miR-590-3p protects against ischaemia/reperfusion injury in an oxygen-glucose deprivation and reoxygenation cellular model by regulating HMGB1/TLR4/MyD88/NF-κB signalling

miR-590-3p has been reported to be reduced in myocardial ischaemia-reperfusion (I/R) injury, but its specific role in cerebral I/R injury is still uncertain. Thus, we explored the function and mechanism of miR590-3p in cerebral I/R injury using a cellular model. miR-590-3p, high mobility group Box 1 (HMGB1), and signalling-related factor levels were assessed using qPCR or a western blot analysis. Cell apoptosis was measured by flow cytometry. Inflammatory factors were detected by ELISA. The target of miR-590-3p was confirmed by dual-luciferase reporter assay and western blot analysis. We found that miR-590-3p was decreased and HMGB1 was increased in the OGD/R model. Upregulation of miR-590-3p reduced cell apoptosis and inflammation in the OGD/R model, and the TLR4/MyD88/NF-κB signalling pathway was suppressed. However, inhibition of miR-590-3p showed the opposite effects. Moreover, HMGB1 was verified as a target gene of miR-590-3p. HMGB1 reversed the decrease in apoptosis and inflammation caused by overexpression of miR590-3p, and the TLR4/MyD88/NF-κB signalling pathway was activated. Our results suggest that miR-590-3p regulates the TLR4/MyD88/NF-κB pathway by interacting with HMGB1 to protect against OGD/R-induced I/R injury. Thus, miR-590-3p may serve as a potential therapeutic target in cerebral I/R repair

Severe Stroke Patients With Left-Sided Occlusion of the Proximal Anterior Circulation Benefit More From Thrombectomy

Background and Purpose: Endovascular thrombectomy improves the functional independence of patients with proximal anterior circulation occlusion. However, a subset of patients fail to benefit from thrombectomy procedures, the reasons for which remain poorly defined. In this study, we investigated whether the effectiveness of thrombectomy was affected by left- or right-sided occlusion among patients with similar stroke severities.Methods: Patients with proximal anterior circulation occlusion (internal carotid or M1 of middle cerebral artery) treated with the Solitaire stent retriever within 8 h of the onset of acute ischemic stroke were enrolled from the Yijishan Hospital of Wannan Medical College. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS) on admission. The functional outcomes were assessed using the modified Rankin scale (mRS) at 90 days.Results: We enrolled 174 patients including 90 left-sided occlusion and 84 right-sided occlusion. The NIHSS scores on admission were higher in the left-sided (median, 19; interquartile range, 16 to 20) compared to the right-sided occlusion group (median, 15, interquartile range, 13 to 18) (P < 0.001). Following adjustment for potential risk factors, patients with left-sided occlusion had higher rates of functional independence (mRS ≤ 2) and lower rates of mortality (mRS = 6) compared to the right-sided occlusion patients (39.5 vs. 19.6% and 28.9 vs. 47.8%, respectively) in the severe stroke group (NIHSS ≥ 15).Conclusions: In severe stroke patients with proximal anterior circulation occlusion, stent retriever thrombectomy within 8 h of the onset of symptoms provides more benefits to left-sided occlusion

Efficacy and safety of calcitonin gene‐related peptide antagonists in migraine treatment: A meta‐analysis

Abstract Introduction We systematically reviewed the efficacy and safety of Calcitonin Gene‐Related Peptide (CGRP) antagonists for migraine treatment. Methods Various databases including PubMed, Embase, The Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), WanFang Data were electronically searched for randomized controlled trials (RCTs) on CGRP antagonists for migraine treatment since inception to March 2021. The trials were screened for inclusion, after which the methodological quality of the included trials was assessed. Then meta‐analysis was performed using the Revman 5.3 software. Results A total of 26 RCTs involving 21,736 patients were included. The CGRP antagonists group included 13,635 patients while the control group included 8101 patients. Meta‐analysis showed that compared to the control group, CGRP antagonists were associated with various significant effects, including the following outcome indicators: (1) number of patients with ≥50% reduction from baseline in mean monthly migraine days (RR = 1.50, 95% CI [1.39,1.62], p < .00001); (2) number of patients with pain free at 2 h postdose (RR = 1.98, 95% CI [1.77, 2.20], p < .00001), and (3) number of patients with 2–24 h sustained pain free postdose (RR = 2.18, 95% CI [1.93, 2.46], p < .00001). However, the number of patients with any adverse events was significantly high in the antagonists group, relative to the control group (RR = 1.08, 95% CI [1.04, 1.12], p < .0001). Conclusions CGRP antagonists are significantly effective for migraine treatment; however, they are associated with various adverse events. Due to limitations with regards to quantity and quality of the included studies, the above conclusions should be verified by more high quality studies

The Pathogenesis of Necroptosis-Dependent Signaling Pathway in Cerebral Ischemic Disease

Necroptosis is the best-described form of regulated necrosis at present, which is widely recognized as a component of caspase-independent cell death mediated by the concerted action of receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3). Mixed-lineage kinase domain-like (MLKL) was phosphorylated by RIPK3 at the threonine 357 and serine 358 residues and then formed tetramers and translocated onto the plasma membrane, which destabilizes plasma membrane integrity leading to cell swelling and membrane rupture. Necroptosis is downstream of the tumor necrosis factor (TNF) receptor family, and also interaction with NOD-like receptor pyrin 3 (NLRP3) induced inflammasome activation. Multiple inhibitors of RIPK1 and MLKL have been developed to block the cascade of signal pathways for procedural necrosis and represent potential leads for drug development. In this review, we highlight recent progress in the study of roles for necroptosis in cerebral ischemic disease and discuss how these modifications delicately control necroptosis

MST4 Kinase Inhibitor Hesperadin Attenuates Autophagy and Behavioral Disorder via the MST4/AKT Pathway in Intracerebral Hemorrhage Mice

Background. The aim of this study was to explore the role of hesperadin in intracerebral hemorrhage (ICH) mice, with the involvement of the mammalian ste20-like kinase 4 (MST4)/AKT signaling pathway. Methods. All mice were divided into four groups: sham group, sham+hesperidin group, ICH group, and ICH+hesperadin group. The effects of hesperadin were assessed on the basis of brain edema and neurobehavioral function. Furthermore, we observed MST4, AKT, phosphorylation of AKT (pAKT), and microtubule-associated protein light chain 3 (LC3) by western blotting. Protein localization of MST4 and LC3 was determined by immunofluorescence. Results. The expression of MST4 was upregulated at 12 h and 24 h after ICH. Brain edema was significantly decreased and neurological function was improved in the hesperadin treatment group compared to the ICH group (P<0.05). Hesperadin decreases the expressions of MST and increases pAKT after ICH. Autophagy significantly increased in the ICH group, while hesperadin reduced this increase. Conclusion. Hesperadin provides neuroprotection against ICH by inhibiting the MST4/AKT signaling pathway

Oxygen therapy in patients with retinal artery occlusion: A meta-analysis.

BACKGROUND:Oxygen therapy has been widely used for RAO (retinal artery occlusion) patients; however, inconsistent results have been reported. METHODS:PubMed, Web of Science, EMBASE, Medline (OvidSP), Cochrane, China National Knowledge Infrastructure (CNKI), and Wanfang Database were examined. The primary endpoint was visual acuity (VA), and RevMan software 5.3 was used to statistically analyze the outcomes. RESULTS:Seven randomized controlled trials (RCTs) met the inclusion criteria. Patients who received oxygen therapy exhibited probability of visual improvement about 5.61 times compared with the control group who did not receive oxygen therapy (OR = 5.61; 95% CI, 3.60-8.73; p < 0.01). No statistically significant difference was observed between oxygen inhalation methods (Chi2 = 0.18, df = 1, p = 0.67), combined therapy (Chi2 = 0.21, df = 1, p = 0.64), or RAO type (Chi2 = 0.06, df = 1, p = 0.81). Conversely, 100% oxygen (Chi2 = 4.55, df = 1, p < 0.05) and hyperbaric oxygen (Chi2 = 4.55, df = 1, p < 0.05) significantly improved VA in RAO patients. Better effect was showed in period within 3 months (Chi2 = 5.76, df = 1, p < 0.05). The most effective treatment length was over 9 hours (Chi2 = 6.58, df = 1, p < 0.05). CONCLUSION:Oxygen therapy demonstrated beneficial effects in improving VA in RAO patients, particularly when patients were treated with 100% hyperbaric oxygen and for over 9 hours

RD26 mediates crosstalk between drought and brassinosteroid signalling pathways

Brassinosteroids (BRs) regulate plant growth and stress responses via the BES1/BZR1 family of transcription factors, which regulate the expression of thousands of downstream genes. BRs are involved in the response to drought, however the mechanistic understanding of interactions between BR signalling and drought response remains to be established. Here we show that transcription factor RD26 mediates crosstalk between drought and BR signalling. When overexpressed, BES1 target gene RD26 can inhibit BR-regulated growth. Global gene expression studies suggest that RD26 can act antagonistically to BR to regulate the expression of a subset of BES1-regulated genes, thereby inhibiting BR function. We show that RD26 can interact with BES1 protein and antagonize BES1 transcriptional activity on BR-regulated genes and that BR signalling can also repress expression of RD26 and its homologues and inhibit drought responses. Our results thus reveal a mechanism coordinating plant growth and drought tolerance