyde (MDA) and glutathione (GSH) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) activities as oxidative stress factors, tumor necrosis factor-α (TNF-α) and interleukin 1 beta (IL-1β) levels as inflammatory mediators were assessed in kidney tissue.ResultsThe results of this study demonstrated that berberine was able to protect remarkably the kidney from CP-induced injury through decreasing the level of BUN, Cr, NGAL, KIM-1, NO, MDA TNF-α, IL-1β and increasing the level of GSH, CAT, SOD, and GPx activities.Conclusion
Berberine may be employed as a natural agent to prevent cyclophosphamide-induced nephrotoxicity through anti-oxidant and anti-inflammatory effects.
... Consistent with these results, Wang et al. (21) showed that supplementation of 100 mg/kg BBR suppressed proinflammatory cytokines in hepatitis-induced mice. Lou et al. (54) reported that BBR effectively inhibits IL-6 and TNF-α production in a concentration-dependent manner, which demonstrates its anti-inflammatory activity in hepatocytes. Hesari et al. (55) showed that BBR could prevent inflammation via reducing IL-1, TNFα, IL-6, and MCP-1, inhibiting PGE2 and COX-2 transcriptional activity in colon and other human cancer cells. ...
As in dairy cattle, goats during the transition period face risk factors, in particular negative energy balance (NEB), inflammation, and impairment of the antioxidant response. The current study determined the effects of pre- and post-partum berberine (BBR) supplementation on antioxidant status and inflammation response during the transition period in dairy goats. Twenty-four primiparous Saanen goats were randomly divided into four groups: control (CON, without BBR) and supplemented with 1 g/day BBR (BBR1), 2 g/day BBR (BBR2), or 4 g/day BBR (BBR4). The blood samples were collected weekly from 21 days pre-partum to 21 days post-partum. Compared with CON, supplementation with either BBR2 or BBR4 decreased (P ≤ 0.05) the levels of plasma non-esterified fatty acids (NEFA) at kidding and thereafter an increased (P ≤ 0.05) the plasma levels of glucose and insulin. Following BBR ingestion, blood antioxidant status elevated throughout the transition period, so that total antioxidant capacity (TAC), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase activity were increased (P ≤ 0.05) and plasma malondialdehyde (MDA) was decreased (P ≤ 0.05). Likewise, paraoxonase (PON) was reduced (P ≤ 0.05) in goats fed BBR2 and BBR4. The levels of haptoglobin, ceruloplasmin, and bilirubin were reduced (P ≤ 0.05) by BBR2 and BBR4 immediately before kidding and thereafter. The results demonstrated that supplementation of either 2 or 4 g/day BBR enhanced antioxidant capacity and immune function of transition goats and improved post-partum performance showing its beneficial effect to mitigate oxidative stress and inflammation during the transition period in dairy goats.
... J.Xing et al., 2011). BBR ameliorated insulin resistance in HepG2 cells by modifying Ser/Thr phosphorylation of insulin receptor substrate-1 (IRS-1) and downstream Akt signaling cascade(Lou et al., 2011). These promising findings show that BBR may halt the progression of metabolic syndrome and may also be effective in metabolic disorders such as diabetes, hypertension, etc. ...
Liver diseases are life‐threatening illnesses and are the major cause of mortality and morbidity worldwide. These may include liver fibrosis, liver cirrhosis, and drug‐induced liver toxicity. Liver diseases have a wide prevalence globally and the fifth most common cause of death among all gastrointestinal disorders. Several novel therapeutic approaches have emerged for the therapy of liver diseases that may provide better clinical outcomes with improved safety. The use of phytochemicals for the amelioration of liver diseases has gained considerable popularity. Berberine (BBR), an isoquinoline alkaloid of the protoberberine type, has emerged as a promising molecule for the treatment of gastrointestinal disorders. Accumulating studies have proved the hepatoprotective effects of BBR. BBR has been shown to modulate multiple signaling pathways implicated in the pathogenesis of liver diseases including Akt/FoxO2, PPAR‐γ, Nrf2, insulin, AMPK, mTOR, and epigenetic pathways. In the present review, we have emphasized the important pharmacological activities and mechanisms of BBR in liver diseases. Further, we have reviewed various pharmacokinetic and toxicological barriers of this promising phytoconstituent. Finally, formulation‐based novel approaches are also summarized to overcome the clinical hurdles for BBR.
... This compound ( Figure 3C) can be found in roots, rhizome and the stem bark of plants, and it has been used since ancient times in Chinese medicine. Berberine has several positive effects, such as antimicrobial [66], antiinflammatory [67], anti-arhythmic [68] and antitumor activity [52]. Regarding antitumor activity, it has been observed that berberine and its derivatives are able to inhibit hTopIB in a dose-dependent manner. ...
Natural products are widely used as source for drugs development. An interesting example is represented by natural drugs developed against human topoisomerase IB, a ubiquitous enzyme involved in many cellular processes where several topological problems occur due the formation of supercoiled DNA. Human topoisomerase IB, involved in the solution of such problems relaxing the DNA cleaving and religating a single DNA strand, represents an important target in anticancer therapy. Several natural compounds inhibiting or poisoning this enzyme are under investigation as possible new drugs. This review summarizes the natural products that target human topoisomerase IB that may be used as the lead compounds to develop new anticancer drugs. Moreover, the natural compounds and their derivatives that are in clinical trial are also commented on.
... Therefore, the two types S. sobrinus and S. mutans have been applied as an important indicator for evaluation of caries risk (Loesche, 1986;Yadav & Prakash, 2016). , immunomodulation and antiinflammatory (Javadzadeh & Fallah, 2012), central nervous system (Peng et al., 2004), endocrine (Lou et al., 2011), respiratory (Lee et al., 2003), gastrointestinal (Lin et al., 2005), skin (Seki & Morohashi, 1993) and antimicrobial effects (Zarei et al., 2015). Berberine, berberamine and palmatine are the main alkaloid constituents that have been detected in this plant. ...
Objectives
The aim of this in‐vitro study was to determine the antimicrobial capacity of a Berberis vulgaris plant extract on the bacteria being associated with caries including, Streptococcus mutans, S. sobrinus, S. sanguinis, S. salivaris and Lactobacillus rhamnosus.
Material and methods
Chlorhexidine 2% (CHX) mouthwash and ampicillin (10 μg/disk) were applied as positive control groups. Inhibition zone, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) related to stem, leaf and fruit of B. vulgaris plant were recorded for every five bacteria. Data were analyzed using SPSS ver. 22, one‐way ANOVA repeated measure and post hoc Tukey statistical test. The significance level was set at p < 0.05.
Results
There were no significant differences between the antimicrobial capacity of the positive controls and the extract from the stem and fruit of B. vulgaris (p > 0.05). The MIC values of the extract from the stem were significantly lower against S. sobrinus (64 μg/ml) and L. rhamnosus (128 μg/ml). The MIC value of the extract against S. mutans was significantly lower in the fruit group (64 μg/mL). The MBC value of the extract against S. sobrinus and L. rhamnosus was significantly lower in the stem group (128 μg/ml). The MBC value against S. mutans was significantly lower in the fruit group (128 μg/ml).
Conclusions
The results showed that CHX and B. vulgaris plant extract have similar antimicrobial activity against bacteria being associated with caries. Therefore, B. vulgaris, which shows antibacterial capacity, could be considered for further investigation as a safe, phytotherapeutic mouthwash to prevent dental caries.
... It is an effective component of Coptis chinensis to lower blood sugar. Previous studies have concluded that it inhibits inflammation and improves insulin resistance (Lou et al., 2011). In addition, studies on AChE inhibiting the activity of benzylisoquinoline alkaloids indicate that berberine may be an inhibitor of AChE (D. K. Kim et al., 2004). ...
... It also inhibited liver GNG of the LKB1-AMPK-TORC2 signaling pathway and improved LPS-induced b-cell damage through LPS4-dependent JNK/NF-kB signaling pathway . In addition, BBR exerted its anti-inflammatory effect through insulin sensitization, reduced cytokine production and serine phosphorylation, and increased insulin-mediated tyrosine phosphorylation (Lou et al., 2011). ...
Insulin resistance (IR) is likely to induce metabolic syndrome and type 2 diabetes mellitus (T2DM). Gluconeogenesis (GNG) is a complex metabolic process that may result in glucose generation from certain non-carbohydrate substrates. Chinese herbal medicine astragalus polysaccharides and berberine have been documented to ameliorate IR, and combined use of astragalus polysaccharide (AP) and berberine (BBR) are reported to synergistically produce an even better effect. However, what change may occur in the GNG signaling pathway of IR-HepG2 cells in this synergistic effect and whether AP-BBR attenuates IR by regulating the GNG signaling pathway remain unclear. For the first time, we discovered in this study that the optimal time of IR-HepG2 cell model formation was 48 h after insulin intervention. AP-BBR attenuated IR in HepG2 cells and the optimal concentration was 10 mg. AP-BBR reduced the intracellular H2O2 content with no significant effect on apoptosis of IR-HepG2 cells. In addition, a rapid change was observed in intracellular calcium current of the IR-HepG2 cell model, and AP-BBR intervention attenuated this change markedly. The gene sequencing results showed that the GNG signaling pathway was one of the signaling pathways of AP-BBR to attenuate IR in IR-Hepg2 cells. The expression of p-FoxO1Ser256 and PEPCK protein was increased, and the expression of GLUT2 protein was decreased significantly in the IR-HepG2 cell model, and both of these effects could be reversed by AP-BBR intervention. AP-BBR attenuated IR in IR-HepG2 cells, probably by regulating the GNG signaling Pathway.
... 7 The anti-inflammatory effect of BER using acute phase proteins and proinflammatory cytokines as markers has been studied in multiple in vitro and in vivo studies. [34][35][36][37] In different cell lines such as immune cells, hepatocytes, adipose tissues, islets β-cells, BER could suppress the production of MCP1 (monocyte chemoattractant protein 1), interleukin (IL)-6, IL-1β, CRP and HP (hepatoglobin). Despite multiple in vitro studies, the numbers of human studies evaluating the effect of BER on inflammatory biomarkers are rare. ...
Objectives:
Clinical evidence suggests the beneficial effects of Berberine (BER) on inflammatory markers. However, these results are controversial. The aim of this systematic review was to assess the effects of BER on C-reactive protein (CRP) using clinical trials in adults.
Design:
Systematic review and meta-analysis.
Main outcome measures:
We searched randomized controlled trials in PubMed and Scopus up to November 2018. The mean differences (MD) and confidence interval (CI) of CRP (mg/L) concentrations were pooled with a random- or a fixed-effects model depending on the results of heterogeneity tests.
Results:
Of 1242 studies identified, 5 were included in the meta-analysis. Pooled analysis showed that serum levels of CRP were decreased after BER supplementation (MD:-0.64 mg/L, 95% CI(-0.67 to -0.61) P < 0.001)) without any significant heterogeneity (I2 = 0.0% and P = 0.984).
Conclusion:
This meta-analysis showed BER supplementation may ameliorate the state of chronic inflammation. Patients with cardiovascular disease and diabetes are two important groups which may benefit from BER supplementation. Further well-designed investigations with larger samples are needed to ascertain the long-term effects of BER on chronic inflammation.
... [67] Lou et al. claimed that berberine could attenuate the insulin resistance of liver cell by alleviating the inflammatory response. [68] Palmitic acid was common used for inducing hepatocyte insulin resistance animal model. Berberine could inhibit the production of IL-6 and TNF-α, and regulate the phosphorylation of serine site on IRS-1 to improve the impaired insulin signaling pathway induced by palmitate. ...
Type 2 diabetes is a serious metabolic disease as a long‐term threat to human health. Insulin resistance is not only the basis and major feature of type 2 diabetes, but also the main etiology of diseases such as hypertension, hyperlipidemia, and coronary heart disease. It has been shown that TCMs play an important role in the treatment of type 2 diabetes, through attenuating insulin resistance, whereas the mechanism involved is not yet well understood. Therefore, it is important to elucidate the pharmacological mechanism of these bioactive compounds so that one can pave the way for the modernization of TCMs. In this review article, we focus on the recent progresses of some bioactive ingredients from TCMs with different functional groups, which exhibit therapeutic potential for the treatment of diabetic insulin resistance. It is expected that this review can provide new references for developing TCM‐derived drugs against diabetes and insulin resistance in the future.
... Berberine is able to effectively inhibit the production of IL-6 and TNF-α in HepG2 cells. Its mechanism of action for anti-inflammation could be attributed to the inhibition of ERK1/2 activation [32] . This anti-inflammatory activity was similar to the data in a recent study reporting that berberine inhibited the LPS-induced inflammatory response in macrophages [26] . ...
... Inflammation and oxidation are closely associated with DM. After treatment with berberine, decrease levels of proinflammatory cytokines, such as TNF-a, IL-6, iNOS, MCP-1 and COX-2, were observed (Jeong et al. 2009;Lou et al. 2011), while IL-10 levels were elevated in diabetic animals, in related cells, and in patients . The levels of AR, SOD, GSH-px and GSH increased, while MDA decreased, indicating that oxidation was inhibited (Zhou and Zhou 2011;Lao-Ong et al. 2012). ...
Context: Coptidis rhizome (CR), also known as Huanglian in Chinese, is the rhizome of Coptis chinensis Franch., C. deltoidea C.Y. Cheng et Hsiao, or C. teeta Wall (Ranunculaceae). It has been widely used to treat bacillary dysentery, diabetes, pertussis, sore throat, aphtha, and eczema in China.
Objectives: The present paper reviews the latest advances of CR, focusing on the botany, phytochemistry, traditional usages, pharmacokinetics, pharmacology and toxicology of CR and its future perspectives.
Methods: Studies from 1985 to 2018 were reviewed from books; PhD. and MSc. dissertations; the state and local drug standards; PubMed; CNKI; Scopus; the Web of Science; and Google Scholar using the keywords Coptis, Coptidis Rhizoma, Huanglian, and goldthread.
Results: Currently, 128 chemical constituents have been isolated and identified from CR. Alkaloids are the characteristic components, together with organic acids, coumarins, phenylpropanoids and quinones. The extracts/compounds isolated from CR cover a wide pharmacological spectrum, including antibacterial, antivirus, antifungal, antidiabetic, anticancer and cardioprotective effects. Berberine is the most important active constituent and the primary toxic component of CR.
Conclusions: As an important herbal medicine in Chinese medicine, CR has the potential to treat various diseases. However, further research should be undertaken to investigate the clinical effects, toxic constituents, target organs and pharmacokinetics, and to establish criteria for quality control, for CR and its related medications. In addition, the active constituents, other than alkaloids, in both raw and processed products of CR should be investigated.
... BBR has been shown to be an effective therapeutic approach to treat insulin resistance and type 2 diabetes (Pang et al. 2015). BBR has anti-inflammatory effects in macrophages, hepatocytes, and adipocytes (Choi 2016;Lou et al. 2011). In addition, studies have revealed that BBR improves high fat diet induced hyperglycemia, glucose intolerance, and hepatic steatosis (Guo et al. 2016). ...
Obesity is associated with skeletal muscle insulin resistance and the development of metabolic syndrome. Undifferentiated skeletal muscle cells are sensitive to oxidative stress. Berberine hydrochloride (BBR) improves insulin resistance and exhibits anti-inflammatory properties. However, the underlying mechanism and the cell signaling pathways involved remain largely elusive. We therefore investigated the anti-inflammatory effects of BBR and the signaling pathways using skeletal C2C12 myoblast cells. Undifferentiated C2C12 myoblast cells were treated with interleukin-1β alone or in combination with tumor necrosis factor-α in the presence or absence of BBR. We found that BBR reduced the cytokine-induced expression of inducible nitric oxide synthase and stress-related kinases including p-38 mitogen-activated protein kinase, nuclear factor kappa B (NF-κB), and stress-activated protein kinases/Jun amino-terminal kinases (SAPK/JNK) in C2C12 myoblast cells. Furthermore, BBR reversed cytokine-mediated suppression of AMP-activated protein kinase (AMPKα), sirtuin-1 (SIRT-1), and PPAR-γ coactivator-1α (PGC-1α). In addition, cytokine-induced reduction of mitochondrial marker proteins and function were rescued after BBR treatment. Catalase, an antioxidant enzyme, was elevated after BBR treatment. Our results demonstrate that BBR ameliorates cytokine-induced inflammation. The anti-inflammatory effect of BBR in skeletal progenitor cells is mediated through pathways including activation of the AMPKα-SIRT-1-PGC-1α, inhibition of the mitogen-activated protein kinase 4 (MKK4)-SAPK/JNK-C-JUN, as well as protection of mitochondrial bioenergetics. BBR may be a potential medication for metabolic syndrome.
... Inflammatory factors IL-6 and TNF-α have been confirmed to be involved in the development of insulin resistance. Berberine was found to have the effect of reducing the production of hepatocellular IL-6 and TNF-α [35]. ...
... Berberine (BBR) is a natural compound extracted from the traditional Chinese herb Coptis chinensis and has for many years been known to have a good effect on diarrhea. Studies have shown that BBR also has potential therapeutic effects in diabetes (Zhang et al., 2010), hyperlipidemia (Kong et al., 2004;Kim et al., 2009), heart disease (Lau et al., 2001;Zeng et al., 2003), and inflammation (Choi et al., 2006;Lou et al., 2011). In addition, BBR was found to have a neuroprotective effect on multiple central nervous system diseases, such as Alzheimer's disease and epilepsy (Kulkarni and Dhir, 2010;Gao et al., 2014;Hussien et al., 2018). ...
Epilepsy is a neuronal dysfunction syndrome characterized by transient and diffusely abnormal discharges of neurons in the brain. Previous studies have shown that mutations in the syntaxin 1b (stx1b) gene cause a familial, fever-associated epilepsy syndrome. It is unclear as to whether the stx1b gene also correlates with other stimulations such as flashing and/or mediates the effects of antiepileptic drugs. In this study, we found that the expression of stx1b was present mainly in the brain and was negatively correlated with seizures in a pentylenetetrazole (PTZ)-induced seizure zebrafish model. The transcription of stx1b was inhibited by PTZ but rescued by valproate, a broad-spectrum epilepsy treatment drug. In the PTZ–seizure zebrafish model, stx1b knockdown aggravated larvae hyperexcitatory swimming and prompted abnormal trajectory movements, particularly under lighting stimulation; at the same time, the expression levels of the neuronal activity marker gene c-fos increased significantly in the brain. In contrast, stx1b overexpression attenuated seizures and decreased c-fos expression levels following PTZ-induced seizures in larvae. Thus, we speculated that a deficiency of stx1b gene expression may be related with the onset occurrence of clinical seizures, particularly photosensitive seizures. In addition, we found that berberine (BBR) reduced larvae hyperexcitatory locomotion and abnormal movement trajectory in a concentration-dependent manner, slowed down excessive photosensitive seizure-like swimming, and assisted in the recovery of the expression levels of STX1B. Under the downregulation of STX1B, BBR’s roles were limited: specifically, it only slightly regulated the levels of the two genes stx1b and c-fos and the hyperexcitatory motion of zebrafish in dark conditions and had no effect on the overexcited swimming behavior seen in conjunction with lighting stimulation. These findings further demonstrate that STX1B protein levels are negatively correlated with a seizure and can decrease the sensitivity of the photosensitive response in a PTZ-induced seizure zebrafish larvae; furthermore, STX1B may partially mediate the anticonvulsant effect of BBR. Additional investigation regarding the relationship between STX1B, BBR, and seizures could provide new cues for the development of novel anticonvulsant drugs.
... It also has the ability to inhibit TNF-α and IL-6 production in HepG2 cells. The anti-inflammatory effect of berberine may be due to the inhibition of ERK1/2 activation [66]. Its anti-inflammatory effect was postulated through the inhibition of LPS-induced inflammatory response in macrophages [64]. ...
Background/Objective: Intestinal fibrosis, a prominent consequence of inflammatory bowel disease (IBD), presents considerable difficulty owing to the absence of licensed antifibrotic therapies. This review assesses the therapeutic potential of phytochemicals as alternate methods for controlling intestinal fibrosis. Phytochemicals, bioactive molecules originating from plants, exhibit potential antifibrotic, anti-inflammatory, and antioxidant activities, targeting pathways associated with inflammation and fibrosis. Compounds such as Asperuloside, Berberine, and olive phenols have demonstrated potential in preclinical models by regulating critical signaling pathways, including TGF-β/Smad and NFκB, which are integral to advancing fibrosis. Results: The main findings suggest that these phytochemicals significantly reduce fibrotic markers, collagen deposition, and inflammation in various experimental models of IBD. These phytochemicals may function as supplementary medicines to standard treatments, perhaps enhancing patient outcomes while mitigating the adverse effects of prolonged immunosuppressive usage. Nonetheless, additional clinical trials are necessary to validate their safety, effectiveness, and bioavailability in human subjects. Conclusions: Therefore, investigating phytochemicals may lead to crucial advances in the formulation of innovative treatment approaches for fibrosis associated with IBD, offering a promising avenue for future therapeutic development.
Osteoarthritis (OA) is a prevalent chronic condition that primarily impacts the articular cartilage and surrounding bone tissue, resulting in joint inflammation and structural deterioration. The etiology of OA is multifaceted and intricately linked to the oxidative stress response of joint tissue. Oxidative stress (OS) in OA leads to the creation of reactive oxygen species (ROS) and other oxidizing agents, resulting in detrimental effects on chondrocytes. This oxidative damage diminishes the flexibility and robustness of cartilage, thereby expediting the progression of joint deterioration. Therefore, the antioxidant effect is crucial in the treatment of OA. Currently, a considerable number of components found in traditional Chinese medicine (TCM) have been scientifically demonstrated to exhibit remarkable antioxidant and anti-inflammatory properties. Nevertheless, the utilization of this program is considerably constrained as a result of intrinsic deficiencies, notably stability concerns. The successful amalgamation of TCM components with nanotechnology has properly tackled these concerns and enhanced the efficacy of therapeutic results. The objective of this study is to delineate the antioxidant characteristics of nano-TCM and assess the current inventory of literature pertaining to the application of nano-TCM in the treatment of OA. In conclusion, this paper will now turn to the constraints and potential avenues for the advancement of nano-TCM within the realm of OA therapy.
Background: Insulin resistance is one of the main factors that lead to the development of type 2 diabetes mellitus (T2DM). The effect of alkaloids on insulin resistance has been extensively examined according to multiple scientific researches.
Objective: In this work, we aimed to summarize the interesting results from preclinical and clinical studies that assessed the effects of natural alkaloids (berberine, nigelladine A, piperine, trigonelline, capsaicin, nuciferine, evodiamine, mahanine, and magnoflorine) on impaired insulin sensitivity and worsened insulin resistance, which play a pivotal role in the pathogenesis of type 2 diabetes.
Methods: In the current review, PubMed, ScienceDirect, Springer, and Google Scholar databases were used. The inclusion criteria were based on the following keywords and phrases: insulin sensitivity, insulin resistance, alkaloids and insulin resistance, alkaloids and type 2 diabetes, mechanisms of action, and alkaloids.
Results: The outcomes reported in this review demonstrated that the selected alkaloids increased insulin sensitivity and reduced insulin resistance in vitro and in vivo evidence, as well as in clinical trials, through improving insulin-signaling transduction mainly in hepatocytes, myocytes, and adipocytes, both at cellular and molecular levels. Insulin signaling components (InsR, IRS-1, PI3K, Akt, etc.), protein kinases and phosphatases, receptors, ion channels, cytokines, adipokines, and microRNAs, are influenced by alkaloids at transcriptional and translational levels, also in terms of function (activity and/or phosphorylation). Multiple perturbations associated with insulin resistance, such as ectopic lipid accumulation, inflammation, ER stress, oxidative stress, mitochondrial dysfunction, gut microbiota dysbiosis, and β-cell failure, are reversed after treatment with alkaloids. Furthermore, various indices and tests are employed to assess insulin resistance, including the Matsuda index, insulin sensitivity index (ISI), oral glucose tolerance test (OGTT), and insulin tolerance test (ITT), which are all enhanced by alkaloids. These improvements extend to fasting blood glucose, fasting insulin, and HbA1c levels as well. Additionally, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and the Homeostasis Model Assessment of β-cell function (HOMA-β) are recognized as robust markers of insulin sensitivity and β-cell function, and it is noteworthy that alkaloids also lead to improvements in these two markers.
Conclusion: Based on the findings of the current review, alkaloids may serve as both preventive and curative agents for metabolic disorders, specifically type 2 diabetes. Nonetheless, there is an urgent need for additional clinical trials to explore the potential benefits of alkaloids in both healthy individuals and those with type 2 diabetes. Additionally, it is crucial to assess any possible side effects and interactions with antidiabetic drugs.
Oxidative stress is a major cause of hepatic insulin resistance. This study investigated whether (E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HM-chromanone), a homoisoflavonoid compound isolated from Portulaca oleracea L., alleviates insulin resistance and inhibits gluconeogenesis by reducing palmitate (PA)-induced reactive oxygen species (ROS)/c-Jun NH2-terminal kinase (JNK) activation in HepG2 cells. PA treatment (0.5 mM) for 16 h resulted in the highest production of ROS and induced insulin resistance in HepG2 cells. HM-chromanone, like N-acetyl-1-cysteine, significantly decreased PA-induced ROS production in the cells. HM-chromanone also significantly inhibited PA-induced JNK activation, showing a significant reduction in tumor necrosis factor and interleukin expression levels. Thus, HM-chromanone decreased the phosphorylation of Ser307 in insulin receptor substrate 1, while increasing phosphorylation of serine–threonine kinase (AKT), thereby restoring the insulin signaling pathway impaired by PA. HM-chromanone also significantly increased the phosphorylation of forkhead box protein O, thereby inhibiting the expression of gluconeogenic enzymes and reducing glucose production in PA-treated HepG2 cells. HM-chromanone also increased glycogen synthesis by phosphorylating glycogen synthase kinase-3β. Therefore, HM-chromanone may alleviate insulin resistance and inhibit gluconeogenesis by regulating PA-induced ROS/JNK activation in HepG2 cells.
Mycotoxin contamination in feed a common problem in broiler chickens. The present systematic review and meta-analysis examined the impact of mycotoxin and efficacy of various feed additives on production performance of broiler chickens fed mycotoxin-contaminated diets (MCD). A total of 28 studies comprising 45 mycotoxin-challenged experiments were selected following PRISMA guidelines. Feed additives included in the analyses were commercial mycotoxin binder (CMB), mycotoxin binder (MB), mannan-oligosaccharides (MOS), organic acid (OA), probiotics (PRO), protein supplementation (PROT), phytobiotics (PHY), additive mixture (MIX), and a combination of CMB + other feed additives (CMB+). Random effects model and a frequentist network meta-analysis (NMA) were performed to rank the efficacy of feed additives, reported as standardized means difference (SMD) at 95% confidence intervals (95% CI). Overall, broiler chickens fed MCD had significantly lower final BW (SMD = 198; 95% CI = 198 to 238) and higher FCR (SMD = 0.17; 95% CI = 0.13 to 0.21). Treatments with MB, MOS, PHY, and MIX improved BW of birds fed MCD (P < 0.05) but lower compared to CON (P < 0.05). The NMA demonstrated that the CMB + was the highest performing additive (P-score = 0.791) to remedy mycotoxicosis. The MOS, MB, and OA also showed high efficacy based. Adverse effects on organ weights were observed on the increase of liver and heart and the decrease of intestinal tract (P < 0.001). Altogether, several feed additives may help to ameliorate mycotoxicosis in broiler chickens although the efficacy was low pertaining to the severity of the mycotoxicosis.
Purpose
Human carcinoma cells with different p53 status exposed to a combination of bioactive substances, resveratrol and berberine, revealed different responses in cell viability via p53-dependant apoptosis pathway activation.
Materials and methods
Using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, we investigated various and opposing effects in hepatocellular carcinoma cells, Hep-G2 and Hep-3B with different p53-status.
Results
Cells decreased in viability after treatment with dose-dependent concentrations of resveratrol and berberine. Hep-3B p53 mutants were more sensitive in comparison to the p53 wild type Hep-G2 cell line. A synergistic effect was observed after treatment of Hep-3B cells with a combination of resveratrol/berberine ratios in favor of resveratrol (2:1, 3:1). The results suggest that an effective concentration of berberine, in the presence of resveratrol, could be decreased even to 50% (half the IC50 for berberine) in cancer treatment. Combined treatment with berberine and resveratrol, at the investigated concentrations and fractions, significantly reduces the viability of wild type p53 Hep-G2 and null p53-mutant Hep-3B cells by 20% and 40%, respectively.
Conclusions
Stronger toxic effects on viability and proliferation were observed in Hep-3B cells what is consistent with the assumptions that null p53-mutants activate apoptosis canonical pathway. In conclusion, p53 status in human hepatocellular cancer cell lines modulates responses to plant-derived therapies.
Purpose
Cyclophosphamide is an alkylating agent with nephrotoxicity that constraints its clinical application. Berberine is an isoquinoline derivative alkaloid with biological functions like antioxidant and anti-inflammatory. The current research intended to examine the nephroprotective impacts of berberine against cyclophosphamide-stimulated nephrotoxicity.
Methods
Forty animal subjects were randomly separated into five categories of control (Group I). Cyclophosphamide (200 mg/kg, i.p., on 7th day) (Group II), and groups III and IV that received berberine 50 and 100 mg/kg orally for seven days and a single injection of cyclophosphamide on 7th day. Group V as berberine (100 mg/kg, alone). On day 8, blood samples were drawn from the retro-orbital sinus to determine serum levels of blood urea nitrogen (BUN), creatinine (Cr), Neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) as biomarkers for kidney injury. Nitric oxide (NO), malondialdehyde (MDA) and glutathione (GSH) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) activities as oxidative stress factors, tumor necrosis factor- α (TNF-α) and interleukin 1 beta (IL-1β) levels as inflammatory mediators were assessed in kidney tissue.
Results
The results of this study demonstrated that berberine was able to protect remarkably the kidney from CP-induced injury through decreasing the level of BUN, Cr, NGAL, KIM-1, NO, MDA TNF-α, IL-1β and increasing the level of GSH, CAT, SOD and GPx activities.
Conclusion
Berberine may be employed as a natural agent to prevent cyclophosphamide-induced nephrotoxicity through anti-oxidant and anti-inflammatory effects.
Previous studies have shown that berberine can improve metabolic disturbances in non-psychiatric patients, but no clinical research has been conducted in schizophrenia. This study was a randomized, double-blind, placebo-controlled clinical trial. Eligible patients diagnosed with schizophrenia were randomized to receive placebo or berberine (900mg/day) as an adjunctive treatment for eight weeks. Peripheral glycolipid metabolism parameters were measured at baseline, week 4, and week 8. Sixty-five patients were included, and forty-nine patients completed the 8-week trial. Berberine led to significant declines in total cholesterol, low-density lipoprotein cholesterol, fasting serum insulin, and insulin resistance(all p<0.05) compared with placebo. Baseline body mass index and serum prolactin concentration could predict the effect of berberine on insulin resistance. Berberine adjunctive treatment may reduce the risk of glycolipid metabolic disturbances in patients with schizophrenia.
Background
: Berberine (BBR) has been widely used to treat non-alcoholic fatty liver disease (NAFLD). The metabolites of BBR were believed to contribute significantly to its pharmacological effects. Oxyberberine (OBB), a gut microbiota-mediated oxidative metabolite of BBR, has been firstly identified in our recent work.
Purpose
: Here, we aimed to comparatively investigate the anti-NAFLD properties of OBB and BBR.
Methods
: The anti-NAFLD effect was evaluated in high-fat diet-induced obese NAFLD rats with biochemical/ELISA tests and histological staining. The related gene and protein expressions were detected by qRT-PCR and Western blotting respectively. Molecular docking and dynamic simulation were also performed to provide further insight.
Results
: Results indicated OBB remarkably and dose-dependently attenuated the clinical manifestations of NAFLD, which (100 mg/kg) achieved similar therapeutic effect to metformin (300 mg/kg) and was superior to BBR of the same dose. OBB significantly inhibited aberrant phosphorylation of IRS-1 and up-regulated the downstream protein expression and phosphorylation (PI3K, p-Akt/Akt and p-GSK-3β/GSK-3β) to improve hepatic insulin signal transduction. Meanwhile, OBB treatment remarkably alleviated inflammation via down-regulating the mRNA expression of MCP-1, Cd68, Nos2, Cd11c, while enhancing Arg1 mRNA expression in white adipose tissue. Moreover, OBB exhibited closer affinity with AMPK in silicon and superior hyperphosphorylation of AMPK in vivo, leading to increased ACC mRNA expression in liver and UCP-1 protein expression in adipose tissue. Conclusion: Taken together, compared with BBR, OBB was more capable of maintaining lipid homeostasis between liver and WAT via attenuating hepatic insulin pathway and adipocyte inflammation, which was associated with its property of superior AMPK activator.
Accompanying with diabetes mellitus‐induced osteoporosis (DM‐OS), diabetic patients show poor peri‐implant osteogenesis after implantation for dentition defect. Berberine (BBR), a candidate oral hypoglycemic agent, is a promising agent for treating DM‐OS. In this study, BBR was applied on DM rats and high‐glucose‐cultured bone mesenchymal stem cells (BMSCs) to investigate its therapeutic mechanism on DM‐OS, thus laying a theoretical basis for the future application of BBR in implant restoration. Phenotypes were assessed in the DM rats after 4 w of gavage with BBR. Furthermore, BMSCs were cultured with high glucose and BBR. Cell Counting Kit‐8, 2′,7′‐dichlorofluorescin diacetate (H2DCF‐DA), quantitative real‐time PCR (qRT‐PCR), and western blot were performed to estimate the cell proliferation, oxidative stress, and osteogenic differentiation. Moreover, the DM rats treated with BBR and insulin receptor substrate‐1 anti‐sense oligonucleotide (IRS‐1‐ASO) underwent a 4‐w implant‐healing period and then micro computed tomography (Micro‐CT) and histology were performed to verify the mechanism. Results showed that the 4‐w administration of BBR markedly improved the glucose metabolism and bone metabolism in the DM rats. in vitro experiments revealed that BBR alleviated high‐glucose‐inhibited osteogenesis of the BMSCs by upregulating reactive oxygen species (ROS)‐mediated IRS‐1 signaling. Besides, injection of IRS‐1‐ASO abolished the BBR promotion of implant osseointegration in the DM rats. In conclusion, targeting ROS‐mediated IRS‐1 signaling, BBR acted as an efficient agent to advance osseointegration in DM, which indicated that BBR use is a good strategy for future implants restoration in diabetic patients.
Aims:
This essay explores the anti-cancer activity of specific Chinese herbal medicines to clarify how effective Chinese herbal medicine is used for handling hepatocellular carcinoma.
Methods:
Literature form publica domain were studied and an analysis of anti-cancer activity of specific Chinese herbal medicines is presented in this review.
Results:
Hepatocellular carcinoma is one of the most dangerous malignant tumors in the world. The operative diagnosis of liver cancer remains a significant challenge. Although surgery tissue resection is encouraging, a high risk of recurrence and metastasis, illustrating disease-related mortality is desperately required to enhance postoperative preventive and therapeutic clinical procedures. The almost only effective clinical intervention seems to be developing advanced targeted therapies such as sorafenib for hepatocellular carcinoma patients, but there is little research in this field. Because their preventative/therapeutic properties strengthen Chinese herbal medicinal compounds, they are deemed relevant to the treatment of hepatocellular carcinoma. Conclusion: Chinese herbal medicine derivates provide multifaceted, orientated and orchestrated therapy, making it an ideal candidate for inhibiting hepatocellular tumor production and metastasis.
Objectives:
Paclitaxel (PTX) as an anticancer drug used against solid cancers, possesses adverse reactions such as neuropathic pain which has confined its use. PTX-induced neuropathic pain is mediated via activation of oxidative stress. Berberine (BER), an isoquinoline phytochemical found in several plants, exerts strong antioxidant and painkilling properties. In the current study, we aimed to evaluate pain-relieving effect of BER in a mouse model of PTX-induced neuropathic pain.
Methods:
This study was done using 42 male albino mice that were randomly divided into 6 groups (n = 7) as follow: Sham-operated (not treated with PTX), negative control group (PTX-treated mice receiving normal saline), BER 5, 10, and 20 mg/kg (PTX-treated mice receiving BER) and positive control group (PTX-treated mice receiving imipramine 10 mg/kg). Neuropathic pain was induced by intraperitoneal administration of four doses of PTX (2 mg/kg/day) on days 1, 3, 5 and 7. Then, on day 7, hot plate test was done to assess latency to heat to measure possible anti-neuropathic pain effect of BER.
Results:
Four doses of PTX 2 mg/kg/day induced neuropathy that was reduced by BER at all time-points (i.e. 0, 30, 60, 90 and 120 min) after injection (P < 0.001 in comparison to control). The statistical analysis of data showed significant differences between groups (P < 0.001 in comparison to negative control), at 30, 60, 90 and 120 min after injection of BER 5, 10 and 20 mg/kg; in other words, 30, 60, 90 and 120 min after BER administration, neuropathic pain was significantly reduced as compared to normal saline-treated mice.
Conclusion:
Altogether, our results showed that PTX could induce neuropathic pain as reflected by hyperalgesia and BER could alleviate PTX-induced thermal hyperalgesia.
Objective
To evaluate the anti-inflammatory effect of berberine (BBR) on the lipopolysaccharide (LPS)-induced acute phase response and its modulation of the altered bile acid metabolism induced by LPS treatment.
Methods
An acute phase response was induced by intraperitoneal injection of LPS (5 mg/kg, ip) in C57BL/6 J mice, and the BBR treatment group was orally administered with BBR (200 mg/ky, ig). The levels of TNFα, IL-1β and IL-6 in the serum were measured using an ELISA kit, and their expression levels in the liver were measured using qRT-PCR. The bile acid pool was measured using a commercial bile acid kit, and the expression levels of enzymes involved in bile acid metabolism were measured by qRT-PCR. The expression levels of CYP7A1, p65 NF-κB and the MAPK signaling pathway was measured using Western blotting.
Results
LPS treatment suppressed the expression of CYP7A1 and CYP8B1, and the total bile acid pool was also reduced. Pretreatment with BBR inhibited the pro-inflammatory biomarkers TNFα and IL-1β in the serum, as well as the expression of TNFα, IL-1β and iNOS mRNA in the liver. BBR treatment did not affect the reduction in the bile acid pool size induced by LPS, but significantly increased the concentration of bile acids in the liver, which was consistent with the upregulated expression of CYP7A1 and CYP8B1. The MAPK signaling pathway was activated by BBR treatment, while the p65 NF-κB signaling pathway was inhibited.
Conclusion
BBR can offer an anti-inflammatory effect and reverse the inhibition of CYP7A1 and CYP8B1 expression caused by LPS treatment, as well as induce the production of bile acids in liver, probably via MAPK signaling; However, treatment with BBR had no effect on the size of total bile acid pool.
Tumor necrosis factor-alpha (TNF) has recently been shown to induce insulin resistance. We have examined the possible effect of TNF on the early events in insulin transmembrane signaling. Incubation of the insulin-sensitive rat hepatoma Fao cells with 5 nM TNF for 1 h led to a 65% decrease in insulin-induced tyrosine phosphorylation of both the insulin receptor beta-subunit and IPS-1, its major cytosolic substrate. TNF-induced impairment of tyrosine phosphorylation was maximal at 0.5 nM and was not accompanied by any reduction in insulin binding. Sixteen hours of TNF incubation led to further impairment in insulin-induced tyrosine phosphorylation of these proteins. Our findings suggest that TNF may exert its anti-insulin effect by interrupting the early insulin-stimulated tyrosine phosphorylation events, which are crucial to insulin transmembrane signature.
To examine the mechanism by which free fatty acids (FFA) induce insulin resistance in human skeletal muscle, glycogen, glucose-6-phosphate, and intracellular glucose concentrations were measured using carbon-13 and phosphorous-31 nuclear magnetic resonance spectroscopy in seven healthy subjects before and after a hyperinsulinemic-euglycemic clamp following a five-hour infusion of either lipid/heparin or glycerol/heparin. IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity was also measured in muscle biopsy samples obtained from seven additional subjects before and after an identical protocol. Rates of insulin stimulated whole-body glucose uptake. Glucose oxidation and muscle glycogen synthesis were 50%-60% lower following the lipid infusion compared with the glycerol infusion and were associated with a approximately 90% decrease in the increment in intramuscular glucose-6-phosphate concentration, implying diminished glucose transport or phosphorylation activity. To distinguish between these two possibilities, intracellular glucose concentration was measured and found to be significantly lower in the lipid infusion studies, implying that glucose transport is the rate-controlling step. Insulin stimulation, during the glycerol infusion, resulted in a fourfold increase in PI 3-kinase activity over basal that was abolished during the lipid infusion. Taken together, these data suggest that increased concentrations of plasma FFA induce insulin resistance in humans through inhibition of glucose transport activity; this may be a consequence of decreased IRS-1-associated PI 3-kinase activity.
Tumor necrosis factor-alpha (TNF) has recently been shown to induce insulin resistance. We have examined the possible effect of TNF on the early events in insulin transmembrane signaling. Incubation of the insulin-sensitive rat hepatoma Fao cells with 5 nM TNF for 1 h led to a 65% decrease in insulin-induced tyrosine phosphorylation of both the insulin receptor beta-subunit and IRS-1, its major cytosolic substrate. TNF-induced impairment of tyrosine phosphorylation was maximal at 0.5 nM and was not accompanied by any reduction in insulin binding. Sixteen hours of TNF incubation led to further impairment in insulin-induced tyrosine phosphorylation of these proteins. Our findings suggest that TNF may exert its anti-insulin effect by interrupting the early insulin-stimulated tyrosine phosphorylation events, which are crucial to insulin transmembrane signaling.
Tumor necrosis factor-α (TNF-α) is an important mediator of insulin resistance in obesity and diabetes through its ability
to decrease the tyrosine kinase activity of the insulin receptor (IR). Treatment of cultured murine adipocytes with TNF-α
was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of
the IR tyrosine kinase activity in vitro. Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-α-mediated
inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-α.
An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-α induces
insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.
The function of Akt (protein kinase B) is regulated by phosphorylation on two sites conserved within the AGC kinase family:
the activation loop (Thr-308) in the kinase core and a hydrophobic phosphorylation site on the carboxyl terminus (Ser-473).
Thr-308 is phosphorylated by the phosphoinositide-dependent kinase-1, (PDK-1), whereas the mechanism of phosphorylation of
the hydrophobic site, tentatively referred to as the PDK-2 site, is unknown. Here we report that phosphorylation of the hydrophobic
motif requires catalytically competent Akt. First we show that a kinase-inactive construct of Akt fails to incorporate phosphate
at Ser-473 following IGF-1 stimulation in vivo but does incorporate phosphate at Thr-308 and a second carboxyl-terminal site, Thr-450; this ligand triggers the phosphorylation
of both sites in wild-type enzyme. Neither does a catalytically inactive construct in which phosphorylation at the activation
loop is blocked, T308A, become phosphorylated on the hydrophobic site in response to stimulation. Second, we show that Akt
autophosphorylates on the hydrophobic site in vitro: phosphorylation of the activation loop by PDK-1 triggers the phosphorylation of the hydrophobic site in kinase-active, but
not thermally inactivated, Akt α. Thus, Akt is regulated by autophosphorylation at the Ser-473 hydrophobic site.
The molecular mechanism whereby tumor necrosis factor-alpha (TNF-alpha) induces insulin resistance in obesity is not well understood. Previously, we have shown that inhibition of TNF-alpha improved hepatic insulin sensitivity in obese Zucker rats without altering the tyrosine phosphorylation of liver insulin receptors (IRs), which indicates that the TNF-alpha and insulin-signaling cascades interact distally to the IR. To assess the effects of TNF-alpha on signaling molecules downstream from the IR, we analyzed the tyrosine phosphorylation patterns of liver homogenate proteins from TNF-alpha-neutralized fa/fa rats and showed that focal adhesion kinase (FAK) was consistently hyperphosphorylated (4.5-fold). Moreover, intravenous insulin increased hepatic FAK phosphorylation in a time-dependent manner in Sprague-Dawley rats, which suggests that TNF-alpha may induce hepatic insulin resistance by preventing FAK phosphorylation in response to insulin treatment. To explore the cellular mechanism whereby TNF-alpha regulates phosphorylation of FAK in the liver, we measured c-Src kinase activity and the abundance of 3 major protein tyrosine phosphatases (PTPs) (PTP-1B, leukocyte antigen-related tyrosine phosphatase [LAR], and src homology 2 domain-containing protein-tyrosine phosphatase [SHPTP-2]) in liver homogenates from obese Zucker rats after TNF-alpha blockade. Hepatic c-Src kinase activity was unaltered, but LAR protein was reduced by 75%. In addition, TNF-alpha blockade reduced hepatic PTP activity toward tyrosine phosphorylated FAK by 70%, and this was accounted for by immunodepletion of LAR. Incubation of HepG2 cells with TNF-alpha increased LAR protein levels in a dose-dependent manner. Additionally, pretreatment with TNF-alpha abolished insulin-stimulated tyrosine phosphorylation of FAK in HepG2 cells but had no effect on IR tyrosine phosphorylation or expression. These data suggest that TNF-alpha promotes LAR expression and thus prevents insulin-mediated tyrosine phosphorylation of FAK. This probably represents the interface between TNF-alpha and insulin signaling in the liver.
Skeletal muscle and adipose tissue lipolysis rates were quantitatively compared in 12 healthy nonobese and 14 insulin-resistant obese subjects for 3.5 h after an oral glucose load using microdialysis measurements of interstitial glycerol concentrations and determinations of local blood flow with 133Xe clearance in the gastrocnemius muscle and in abdominal subcutaneous adipose tissue. Together with measurements of arterialized venous plasma glycerol, the absolute rates of glycerol mobilization were estimated. In the basal state, skeletal muscle and adipose tissue glycerol levels were 50% higher (P < 0.05-0.01) and adipose tissue blood flow (ATBF) and muscle blood flow (MBF) rates were 30-40% lower (P < 0.02-0.05) in obese versus nonobese subjects. After glucose ingestion, adipose tissue glycerol levels were rapidly and transiently reduced, whereas in muscle, a progressive and less pronounced fall in glycerol levels was evident. MBF remained unchanged in both study groups, whereas ATBF increased more markedly (P < 0.01) in the nonobese versus obese subjects after the oral glucose load. The fasting rates of glycerol release per unit of tissue weight from skeletal muscle were between 20 and 25% of that from adipose tissue in both groups. After glucose ingestion, the rates of glycerol release from skeletal muscle and from adipose tissue were almost identical in nonobese and obese subjects. However, the kinetic patterns differed markedly between tissues; in adipose tissue, the rate of glycerol mobilization was suppressed by 25-30% (P < 0.05) after glucose ingestion, whereas no significant reduction was registered in skeletal muscle. We conclude that significant amounts of glycerol are released from skeletal muscle, which suggests that muscle lipolysis provides an important endogenous energy source in humans. In response to glucose ingestion, the regulation of skeletal muscle glycerol release differs from that in adipose tissue; although the rate of glycerol release from adipose tissue is clearly suppressed, the rate of glycerol mobilization from skeletal muscle remains unaltered. In quantitative terms, the rate of glycerol release per unit of tissue weight in adipose tissue and in skeletal muscle is similar in nonobese and obese subjects in both the postabsorptive state and after glucose ingestion.
To determine causes of interindividual variation in insulin requirements, we recruited 20 type 2 diabetic patients with stable glucose control and insulin doses for >1 year on combination therapy with bedtime NPH insulin and metformin. Insulin absorption (increase in free and total insulin over 8 h after a subcutaneous dose of regular insulin) and actions of intravenous (6-h 0.3 mU x kg(-1) x min(-1) euglycemic insulin clamp combined with [3-3H]glucose) and subcutaneous (glucose infusion rate required to maintain isoglycemia and suppression of free fatty acids [FFAs]) insulin, liver fat content (proton spectroscopy), visceral fat (magnetic resonance imaging), weight, and body composition were determined. We found the following variation in parameters: insulin dose range 10-176 U (mean 42 U, fold variation 17.6x) or 0.13-1.39 U/kg (0.44 U/kg, 10.7x), absorbed insulin 10.6x, action of subcutaneous insulin to suppress FFAs 7.5 x and to stimulate glucose metabolism (M value) 11.5x, body weight 67-127 kg (91 kg, 1.9x), liver fat 2-28% (12%, 14x), and visceral fat 179-2,053 ml (1,114 ml, 11.5x). The amount of insulin absorbed, measured as either free or total insulin, was significantly correlated with its ability to suppress FFAs and stimulate glucose metabolism but not with the insulin dose per se. The actions of absorbed insulin were, on the other hand, significantly correlated with the daily insulin dose (r = 0.70 for action on FFAs, P < 0.001, and r = -0.61 for M value, P < 0.005). Actions of subcutaneous and intravenous insulin to suppress FFAs were significantly correlated (r = 0.82, P < 0.001, R2 = 67%). Of the measures of adiposity, the percent hepatic fat was the parameter best correlated with the daily insulin dose (r = 0.76, P < 0.001). The percent hepatic fat was also significantly correlated with the ability of intravenous insulin to suppress endogenous glucose production (r = 0.72, P < 0.005). We conclude that the major reason for interindividual variation in insulin requirements in type 2 diabetes is the variation in insulin action. Variation in hepatic fat content may influence insulin requirements via an effect on the sensitivity of endogenous glucose production to insulin.
Incubation of rat hepatoma Fao cells with insulin leads to a transient rise in Tyr phosphorylation of insulin receptor substrate (IRS) proteins. This is followed by elevation in their P-Ser/Thr content, and their dissociation from the insulin receptor (IR). Wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, abolished the increase in the P-Ser/Thr content of IRS-1, its dissociation from the IR, and the decrease in its P-Tyr content following 60 min of insulin treatment, indicating that the Ser kinases that negatively regulate IRS-1 function are downstream effectors of PI3K. PKCzeta fulfills this criterion, being an insulin-activated downstream effector of PI3K. Overexpression of PKCzeta in Fao cells, by infection of the cells with adenovirus-based PKCzeta construct, had no effect on its own, but it accelerated the rate of insulin-stimulated dissociation of IR.IRS-1 complexes and the rate of Tyr dephosphorylation of IRS-1. The insulin-stimulated negative regulatory role of PKCzeta was specific and could not be mimic by infecting Fao cells with adenoviral constructs encoding for PKC alpha, delta, or eta. Because the reduction in P-Tyr content of IRS-1 was accompanied by a reduced association of IRS-1 with p85, the regulatory subunit of PI3K, it suggests that this negative regulatory process induced by PKCzeta, has a built-in attenuation signal. Hence, insulin triggers a sequential cascade in which PI3K-mediated activation of PKCzeta inhibits IRS-1 functions, reduces complex formation between IRS-1 and PI3K, and inhibits further activation of PKCzeta itself. These findings implicate PKCzeta as a key element in a multistep negative feedback control mechanism of IRS-1 functions.
The cytokines TNF and IL-6 play a critical role early in liver regeneration following partial hepatectomy (PH). Since IL-6 activates signal transducers and activators of transcription (STATs), we examined whether the suppressors of cytokine signaling (SOCS) may be involved in terminating IL-6 signaling. We show here that SOCS-3 mRNA is induced 40-fold 2 hours after surgery. SOCS-2 and CIS mRNA are only weakly induced, and SOCS-1 is not detectable. SOCS-3 induction after PH is transient and correlates with a decrease in STAT-3 DNA binding and a loss of tyrosine 705 phosphorylation. This response is markedly reduced in IL-6 knockout (KO) mice. TNF injection induces SOCS-3 mRNA in wild-type mice (albeit weakly compared with the increase observed after PH) but not in TNF receptor 1 or IL-6 KO mice. In contrast, IL-6 injection induces SOCS-3 in these animals, demonstrating a requirement for IL-6 in SOCS-3 induction. IL-6 injection into wild-type mice also induces SOCS-1, -2, and CIS mRNA, in addition to SOCS-3. Together, these results suggest that SOCS-3 may be a key component in downregulating STAT-3 signaling after PH and that SOCS-3 mRNA levels in the regenerating liver are regulated by IL-6.
The primary genetic, environmental, and metabolic factors responsible for causing insulin resistance and pancreatic beta-cell failure and the precise sequence of events leading to the development of type 2 diabetes are not yet fully understood. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues are an early manifestation of conditions characterized by insulin resistance and are detectable before the development of postprandial or fasting hyperglycemia. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes. It is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. Adverse metabolic consequences of increased FFA flux, to be discussed in this review, are extremely wide ranging and include, but are not limited to: 1) dyslipidemia and hepatic steatosis, 2) impaired glucose metabolism and insulin sensitivity in muscle and liver, 3) diminished insulin clearance, aggravating peripheral tissue hyperinsulinemia, and 4) impaired pancreatic beta-cell function. The precise biochemical mechanisms whereby fatty acids and cytosolic triglycerides exert their effects remain poorly understood. Recent studies, however, suggest that the sequence of events may be the following: in states of positive net energy balance, triglyceride accumulation in "fat-buffering" adipose tissue is limited by the development of adipose tissue insulin resistance. This results in diversion of energy substrates to nonadipose tissue, which in turn leads to a complex array of metabolic abnormalities characteristic of insulin-resistant states and type 2 diabetes. Recent evidence suggests that some of the biochemical mechanisms whereby glucose and fat exert adverse effects in insulin-sensitive and insulin-producing tissues are shared, thus implicating a diabetogenic role for energy excess as a whole. Although there is now evidence that weight loss through reduction of caloric intake and increase in physical activity can prevent the development of diabetes, it remains an open question as to whether specific modulation of fat metabolism will result in improvement in some or all of the above metabolic derangements or will prevent progression from insulin resistance syndrome to type 2 diabetes.
We determined whether interindividual variation in hepatic insulin sensitivity could be attributed to variation in liver fat content (LFAT) independent of obesity. We recruited 30 healthy nondiabetic men whose LFAT (determined by proton spectroscopy); intraabdominal, sc, and total (determined by magnetic resonance imaging) fat; and insulin sensitivity of endogenous glucose rate of production (R(a)) and suppression of serum FFA [euglycemic insulin clamp combined with [3-(3)H]glucose (0-300 min); insulin infusion rate, 0.3 mU/kg.min, 120-300 min] were measured. The men were divided into groups of low (mean +/- SD, 1.7 +/- 0.2%) and high (10.5 +/- 2.0%) LFAT based on their median fat content. The low and high LFAT groups were comparable with respect to age (44 +/- 2 vs. 42 +/- 2 yr), body mass index (25 +/- 1 vs. 26 +/- 1 kg/m(2) ), waist to hip ratio (0.953 +/- 0.013 vs. 0.953 +/- 0.013), maximal oxygen uptake (35.6 +/- 1.5 vs. 33.5 +/- 1.5 ml/kg.min), and intraabdominal, sc, and total fat. The high compared with the low LFAT group had several features of insulin resistance, including fasting hyperinsulinemia (7.3 +/- 0.6 vs. 5.3 +/- 0.6 mU/liter; P < 0.02, high vs. low LFAT) hypertriglyceridemia (1.4 +/- 0.2 vs. 0.9 +/- 0.1 mmol/liter; P < 0.02), a low high density lipoprotein (HDL) cholesterol concentration (1.4 +/- 0.1 vs. 1.6 +/- 0.1 mmol/liter; P < 0.05), and a higher ambulatory 24-h systolic blood pressure (130 +/- 3 vs. 122 +/- 3 mm Hg; P < 0.05). Basal glucose R(a) and serum FFA were comparable between the groups, whereas insulin suppression of glucose R(a) [51 +/- 8 vs. 20 +/- 12 mg/m(2).min during 240-300 min (P < 0.05) or -55 +/- 7 vs. -85 +/- 12% below basal (P < 0.05, high vs. low LFAT)] and of serum FFA (299 +/- 33 vs. 212 +/- 13 micromol/liter; 240-300 min; P < 0.02) were impaired in the high compared with the low LFAT group. Insulin stimulation of glucose Rd were comparable in the men with high LFAT (141 +/- 12 mg/m(2).min) and those with low LFAT (156 +/- 14 mg/m(2).min; P = NS). Fat accumulation in the liver is, independent of body mass index and intraabdominal and overall obesity, characterized by several features of insulin resistance in normal weight and moderately overweight subjects.
Obesity and diabetes are increasing in the United States.
To estimate the prevalence of obesity and diabetes among US adults in 2001.
Random-digit telephone survey of 195 005 adults aged 18 years or older residing in all states participating in the Behavioral Risk Factor Surveillance System in 2001.
Body mass index, based on self-reported weight and height and self-reported diabetes.
In 2001 the prevalence of obesity (BMI > or =30) was 20.9% vs 19.8% in 2000, an increase of 5.6%. The prevalence of diabetes increased to 7.9% vs 7.3% in 2000, an increase of 8.2%. The prevalence of BMI of 40 or higher in 2001 was 2.3%. Overweight and obesity were significantly associated with diabetes, high blood pressure, high cholesterol, asthma, arthritis, and poor health status. Compared with adults with normal weight, adults with a BMI of 40 or higher had an odds ratio (OR) of 7.37 (95% confidence interval [CI], 6.39-8.50) for diagnosed diabetes, 6.38 (95% CI, 5.67-7.17) for high blood pressure, 1.88 (95% CI,1.67-2.13) for high cholesterol levels, 2.72 (95% CI, 2.38-3.12) for asthma, 4.41 (95% CI, 3.91-4.97) for arthritis, and 4.19 (95% CI, 3.68-4.76) for fair or poor health.
Increases in obesity and diabetes among US adults continue in both sexes, all ages, all races, all educational levels, and all smoking levels. Obesity is strongly associated with several major health risk factors.
The current study was undertaken to examine metabolic and body composition correlates of fatty liver in type 2 diabetes mellitus (DM). Eighty-three men and women with type 2 DM [mean body mass index (BMI): 34 +/- 0.5 kg/m2] and without clinical or laboratory evidence of liver dysfunction had body composition assessments of fat mass (FM), visceral adipose tissue (VAT), liver and spleen computed tomography (CT) attenuation (ratio of liver to spleen), muscle CT attenuation, and thigh adiposity; these assessments were also performed in 12 lean and 15 obese nondiabetic volunteers. Insulin sensitivity was measured with a euglycemic insulin infusion (40 mU. m-2. min-1) combined with systemic indirect calorimetry to assess glucose and lipid oxidation, and with infusions of [2H2]glucose for assessment of endogenous glucose production. A majority of those with type 2 DM (63%) met CT criteria for fatty liver, compared with 20% of obese and none of the lean nondiabetic volunteers. Fatty liver was most strongly correlated with VAT (r = -0.57, P < 0.0001) and less strongly but significantly associated with BMI (r = -0.42, P < 0.001) and FM (r = -0.37, P < 0.001), but only weakly associated with subcutaneous adiposity (r = -0.29; P < 0.01). Fatty liver was also correlated with subfascial adiposity of skeletal muscle (r = -0.44; P < 0.01). Volunteers with type 2 DM and fatty liver were substantially more insulin resistant those with type 2 DM but without fatty liver (P < 0.001) and had higher levels of plasma free fatty acids (P < 0.01) and more severe dyslipidemia (P < 0.01), a pattern observed in both genders. Plasma levels of cytokines were increased in relation to fatty liver (r = -0.34; P < 0.01). In summary, fatty liver is relatively common in overweight and obese volunteers with type 2 DM and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inflammatory markers.
To explore the anti-diabetic effects of berberine and its influence on insulin secretion.
Impaired glucose tolerance rats induced by iv injection of streptozotocin 30 mg/kg were treated with berberine 187.5 and 562.5 mg/kg while fed with high fat laboratory chow. After rats were treated for 4 weeks, oral glucose tolerance was determined, and for 8 weeks, the fasting blood glucose, insulin, lipid series were determined. In insulin secretion experiments, berberine 93.75, 187.5, and 562.5 mg/kg was administered orally to BALB/c mice at a bolus. The murine serum was collected 2 h after the berberine administration for insulin determination. Insulin released from HIT-T15 cells and pancreatic islets incubated with berberine 1-100 micromol/L for 12 h was determined.
The levels of fasting blood glucose (7.4+/-1.5 or 7.3+/-1.3 vs 9.3+/-1.3 mmol/L), triglycerides (0.61+/-0.22 or 0.63+/-0.17 vs 1.8+/-0.7 mmol/L), total cholesterol (1.8+/-0.3 or 1.9+/-0.3 vs 2.2+/-0.2 mmol/L), free fatty acid (456+/-93 or 460+/-72 vs 550+/-113 micromol/L) and apolipoprotein B (0.37+/-0.02 or 0.42+/-0.05 vs 0.46+/-0.04 g/L) were reduced greatly in berberine-treated groups at doses of 187.5 and 562.5 mg/g/d, respectively as compared with those in control group (P<0.05 or P<0.01), whereas high density lipoprotein-cholesterol (1.5+/-0.3 or 1.4+/-0.3 vs 1.1+/-0.1 g/L), apolipoprotein AI (0.80+/-0.08 or 0.87+/-0.08 vs 0.71+/-0.06 g/L) were significantly increased (P<0.05 or P<0.01), and oral glucose tolerance was improved. In vitro experiment showed that berberine 1-10 micromol/L facilitated insulin secretion of HIT-T15 cells and murine pancreatic islets in a dose-dependent manner. Meanwhile murine serum insulin level (27.5+/-2.7 or 29+/-4 or 29+/-4 vs 24.3+/-2.8 pIU/L) was undoubtedly promoted and blood glucose (4.52+/-0.31 or 4.45+/-0.29 or 4.30+/-0.19 vs 4.87+/-0.21 mmol/L) was reduced after berberine administration at doses of 93.75, 187.5, and 562.5 mg/kg, respectively in the BALB/c mice.
Berberine possesses anti-diabetic effects, which is related to the property of stimulating insulin secretion and modulating lipids.
Ser/Thr phosphorylation of insulin receptor substrate (IRS) proteins negatively modulates insulin signaling. Therefore, the identification of serine sites whose phosphorylation inhibit IRS protein functions is of physiological importance. Here we mutated seven Ser sites located proximal to the phosphotyrosine binding domain of insulin receptor substrate 1 (IRS-1) (S265, S302, S325, S336, S358, S407, and S408) into Ala. When overexpressed in rat hepatoma Fao or CHO cells, the mutated IRS-1 protein in which the seven Ser sites were mutated to Ala (IRS-1(7A)), unlike wild-type IRS-1 (IRS-1(WT)), maintained its Tyr-phosphorylated active conformation after prolonged insulin treatment or when the cells were challenged with inducers of insulin resistance prior to acute insulin treatment. This was due to the ability of IRS-1(7A) to remain complexed with the insulin receptor (IR), unlike IRS-1(WT), which underwent Ser phosphorylation, resulting in its dissociation from IR. Studies of truncated forms of IRS-1 revealed that the region between amino acids 365 to 430 is a main insulin-stimulated Ser phosphorylation domain. Indeed, IRS-1 mutated only at S408, which undergoes phosphorylation in vivo, partially maintained the properties of IRS-1(7A) and conferred protection against selected inducers of insulin resistance. These findings suggest that S408 and additional Ser sites among the seven mutated Ser sites are targets for IRS-1 kinases that play a key negative regulatory role in IRS-1 function and insulin action. These sites presumably serve as points of convergence, where physiological feedback control mechanisms, which are triggered by insulin-stimulated IRS kinases, overlap with IRS kinases triggered by inducers of insulin resistance to terminate insulin signaling.
We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalpha superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically.
Berberine has been shown to have antidiabetic properties, although its mode of action is not known. Here, we have investigated the metabolic effects of berberine in two animal models of insulin resistance and in insulin-responsive cell lines. Berberine reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in db/db mice. Similarly, berberine reduced body weight and plasma triglycerides and improved insulin action in high-fat-fed Wistar rats. Berberine downregulated the expression of genes involved in lipogenesis and upregulated those involved in energy expenditure in adipose tissue and muscle. Berberine treatment resulted in increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 adipocytes and L6 myotubes, increased GLUT4 translocation in L6 cells in a phosphatidylinositol 3' kinase-independent manner, and reduced lipid accumulation in 3T3-L1 adipocytes. These findings suggest that berberine displays beneficial effects in the treatment of diabetes and obesity at least in part via stimulation of AMPK activity.
TLR4 is the receptor for LPS and plays a critical role in innate immunity. Stimulation of TLR4 activates proinflammatory pathways and induces cytokine expression in a variety of cell types. Inflammatory pathways are activated in tissues of obese animals and humans and play an important role in obesity-associated insulin resistance. Here we show that nutritional fatty acids, whose circulating levels are often increased in obesity, activate TLR4 signaling in adipocytes and macrophages and that the capacity of fatty acids to induce inflammatory signaling in adipose cells or tissue and macrophages is blunted in the absence of TLR4. Moreover, mice lacking TLR4 are substantially protected from the ability of systemic lipid infusion to (a) suppress insulin signaling in muscle and (b) reduce insulin-mediated changes in systemic glucose metabolism. Finally, female C57BL/6 mice lacking TLR4 have increased obesity but are partially protected against high fat diet-induced insulin resistance, possibly due to reduced inflammatory gene expression in liver and fat. Taken together, these data suggest that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.
Berberine (BBR), an isoquinoline alkaloid, has a wide range of pharmacological effects, yet its exact mechanism is unknown. In order to understand the anti-adipogenic effect of BBR, we studied the change of expression of several adipogenic enzymes of 3T3-L1 cells by BBR treatment. First, we measured the change of leptin and glycerol in the medium of 3T3-L1 cells treated with 1 micrometer, 5 micrometer and 10 micrometer concentrations of BBR. We also measured the changes of adipogenic and lipolytic factors of 3T3-L1. In 3T3-L1 cells, both leptin and adipogenic factors (SREBP-1c, C/EBP-alpha, PPAR-gamma, fatty acid synthase, acetyl-CoA carboxylase, acyl-CoA synthase and lipoprotein lipase) were reduced by BBR treatment. Glycerol secretion was increased, whereas expression of lipolytic enzymes (hormone-sensitive lipase and perilipin) mRNA was slightly decreased. Next, we measured the change of inflammation markers of 3T3-L1 cells by BBR treatment. This resulted in the down-regulation of mRNA level of inflammation markers such as TNF-alpha, IL-6, C- reactive protein and haptoglobin. Taken together, our data shows that BBR has both anti-adipogenic and anti-inflammatory effects on 3T3-L1 adipocytes, and the anti-adipogenic effect seems to be due to the down-regulation of adipogenic enzymes and transcription factors.
Recent evidence indicates that inflammatory pathways are causally involved in insulin resistance. In particular, Ikappa Balpha kinase beta (IKKbeta ), which can impair insulin signaling directly via serine phosphorylation of insulin receptor substrates (IRS) and/or indirectly via induction of transcription of proinflammatory mediators, has been implicated in free fatty acid (FFA)-induced insulin resistance in skeletal muscle. However, it is unclear whether liver IKKbeta activation plays a causal role in hepatic insulin resistance caused by acutely elevated FFA. In the present study, we wished to test the hypothesis that sodium salicylate, which inhibits IKKbeta , prevents hepatic insulin resistance caused by short-term elevation of FFA. To do this, overnight-fasted Wistar rats were subject to 7-h i.v. infusion of either saline or Intralipid plus 20 U/ml heparin (IH; triglyceride emulsion that elevates FFA levels in vivo) with or without salicylate. Hyperinsulinemic-euglycemic clamp with tracer infusion was performed to assess insulin-induced stimulation of peripheral glucose utilization and suppression of endogenous glucose production (EGP). Infusion of IH markedly decreased (P < 0.05) insulin-induced stimulation of peripheral glucose utilization and suppression of EGP, which were completely prevented by salicylate co-infusion. Furthermore, salicylate reversed IH-induced 1) decrease in Ikappa Balpha content; 2) increase in serine phosphorylation of IRS-1 (Ser 307) and IRS-2 (Ser 233); 3) decrease in tyrosine phosphorylation of IRS-1 and IRS-2; and 4) decrease in serine 473-phosphorylated Akt in the liver. These results demonstrate that inhibition of IKKbeta prevents FFA-induced impairment of hepatic insulin signaling, thus implicating IKKbeta as a causal mediator of hepatic insulin resistance caused by acutely elevated plasma FFA.
It has recently been known that berberine, an alkaloid of medicinal plants, has anti-hyperglycemic effects. To explore the mechanism underlying this effect, we used 3T3-L1 adipocytes for analyzing the signaling pathways that contribute to glucose transport. Treatment of berberine to 3T3-L1 adipocytes for 6 h enhanced basal glucose uptake both in normal and in insulin-resistant state, but the insulin-stimulated glucose uptake was not augmented significantly. Inhibition of phosphatidylinositol 3-kinase (PI 3-K) by wortmannin did not affect the berberine effect on basal glucose uptake. Berberine did not augment tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate (IRS)-1. Further, berberine had no effect on the activity of the insulin-sensitive downstream kinase, atypical protein kinase C (PKCzeta/lambda). However, interestingly, extracellular signal-regulated kinases (ERKs), which have been known to be responsible for the expression of glucose transporter (GLUT)1, were significantly activated in berberine-treated 3T3-L1 cells. As expected, the level of GLUT1 protein was increased both in normal and insulin-resistant cells in response to berberine. But berberine affected the expression of GLUT4 neither in normal nor in insulin-resistant cells. In addition, berberine treatment increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 cells, which has been reported to be associated with GLUT1-mediated glucose uptake. Together, we concluded that berberine increases glucose transport activity of 3T3-L1 adipocytes by enhancing GLUT1 expression and also stimulates the GLUT1-mediated glucose uptake by activating GLUT1, a result of AMPK stimulation.
Berberine, a natural plant alkaloid, is usually used as an antibiotic drug. The potential glucose-lowering effect of berberine was noted when it was used for diarrhea in diabetic patients. In vitro and in vivo studies have then showed its effects on hyperglycemia and dyslipidemia.
The objective of the study was to evaluate the efficacy and safety of berberine in the treatment of type 2 diabetic patients with dyslipidemia.
One hundred sixteen patients with type 2 diabetes and dyslipidemia were randomly allocated to receive berberine (1.0 g daily) and the placebo for 3 months. The primary outcomes were changes in plasma glucose and serum lipid concentrations. Glucose disposal rate (GDR) was measured using a hyperinsulinemic euglycemic clamp to assess insulin sensitivity.
In the berberine group, fasting and postload plasma glucose decreased from 7.0 +/- 0.8 to 5.6 +/- 0.9 and from 12.0 +/- 2.7 to 8.9 +/- 2.8 mm/liter, HbA1c from 7.5 +/- 1.0% to 6.6 +/- 0.7%, triglyceride from 2.51 +/- 2.04 to 1.61 +/- 1.10 mm/liter, total cholesterol from 5.31 +/- 0.98 to 4.35 +/- 0.96 mm/liter, and low-density lipoprotein-cholesterol from 3.23 +/- 0.81 to 2.55 +/- 0.77 mm/liter, with all parameters differing from placebo significantly (P < 0.0001, P < 0.0001, P < 0.0001, P = 0.001, P < 0.0001, and P <0.0001, respectively). The glucose disposal rate was increased after berberine treatment (P = 0.037), although no significant change was found between berberine and placebo groups (P = 0.063). Mild to moderate constipation was observed in five participants in the berberine group.
Berberine is effective and safe in the treatment of type 2 diabetes and dyslipidemia.
A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
We used KO mice lacking either TNF receptor 1 (TNFR-1) or receptor 2 (TNFR-2) to determine whether signaling at the start of liver regeneration after partial hepatectomy (PH) involves only one or both TNF receptors and to analyze in more detail the abnormalities caused by lack of TNFR-1 receptor, which is required for the initiation of liver regeneration. Lack of TNFR-2 had little effect on NF-κB and STAT3 binding, and no effect in interleukin-6 production after PH, but caused a delay in AP-1 and C/EBP binding and in the expression of c-jun and c-myc messenger RNA (mRNA). In contrast to mice lacking TNFR-1, which had deficient hepatocyte DNA synthesis and massive lipid accumulation in hepatocytes, TNFR-2 KO mice had normal liver structure and similar levels of hepatocyte DNA replication as those of wild type mice. We conclude that TNFR-1, but not TNFR-2, is necessary for liver regeneration, and that NF-κB and STAT3 binding are activated by signals transduced by TNFR-1. Inhibition of AP-1 and C/EBP binding and in the expression of c-jun and c-myc mRNA in the first 4 hours after PH, as well as the apparent lack of Fos in AP-1 complexes, had no effect on the timing or extent of DNA replication.
Berberine (BBR) has been shown to improve several metabolic disorders, such as obesity, type 2 diabetes, and dyslipidemia, by stimulating AMP-activated protein kinase (AMPK). However, the effects of BBR on proinflammatory responses in macrophages are poorly understood. Here we show that BBR represses proinflammatory responses through AMPK activation in macrophages. In adipose tissue of obese db/db mice, BBR treatment significantly downregulated the expression of proinflammatory genes such as TNF-alpha, IL-1beta, IL-6, monocyte chemoattractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Consistently, BBR inhibited LPS-induced expression of proinflammatory genes including IL-1beta, IL-6, iNOS, MCP-1, COX-2, and matrix metalloprotease-9 in peritoneal macrophages and RAW 264.7 cells. Upon various proinflammatory signals including LPS, free fatty acids, and hydrogen peroxide, BBR suppressed the phosphorylation of MAPKs, such as p38, ERK, and JNK, and the level of reactive oxygen species in macrophages. Moreover, these inhibitory effects of BBR on proinflammatory responses were abolished by AMPK inhibition via either compound C, an AMPK inhibitor, or dominant-negative AMPK, implying that BBR would downregulate proinflammatory responses in macrophages via AMPK stimulation.
A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
Insulin resistance is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM). We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. However, the mechanism by which TNF-alpha interferes with insulin action is not known. Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. The physiological significance of the improvements in IR signaling was indicated by a concurrent reduction in plasma glucose, insulin, and free fatty acid levels. These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.
Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An
induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity
and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats
caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for
TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.
Evidence is reviewed that free fatty acids (FFAs) are one important link between obesity and insulin resistance and NIDDM. First, plasma FFA levels are elevated in most obese subjects. Second, physiological elevations in plasma FFA concentrations inhibit insulin stimulated peripheral glucose uptake in a dose-dependent manner in normal controls and in patients with NIDDM. Two possible mechanisms are identified: 1) a fat-related inhibition of glucose transport or phosphorylation, which appears after 3-4 h of fat infusion, and 2) a decrease in muscle glycogen synthase activity, which appears after 4-6 h of fat infusion. Third, FFAs stimulate insulin secretion in nondiabetic individuals. Some of this insulin is transmitted in the peripheral circulation and is able to compensate for FFA-mediated peripheral insulin resistance. FFA-mediated portal hyperinsulinemia counteracts the stimulation of FFAs on hepatic glucose production (HGP) and thus prevents hepatic glucose overproduction. We speculate that, in obese individuals who are genetically predisposed to develop NIDDM, FFAs will eventually fail to promote insulin secretion. The stimulatory effect of FFAs on HGP would then become unchecked, resulting in hyperglycemia. Hence, continuously elevated levels of plasma FFAs may play a key role in the pathogenesis of NIDDM in predisposed individuals by impairing peripheral glucose utilization and by promoting hepatic glucose overproduction.
Obesity is highly associated with insulin resistance and is the biggest risk factor for non-insulin-dependent diabetes mellitus. The molecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-alpha is a candidate mediator of insulin resistance in obesity, as it is overexpressed in the adipose tissues of rodents and humans and it blocks the action of insulin in cultured cells and whole animals. To investigate the role of TNF-alpha in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of TNF-alpha resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNFalpha-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues. These results indicate that TNF-alpha is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.
Tumor necrosis factor-alpha (TNF-alpha) has been shown to induce insulin resistance in cultured cells as well as in animal models. The aim of this study was to map the in vivo mechanism whereby TNF-alpha contributes to the pathogenesis of impaired insulin signaling, using obese and lean Zucker rats in which TNF-alpha activity was inhibited through adenovirus-mediated gene transfer. We employed a replication-incompetent adenovirus-5 (Ad5) vector to endogenously express a TNF inhibitor (TNFi) gene, which encodes a chimeric protein consisting of the extracellular domain of the human 55-kDa TNF receptor joined to a mouse IgG heavy chain. Control animals consisted of rats infected with the same titer of adenovirus carrying the lac-z complementary DNA, encoding for beta-galactosidase. There was a significant reduction in plasma insulin and free fatty acid levels in TNFi obese rats 2 days following Ad5 administration. The peripheral insulin sensitivity index was 50% greater, whereas hepatic glucose output was completely suppressed during hyperinsulinemic glucose clamps in TNFi obese animals, with no differences observed between the two lean groups.
Background
Insulin resistance, dyslipidaemia and abnormal nonesterified fatty acid (NEFA) metabolism are features of the ‘metabolic syndrome’, but the mechanisms of these relationships are uncertain.Materials and methodsWe studied associations between insulin resistance and lipoprotein concentrations by retrospective analysis of euglycaemic hyperinsulinaemic clamp data from 867 normoglycaemic subjects in 21 European centres. Data on NEFA concentrations were available in a subgroup of 541 subjects from 9 clinical centres. These subjects' characteristics do not vary significantly from those of the whole cohort.ResultsAfter adjustment for the effects of age, sex, obesity and intercentre variability, regression analysis showed relationships between triglycerides and markers of insulin sensitivity. There were significant correlations between triglycerides and fasting plasma glucose (P P P P P P P P The results in this large cohort of healthy European subjects suggest that triglyceride concentrations depend upon both insulin's gluco-regulation (estimated by glucose uptake) and antilipolytic insulin action (measured by NEFA levels) during an euglycaemic clamp.
Tumor necrosis factor alpha (TNF-alpha) has well-described effects on lipid metabolism in the context of acute inflammation, as in sepsis. Recently, increased TNF-alpha production has been observed in adipose tissue derived from obese rodents or human subjects and TNF-alpha has been implicated as a causative factor in obesity-associated insulin resistance and the pathogenesis of type 2 diabetes. Thus, current evidence suggests that administration of exogenous TNF-alpha to animals can induce insulin resistance, whereas neutralization of TNF-alpha can improve insulin sensitivity. Importantly, results from knockout mice deficient in TNF-alpha or its receptors have suggested that TNF-alpha has a role in regulating in vivo insulin sensitivity. However, the absence of TNF-alpha action might only partially protect against obesity-induced insulin resistance in mice. Multiple mechanisms have been suggested to account for these metabolic effects of TNF-alpha. These include the downregulation of genes that are required for normal insulin action, direct effects on insulin signaling, induction of elevated free fatty acids via stimulation of lipolysis, and negative regulation of PPAR gamma, an important insulin-sensitizing nuclear receptor. Although current evidence suggests that neutralizing TNF-alpha in type 2 diabetic subjects is not sufficient to cause metabolic improvement, it is still probable that TNF-alpha is a contributing factor in common metabolic disturbances such as insulin resistance and dyslipidemia.
For many years, the Randle glucose fatty acid cycle has been invoked to explain insulin resistance in skeletal muscle of patients with type 2 diabetes or obesity. Increased fat oxidation was hypothesized to reduce glucose metabolism. The results of a number of investigations have shown that artificially increasing fat oxidation by provision of excess lipid does decrease glucose oxidation in the whole body. However, results obtained with rodent or human systems that more directly examined muscle fuel selection have found that skeletal muscle in insulin resistance is accompanied by increased, rather than decreased, muscle glucose oxidation under basal conditions and decreased glucose oxidation under insulin-stimulated circumstances, producing a state of "metabolic inflexibility." Such a situation could contribute to the accumulation of triglyceride within the myocyte, as has been observed in insulin resistance. Recent knowledge of insulin receptor signaling indicates that the accumulation of lipid products in muscle can interfere with insulin signaling and produce insulin resistance. Therefore, although the Randle cycle is a valid physiological principle, it may not explain insulin resistance in skeletal muscle.
We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing
insulin signaling. Activation or overexpression of the IκB kinase β (IKKβ) attenuated insulin signaling in cultured cells,
whereas IKKβ inhibition reversed insulin resistance. Thus, IKKβ, rather than the cyclooxygenases, appears to be the relevant
molecular target. Heterozygous deletion (Ikkβ
+/−) protected against the development of insulin resistance during high-fat feeding and in obese Lepob/ob
mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes
mellitus and identify the IKKβ pathway as a target for insulin sensitization.
Berberine, is an alkaloid from Hydrastis canadensis L., Chinese herb Huanglian, and many other plants. It is widely used in traditional Chinese medicine as an antimicrobial in the treatment of dysentery and infectious diarrhea. This manuscript describes cardiovascular effects of berberine and its derivatives, tetrahydroberberine and 8-oxoberberine. Berberine has positive inotropic, negative chronotropic, antiarrhythmic, and vasodilator properties. Both derivatives of berberine have antiarrhythmic activity. Some cardiovascular effects of berberine and its derivatives are attributed to the blockade of K+ channels (delayed rectifier and K(ATP)) and stimulation of Na+ -Ca(2+) exchanger. Berberine has been shown to prolong the duration of ventricular action potential. Its vasodilator activity has been attributed to multiple cellular mechanisms. The cardiovascular effects of berberine suggest its possible clinical usefulness in the treatment of arrhythmias and/or heart failure.
Recent studies have implicated fatty acid-dependent activation of the serine kinase IKKbeta, which plays a key role in tissue inflammation, in the pathogenesis of insulin resistance. High doses of salicylates have recently been shown to inhibit IKKbeta activity and might therefore ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. To test this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin ( approximately 7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-(2)H2]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a approximately 25% reduction in fasting plasma glucose, associated with a approximately 15% reduction in total cholesterol and C-reactive protein, a approximately 50% reduction in triglycerides, and a approximately 30% reduction in insulin clearance, despite no change in body weight. During a mixed-meal tolerance test, the areas under the curve for plasma glucose and fatty acid levels decreased by approximately 20% and approximately 50%, respectively. Aspirin treatment also resulted in a approximately 20% reduction in basal rates of hepatic glucose production and a approximately 20% improvement in insulin-stimulated peripheral glucose uptake under matched plasma insulin concentrations during the clamp. In conclusion, these data support the hypothesis that IKKbeta represents a new target for treating type 2 diabetes mellitus.
The action of berberine was compared with metformin and troglitazone (TZD) with regard to the glucose-lowering action in vitro. HepG2 cell line, phenotypically similar to human hepatocytes, was used for glucose consumption (GC) studies. Cell proliferation was measured by methylthiotetrazole (MTT) assay. In moderate high glucose concentration (11.1 mmol/L), GC of HepG2 cells was increased by 32% to 60% (P <.001 to P <.0001) with 5 x 10(-6) mol/L to 1 x 10(-4) mol/L berberine, which was comparable to that with 1 x 10(-3) mol/L metformin. The glucose-lowering effect of berberine decreased as the glucose concentration increased. The maximal potency was reached in the presence of 5.5 mmol/L glucose, and it was abolished when the glucose concentration increased to 22.2 mmol/L. The effect was not dependent on insulin concentration, which was similar to that of metformin and was different from that of TZD, whose glucose-lowering effect is insulin dependent. TZD had a better antihyperglycemic potency than metformin when insulin was added (P <.001). In the meantime, a significant toxicity of the drug to HepG2 cells was also observed. The betaTC3 cell line was used for insulin release testing, and no secretogogue effect of berberine was observed. These observations suggest that berberine is able to exert a glucose-lowering effect in hepatocytes, which is insulin independent and similar to that of metformin, but has no effect on insulin secretion.
Interleukin (IL)-6 is one of several proinflammatory cytokines that have been associated with insulin resistance and type 2 diabetes. A two- to threefold elevation of circulating IL-6 has been observed in these conditions. Nonetheless, little evidence supports a direct role for IL-6 in mediating insulin resistance. Here, we present data that IL-6 can inhibit insulin receptor (IR) signal transduction and insulin action in both primary mouse hepatocytes and the human hepatocarcinoma cell line, HepG2. This inhibition depends on duration of IL-6 exposure, with a maximum effect at 1-1.5 h of pretreatment with IL-6 in both HepG2 cells and primary hepatocytes. The IL-6 effect is characterized by a decreased tyrosine phosphorylation of IR substrate (IRS)-1 and decreased association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 in response to physiologic insulin levels. In addition, insulin-dependent activation of Akt, important in mediating insulin's downstream metabolic actions, is markedly inhibited by IL-6 treatment. Finally, a 1.5-h preincubation of primary hepatocytes with IL-6 inhibits insulin-induced glycogen synthesis by 75%. These data suggest that IL-6 plays a direct role in insulin resistance at the cellular level in both primary hepatocytes and HepG2 cell lines and may contribute to insulin resistance and type 2 diabetes.
Insulin resistance plays an important role in the pathogenesis of human type 2 diabetes. In humans, a negative correlation between insulin sensitivity and intramyocellular lipid (IMCL) content has been shown; thus, IMCL becomes a marker for insulin resistance. Recently, magnetic resonance spectroscopy (MRS) has been established as a dependable method for selective detection and quantification of IMCL in humans. To validate the interrelation between insulin sensitivity and IMCL in an animal model of type 2 diabetes, we established volume selective (1)H-MRS at 7 Tesla to noninvasively assess IMCL in the rat. In male obese Zucker Diabetic Fatty rats and their lean littermates, IMCL levels were determined repeatedly over 4 months, and insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp method at 6-7 and at 22-24 weeks of age. A distinct relation between IMCL and insulin sensitivity was demonstrated as well as age dependence for both parameters. Rosiglitazone treatment caused a clear reduction of IMCL and hepatic fat despite increased body weight, and a marked improvement of insulin sensitivity. Thus, the insulin sensitizing properties of rosiglitazone were consistent with a redistribution of lipids from nonadipocytic (skeletal muscle, liver) back into fat tissue.
Obesity and type 2 diabetes are associated with a state of abnormal inflammatory response. While this correlation has also been recognized in the clinical setting, its molecular basis and physiological significance are not yet fully understood. Studies in recent years have provided important insights into this curious phenomenon. The state of chronic inflammation typical of obesity and type 2 diabetes occurs at metabolically relevant sites, such as the liver, muscle, and most interestingly, adipose tissues. The biological relevance of the activation of inflammatory pathways became evident upon the demonstration that interference with these pathways improve or alleviate insulin resistance. The abnormal production of tumor necrosis factor alpha (TNF-alpha) in obesity is a paradigm for the metabolic significance of this inflammatory response. When TNF-alpha activity is blocked in obesity, either biochemically or genetically, the result is improved insulin sensitivity. Studies have since focused on the identification of additional inflammatory mediators critical in metabolic control and on understanding the molecular mechanisms by which inflammatory pathways are coupled to metabolic control. Recent years have seen a critical progress in this respect by the identification of several downstream mediators and signaling pathways, which provide the crosstalk between inflammatory and metabolic signaling. These include the discovery of c-Jun N-terminal kinase (JNK) and I kappa beta kinase (I kappa K) as critical regulators of insulin action activated by TNF-alpha and other inflammatory and stress signals, and the identification of potential targets. Here, the role of the JNK pathway in insulin receptor signaling, the impact of blocking this pathway in obesity and the mechanisms underlying JNK-induced insulin resistance will be discussed.
Our preliminary study demonstrated that 70% ethanol Cortidis Rhizoma extracts (CR) had a hypoglycemic action in diabetic animal models. We determined whether CR fractions acted as anti-diabetic agent, and a subsequent investigation of the action mechanism of the major compound, berberine ([C(20)H(18)NO(4)](+)), was carried out in vitro. The 20, 40 and 60% methanol fractions from the XAD-4 column contained the most insulin sensitizing activities in 3T3-L1 adipocytes. The common major peak in these fractions was berberine. Treatment with 50 microM berberine plus differentiation inducers significantly reduced triglyceride accumulation by decreased differentiation of 3T3-L1 fibroblasts to adipocytes and triglyceride synthesis. Significant insulin sensitizing activity was observed in 3T3-L1 adipocytes which were given 50 microM berberine plus 0.2 nM insulin to reach a glucose uptake level increased by 10 nM of insulin alone. This was associated with increased glucose transporter-4 translocation into the plasma membrane via enhancing insulin signaling pathways and the insulin receptor substrate-1-phosphoinositide 3 Kinase-Akt. Berberine also increased glucose-stimulated insulin secretion and proliferation in Min6 cells via an enhanced insulin/insulin-like growth factor-1 signaling cascade. Data suggested that berberine can act as an effective insulin sensitizing and insulinotropic agent. Therefore, berberine can be used as anti-diabetic agent for obese diabetic patients.
Effect of berberine on the gene expression of IRS-1/-2, p85 in 2-type diabetic rats
- Shu Shi
- Liu Xiaomei
- Song Lina
- Zhou Jinfang
- Song Jumin
Shi, Shu, Liu Xiaomei, Song Lina, Zhou Jinfang, Song Jumin. 2009. Effect of berberine on the gene expression of IRS-1/-2, p85 in 2-type diabetic rats. Zhejiang Journal of Traditional Chinese Medicine 44: 254–257.