Current Issue : October - December Volume : 2020 Issue Number : 4 Articles : 5 Articles
Angiotensin (Ang)-(1-7) is a beneficial reninâ??angiotensin system (RAS) hormone that elicits\nprotective cardiometabolic effects in young animal models of hypertension, obesity, and metabolic\nsyndrome. The impact of Ang-(1-7) on cardiovascular and metabolic outcomes during aging,\nhowever, remains unexplored. This study tested the hypothesis that Ang-(1-7) attenuates age-related\nelevations in blood pressure and insulin resistance in mice. Young adult (two-month-old) and aged\n(16-month-old) male C57BL/6J mice received Ang-(1-7) (400 ng/kg/min) or saline for six-weeks via a\nsubcutaneous osmotic mini-pump. Arterial blood pressure and metabolic function indices (body\ncomposition, insulin sensitivity, and glucose tolerance) were measured at the end of treatment.\nAdipose and cardiac tissue masses and cardiac RAS, sympathetic and inflammatory marker gene\nexpression were also measured. We found that chronic Ang-(1-7) treatment decreased systolic\nand mean blood pressure, with a similar trend for diastolic blood pressure. Ang-(1-7) also improved\ninsulin sensitivity in aged mice to levels in young mice, without effects on glucose tolerance or body\ncomposition. The blood pressureâ??lowering effects of Ang-(1-7) in aged mice were associated with\nreduced sympathetic outflow to the heart. These findings suggest Ang-(1-7) may provide a novel\npharmacological target to improve age-related cardiometabolic risk....
Recently, we developed the fatty acid-binding protein 3 (FABP3) ligand MF1\n(4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid) as a therapeutic\ncandidate for Alpha-synucleinopathies. MF1 shows affnity towards \n-aminobutyric acid type-A (GABAA)\nreceptor, but its effect on the receptor remains unclear. Here, we investigate the pharmacological\nproperties of MF1 on the GABAA receptor overexpressed in Neuro2A cells. While MF1 \nalone failed to evoke GABA currents, MF1 promoted GABA currents during GABA exposure. MF1-promoted GABA currents were blocked by flumazenil treatment, suggesting\nthat MF1 enhances receptor function via the benzodiazepine recognition site. Acute and chronic\nadministration of MF1 (0.1, 0.3 and 1.0 mg/kg, p.o.) significantly attenuated status epilepticus (SE)\nand the mortality rate in pilocarpine (PILO: 300 mg/kg, i.p.)-treated mice, similar to diazepam (DZP:\n5.0 mg/kg, i.p.). The anti-epileptic effects of DZP (5.0 mg/kg, i.p.) and MF1 (0.3 mg/kg, p.o.) were\ncompletely abolished by flumazenil (25 mg/kg, i.p.) treatment. Pentylenetetrazol (PTZ: 90 mg/kg,\ni.p.)-induced seizures in mice were suppressed by DZP (5.0 mg/kg, i.p.), but not MF1. Collectively,\nthis suggests that MF1 is a mild enhancer of the GABAA receptor and exercises anti-epileptic effects\nthrough the receptorâ??s benzodiazepine recognition site in PILO-induced SE models....
Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their\neffects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma\n(HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced\ndiabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks.\nGlycemic control, hepatocarcinogenesis, and liver histology were compared between the groups.\nFasting blood glucose levels were significantly lower in the liraglutide group than in the control\ngroup (210.0 17.3 mg/dL vs. 601.8 123.6 mg/dL), and fasting insulin levels were significantly\nincreased by liraglutide (0.18 0.06 ng/mL vs. 0.09 0.03 ng/mL). Liraglutide completely suppressed\nhepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 3.87;\naverage tumor size, 8.1 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and\nhepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and\ninsulin-positive -cells were observed in the pancreas in liraglutide-treated mice but not in control\nmice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic\nmice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes....
Background: General anesthetics depress neuronal activity. The depression and\nuncoupling of cortico-hippocampal activity may contribute to anesthetic-induced amnesia. However,\nthe molecular targets involved in this process are not fully characterized. GABAA receptors,\nespecially the type with 3 subunits, represent a main molecular target of propofol. We therefore\nhypothesized that GABAA receptors with 3 subunits mediate the propofol-induced disturbance\nof cortico-hippocampal interactions. Methods: We used local field potential (LFP) recordings\nfrom chronically implanted cortical and hippocampal electrodes in wild-type and 3(N265M)\nknock-in mice. In the 3(N265M) mice, the action of propofol via 3subunit containing GABAA\nreceptors is strongly attenuated. The analytical approach contained spectral power, phase locking,\nand mutual information analyses in the 2â??16 Hz range to investigate propofol-induced effects on\ncortico-hippocampal interactions. Results: Propofol caused a significant increase in spectral power\nbetween 14 and 16 Hz in the cortex and hippocampus of wild-type mice. This increase was absent in\nthe 3(N265M) mutant. Propofol strongly decreased phase locking of 6â??12 Hz oscillations in wild-type\nmice. This decrease was attenuated in the 3(N265M) mutant. Finally, propofol reduced the mutual\ninformation between 6â??16 Hz in wild-type mice, but only between 6 and 8 Hz in the 3(N265M)\nmutant. Conclusions: GABAA receptors containing 3 subunits contribute to frequency-specific\nperturbation of cortico-hippocampal interactions. This likely explains some of the amnestic actions\nof propofol....
Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet\nmedical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical\ntrials; however, cisplatin treatment is associated with hypoxia that, in turn, promotes cancer stem cell\n(CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased\ncisplatin effcacy in the clinic for the treatment of TNBC. In this report we analyzed clinical datasets of\nTNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression.\nA similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We, thus,\ndeveloped a new therapeutic approach to inhibit EGFR and hypoxia by combination treatment with\nmetformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both\nCD44+/CD24 and ALDH+ CSCs. We demonstrated a similar inhibition effcacy on organotypic\ncultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in\nthe clinic; this study illustrates a novel, clinically translatable therapeutic approach to treat patients\nwith TNBC....
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