Disruption of Bioenergetics in the Intestine of Wistar Rats Caused by Hydrogen Sulfide and Thiosulfate: A Potential Mechanism of Chronic Hemorrhagic Diarrhea in Ethylmalonic Encephalopathy.

Ethylmalonic encephalopathy (EE) is a severe inherited metabolic disorder that causes tissue accumulation of hydrogen sulfide (sulfide) and thiosulfate in patients. Although symptoms are predominantly neurological, chronic hemorrhagic diarrhea associated with intestinal mucosa abnormalities is also commonly observed. Considering that the pathophysiology of intestinal alterations in EE is virtually unknown and that sulfide and thiosulfate are highly reactive molecules, the effects of these metabolites were investigated on bioenergetic production and transfer in the intestine of rats. We observed that sulfide reduced NADH- and FADH2-linked mitochondrial respiration in the intestine, which was avoided by reduced glutathione (GSH) but not by melatonin. Thiosulfate did not change respiration. Moreover, both metabolites markedly reduced the activity of total, cytosolic and mitochondrial isoforms of creatine kinase (CK) in rat intestine. Noteworthy, the addition of GSH but not melatonin, apocynin, and Trolox (hydrosoluble vitamin E) prevented the change in the activities of total CK and its isoforms caused by sulfide and thiosulfate, suggesting a direct protein modification on CK structure by these metabolites. Sulfide further increased thiol content in the intestine, suggesting a modulation in the redox state of these groups. Finally, sulfide and thiosulfate decreased the viability of Caco-2 intestinal cells. Our data suggest that bioenergetic impairment caused by sulfide and thiosulfate is a mechanism involved in the gastrointestinal abnormalities found in EE.

Mesenchymal stromal cell-derived membrane particles: A novel cell-free therapy for inflammatory bowel diseases.

Inflammatory bowel diseases (IBD), including ulcerative colitis, are chronic and idiopathic inflammations of the gastrointestinal tract. A disruption of the epithelial barrier and an imbalance between Th1 and Th2 subsets are associated with the onset and progression of these diseases. Mesenchymal stromal cells (MSC) are a promising therapy for IBD. However, cell-tracking studies have shown that intravenously infused MSC localize to the lungs and present short-term survival. To reduce practical complexities arising from living cells, we generated membrane particles (MP) from MSC membranes, which possess some of the immunomodulatory properties of MSC. This study investigated the effect of MSC-derived MP and conditioned media (CM) as cell-free therapies in the dextran sulfate sodium (DSS)-induced colitis model. Acute colitis was induced in C57BL/6 mice by oral administration of 2% DSS in drinking water ad libitum from days 0 to 7. Mice were treated with MP, CM, or living MSC on days 2 and 5. Our findings revealed that MP, CM, and living MSC ameliorated DSS-induced colitis by reducing colonic inflammation, the loss of colonic goblet cells, and intestinal mucosa permeability, preventing apoptosis of damaged colonic cells and balancing Th1 and Th2 activity. Therefore, MSC-derived MP have high therapeutic potential for treating IBD, overcoming the deficiencies of living MSC therapy, and opening novel frontiers in inflammatory diseases medicine.

Polymorphisms in ACE1, TMPRSS2, IFIH1, IFNAR2, and TYK2 Genes Are Associated with Worse Clinical Outcomes in COVID-19.

Although advanced age, male sex, and some comorbidities impact the clinical course of COVID-19, these factors only partially explain the inter-individual variability in disease severity. Some studies have shown that genetic polymorphisms contribute to COVID-19 severity; however, the results are inconclusive. Thus, we investigated the association between polymorphisms in ACE1, ACE2, DPP9, IFIH1, IFNAR2, IFNL4, TLR3, TMPRSS2, and TYK2 and the clinical course of COVID-19. A total of 694 patients with COVID-19 were categorized as: (1) ward inpatients (moderate symptoms) or patients admitted at the intensive care unit (ICU; severe symptoms); and (2) survivors or non-survivors. In females, the rs1990760/IFIH1 T/T genotype was associated with risk of ICU admission and death. Moreover, the rs1799752/ACE1 Ins and rs12329760/TMPRSS2 T alleles were associated with risk of ICU admission. In non-white patients, the rs2236757/IFNAR2 A/A genotype was associated with risk of ICU admission, while the rs1799752/ACE1 Ins/Ins genotype, rs2236757/IFNAR2 A/A genotype, and rs12329760/TMPRSS2 T allele were associated with risk of death. Moreover, some of the analyzed polymorphisms interact in the risk of worse COVID-19 outcomes. In conclusion, this study shows an association of rs1799752/ACE1, rs1990760/IFIH1, rs2236757/IFNAR2, rs12329760/TMPRSS2, and rs2304256/TYK2 polymorphisms with worse COVID-19 outcomes, especially among female and non-white patients.