Insulin resistance and inflammation are strongly linked to non-alcoholic fatty liver disease (NAFLD) as a feature of the metabolic syndrome. Furthermore, the role of dysregulation of miR-34a, miR-451, and miR-33a in pathogenesis and progression of NAFLD has been identified. trans-Chalcone is a simple chalcone with anti-diabetic and anti-inflammatory activities. However, to the best of our knowledge, miRNA-dependent mechanisms of these protective effects under pathologic conditions are not understood. Thus, this study, for the first time, aimed to evaluate the effects of trans-Chalcone on miR-34a, miR-451, and miR-33a signaling pathways in the liver of high-fat (HF) emulsion-fed rats. To this aim, twenty-one rats were randomly and equally divided into three groups: control, which was gavaged with 10% tween 80; HF, which was gavaged with HF emulsion and 10% tween 80; and HF + trans-Chalcone (HF + TC), which was gavaged with HF emulsion and trans-Chalcone. Then, circulating levels of glucose and insulin were measured and used for the calculation of HOMA-IR. Hepatic expression levels of miR-34a, miR-451, miR-33a, SIRT1, and ABCA1 and also protein levels of ABCA1 and IL-8 were assayed. In this study, trans-chalcone increased hepatic cholesterol efflux and prevented insulin resistance and liver inflammation in HF emulsion-fed rats. These protective effects were modulated through the down-regulation of miR-34a and its associated elevation of SIRT1, the up-regulation of miR-451 which was associated with a reduction in IL-8, and the inhibition of miR-33a which was related to the elevation of ABCA1 in the liver of HF emulsion-fed rats. Therefore, trans-Chalcone exerts its beneficial effects by targeting hepatic miR-34a-, miR-451-, and miR-33a-related pathways.

Non-alcoholic steatohepatitis (NASH) is an inflammatory and progressive form of non-alcoholic fatty liver disease. However, there are no FDA-approved drugs for this condition. Lipids accumulated in NASH have a direct role in the progression of this disease. Therefore, this study for the first time explored the preventive effect of trans-chalcone on NASH through the modulation of sterol regulatory element binding protein (SREBP)-1c, SREBP-2, hepatic fatty acid synthesis (FAS) enzyme, proliferator-activated receptor (PPAR)-α, and PPAR-γ2 levels, which are involved in hepatic lipid metabolism. In this study, male rats were randomly divided into three groups (n = 7): Control, received 10% tween 80; NASH, received 10% tween 80 and 10 ml/kg high-fat emulsion (high-fat diet, HFD); and NASH + TC, received 20 mg/kg trans-chalcone and 10 ml/kg HFD. All treatments were performed by once-daily oral gavage for 6 weeks. Liver and blood samples were collected and serum levels of alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride, total cholesterol, low-density lipoprotein (LDL)-cholesterol, and high-density lipoprotein (HDL)-cholesterol, as well as hepatic levels of SREBP-1c, SREBP-2, FAS, PPAR-α, and PPAR-γ2, were measured. Moreover, hematoxylin and eosin stained tissues were used for histological analysis. In this study, treatment of HFD-fed rats with trans-chalcone significantly reduced abnormalities in liver histology, serum levels of liver injury markers, liver index, and hepatic levels of SREBP-1c, SREBP-2, FAS, and PPAR-γ2. Furthermore, trans-chalcone significantly increased hepatic PPARα levels in these rats. Therefore, it seems that trans-chalcone protects the liver of HFD-fed rats against NASH development through reduction of SREBP-1c/ FAS- and PPAR-γ2-related lipogenesis, attenuation of SREBP-2-related cholesterol synthesis, and elevation of PPARα-related fatty acid oxidation.

Diabetes is a common metabolic disease which leads to diabetic peripheral neuropathy (DPN). Recently, the role of micro-ribonucleic acid-96 (miR-96) in alleviating neuropathic pain by inhibiting the expression of Na_V1.3, an isoform of voltage-gated sodium channels, has been shown. Peripheral nerve injuries result in Na_V1.3 elevation. Exercise has beneficial role in diabetes management and peripheral neuropathy. However, the effects of exercise on miR-96 and its target gene Na_V1.3 in diabetic rats are unknown. Therefore, the present study investigated the effects of exercise training on the expression of miR-96 and Na_V1.3 in diabetic rats. For this purpose, rats were randomly divided into four groups: control, exercise, diabetic and diabetic-exercise groups. Type 2 diabetes was induced by a high-fat diet and the administration of streptozotocin (STZ) (35 mg/kg, i.p.). The exercise groups were subjected to swimming exercise 5 days/week for 10 weeks. At the end of the treatment period, thermal pain threshold, determined through the tail-flick test, and the expression levels of miR-96 and its target gene Na_V1.3 were determined by reverse transcription -polymerase chain reaction (RT-PCR) in the sciatic nerve tissues of the rats. Data of the present study indicated that diabetes diminished miR-96 expression levels, but significantly upregulated Na_V1.3 expression in the sciatic nerve. On exercise training, miR-96 expression was reversed with concurrent down-regulation of the Na_V1.3 expression. This study introduced a new and potential miRNA-dependent mechanism for exercise-induced protective effects against diabetic thermal hyperalgesia.