Hypoperfusion intensity ratio and hemorrhagic transformation in patients with successful recanalization after thrombectomy.

BACKGROUND AND PURPOSE: Hemorrhagic transformation remains a potentially devastating complication of acute ischemic stroke. We aimed to evaluate whether the hypoperfusion intensity ratio (HIR), a parameter derived from CT perfusion imaging, is associated with the development of hemorrhagic transformation in patients with anterior large-artery occlusion who had undergone thrombectomy. MATERIALS AND METHODS: We retrospectively reviewed data from consecutive acute ischemic stroke patients who had achieved successful recanalization (thrombolysis in cerebral infarction score ≥ 2b) between January 2020 and December 2023. HIR was defined as the ratio of the volume of lesions with a time-to-maximum (TMax) > 6 s to those with a Tmax > 10 s delay. The primary outcome, based on the European Cooperative Acute Stroke Study, was hemorrhagic transformation (HT), diagnosed by follow-up imaging assessment in 24 h windows, and radiologically classified as hemorrhagic infarction (HI) and parenchymal hematoma (PH). The secondary outcome was a 3-month mRS score of ≥3. RESULTS: Among 168 patients, 35/168 developed hemorrhagic transformation HT; 14/168 developed hemorrhagic infarction HI, and 21/168 developed parenchymal hematoma PH. After adjusting the latent covariates, increased hypoperfusion intensity ratio (per 0.1, adjusted OR [aOR] 1.68, 95% CI 1.26-2.25), ASPECTS (aOR 0.44, 95% CI 0.27-0.72), onset-to-puncture (aOR 1.01, 95% CI 1.00-1.02), and cardioembolism (aOR 5.6, 95% CI 1.59-19.7) were associated with hemorrhagic transformation in multivariable regression. The receiver operating characteristic curve indicated that HIR can predict HT accurately (area under the curve = 0.81; 95% CI, 0.738-0.882; P < 0.001) and predict PH (area under the curve = 0.801; 95% CI, 0.727-0.875; P < 0.001). CONCLUSIONS: Upon admission, hypoperfusion intensity ratio, an imaging parameter, predicted hemorrhagic transformation after reperfusion therapy in this patient population.ABBREVIATIONS: HT = hemorrhagic transformation; HIR = hypoperfusion intensity ratio; LVO = left vessel occlusion; EVT = endovascular thrombectomy; AIS = arterial ischemic stroke; OTP = onset-to-puncture; HI = hemorrhagic infarction; PH = parenchymal hematoma.

miR-206 alleviates LPS-induced inflammatory injury in cardiomyocytes via directly targeting USP33 to inhibit the JAK2/STAT3 signaling pathway.

Previous reports have confirmed that miR-206 participates in inflammatory cardiomyopathy, but its definite mechanism remains elusive. This study aims to elucidate the potential mechanism of miR-206 in septic cardiomyopathy (SCM). The primary mouse cardiomyocytes were isolated and exposed to lipopolysaccharides (LPS) to construct a septic injury model in vitro. Then, the gene transcripts and protein levels were detected by RT-qPCR and/or Western blot assay. Cell proliferation, apoptosis, and inflammatory responses were evaluated by CCK-8/EdU, flow cytometry, and ELISA assays, respectively. Dual luciferase assay, Co-IP, and ubiquitination experiments were carried out to validate the molecular interactions among miR-206, USP33, and JAK2/STAT3 signaling. miR-206 was significantly downregulated, but USP33 was upregulated in LPS-induced cardiomyocytes. Gain-of-function of miR-206 elevated the proliferation but suppressed the inflammatory responses and apoptosis in LPS-induced cardiomyocytes. USP33, as a member of the USP protein family, was confirmed to be a direct target of miR-206 and could catalyze deubiquitination of JAK2 to activate JAK2/STAT3 signaling. Rescue experiments presented that neither upregulation of USP33 nor JAK2/STAT3 signaling activation considerably reversed the protective effects of miR-206 upregulation in LPS-induced cardiomyocytes. The above data showed that miR-206 protected cardiomyocytes from LPS-induced inflammatory injuries by targeting the USP33/JAK2/STAT3 signaling pathway, which might be a novel target for SCM treatment.

USF2 activates RhoB/ROCK pathway by transcriptional inhibition of miR-206 to promote pyroptosis in septic cardiomyocytes.

Septic cardiomyopathy (SCM) is one of the most serious complications of sepsis. The present study investigated the role and mechanism of upstream stimulatory factor 2 (USF2) in SCM. Serum samples were extracted from SCM patients and healthy individuals. A murine model of sepsis was induced by caecal ligation and puncture (CLP) surgery. Myocardial injury was examined by echocardiography and HE staining. ELISA assay evaluated myocardial markers (CK-MB, cTnI) and inflammatory cytokines (TNF-α, IL-1ß, IL-18). Primary mouse cardiomyocytes were treated with lipopolysaccharide (LPS) to simulate sepsis in vitro. RT-qPCR and Western blot were used for analyzing gene and protein levels. CCK-8 assay assessed cell viability. NLRP3 was detected by immunofluorescence. ChIP, RIP and dual luciferase reporter assays were conducted to validate the molecular associations. USF2 was increased in serum from SCM patients, septic mice and primary cardiomyocytes. USF2 silencing improved the survival of septic mice and attenuated sepsis-induced myocardial pyroptosis and inflammation in vitro and in vivo. Mechanistically, USF2 could directly bind to the promoter of miR-206 to transcriptionally inhibit its expression. Moreover, RhoB was confirmed as a target of miR-206 and could promote ROCK activation and NLRP3 inflammasome formation. Moreover, overexpression of RhoB remarkably reversed the protection against LPS-induced inflammation and pyroptosis mediated by USF2 deletion or miR-206 overexpression in cardiomyocytes. The above findings elucidated that USF2 knockdown exerted a cardioprotective effect on sepsis by decreasing pyroptosis and inflammation via miR-206/RhoB/ROCK pathway, suggesting that USF2 may be a novel drug target in SCM.