Depression is one of the major psychiatric diseases affecting the quality of life for individuals worldwide. Numerous reports have investigated depression, although its etiology remains to be elucidated. microRNA (miR)-146a is suggested to regulate innate immune and inflammatory responses. However, it is unclear whether miR-146a is involved in depression. Depression model mice were established using lipopolysaccharide-induced depression and chronic unpredictable mild stress, separately. miR-146a mimic and short interfering RNA were used to treat depressed mice. Depression-like behaviors and levels of pro-inflammatory cytokines were measured, while ionized calcium binding adapter molecule 1 (Iba-1) expression in hippocampus was quantified by immunohistochemistry. Neuroinflammatory factor levels in hippocampus were measured by western blotting. BV-2 cells were used to confirm that miR-146a suppressed microglia activation. Compared with control mice, the two depressed mouse models showed clearly decreased sucrose preference and significantly increased immobility time in the forced swimming test and tail suspension test (P<0.05). miR-146a overexpression significantly increased sucrose preference and reduced immobility time in depressed mice (P<0.05). However, total distance traveled in the locomotor activity test did not differ among groups. Compared with controls, expression levels of Iba-1, inducible nitric oxide, IL-1β, TNF-α, interleukin 1 receptor associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6) and phosphorylated NF-κB p65 were significantly increased in depressed mice (P<0.05). miR-146a overexpression effectively inhibited expression of these neuroinflammatory proteins, while miR-146a silencing significantly upregulated their expression (P<0.05). Consistent with these in vivo results, miR-146a mimic treatment inhibited TNF-α, IL-1β, IRAK1 and TRAF6 expression in BV-2 cells. miR-146a improved depressive behaviors in depressed model mice by inhibiting microglial activation and neuroinflammatory factor expression.

The presence of multiple comorbidities in patients facing myocardial ischemia-reperfusion (IR) injury is the main obstacle for cardioprotection. This study investigated the effect of melatonin postconditioning combined with sitagliptin pretreatment on cardioprotection in diabetic aged rats by evaluating oxidative stress, apoptosis and involvement of the AMPK/SIRT1 pathway. The type-2 highfat/ streptozotocin experimental model in aged Sprague-Dawley rats (n=78) was used. The animals underwent left coronary occlusion for 30 min, followed by 3 h reperfusion. Diabetic rats were pretreated with sitagliptin (20 mg/kg, i.p.) and received melatonin (10 mg/kg, i.p.) early in reperfusion. Myocardial infarct size, histological changes, oxidative markers, mitochondrial reactive oxygen species (mitoROS) and expression of proteins regulating apoptosis and AMPK/SIRT1 activity were measured. The infarct sizesparing effect of the combination of melatonin plus sitagliptin was greater than that observed in individual treatments (P<0.01). Combination therapy significantly reduced IR-induced elevation of 8-isoprostane, mitoROS and proapoptotic proteins Bax and cleaved caspase-3, and increased IR-induced downregulation of mitochondrial superoxide-dismutase, glutathione, anti-apoptotic protein Bcl2, phosphorylated AMPK and SIRT1 (P<0.01, P<0.001). Inhibition of AMPK via compound-C completely reversed combinationinduced cardioprotection. Thus, improving cardiac antioxidative and antiapoptotic responses via upregulation of AMPK/SIRT1 activity may represent a central mechanism through which melatonin plus sitagliptin attenuate myocardial IR injury in diabetic-aged rats.

Background. Depression was a common life-threatening psychiatric disorder and occurs more frequently in women than in men. Long noncoding RNAs (lncRNAs), such as LINC00473, had been reported to be involved in the progression of depression. Methods. Chronic unpredictable moderate stress in mice (CUMS) was applied to construct a depression model. Subsequently, RT-qPCR was applied to check the level of LINC00473 and microRNA-497-5p (miR-497-5p) in the hippocampal region of the mice induced by CUMS. CUMS mice were injected with lentiviral vectors of LINC00473 (LV-LINC00473), miR-497-5p inhibitor, short hairpin- (sh-) brain-derived neurotrophic factor (sh-BDNF), or miR-497-5p mimic to evaluate depressive behaviors, including sucrose preference test, forced swim test, elevated plus maze, and tail suspension test. Moreover, the production of hypothalamic neurotransmitters was assessed with the usage of ELISA kits. Dual-luciferase reporter assay, RNA pull-down, and RIP analysis were performed to measure the relationship between miR-497-5p and LINC00473 or BDNF. Further, western blot was employed to determine the protein level of BDNF. Results. We discovered that LINC00473 level was downregulated in the female mice with depression, but not in male mice. Besides, the depressive behaviors induced by CUMS in mice, including the decrease of sucrose preference and time in open arm, as well as the increase of immobility time and swimming resting time were all ameliorated by LINC00473 overexpression. Moreover, the concentration of neurotransmitters was decreased in CUMS-induced mouse hypothalamus, which was blocked by LV-LINC00473 lentiviral vector administration. Mechanistically, LINC00473 directly targeted miR-497-5p. Absence of miR-497-5p revealed the antidepression effects on CUMS-induced mice, and miR-497-5p upregulation could counter the antidepressive impacts of LINC00473 upregulation on CUMS-induced mice. Furthermore, LINC00473 could target miR-497-5p to modulate BDNF level. Knockdown of BDNF could abrogate the improving influences of miR-497-5p suppression on CUMS-induced depression. Conclusions. LINC00473 ameliorated CUMS-caused depression by encouraging BDNF expression via binding to miR-497-5p, which might provide a potential therapeutic target for depression in females.