, in Wuhan, China. There are over 1,800,000 confirmed cases worldwide. 1 The pathological process of severe COVID-19 pneumonia is an inflammation reaction characterized by the destruction of the deep airway and alveolar. 2 It is currently considered that lung injury is not only associated with the direct virus-induced damage, but also the immune responses triggered by COVID-19 that lead to the activation of immune cells to release a large number of pro-and anti-inflammatory cytokines. Histologic examination has shown diffuse alveolar damage and mucinous exudate, which is similar to acute respiratory distress syndrome. 2 Aggravation of symptoms always occurs during 5-7 days after onset in patients with COVID-19 pneumonia and severe cases develop rapidly to acute respiratory failure. 3 Therefore, it is important to strengthen the treatment to suppress the proinflammatory response and control the cytokine storm at this stage. Methylprednisolone are the classical immunosuppressive drugs, which are important to stop or delay the progress of the pneumonia, and have been proved to be effective for the treatment of acute respiratory distress syndrome (ARDS). In a recent study, Wu et al. 4 found the administration of methylprednisolone appeared to reduce the risk of death in COVID-19 pneumonia patients with ARDS, however, of those who received methylprednisolone treatment, 23 of 50 patients died. This is a rather high mortality rate of~50%; therefore, in terms of the indication, timing, dosage and duration, the application of methylprednisolone warrants further investigation. In another study, Zhou et al. 5 endorsed the potential benefits of low-dose corticosteroids treatment in a subset of critically ill patients with COVID-19 pneumonia, however, the data was limited to only 15 patients and no control group. Although this is an important issue with regard to the challenges in the treatment of severe COVID-19 pneumonia, the clinical applicability of methylprednisolone needs to be tempered owing to the unanswered questions that remain. To address this issue, we performed a retrospective cohort study comparing the clinical outcomes of COVID-19 pneumonia patients with or without methylprednisolone treatment. We studied 46 severe patients with COVID-19 pneumonia at the

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Myocardial microRNAs (myo-miRs) are released into the circulation after acute myocardial infarction (AMI). How they impact remote organs is however largely unknown. Here we show that circulating myo-miRs are carried in exosomes and mediate functional crosstalk between the ischemic heart and the bone marrow (BM). In mice, we find that AMI is accompanied by an increase in circulating levels of myo-miRs, with miR-1, 208, and 499 predominantly in circulating exosomes and miR-133 in the non-exosomal component. Myo-miRs are imported selectively to peripheral organs and preferentially to the BM. Exosomes mediate the transfer of myo-miRs to BM mononuclear cells (MNCs), where myo-miRs downregulate CXCR4 expression. Injection of exosomes isolated from AMI mice into wild-type mice downregulates CXCR4 expression in BM-MNCs and increases the number of circulating progenitor cells. Thus, we propose that myo-miRs carried in circulating exosomes allow a systemic response to cardiac injury that may be leveraged for cardiac repair.

All together, the evidence generated by our study elucidates the role of lncRNA TUG1 as a miRNA sponge in CAVD, and sheds new light on lncRNA-directed diagnostics and therapeutics in CAVD.

Rationale: Atherosclerotic cardiovascular diseases are the leading cause of mortality worldwide. Atherosclerotic cardiovascular diseases are considered as chronic inflammation processes. In addition to risk factors associated with the cardiovascular system itself, pathogenic bacteria such as the periodontitis-associated Porphyromonas gingivalis ( P gingivalis ) are also closely correlated with the development of atherosclerosis, but the underlying mechanisms are still elusive. Objective: To elucidate the mechanisms of P gingivalis -accelerated atherosclerosis and explore novel therapeutic strategies of atherosclerotic cardiovascular diseases. Methods and Results: Bmal1 −/− (brain and muscle Arnt-like protein 1) mice, ApoE −/− mice, Bmal1 −/− ApoE −/− mice, conditional endothelial cell Bmal1 knockout mice ( Bmal1 fl/fl ; Tek -Cre mice), and the corresponding jet-legged mouse model were used. P gingivalis accelerates atherosclerosis progression by triggering arterial oxidative stress and inflammatory responses in ApoE −/− mice, accompanied by the perturbed circadian clock. Circadian clock disruption boosts P gingivalis -induced atherosclerosis progression. The mechanistic dissection shows that P gingivalis infection activates the TLRs-NF-κB signaling axis, which subsequently recruits DNMT-1 to methylate the BMAL1 promoter and thus suppresses BMAL1 transcription. The downregulation of BMAL1 releases CLOCK, which phosphorylates p65 and further enhances NF-κB signaling, elevating oxidative stress and inflammatory response in human aortic endothelial cells. Besides, the mouse model exhibits that joint administration of metronidazole and melatonin serves as an effective strategy for treating atherosclerotic cardiovascular diseases. Conclusions: P gingivalis accelerates atherosclerosis via the NF-κB-BMAL1-NF-κB signaling loop. Melatonin and metronidazole are promising auxiliary medications toward atherosclerotic cardiovascular diseases.

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Myocardial infarction (MI), a main cause of heart failure, leads to irreversible cardiomyocytes loss and cardiac function impairment. Current clinical treatments for MI are largely ineffective as they mostly aim to alleviate symptoms rather than repairing the injured myocardium. Thus, development of more effective therapies is compelling. This study aims to investigate whether the extracellular vesicles (EVs) carrying specific anti-apoptotic miRNA can be efficiently internalized into myocardium to achieve desired therapeutic outcomes. Methods : EVs were isolated from HEK293T cells overexpressing miRNA-21 (miR21-EVs) and identified. The RNase resistant rate of miR21-EVs was calculated by real-time PCR and compared with liposomes and polyethylenimine (PEI). Confocal laser scanning microscopy was used for visualizing the cellular internalization of miR21-EVs in primary cultured mouse neonatal cardiomyocytes (CMs), H9c2 rat cardiomyoblasts, and human umbilical vein endothelial cells (HUVECs). The effect of miR21-EVs on the expression of PDCD4, a pro-apoptotic protein that plays an important role in regulating myocardial apoptosis, was also evaluated in these three cell types by real-time PCR and Western blot analysis. In vivo , miR21-EVs was directly injected into the infarct zone following ligation of the left anterior descending of coronary artery in mice. The miR21-EVs distribution and blood vessel (capillary and arteriole) density were evaluated by immunofluorescence staining. Fluorescence in situ hybridization of miRNA-21 was also carried out to confirm the miR21-EVs distribution in vitro and in vivo . The protein level of PDCD4 in myocardium was assessed by immunohistochemical staining. The anti-apoptotic effect of miR21-EVs in cardiomyocytes and endothelial cells were measured using TUNEL staining. Four weeks after injection, the cardiac histological and functional recovery was evaluated by histochemistry staining and echocardiography, respectively. Results : In contrast to liposomes and PEI, EVs significantly inhibited miRNA-21 degradation. MiR21-EVs efficiently delivered miRNA-21 into cardiomyocytes and endothelial cells within 4 hours. Exogenous miRNA-21 in turn significantly reduced PDCD4 expression and attenuated cell apoptosis in vitro . Consistently and importantly, in a preclinical MI animal model, miRNA-21-loaded EVs effectively sent miRNA-21 into cardiomyocytes and endothelial cells, drastically inhibited cell apoptosis and led to significant cardiac function improvement. Conclusion : Our results suggest the cell-derived, genetically engineered EVs may be used therapeutically for the delivery of miRNAs for the rescue of MI and may benefit patients in the future.

Previously, we found that the miR-217 expression level was increased in hearts from chronic heart failure (CHF) patients by using miRNA profile analysis. This study aimed to explore the role of miR-217 in cardiac dysfunction. Heart tissue samples from CHF patients were used to detect miR-217 expression levels. A type 9 recombinant adeno-associated virus (rAAV9) was employed to manipulate miR-217 expression in mice with thoracic aortic constriction (TAC)-induced cardiac dysfunction. Cardiac structure and function were measured by echocardiography and invasive pressure-volume analysis. The expression levels of miR-217 were increased in hearts from both CHF patients and TAC mice. Overexpression of miR-217 in vivo aggravated pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction, whereas miR-217-TUD-mediated downregulation of miR-217 reversed these effects. PTEN was predicted and validated as a direct target of miR-217, and re-expression of PTEN attenuated miR-217-mediated cardiac hypertrophy and cardiac dysfunction. Importantly, cardiomyocyte-derived miR-217-containing exosomes enhanced proliferation of fibroblasts in vitro. All of these findings show that miR-217 participates in cardiac hypertrophy and cardiac fibrosis processes through regulating PTEN, which suggests a promising therapeutic target for CHF.