Objective Emerging evidence suggests that brain angiotensin-(1–7) (Ang-(1–7)) deficiency contributes to the pathogenesis of Alzheimer’s disease (AD). Meanwhile, our previous studies revealed that restoration of brain Ang-(1–7) levels provided neuroprotection by inhibition of inflammatory responses during AD progress. However, the potential molecular mechanisms by which Ang-(1–7) modulates neuroinflammation remain unclear. Materials and Methods APP/PS1 mice were injected intraperitoneally with AVE0991 (a nonpeptide analogue of Ang-(1–7)) once a day for 30 consecutive days. Cognitive functions, neuronal and synaptic integrity, and inflammation-related markers were assessed. Since astrocytes played a crucial role in AD-related neuroinflammation whilst long noncoding RNAs (lncRNAs) were reported to participate in modulating inflammatory responses, astrocytes of APP/PS1 mice were isolated for high-throughput lncRNA sequencing to identify the most differentially expressed lncRNA following AVE0991 treatment. Afterward, the downstream pathways of this lncRNA in the anti-inflammatory action of AVE0991 were investigated using primary astrocytes. Results AVE0991 rescued spatial cognitive impairments and alleviated neuronal and synaptic damage in APP/PS1 mice. The levels of Aβ 1-42 in the brain of APP/PS1 mice were not affected by AVE0991. By employing high-throughput lncRNA sequencing, our in vitro study demonstrated for the first time that AVE0991 suppressed astrocytic NLRP3 inflammasome-mediated neuroinflammation via a lncRNA SNHG14-dependent manner. SNHG14 acted as a sponge of miR-223-3p while NLRP3 represented a direct target of miR-223-3p in astrocytes. In addition, miR-223-3p participated in the AVE0991-induced suppression of astrocytic NLRP3 inflammasome. Conclusion Our results suggest that Ang-(1–7) analogue AVE0991 inhibits astrocyte-mediated neuroinflammation via SNHG14/miR-223-3p/NLRP3 pathway and offers neuroprotection in APP/PS1 mice. These findings reveal the underlying mechanisms by which Ang-(1–7) inhibits neuroinflammation under AD condition and uncover the potential of its nonpeptide analogue AVE0991 in AD treatment.

Purpose Our previous study has shown that AVE 0991, a nonpeptide analogue of Ang-(1-7), ameliorates cognitive decline and inhibits NLRP3 inflammasome of astrocytes in Alzheimer’s disease model mice. Additionally, several studies have suggested that activation of autophagy appears to effectively inhibit the progression of neuroinflammation. However, it is unclear whether AVE 0991 can modulate astrocyte autophagy to suppress neuroinflammation in Alzheimer’s disease. Materials and Methods APP/PS1 mice and Aβ-treated primary astrocytes were used as the research objects in vivo and in vitro, respectively. Water maze test was used to evaluate cognitive function of mice, Nissl staining and immunofluorescence staining was used to assess neuronal damage. ELISA kits were used to detect the levels of Ang-(1-7) and Aβ in the cortex, and qRT-PCR was used to detect the expression of cortical inflammation-related mediators. The expression of autophagy-related proteins in cortex were detected by Western blot. The upstream molecular responses involved in inflammation inhibition by AVE 0991 were validated by means of using the Mas1 antagonist and autophagy inhibitor. Results We found that 30 days of intraperitoneal administration of AVE 0991 improved. Aβ deposition, neuronal death, and cognitive deficits in APP/PS1 Alzheimer’s disease model mice. Moreover, AVE 0991 treatment greatly suppressed astrocyte-mediated inflammation and up-regulated the expression of autophagy. Furthermore, the inhibitory effect of AVE 0991 on the expression of inflammatory factors was reversed by 3-MA, an autophagy inhibitor. Conclusion These findings suggest that regulation of autophagy is critical for inhibiting astrocyte neuroinflammatory responses and demonstrate a potential neuroprotective mechanism by which AVE 0991 could suppress neuroinflammatory responses by enhancing autophagy.

Neuron-specific enolase (NSE) is considered a biomarker for the severity of nervous system diseases. We sought to explore whether serum NSE concentration in ischemic stroke patients undergoing mechanical thrombectomy (MT) is related to 3-month functional outcome and symptomatic intracranial hemorrhage (sICH). Patients and Methods: We retrospectively collected the data of acute ischemic stroke patients with anterior circulation infarction receiving MT within 6 h in our stroke center. Favorable outcome and poor outcome at 3 months were defined as modified Rankin Scale (mRS) score 0-2 and 3-6, respectively. sICH was defined according to the Heidelberg bleeding classification. We used multivariate logistic regression model and receiver operating characteristic curves to investigate the correlation between NSE and clinical outcomes. Results: Among the 426 patients enrolled, 40 (9.4%) patients developed sICH. Three-month favorable outcome in 160 (37.6%) and poor outcome in 266 (62.4%) patients were observed. Serum NSE levels was significantly correlated with 3-month mRS score (R = 0.473, P < 0.001). A cutoff value of 15.29 and 23.12 ng/mL for serum NSE was detected in discriminating 3-month poor outcome (area under the curve, 0.724) and sICH (area under the curve, 0.716), respectively. Multivariate analysis showed that high serum NSE levels were independently associated with 3-month poor outcome (odds ratio [OR] 5.049, 95% confidence interval [CI] 2.933-8.689, P<0.001) and sICH (OR 5.111,, P < 0.001). Conclusion:Our study demonstrated that high serum NSE levels after receiving MT were independently associated with 3-month poor outcome and sICH in acute ischemic stroke patients. Serum NSE levels could be a good predictor of clinical outcomes for patients receiving MT.

BACKGROUND: Previous meta-analyses using traditional pairwise comparisons did not support intensive systolic blood pressure (SBP) control in patients with diabetes and included trials published before 2015. We aimed to identify the optimal SBP control targets in patients with type 2 diabetes using a systematic review and network meta-analysis of accumulating evidence. METHODS: We systematically searched PubMed, Embase, and Cochrane Library from inception to August 29, 2022 for randomized controlled trials comparing different blood pressure targets, antihypertensive agents against placebo, or dual antihypertensive agents against single agent in patients with type 2 diabetes. Network meta-analysis was used to obtain pooled results of direct and indirect comparisons of each 5 mm Hg SBP category in association with clinical outcomes adjusted for baseline risk and intervention duration (PROSPERO [International Prospective Register of Systematic Reviews], CRD 42022316697). RESULTS: We identified 30 trials including 59 934 patients with type 2 diabetes. The mean achieved SBP levels ranged from 117 mm Hg to 144 mm Hg among treatment groups. A total of 7799 major cardiovascular diseases events and 4130 deaths were reported. The lowest risk of major cardiovascular diseases was found in patients with achieved SBP level of 120 to 124 mm Hg. The hazard ratio and 95% CI were 0.73 (0.52–1.02) compared with 130 to 134 mm Hg, 0.60 (0.41–0.85) compared with 140 to 144 mm Hg, and 0.41 (0.26–0.63) compared with ≥150 mm Hg. Similar results were found for cardiovascular diseases components including stroke, myocardial infarction, heart failure, and cardiovascular mortality. All-cause mortality was reduced at an achieved SBP <140 mm Hg but further reduction did not show additional benefits. CONCLUSIONS: Our findings support an intensive blood pressure-lowering strategy to prevent major cardiovascular diseases in patients with type 2 diabetes.

Background and Purpose Insulin resistance plays a pivotal role in the pathophysiology of ischemic stroke. This study aimed to determine the relationship between the novel metabolic score for insulin resistance (METS-IR) and symptomatic intracranial hemorrhage (sICH) after endovascular thrombectomy (EVT) in stroke patients. Methods We retrospectively included patients with large artery occlusion in the anterior circulation and treated by EVT from 2 stroke centers (Nanjing First Hospital from September 2019 to April 2022, and Jinling Hospital from September 2019 to July 2021). The METS-IR was used as an alternative marker of insulin resistance and calculated using laboratory data after admission. sICH was diagnosed according to the Heidelberg Bleeding Classification. Results Of the 410 enrolled patients (mean age, 69.8 ± 11.7 years; 60.7% men), 50 (12.2%) were diagnosed as sICH. After adjusting for demographic characteristics, poor collateral status, and other potential confounders, higher METS-IR was revealed to be independently associated with sICH (odds ratio, 1.076; 95% confidence interval, 1.034−1.120; P = 0.001). Similar significant results were obtained when defining METS-IR as a categorical variable. The restricted cubic spline uncovered a linear relationship between METS-IR and sICH ( P < 0.001 for linearity). Furthermore, adding METS-IR to the conventional model significantly improved the risk prediction for sICH (net reclassification improvement = 15.8%, P = 0.035; integrated discrimination index = 2.6%; P = 0.017). Conclusion This study demonstrated a significant association between METS-IR score and sICH in ischemic stroke patients treated with EVT. It could help monitor and manage sICH in patients after EVT.