Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.

Aims: Myocardial infarction (MI) is a leading cause of death globally. MicroRNAs (miRNAs) have been identified as a novel class of MI injury regulators. Hydrogen sulfide (H 2 S) is a gaseous signaling molecule that regulates cardiovascular function. The purpose of this study was to explore the role of the miR-30 family in protecting against MI injury by regulating H 2 S production. Results: The expression of miR-30 family was upregulated in the murine MI model as well as in the primary cardiomyocyte hypoxic model. However, the cystathionine-c-lyase (CSE) expression was significantly decreased. The overexpression of miR-30 family decreased CSE expression, reduced H 2 S production, and then aggravated hypoxic cardiomyocyte injury. In contrast, silencing the whole miR-30 family can protect against hypoxic cell injury by elevating CSE and H 2 S level. Nonetheless, the protective effect was abolished by cotransfecting with CSE-siRNA. Systemic delivery of a locked nucleic acid (LNA)-miR-30 family inhibitor correspondingly increased CSE and H 2 S level, then reduced infarct size, decreased apoptotic cell number in the peri-infarct region, and improved cardiac function in response to MI. However, these cardioprotective effects were absent in CSE knockout mice. MiR-30b overexpression in vivo aggravated MI injury because of H 2 S reduction, and this could be rescued by Spropargyl-cysteine (SPRC), which is a novel modulator of CSE, or further exacerbated by propargylglycine (PAG), which is a selective inhibitor of CSE. Innovation and Conclusion: Our findings reveal a novel molecular mechanism for endogenous H 2 S production in the heart at the miRNA level and demonstrate the therapeutic potential of miR-30 family inhibition for ischemic heart diseases by increasing H 2 S production. Antioxid. Redox Signal. 22,[224][225][226][227][228][229][230][231][232][233][234][235][236][237][238][239][240]

Aims: Macrophages are of key importance for tissue repair after myocardial infarction (MI).Hydrogen sulfide (H 2 S) has been shown to exert cardioprotective effects in MI. However, the mechanisms by which H 2 S modulates cardiac remodeling and repair post-MI remain to be clarified. Results: In our current study, we showed H 2 S supplementation ameliorated InnovationWe show here H 2 S supplementation ameliorated pathological remodeling and dysfunction post-MI, accompanied by an increase in M2-polarized macrophages. And we present evidence for a novel mechanism by which macrophage polarization triggered by H 2 S is due to the increase of mitochondrial biogenesis which enhanced lipolysis and fatty acid release, and provided the respiratory substrates for FAO. Our study shows for the first time that H 2 S supplementation, such as H 2 S donors or activators of H 2 S biosynthesis could represent a promising novel therapeutic strategy for MI treatment via stimulation of M2 macrophage polarization.

Hydrogen sulfide exists widely in mammalian tissues and plays a vital role in physiological and pathophysiological processes. However, striking differences with orders of magnitude were observed for the detected hydrogen sulfide concentrations in biological matrices among different measurements in literature, which lead to the uncertainty for examination the biological relevance of hydrogen sulfide. Here, we developed and validated a liquid chromatography- mass spectrometry (LC-MS/MS) method for the determination of hydrogen sulfide in various biological matrices by determination of a derivative of hydrogen sulfide and monobromobimane named sulfide dibimane (SDB). 36S-labeled SDB was synthesized and validated for using as an internal standard. This method has been successfully used to measure hydrogen sulfide levels in a broad range of biological matrices, such as blood, plasma, tissues, cells, and enzymes, across different species. Moreover, a novel mode that hydrogen sulfide could loosely and non-covalently bind to human serum protein (HSA) and hemoglobin (HB) was revealed by using the developed method.

Aims: Anemia of inflammation is quite prevalent in hospitalized patients with poor prognosis. Concerns about the effectiveness and safety of iron supplementation have arisen, driving the demand for alternative therapies. Induction of hepatic hepcidin, the master hormone of iron homeostasis, causes anemia under inflammatory conditions. Previous studies indicated that hydrogen sulfide (H 2 S), the third gasotransmitter and a well-known regulator of inflammation, may inhibit the secretion of inflammatory cytokines. We thus investigated the effect of H 2 S on inflammatory hepcidin induction. Results: H 2 S suppressed lipopolysaccharide (LPS)-induced hepcidin production and regulated iron homeostasis in mice by decreasing serum interleukin-6 (IL-6) and Janus kinase 2 ( JAK2)/signal transducer and activator of transcription 3 (STAT3) activation; similar results were obtained in Huh7 cells exposed to conditioned medium from LPS-challenged THP-1 macrophages. Intriguingly, we found H 2 S also attenuated hepcidin levels in Huh7 cells and mouse primary hepatocytes in a sirtuin 1 (SIRT1)-dependent manner. By promoting SIRT1 expression and stabilizing SIRT1-STAT3 interactions, H 2 S ameliorated IL-6-induced STAT3 acetylation, resulting in reduced hepcidin production. Inhibition and silencing of SIRT1 diminished H 2 S-mediated suppression of hepcidin, as opposed to SIRT1 activation and overexpression. Consistent results were observed in vivo. Furthermore, knockout of cystathionine c-lyase (CSE), an endogenous H 2 S synthase, exaggerated inflammatory hepcidin expression in mice. Innovation: For the first time, we elucidated the effects and possible mechanisms of H 2 S on inflammatory hepcidin and established a novel regulatory link between SIRT1 and hepcidin. Conclusion: Our work demonstrates that H 2 S attenuates inflammation-induced hepatic hepcidin via multipathways and suggests new treatment strategies for anemia of inflammation. Antioxid. Redox Signal. 24, 70-83.

Carnosine (β-alanyl-L-histidine), described as an enigmatic peptide for its antioxidant, anti-aging and especially antiproliferation properties, has been demonstrated to play an anti-tumorigenic role in certain types of cancer. However, its function in human gastric carcinoma remains unclear. In this study, the effect of carnosine on cell proliferation and its underlying mechanisms were investigated in the cultured human gastric carcinoma cells. The mTOR signaling axis molecules were analyzed in carnosine treated cells. The results showed that treatment with carnosine led to proliferation inhibition, cell cycle arrest in the G0/G1 phase, apoptosis increase, and inhibition of mTOR signaling activation by decreasing the phosphorylation of Akt, mTOR and p70S6K, suggesting that proliferation inhibition of carnosine in human gastric carcinoma was through the inhibition of Akt/mTOR/p70S6K pathway, and carnosine would be a mimic of rapamycin.

Myocardial infarction (MI) triggers an inflammatory reaction, in which macrophages are of key importance for tissue repairing. Infiltration and/or migration of macrophages into the infarct area early after MI is critical for infarct healing, vascularization, and cardiac function. Hydrogen sulfide (H2S) has been demonstrated to possess cardioprotective effects post MI and during the progress of cardiac remodeling. However, the specific molecular and cellular mechanisms involved in macrophage recruitment by H2S remain to be identified. In this study, the NaHS (exogenous sources of H2S) treatment exerted an increased infiltration of macrophages into the infarcted myocardium at early stage of MI cardiac tissues in both wild type (WT) and cystathionine-γ-lyase-knockout (CSE-KO) mice. And NaHS accelerated the migration of macrophage cells in vitro. While, the inhibitors not only significantly diminished the migratory ability in response to NaHS, but also blocked the activation of phospho-Src, -Pyk2, -FAK397, and -FAK925. Furthermore, NaHS induced the internalization of integrin β1 on macrophage surface, but, integrin β1 silencing inhibited macrophage migration and Src signaling activation. These results indicate that H2S may have the potential as an anti-infarct of MI by governing macrophage migration, which was achieved by accelerating internalization of integrin β1 and activating downstream Src-FAK/Pyk2-Rac pathway.

ZNF703, a member of the NET/Nlz family of zinc finger transcription factors, contributes to aspects of developmental growth and patterning across evolutionarily diverse species. ZNF703 has been identified as a novel oncogene in human breast cancer. In the present study, we investigated the expression of ZNF703 in gastric carcinoma and attempted to determine, using cell line models, its biological actions. Using immunohistochemistry, we analyzed the ZNF703 protein expression in 120 clinicopathologically characterized gastric cancer cases. Using RNA interference, we investigated the effects of ZNF703 depletion on tumor proliferation and metastasis in vitro. We found that ZNF703 was overexpressed in invasive gastric carcinoma tissues, and its expression levels were closely correlated with the depth of invasion, node metastasis and venous invasion. RNA interference-mediated silencing of the ZNF703 gene in SGC7901 cells inhibited cell proliferation and migration significantly. The results showed that ZNF703 acts as a gastric cancer oncogene and should be considered a therapeutic target for metastatic gastric cancer.