Elevated microRNA-135b-5p relieves neuronal injury and inflammation in post-stroke cognitive impairment by targeting NR3C2.

PURPOSE: Post-stroke cognitive impairment (PSCI) is a series of syndromes that meets the diagnostic criteria of cognitive impairment within 6 months after the clinical event of stroke. With the unpleasing treatment at present, this study aimed to investigate the role of microRNA (miR)-135b-5p in regulating mineralocorticoid receptor (NR3C2) in PSCI. METHODS: The rats were modeled via middle cerebral artery occlusion, and injected with miR-135b-5p agomir or antagomir to figure its role in post-stroke neurological deficits, neuronal injury, neuronal cell apoptosis, and inflammation via Behavioral tests, Nissl's staining, flow cytometry, and TUNEL staining. The expression of miR-135b-5p and NR3C2 in rats was detected by RT-qPCR and western blot analysis. The targeting relationship between miR-135b-5p and NR3C2 was verified by dual luciferase reporter gene assay. RESULTS: Highly expressed miR-135b-5p relieved post-stroke neurological deficits, focal cerebral ischemia-reperfusion (FCIR) neuron injury, and reduced neuronal apoptosis and inflammatory response after FCIR in PSCI rats. Poorly expressed miR-135b-5p and highly expressed NR3C2 were present in FCIR injury in PSCI rats. miR-135b-5p can direct target NR3C2 3'UTR. CONCLUSION: The study highlights that up regulation of miR-135b-5p can reduce neuronal injury and inflammatory response in PSCI by targeting NR3C2, which might be helpful for PSCI treatment.

Silencing lncRNA HOTAIR improves the recovery of neurological function in ischemic stroke via the miR-148a-3p/KLF6 axis.

Ischemic stroke (IS), caused by a permanent or transient local reduction in blood supply to the brain, is one of the most widespread causes of public health problems in modern society. Long non-coding RNA (LncRNA) has been reported to be related to angiogenesis following IS. In this study, we explored the effect and potential molecular mechanism of lncRNA homeobox antisense non-coding RNA (HOTAIR) in IS. Permanent middle cerebral artery occlusion (pMCAO) model and oxygen and glucose deprivation (OGD) model were established. HOTAIR was increased in vivo and in vitro models post-ischemic. HOTAIR knockdown promoted neurological function recovery, manifesting in decreased modified neurological severity score, cerebral infarcted area, apoptosis and inflammation, and improved balance ability, spatial learning and memory ability. Silencing HOTAIR also improved the viability of OGD-induced N2a cells, and attenuated apoptosis and inflammation. HOTAIR can compete with KLF6 to bind to miR-148a-3p. miR-148a-3p knockdown or KLF6 overexpression partially reversed the effect of sh-HOTAIR on OGD-induced N2a cells. HOTAIR suppressed the activation of STAT3 pathway via the miR-148a-3p/KLF6 axis. To summarize, this study demonstrated that lncRNA HOTAIR absorbed miR-148a-3p and up-regulated KLF6 expression through ceRNA mechanism, and inhibited STAT3 pathway, promoted apoptosis and inflammation, and aggravated neurological injury post-IS.

A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer's dementia.

BACKGROUND: New therapies are urgently needed for Alzheimer's disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. RESULTS: A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was - 2.15 points (95% confidence interval, - 3.07 to - 1.23; p < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group. CONCLUSIONS: GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0229391 5. Registered on November 19, 2014.