Sepsis can cause myocardial injury, which is one of the leading causes of death in critically ill patients. The underlying mechanisms associated with sepsis-induced myocardial injury (SIMI) include impaired cardiac contractility, excessive cardiac inflammation, oxidative stress, cardiomyocyte apoptosis, and so on. SIMI is usually accompanied with dynamic changes of microRNAs (miRNAs) expression. And previous studies have shown that miR-214 plays a vital role in the protection of cardiomyocyte subjected to oxidative stress. In this study, we aimed to test whether miRNA-214 plays any roles in sepsis-induced myocardial injury. We performed quantitative real-time polymerase chain reaction in the septic mouse model induced by cecal ligation and puncture (CLP) and found the expression of miR-214 was upregulated. Then we transfected with the miRNA-214 precursor (pre-miR-214) to upregulate miR-214 expression and with the miR-214 inhibitor (anti-miR-214) to downregulate miR-214 expression respectively. Pre-miR-214 mouse model, anti-miR-214 mouse model, and wild-type mice were subjected to CLP or sham surgery. We observed that compared with control wild types, cardiac function, inflammatory response, the degree of myocardial injury, and myocyte apoptosis were remarkably alleviated in CLP-treated pre-miR-214 mice and aggravated in CLP-treated anti-miR-214 mice. Taken together, our study reveals that miR-214 has a protective effect in SIMI and thereby may provide a potential novel approach to treat SIMI.

The infiltration of inflammatory cells into the central nervous system (CNS) through the dysfunctional blood–brain barrier (BBB) was critical in the early stages of MS. However, the mechanisms underlying BBB dysfunction remain unknown. Repulsive guidance molecule-a (RGMa) is involved in the pathogenesis of multiple sclerosis (MS), but its role needs to be further explored. This study aimed to evaluate whether RMGa regulates BBB permeability in endothelial cells and MS, and if so, what mechanism may be involved. We created an experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice and a human brain microvascular endothelial cell (HBMEC) culture. The permeability of the BBB is measured in response to various interventions. Our results showed that RGMa is expressed in the endothelial cells in HBMECs and EAE mice. RGMa and its signaling counterpart, bone morphogenetic protein 2 (BMP2)/bone morphogenetic protein receptor type II (BMPRII), were gradually increased as the disease progressed. Moreover, as EAE progressed and the BBB was disrupted, the downstream effector, yes-associated protein (YAP), as well as the tight junctional proteins zonula occludens 1 (ZO-1) and claudin-5, decreased significantly. The permeability assay revealed that lentivirus-induced RGMa overexpression in HBMECs caused a significant breakdown of the BBB, whereas RGMa knockdown significantly strengthens the integrity of the BBB. Furthermore, specifically activating BMPR II or inhibiting YAP based on RGMa knockdown results in a significant decrease of ZO-1 and claudin-5 in vitro. On the contrary, inhibition of BMPR II or activation of YAP after upregulating RGMa prevents the downregulation of ZO-1 and claudin-5 in HBMECs. In addition, serum-soluble RGMa (sRGMa) levels were significantly higher in MS patients, particularly in MS patients with Gd+ lesions, indicating that the BBB has been disrupted. In conclusion, this study shows that RGMa causes BBB dysfunction in endothelial cells via BMP2/BMPR II/YAP, resulting in BBB integrity disruption in MS and that it could be a novel therapeutic target for BBB permeability in MS.

Rationale:Amniotic fluid embolism (AFE) is a rare obstetrical complication and is a leading cause of maternal death in developed countries. Despite the development of supportive therapeutic measures, the mortality rate remains high.Patient concerns:A 38-year-old nulliparous pregnant woman, who underwent in vitro fertilization-embryo transfer, was admitted for labor at 37 weeks’ gestation. Approximately 30 minutes after delivery of the placenta, the puerpera developed postpartum hemorrhage with uterine atony. Soon after, the patient experienced hypotension, repeated cardiac arrest, refectory hypoxia, and disseminated intravascular coagulopathy.Diagnosis:AFE is diagnosed clinically. The pregnant woman in this case fulfilled the diagnostic criteria for AFE: acute hypotension, cardiac arrest, acute hypoxia, and coagulation disorders within approximately 30 minutes after delivery of the placenta.Interventions:The patient was intubated, connected to a ventilator, and was administered a high dose of vasoactive drugs to maintain blood pressure and underwent an emergency hysterectomy. Considering the risk for recurrent cardiac arrest and severe refractory hypoxia, venoarterial extracorporeal membrane oxygenation was initiated and discontinued as soon as cardiac function was restored based on serial bedside ultrasound assessment.Outcomes:The patient stabilized on day 7 in the intensive care unit and was transferred to the obstetrics ward and, 1 week later, was discharged with no complications. Two months later, follow-up revealed that the patient was in good condition.Lesson:Serial bedside ultrasound was crucial for assessing cardiac function and optimal weaning. Timely application of venoarterial extracorporeal membrane oxygenation and weaning was significant to avoid the occurrence of complications and improve long-term outcomes.

Introduction: Sepsis can cause acute lung injury (ALI), one of the leading causes of death in critically ill patients. The underlying mechanisms of sepsis-induced acute lung injury include excessive inflammation, oxidative stress, cell apoptosis, pulmonary edema, and lung tissue dysfunction. Recent studies have shown that miRNA-21 (miR-21) plays a vital role in sepsis-induced acute kidney injury. Relatively few studies have focused on the protective effects of ALI. This study aimed to determine the potential role of miR-21 in sepsis-induced ALI. Methods: We performed quantitative real-time polymerase chain reaction in a septic mouse model induced by cecal ligation and puncture (CLP) and found that miR-21 expression was upregulated. We then transfected the miR-21 precursor to upregulate miR-21 expression and miR-21 inhibitor to downregulate miR-21 expression. The sham group was exposed only to the cecum. ALI was induced by CLP, and the pre-miR-21+ALI and anti-miR-21+ALI groups were treated with miR-21 precursor or miR-21 inhibitor in the caudal vein before CLP. Pre-miR-21+ALI+PTEN inhibition (Pre-miR-21+ALI+PI) and anti-miR-21+ALI+PTEN inhibition (Anti-miR-21+ALI+PI) groups were treated with PTEN inhibition into the caudal vein after miR-21 transfection. Inflammatory cytokines, oxidative stress indicators, lung tissue cell apoptosis, oxygenation index (OI), lung wet/dry weight ratio, and lung pathological changes in the lung were observed in each group. Results: Compared with ALI mice, inflammatory response, oxidative stress indicators, lung tissue cell apoptosis, and the degree of lung injury were remarkably alleviated in Pre-miR-21+ALI mice and aggravated in Anti-miR-21+ALI mice. Western blot analysis showed that phosphatase and tensin homolog (PTEN) protein expression was decreased in CLP-treated mics. PTEN protein expression was decreased in the Pre-miR-21+ALI group but increased in the Anti-miR-21+ALI group. Moreover, the effect of miR-21 on anti-inflammatory, anti-oxidative stress, and anti-apoptosis enhanced after PTEN inhibition. Conclusion: This study revealed that miR-21 has a protective effect in sepsis-induced ALI by regulating PTEN in mice.

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