Protective Role of Taraxasterol against Cardiovascular Aging and Aging-Induced Desensitization of Insulin Signaling.

BACKGROUND: Cardiovascular disease (CVD) has become one of the leading causes of death and disability worldwide, and its incidence continues to increase because of an aging population. Studies have shown that the function of cardiomyocytes decreases during aging, leading to changes in the functional and structural integrity of the heart, ultimately resulting in CVD. The decrease in the number of functional cardiomyocytes has a negative impact on cardiac function; thus, myocardial aging is one of the main factors that causes heart-related diseases (such as CVD). Therefore, alleviating cardiac aging is one of the main ways of treating aging-related cardiac diseases. In this study, we evaluated the potential effect of taraxasterol on myocardial aging. METHODS: The effect of taraxasterol on the aging of cardiomyocytes was analyzed in vivo and in vitro using a D-galactose treatment mouse model of cardiomyocyte senescence. Furthermore, the effect of taraxasterol on aging-induced desensitization of insulin signaling was also evaluated. RESULTS: The experimental results indicated that taraxasterol could reduce cardiomyocyte senescence, which was evaluated using Sa-ß-gal staining and senescence-related marker molecules (e.g., p16 and p21). We found that taraxasterol could significantly alleviate cardiomyocyte senescence in the in vitro cell model. Furthermore, we found that taraxasterol had the potential to alleviate cardiomyocyte senescence via the regulation of oxidative stress and inflammatory processes. Additionally, taraxasterol could relieve the desensitization of insulin signaling caused by aging. Finally, we showed that cardiovascular aging and fibrosis were alleviated by taraxasterol treatment in vivo. CONCLUSIONS: Taken together, this work illustrated that taraxasterol could reduce cardiac aging and fibrosis and enhance insulin signaling sensitivity, indicating that taraxasterol may be an effective drug or health food additive for treating cardiac aging and fibrosis.

Effects of Valsartan on LN, FN, MDA, Renal Tissue Fibrosis, and Inflammatory Infiltration in DN Rats.

The effects of valsartan on laminin (LN), fibronectin (FN), malondialdehyde (MDA), renal tissue fibrosis, and inflammatory infiltration in diabetic nephropathy (DN) rats are explored. A total of 42 SPF male Sprague D (SD) rats are selected and randomly divided into normal set, model set, valsartan low-dose and high-dose sets, and metformin set with 7 rats in each set. The kidney tissue of all rats is collected after administration. The standard of protein mRNA in kidney tissues is detected by real-time fluorescence quantitative polymerase chain reaction (PCR) method, and the protein standard in kidney tissues is detected by western blot. The experimental results show that the application of valsartan to DN rats can effectively relieve the morphology of the rat kidney tissue, enhance the protein expression in the kidney tissue of the DN rats, and reduce the fibrosis and inflammatory infiltration of the kidney tissue.

Galanin enhanced insulin-mediated intracellular signaling by regulating the stability of membrane-localized insulin/IR.

Previous studies have shown that insulin has the important regulatory effect on the intestinal tract. However, until now, the biological properties of insulin on intestinal cell has not been revealed. Therefore, in the current research, we first studied the cell characteristics and signaling profiles of insulin in the intestinal cell model, and found that insulin can be internalized into the cytoplasm in a time-dependent manner. After internalization, insulin transported into different type of endosomes. More importantly, we explored the effect of galanin on insulin-mediated signaling pathways (galanin is a polypeptide composed of 29 amino acid residues, galanin is widely distributed in the central and peripheral nervous system and has a variety of biological activities), and found that galanin can increase insulin sensitivity by regulating insulin receptor (IR)-mediated signal transduction pathways. We further study the potential molecular mechanism by which galanin enhances insulin sensitivity, and found that galanin could increase the time of insulin acting on the cell membrane. Further experiments showed that galanin could stabilize the membrane-localized insulin/IR, which may be an important new potential mechanism by which galanin improves the biological activity of insulin. This study laid the foundation for exploring the relationship between galanin and insulin sensitivity.

Circ_WBSCR17 aggravates inflammatory responses and fibrosis by targeting miR-185-5p/SOX6 regulatory axis in high glucose-induced human kidney tubular cells.

BACKGROUND: Diabetic nephropathy (DN), a severe microvascular complication of diabetes, has complex pathogenesis. Circular RNAs (circRNAs) exert broad biological functions on human diseases. This study intended to explore the role and mechanism of circ_WBSCR17 in DN. METHODS: DN mice models were constructed using streptozotocin injection, and DN cell models were assembled using high glucose (HG) treatment in human kidney 2 cells (HK-2). The expression of circ_WBSCR17, miR-185-5p and SRY-Box Transcription Factor 6 (SOX6) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of SOX6 and fibrosis markers were examined by western blot. The release of inflammatory cytokines, cell proliferation and apoptosis, were assessed by enzyme-linked immunosorbent assay (ELISA), cell counting kit-8 (CCK-8) assay and flow cytometry assay, respectively. The predicted interaction between miR-185-5p and circ_WBSCR17 or SOX6 was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. RESULT: Circ_WBSCR17 was highly expressed in DN mice models and HG-induced HK-2 cells. Circ_WBSCR17 knockdown or SOX6 knockdown promoted cell proliferation and blocked cell apoptosis, inflammatory responses and fibrosis, while circ_WBSCR17 overexpression or SOX6 overexpression conveyed the opposite effects. MiR-185-5p was a target of circ_WBSCR17 and directly bound to SOX6. MiR-185-5p could reverse the role of circ_WBSCR17 or SOX6. Moreover, the expression of SOX6 was modulated by circ_WBSCR17 through intermediating miR-185-5p. CONCLUSION: Circ_WBSCR17 triggered the dysfunction of HG-induced HK-2 cells, including inflammatory responses and fibrosis, which was accomplished via the miR-185-5p/SOX6 regulatory axis.

Histamine evokes excitatory response of neurons in the cerebellar dentate nucleus via H2 receptors.

Previous studies have shown an excitatory effect of histamine on neurons in two cerebellar nuclei, the fastigial nucleus and the interposed nucleus. Here we investigated action of histamine on the dentate nucleus (DN), another nucleus of the cerebellum, and provided more evidence for motor control by histamine via the cerebellum. Spontaneous unitary discharge of neurons in the DN was extracellularly recorded by use of cerebellar slice preparations. In total 79-recorded neurons, which were from 53 cerebellar slices, 67 neurons (84.8%) had an excitatory response to histamine stimulation, and the rest (15.2%) were not reactive. The histamine-induced excitation of the DN neurons was not blocked by low-Ca(2+)/high-Mg(2+) medium, demonstrating that this effect of histamine was postsynaptic. Triprolidine, an antagonist of histamine H(1) receptors, did not block the excitatory effect of histamine, but ranitidine, an antagonist for H(2) receptors, blocked the excitatory response to histamine in a concentration-dependent manner. Further, histamine H(1) receptor agonist 2-pyridylethylamine did not elicit any response of DN neurons, but H(2) receptor agonist dimaprit had an excitatory action on the DN cells and this action was blocked by ranitidine. These results indicate that histamine excites cerebellar DN neurons via histamine H(2) receptors. Since the DN receives hypothalamocerebellar histaminergic projections and plays a role in initiation and planning of somatic movement, the postsynaptic excitation of the DN neurons by histamine suggests the possibility that the initiation and planning of movement may be modulated by the histaminergic projections.