Oxidative stress and inflammation interact in the development of diabetic atherosclerosis. Intracellular hyperglycemia promotes production of mitochondrial reactive oxygen species (ROS), increased formation of intracellular advanced glycation end-products, activation of protein kinase C, and increased polyol pathway flux. ROS directly increase the expression of inflammatory and adhesion factors, formation of oxidized-low density lipoprotein, and insulin resistance. They activate the ubiquitin pathway, inhibit the activation of AMP-protein kinase and adiponectin, decrease endothelial nitric oxide synthase activity, all of which accelerate atherosclerosis. Changes in the composition of the gut microbiota and changes in microRNA expression that influence the regulation of target genes that occur in diabetes interact with increased ROS and inflammation to promote atherosclerosis. This review highlights the consequences of the sustained increase of ROS production and inflammation that influence the acceleration of atherosclerosis by diabetes. The potential contributions of changes in the gut microbiota and microRNA expression are discussed.

New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis.

Diabetes mellitus is one of the major health problems in the world, the incidence and associated mortality are increasing. Inadequate regulation of the blood sugar imposes serious consequences for health. Conventional antidiabetic drugs are effective, however, also with unavoidable side effects. On the other hand, medicinal plants may act as an alternative source of antidiabetic agents. Examples of medicinal plants with antidiabetic potential are described, with focuses on preclinical and clinical studies. The beneficial potential of each plant matrix is given by the combined and concerted action of their profile of biologically active compounds.

https://www.mdpi.com/2218-273X/9/10/551/pdf

Antidiabetic Potential of Medicinal Plants and Their Active Components.

https://escholarship.org/content/qt3km8b1x7/qt3km8b1x7.pdf?t=qwuott

Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation.

A new research hot spot: The role of NLRP3 inflammasome activation, a key step in pyroptosis, in diabetes and diabetic complications.

Inflammation is an important process involved in several cardiovascular diseases (CVDs), and nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a vital player in innate immunity and inflammation. In this review, we aim to provide a comprehensive summary of the current knowledge on the role and involvement of NLRP3 inflammasome in the pathogenesis and treatment of CVDs. NLRP3 inflammasome functions as a molecular platform, and triggers the activation of caspase-1 and cleavage of pro-IL-1β, pro-IL-18, and gasdermin D (GSDMD). Cleaved NT-GSDMD forms pores in the cell membrane and initiates pyroptosis, inducing cell death and release of many intracellular pro-inflammatory molecules. NLRP3 inflammasome activation is triggered via inter-related pathways downstream of K+ efflux, lysosomal disruption, and mitochondrial dysfunction. In addition, the Golgi apparatus and noncoding RNAs are gradually being recognized to play important roles in NLRP3 inflammasome activation. Many investigations have revealed the association between NLRP3 inflammasome and CVDs, including atherosclerosis, ischemia/reperfusion (I/R) injury and heart failure induced by pressure overload or cardiomyopathy. Some existing medications, including orthodox and natural medicines, used for CVD treatment have been newly discovered to act via NLRP3 inflammasome. In addition, NLRP3 inflammasome pathway components such as NLRP3, caspase-1, and IL-1β may be considered as novel therapeutic targets for CVDs. Thus, NLRP3 inflammasome is a key molecule involved in the pathogenesis of CVDs, and further research focused on development of NLRP3 inflammasome-based targeted therapies for CVDs and the clinical evaluation of these therapies is essential.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ctm2.13

NLRP3 inflammasome, an immune-inflammatory target in pathogenesis and treatment of cardiovascular diseases.

Metformin is a widely used antidiabetic drug for type 2 diabetes that can play a cardioprotective role through multiple pathways. It is a recognized agonist of AMP-activated protein kinase (AMPK) that blocks mitochondrial complex I. The NLRP3 inflammasome has been demonstrated to be activated in diabetic cardiomyopathy (DCM). However, the role of metformin in regulating the NLRP3 signaling pathway in DCM remains unclear. It has been reported that AMPK can inhibit NLRP3 by activating autophagy. The aim of this study was to investigate whether metformin can inhibit the NLRP3 inflammasome by activating the AMPK/mTOR pathway in DCM. In this study, streptozotocin-induced C57BL/6 mice and high glucose-treated primary cardiomyocytes from neonatal mice were treated with metformin or an AMPK inhibitor compound C. Echocardiography, hematoxylin-eosin and Masson staining showed that the function and morphology of the diabetic hearts were improved after metformin treatment, whereas these parameters deteriorated after intervention with an AMPK inhibitor. Immunohistochemical staining, immunofluorescence staining and western blot assays indicated that the expression levels of mTOR, NLRP3, caspase-1, IL-1β and GSDMD-N were decreased in the diabetic model treated with metformin and were reversed after the administration of an AMPK inhibitor in vivo and in vitro. Mechanistically, our results demonstrated that metformin can activate AMPK, thus improving autophagy via inhibiting the mTOR pathway and alleviating pyroptosis in DCM. Thus, we provide novel information for the treatment of DCM.

/pdf/metformin-inhibits-the-nlrp3-inflammasome-via-ampk-mtor-2qv6pjda9q.pdf

Metformin Inhibits the NLRP3 Inflammasome via AMPK/mTOR-dependent Effects in Diabetic Cardiomyopathy.

Silymarin ameliorates diabetic cardiomyopathy via inhibiting TGF‐β1/Smad signaling

Non-: alcoholic fatty liver disease (NAFLD) is prevalent worldwide, especially in patients with type 2 diabetes. Liver enzymes are the main warning signs of liver injury and insulin resistance (IR) is critical to NAFLD. This study was aimed to investigate the association between liver enzymes and insulin resistance in type 2 diabetes patients with NAFLD. Data from 212 diabetes patients with NAFLD were analyzed, including 118 males and 94 females who received care from 2014 to 2015. The patients were divided into three groups by severity (mild n=87, moderate n=89, severe n=36). All patients underwent standard clinical and laboratory examinations. Liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (GGT) were measured, serum fasting glucose and serum fasting insulin were obtained. IR was assessed using the homeostasis model assessment insulin resistance index (HOMA-IR). Age, sex, and BMI did not significantly differ in patients (p>0.05). Compared with normal levels, elevated ALT and AST were associated with a higher HOMA-IR (p=0.0035, p=0.0096, respectively). HOMA-IR did not significantly differ (p>0.05) between patients with normal and elevated GGT. HOMA-IR increased as the levels of liver enzymes increased, and each enzyme showed a significant association with HOMA-IR (p=0.0166, p<0.0001, and p <0.0001). HOMA-IR differs between normal and elevated ALT and AST. Liver enzymes are associated with HOMA-IR in type 2 diabetes patients with NAFLD. These findings can help evaluate the degree of IR and hepatocellular steatosis in patients and prevent the progression of type 2 diabetes and NAFLD in clinical practice.

The Relationship Between Liver Enzymes and Insulin Resistance in Type 2 Diabetes Patients with Nonalcoholic Fatty Liver Disease.

Patients with type 2 diabetes mellitus (T2DM) are usually with poor immunity and easier to suffer from cancer and microbial infections. Herein, we report an efficient anti-diabetic medicinal mushroom, Coriolus versicolor (CV). This study aimed to investigate the anti-diabetic and anti-insulin-resistance effects of CV aqueous extract in myoblasts (L6 cells) and skeletal muscle of T2DM rat. Our results showed that CV extract treatment significantly reduced blood glucose levels of T2DM rats, whereas CV extract increased glucose consumption in insulin resistant L6 cells. Besides, the translocation and expression of glucose transporter 4 were enhanced by CV extract, which indicated that CV extract was effective in diabetic skeletal muscle. Moreover, CV extract treatments resulted in remarkable anti-insulin-resistance effects, which was reflected by the change of gene and protein expression levels in PI3K/Akt and p38 MAPK pathways. PI3K inhibitor, LY29004, and p38 MAPK inhibitor, SB203580 confirmed it further. In conclusion, our results demonstrated that the CV extract exhibited anti-diabetic and anti-insulin-resistance effects in diabetic skeletal muscle, and the effects were mediated by PI3K/Akt and p38 MAPK pathways. These findings are remarkable when considering the use of commercially available CV by diabetic patients who also suffer from cancer or microbial infections.

Coriolus versicolor aqueous extract ameliorates insulin resistance with PI3K/Akt and p38 MAPK signaling pathways involved in diabetic skeletal muscle

Identifying genes significantly related to diseases is a focus in the study of disease mechanisms. In this paper, from the perspective of integrated analysis and dynamic control, a method for identifying genes significantly related to diseases based on logic networks constructed by the LAPP method, referred to as NCCM, is proposed and applied to the study of the mechanism of acute myocardial infarction (AMI). It is found that 82.35% of 17 differential control capability genes (DCCGs) identified by NCCM are significantly correlated with AMI/MI in the literature and DISEASES database. The enrichment analysis of DCCGs shows that AMI is closely related to the positive regulation of vascular-associated smooth muscle cell proliferation and regulation of cytokine production involved in the immune response, in which HBEGF, THBS1, NR4A3, NLRP3, EDN1, and MMP9 play a crucial role. In addition, although the expression levels of CNOT6L and ACYP1 are not significantly different between the control group and the AMI group, NCCM shows that they are significantly associated with AMI. Although this result still needs further verification, it shows that the method can not only identify genes with large differences in expression but also identify genes that are associated with diseases but with small changes in expression.

/pdf/identifying-genes-related-to-acute-myocardial-infarction-9a4ja2st.pdf

Huimin Xian

Papers

Metformin Inhibits the NLRP3 Inflammasome via AMPK/mTOR-dependent Effects in Diabetic Cardiomyopathy.

Silymarin ameliorates diabetic cardiomyopathy via inhibiting TGF‐β1/Smad signaling

The Relationship Between Liver Enzymes and Insulin Resistance in Type 2 Diabetes Patients with Nonalcoholic Fatty Liver Disease.

Coriolus versicolor aqueous extract ameliorates insulin resistance with PI3K/Akt and p38 MAPK signaling pathways involved in diabetic skeletal muscle

Identifying Genes Related to Acute Myocardial Infarction Based on Network Control Capability