Berberine attenuates obesity-induced insulin resistance by inhibiting miR-27a secretion.

INTRODUCTION: Berberine (BBR) is an alkaloid found in plants. It has neuroprotective, anti-inflammatory and lipid-lowering activity. However, the efficacy of treatment with BBR and the mechanisms through which it acts need further study. AIMS: This study investigated the therapeutic effects and the mechanism of action of BBR on obesity-induced insulin resistance in peripheral tissues. METHODS: High-fat-fed C57BL/6J mice and low-fat-fed C57BL/6J mice with miR-27a overexpression were given BBR intervention (100 mg/kg, po), and the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed. Palmitic acid-stimulated hypertrophic adipocyte models were treated with BBR (10 µM). Related indicators and protein expression levels were examined. RESULTS: The AUCs of the OGTT and the ITT in the BBR intervention group were reduced significantly (p < 0.01) (p < 0.05), and the serum biochemical parameters, including FBG, TC, TG and LDL-C were significantly reduced after BBR intervention. In the in vitro experiments, the triglyceride level and volume of lipid droplets decreased significantly after BBR intervention (p < 0.01) (p < 0.05). Likewise, BBR ameliorates skeletal muscle and pancreas insulin signalling pathways in vivo and in vitro. DISCUSSION: The results showed that BBR significantly ameliorated insulin resistance, reduced body weight and percent body fat and improved serum biochemical parameters in mice. Likewise, BBR reduced triglyceride level and lipid droplet volume in hypertrophic adipocytes, BBR improved obesity effectively. Meanwhile, BBR ameliorated the histomorphology of the pancreas, and skeletal muscle and pancreas insulin related signalling pathways of islets in in vitro and in vivo experiments. The results further demonstrated that BBR inhibited miR-27a levels in serum from obese mice and supernatant of hypertrophic adipocytes. miR-27a overexpression in low-fat fed mice indicated that miR-27a caused insulin resistance, and BBR intervention significantly improved the miR-27a induced insulin resistance status. CONCLUSION: This study demonstrates the important role of BBR in obesity-induced peripheral insulin resistance and suggest that the mechanism of its effect may be inhibition of miR-27a secretion.

Alzheimer's Disease: Causal Effect between Obesity and APOE Gene Polymorphisms.

Currently studies on the correlation between obesity and Alzheimer's disease (AD) are still unclear. In addition, few indicators have been used to evaluate obesity, which has failed to comprehen-sively study the correlations between body fat mass, body fat distribution, and AD. Thus, this study innovatively utilized bioinformatics and Mendelian randomization (MR) to explore the key targets of obesity-induced AD, and investigate the causal associations between different types of obesity and key targets. The common targets of obesity and AD were screened using the GeneCards database, and functional and pathway annotations were carried out, thereby revealing the key target. MR analysis was conducted between body anthropometric indexes of obesity and the key target using an IVW model. Bioinformatics analysis revealed Apolipoprotein E (APOE) as the key target of obesity-induced AD. MR results showed that body mass index (BMI) had a negative causal association with APOE2, while body fat percentage (BFP) and trunk fat percentage (TFP) had no significant causal association with APOE2; BMI, BFP, and TFP had a negative causal association with APOE3, and none had any significant causal association with APOE4. In conclusion, there is a correlation between obesity and AD, which is mainly due to the polymorphism of the APOE gene rather than adipose tissue distribution. APOE3 carriers may be more susceptible to obesity, while the risk of AD caused by APOE2 and APOE4 may not be induced by obesity. This study sheds new light on current disputes. At the same time, it is suggested to regulate the body fat mass of APOE3 carriers in the early stage, and to reduce the risk of AD.

Effectiveness of interventions in older adults with cognitive frailty: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: interventions targeting older adults with cognitive frailty have grown rapidly in recent years with inconsistent findings. However, there is no meta-analysis that has synthesised pooled estimates. OBJECTIVE: to synthesise the pooled effect of current targeted interventions in older people with cognitive frailty. METHODS: we conducted a systematic search in PubMed, Embase, Web of Science, the Cochrane Library, the JBI database and three Chinese databases (CNKI, Wan-Fang and VIP) for literature from the inception of the database until 8 March 2022. The mean difference or standardised mean difference with 95% CIs was calculated. The methodological quality was assessed by the Cochrane RoB 2.0. The certainty of evidence was assessed using the GRADE criteria. RESULTS: thirteen randomised controlled trials with a total of 1,089 participants were included. The results of the meta-analysis showed that older adults with cognitive frailty in the intervention groups had significant improvement in frailty score [MD = -1.67, 95% CI (-2.39, -0.95), P < 0.00001, I2 = 97%], global cognitive function [MD = 3.38, 95% CI (1.90, 4.85), P < 0.00001, I2 = 93%], mobility [MD = -0.96, 95% CI (-1.27, -1.66), P < 0.00001, I2 = 0%], muscle strength [SMD = 0.75, 95% CI (0.09, 1.41), P = 0.03, I2 = 85%] and nutritional status [MNA:MD = 5.64, 95% CI (3.99, 7.29), P < 0.00001, I2 = 89%; ALB: MD = 3.23, 95% CI (0.76, 5.71), P = 0.01, I2 = 93%; PALB: MD = 54.52, 95% CI (25.26, 83.77), P = 0.0003, I2 = 96%; TRF: MD = 0.64, 95% CI (0.22, 1.06), P = 0.003, I2 = 97%]. The overall certainty of the evidence ranged from low to moderate. CONCLUSIONS: interventions targeting older adults with cognitive frailty are effective in improving physical frailty, global cognitive function, physical function and nutritional status with low to moderate certainty. More research is still needed in the future to further enrich the evidence in these fields. PROSPERO NUMBER: CRD42022318758.

Berberine mitigates hepatic insulin resistance by enhancing mitochondrial architecture via the SIRT1/Opa1 signalling pathway.

The aberrant changes of fussion/fission-related proteins can trigger mitochondrial dynamics imbalance, which cause mitochondrial dysfunctions and result insulin resistance (IR). However, the relationship between the inner mitochondrial membrane fusion protein optic atrophy 1 (Opa1) and hepatic IR as well as the specific molecular mechanisms of signal transduction has not been fully elucidated. In this study, we explore whether abnormalities in the Opa1 cause hepatic IR and whether berberine (BBR) can prevent hepatic IR through the SIRT1/Opa1 signalling pathway. High-fat diet (HFD)-fed mice and db/db mice are used as animal models to study hepatic IR in vivo. IR, morphological changes, and mitochondrial injury of the liver are examined to explore the effects of BBR. SIRT1/Opa1 protein expression is determined to confirm whether the signalling pathway is damaged in the model animals and is involved in BBR treatment-mediated mitigation of hepatic IR. A palmitate (PA)-induced hepatocyte IR model is established in HepG2 cells in vitro. Opa1 silencing and SIRT1 overexpression are induced to verify whether Opa1 deficiency causes hepatocyte IR and whether SIRT1 improves this dysfunction. BBR treatment and SIRT1 silencing are employed to confirm that BBR can prevent hepatic IR by activating the SIRT1/Opa1 signalling pathway. Western blot analysis and JC-1 fluorescent staining results show that Opa1 deficiency causes an imbalance in mitochondrial fusion/fission and impairs insulin signalling in HepG2 cells. SIRT1 and BBR overexpression ameliorates PA-induced IR, increases Opa1, and improves mitochondrial function. SIRT1 silencing partly reverses the effects of BBR on HepG2 cells. SIRT1 and Opa1 expressions are downregulated in the animal models. BBR attenuates hepatic IR and enhances SIRT1/Opa1 signalling in db/db mice. In summary, Opa1 silencing-mediated mitochondrial fusion/fission imbalance could lead to hepatocyte IR. BBR may improve hepatic IR by regulating the SIRT1/Opa1 signalling pathway, and thus, it may be used to treat type-2 diabetes.

Impact of calorie intake and refeeding syndrome on the length of hospital stay of patients with malnutrition: a systematic review and meta-analysis.

BACKGROUND & AIMS: The decrease of nutritional status has affected one-third hospitalized patients, while there is no widely used definition of malnutrition. Refeeding syndrome is a severe complication of refeeding in people with malnutrition, it includes a series of electrolyte disorders and clinical symptoms. Further research is warranted to determine whether refeeding syndrome prolongs the length of stay, and to verify the effect of different energy intakes during refeeding on the length of stay in people with malnutrition. Our review aimed to explore the effects of refeeding syndrome and initial calorie intake on the length of stay in patients with malnutrition. This study aids the understanding of clinical nutrition strategies to prevent and treat refeeding syndrome. METHODS: PubMed, Embase, Cochrane Library, Web of Knowledge, and two Chinese databases were systematically searched until October 2021. Controlled studies of patients' refeeding process with the outcome of length of stay were included. Effect sizes were expressed as 95% confidence intervals (CIs) and calculated using random-effects models. RESULTS: Eighteen studies involving 3868 participants were included in our review. The pooled length of stay of 2965 patients with refeeding syndrome in 11 studies was 25.55 (95% CI, 20.20-30.90) days. The pooled impact of refeeding syndrome on length of stay of 2634 patients in 10 studies was weighted mean difference (WMD) = 2.91 (95% CI, -0.18 - 6.00; P = 0.065) days. The pooled effect of higher calorie intake of 1234 patients in 8 studies was WMD = -3.04 (95% CI, -5.10 to -0.99, P = 0.003) days. CONCLUSIONS: The average length of stay in patients with refeeding syndrome was 25.55 days with a very high heterogeneity between studies. Refeeding syndrome affects the length of stay in part of, but not all, patients. In the present review, we concluded that higher initial calorie intake may help shorten the length of stay in patients with malnutrition. More well-designed randomized controlled trials are needed to explore the effect of calorie intake during refeeding.

Study on the Effect of PDA-PLGA Scaffold Loaded With Islet Cells for Skeletal Muscle Transplantation in the Treatment of Diabetes.

At present, islet cells transplantation was limited by the way in which islet cells are implanted into the body, their ability to adapt to the microenvironment and the maintenance time for relieving diabetic symptoms. In order to solve this problem, we made PDA-PLGA scaffold loaded with islet cells and used it for skeletal muscle transplantation to investigate its therapeutic effect in the treatment of diabetes. The PLGA scaffold was prepared by the electrospinning method, and modified by polydopamine coating. A rat diabetic model was established to evaluate the efficacy of PDA-PLGA scaffold loaded with RINm5f islet cells through skeletal muscle transplantation. The results showed that the PDA-PLGA scaffold has good biosafety performance. At the same time, transplantation of the stent to the skeletal muscle site had little effect on the serum biochemical indicators of rats, which was conducive to angiogenesis. The PDA-PLGA scaffold had no effect on the secretory function of pancreatic islet cells. The PDA-PLGA scaffold carrying RINm5f cells was transplanted into the skeletal muscle of type I diabetic rats. 1 week after the transplantation of the PDA-PLGA cell scaffold complex, the blood glucose of the treatment group was significantly lower than that of the model group (p < 0.001) and lasted for approximately 3 weeks, which further indicated the skeletal muscle transplantation site was a new choice for islet cell transplantation in the future.

Berberine Potentiates Insulin Secretion and Prevents ß-cell Dysfunction Through the miR-204/SIRT1 Signaling Pathway.

Pancreatic ß-cell dysfunction is a key link during the progression of type 2 diabetes (T2DM), and SIRT1 participates in the regulation of various physiological activities of islet ß-cells. However, as a key link in signal transduction, it is not clear how SIRT1 is regulated. By TargetScan prediction, we found that miR-204, which is enriched in islets, has highly complementary binding sites with SIRT1. Therefore, we speculate that miR-204 may be the upstream regulatory target of SIRT1 in islets and thus participate in the occurrence of ß-cell dysfunction. In this study, we explored the association between miR-204 and ß-cell dysfunction, the therapeutic effects of berberine (BBR) on ß-cell function and the possible mechanisms. We found that miR-204 increased and SIRT1 mRNA and protein levels decreased significantly in islets both in vivo and in vitro. MIN6 cells induced by palmitic acid exhibited increased apoptosis, and the accumulation of insulin and ATP in the supernatant decreased. Importantly, palmitic acid treatment combined with miR-204 silencing showed opposite changes. MiR-204 overexpression in MIN6 cells increased apoptosis and decreased insulin and ATP production and SIRT1 expression. SIRT1 overexpression reversed the damage to ß-cells caused by miR-204. The BBR treatment effectively improved insulin synthesis, reduced miR-204 levels, and increased SIRT1 expression in islet tissue in diabetic mice. Overexpression of miR-204 reversed the protective effect of BBR on apoptosis and insulin secretion in MIN6 cells. Our study identifies a novel correlation between miR-204 and ß-cell dysfunction in T2DM and shows that administration of BBR leads to remission of ß-cell dysfunction by regulating the miR-204/SIRT1 pathway.

Highly bioavailable berberine formulation ameliorates diabetic nephropathy through the inhibition of glomerular mesangial matrix expansion and the activation of autophagy.

Glomerular mesangial matrix expansion and cell autophagy are the most important factors in the development of kidney damage under diabetic conditions. The activation of AMPK might be an important treatment target for diabetic nephropathy. Berberine has multiple effects on all types of diabetic complications as an activator of AMPK. However, the poor bioavailability of berberine limits its clinical applications. Huang-Gui Solid Dispersion (HGSD), a new formulation of berberine developed in our lab, has 4-fold greater bioavailability than berberine. However, its therapeutic application and mechanism still need to be explored. In the present study, the effect of HGSD on kidney function in type 2 diabetic rats and db/db mice was investigated. The results demonstrated that HGSD improved kidney function in these two animal models, decreased the glomerular volume and increased autophagy. Meanwhile, AMPK phosphorylation levels and autophagy-related protein expression were significantly increased, and extracellular matrix protein deposition-related protein expression was decreased after treatment. The present study indicated that HGSD protected against diabetic kidney dysfunction by inhibiting glomerular mesangial matrix expansion and activating autophagy. The mechanism of HGSD in the treatment of diabetic nephropathy might be connected to the activation of AMPK phosphorylation.

Amorphous solid dispersion of Berberine mitigates apoptosis via iPLA2ß/Cardiolipin/Opa1 pathway in db/db mice and in Palmitate-treated MIN6 ß-cells.

Aims: Berberine (BBR) improves beta-cell function in Type 2 diabetes (T2D) because of its anti-apoptotic activity, and our laboratory developed a new preparation named Huang-Gui Solid Dispersion (HGSD) to improve the oral bioavailability of BBR. However, the mechanism by which BBR inhibits beta-cell apoptosis is unclear. We hypothesized that the Group VIA Ca2+-Independent Phospholipase A2 (iPLA2ß)/Cardiolipin(CL)/Opa1 signaling pathway could exert a protective role in T2D by regulating beta-cell apoptosis and that HGSD could inhibit ß-cell apoptosis through iPLA2ß/CL/Opa1 upregulation. Methods: We examined how iPLA2ß and BBR regulated apoptosis and insulin secretion through CL/Opa1 in vivo and in vitro. In in vitro studies, we developed Palmitate(PA)-induced apoptotic cell death model in mouse insulinoma cells (MIN6). iPLA2ß overexpression and silencing technology were used to examine how the iPLA2ß/CL/Opa1 interaction may play an important role in BBR treatment. In in vivo studies, db/db mice were used as a diabetic animal model. The pancreatic islet function and morphology, beta-cell apoptosis and mitochondrial injury were examined to explore the effects of HGSD. The expression of iPLA2ß/CL/Opa1 was measured to explore whether the signaling pathway was damaged in T2D and was involved in HGSD treatment. Results: The overexpression of iPLA2ß and BBR treatment significantly attenuated Palmitate- induced mitochondrial injury and apoptotic death compared with Palmitate-treated MIN6 cell. In addition, iPLA2ß silencing could simultaneously partly abolish the anti-apoptotic effect of BBR and decrease CL/Opa1 signaling in MIN6 cells. Moreover, HGSD treatment significantly decreased beta-cell apoptosis and resulted in the upregulation of iPLA2ß/CL/Opa1 compared to those of the db/db mice. Conclusion: The results indicated that the regulation of iPLA2ß/CL/Opa1 by HGSD may prevent beta-cell apoptosis and may improve islet beta-cell function in Type 2 diabetic mice and in palmitate-treated MIN6 cells.

MiR27a Promotes the Development of Macrophage-like Characteristics in 3T3-L1 Preadipocytes.

Recruitment and polarization of classically activated (M1) macrophages within adipose tissue contribute to chronic low-grade inflammation in obesity. Adipose tissue precursor cells exhibit the capacity to develop macrophage-like characteristics and adipocyte-derived miR27a is known to promote reprogramming of somatic cells. It was unknown whether exogenous addition of miR27a promote the development of macrophage-like characteristics of adipose precursor cells. We examined macrophage surface antigen, phagocytosis and migration ability in 3T3-L1 preadipocytes transfected with miR27a mimics. Transfection of 3T3-L1 preadipocytes with miR27a mimics increased phagocytosis and migration and increased the number of cells expressing the macrophage makers F4/80 and MHC compared to controls. M2 and CD206 macrophage markers were unaltered. In addition, transfection of 3T3-L1 preadipocytes with miR27a mimics reduced PPARγ expression, activated NF-κB and promoted secretion of the inflammatory cytokines MCP-1, TNF-α and IL-1ß compared to controls. The level of anti-inflammatory factors Arg-1, IL-10, Ym1 and Fizz1 were unaltered. Secretion of miR27a was increased in conditioned medium prepared from palmitic acid-treated differentiated 3T3-L1 adipocytes compared to controls. Incubation of 3T3-L1 preadipocytes with this conditioned medium increased phagocytosis and migration compared to controls. Finally, conditioned medium prepared from differentiated 3T3-L1 adipocytes transfection with miR27a inhibitors reduced phagocytosis and migration in 3T3-L1 preadipocytes compared to controls. The data indicate that PPARγ agonists may reverse the activation of NF-κB pathway mediated by miR27a overexpression and reduce phagocytosis and migration of adipose precursor cells. In addition, miR27a may promote the development of macrophage-like characteristics in 3T3-L1 preadipocytes.

Adipogenic miR-27a in adipose tissue upregulates macrophage activation via inhibiting PPARγ of insulin resistance induced by high-fat diet-associated obesity.

Chronic low degree inflammation caused by macrophage activation is a crucial factor underlying insulin resistance induced by obesity. To illustrate the mechanism of regulating of macrophage activation in adipose tissue, the role of adipogenic miR-27a activating M1 macrophage polarization via blocking PPARγ was evaluated. Obese mice model and miR-27a overexpression or knockdown mice model were established and related biochemical index were examined. Raw264.7 and 3T3-L1 were cultured and co-cultured for mimicking the microenvironment of local inflammation. Macrophage infiltration was observed. MiR-27a and cytokines levels in serum and adipose tissue were measured. Macrophage polarization markers and protein expression in insulin or inflammatory signaling pathways were observed. Impaired glucose tolerance and insulin tolerance was observed in 4w, 8w and 12w of high fat diet and miR-27a overexpression mice. Concurrently, miR-27a was increased in serum in a time-dependent manner, along with M1 cytokines and M1 macrophages increasing in adipose tissue clearly. Insulin signaling pathway was blocked, and PPARγ was suppressed. However, NF-κB was activated. On the other hand, activated macrophages and hypertrophic adipocytes induced by miR-27a could increase the ratio of Raw264.7 migration, including improving cytokines generation, and blocking PPARγ expression markedly. The present studies are conducted to clarify that miR-27a has increased along with up-regulation in the process of proinflammatory cytokines generation, macrophage influx and M1 macrophage polarization in obesity. These indicate that miR-27a gives the novel target of intervention for inflammation and insulin resistance in obesity.

The chronic hepatotoxicity assessment of the herbal formula Zishen Yutai pill.

Zishen Yutai pill (ZYP) is an oriental herbal formula, while hepatotoxicity assessment of ZYP was rarely evaluated. Therefore, our aim is to re-evaluate its hepatotoxicity in both normal and carbon tetrachloride (CCl4) induced chronic liver injury rats. In the normal model, two doses of ZYP (1.575 and 9.450 g kg-1 d-1; i.e. 1 × , 6 × clinical doses) were given orally to rats for 24 weeks. In the chronic liver injury model, 10% CCl4 was administered to rats abdominally twice a week at a dose of 5 mL kg-1 for 12 consecutive weeks. Administration time started from 4 weeks after the beginning of CCl4 treatment. Toxicological parameters included mortality, body weight, food consumption, clinical signs, biochemical parameters, gross observation, organ weight, necropsy findings and histopathology were monitored. In the normal model, we found no any mortality or abnormality in clinical signs, relative liver weight, biochemical parameters and histopathology in ZYP treatment groups. In the chronic liver injury model, liver damage related parameter such as ALT was elevated at the high dose of ZYP treatment in contrast to the CCl4-treated group (P < 0.01). In histopathological assessment, there were no significant difference between ZYP treatment groups and CCl4-treated group. No observed adverse effect on livers were established for 9.450 g kg-1 d-1 ZYP in the normal rats and 9.450 g kg-1 d-1 ZYP in the injury rats.

[Research progress in epigenetic regulation of myocardial ischemia/ reperfusion injury by traditional Chinese medicine].

Epigenetic is a hotspot of post-genomic era research, and epigenetic modification is a mechanism in the study of cardiovascular disease. Myocardial ischemia-reperfusion injury (MIRI) is one of the problems in the cardiovascular disease, and many experimental interventions are reported in the protection of the ischemic myocardium in experimental animals. However, with the exception of early reperfusion, none has been translated into clinical practice. There is an advantage of traditional Chinese medicine (TCM) in the regulation of epigenetic modification, and pathogenesis of myocardial ischemia-reperfusion injury. This review article is prepared to cover the research progress in the treatment of myocardial ischemia-reperfusion injury by TCM with a focus on epigenetic regulation. The epigenetic regulation is documented in TCM theory through a systematic review of the protecting drugs in the MIRI development guidelines.

[Phytoestrogens in application prospect of treatment of myocardial ischemia/reperfusion injury].

Reperfusion is the most effective treatment for acute myocardial infarction, markedly reducing mortality and morbidity. Reperfusion however induces necrotic and apoptotic damages to cardiomyocytes, that were viable prior to reperfusion, a process called myocardial ischemia/reperfusion injury(MI/RI). Over the past 30 years, hundreds of experimental interventions (both pharmacologic and nonpharmacologic) have been reported to protect the ischemic myocardium in experimental animals; however, with the exception of early reperfusion, none has been translated into clinical practice. The population-based survey assessed men have about twice the total incidence of morbidity and mortality of women, and the sex gap in morbidity tends to diminish after age 45 years. So hormone replacement therapy (HRT) is given to treat the MI/RI, and lots of studies shows that the side effect is greater for estrogen, compared with phyestrogen. In this article, we review the important pathogenesis of myocardial ischemia reperfusion injury, the prevention and limitations of HRT. And we highlight the mechanism of phyestrogens treatment the MI/RI in experiment. The aim is to provide the theoretically new way of develop the safe and effective products for the researchers.