COVID-19 Mimics Pulmonary Dysfunction in Muscular Dystrophy as a Post-Acute Syndrome in Patients.

Although progressive wasting and weakness of respiratory muscles are the prominent hallmarks of Duchenne muscular dystrophy (DMD) and long-COVID (also referred as the post-acute sequelae of COVID-19 syndrome); however, the underlying mechanism(s) leading to respiratory failure in both conditions remain unclear. We put together the latest relevant literature to further understand the plausible mechanism(s) behind diaphragm malfunctioning in COVID-19 and DMD conditions. Previously, we have shown the role of matrix metalloproteinase-9 (MMP9) in skeletal muscle fibrosis via a substantial increase in the levels of tumor necrosis factor-α (TNF-α) employing a DMD mouse model that was crossed-bred with MMP9-knockout (MMP9-KO or MMP9-/-) strain. Interestingly, recent observations from clinical studies show a robust increase in neopterin (NPT) levels during COVID-19 which is often observed in patients having DMD. What seems to be common in both (DMD and COVID-19) is the involvement of neopterin (NPT). We know that NPT is generated by activated white blood cells (WBCs) especially the M1 macrophages in response to inducible nitric oxide synthase (iNOS), tetrahydrobiopterin (BH4), and tetrahydrofolate (FH4) pathways, i.e., folate one-carbon metabolism (FOCM) in conjunction with epigenetics underpinning as an immune surveillance protection. Studies from our laboratory, and others researching DMD and the genetically engineered humanized (hACE2) mice that were administered with the spike protein (SP) of SARS-CoV-2 revealed an increase in the levels of NPT, TNF-α, HDAC, IL-1ß, CD147, and MMP9 in the lung tissue of the animals that were subsequently accompanied by fibrosis of the diaphragm depicting a decreased oscillation phenotype. Therefore, it is of interest to understand how regulatory processes such as epigenetics involvement affect DNMT, HDAC, MTHFS, and iNOS that help generate NPT in the long-COVID patients.

Human wharton-jelly mesenchymal stromal cells reversed apoptosis and prevented multi-organ damage in a newborn model of experimental asphyxia.

In this study, the effect of applying wharton jelly mesenchymal stromal cells (WJ-MSC) isolated from the human umbilical cord tissue on the neonatal mouse model caused experimental asphyxia in mice was investigated. WJ-MSC surface markers (CD44, CD90, CD105) were characterised by immunofluorescence staining, and pluripotency genes (Nanog, Oct-4, Sox-2) were characterised by qPCR. Blood, prefrontal cortex, cerebellum, hippocampus, lung, heart, kidney, and liver tissues were analysed twenty days after subcutaneously administered WJ-MSC. WJ-MSC administration significantly decreased serum TNF-α, NSE, GFAP, and IL-6 levels in the asphyxia mice. It was determined that WJ-MSC application in tissues accelerated cell regeneration and decreased oxidative stress. In conclusion, this study showed that multiorgan damage in asphyxia could be prevented by applying WJ-MSC at an early stage. Therefore, WJ-MSC application in infants with neonatal asphyxia in the clinic may be an innovative method in the future.

Risk factors for mortality among patients with SARS-CoV-2 infection: A longitudinal observational study.

Recent literature suggests that approximately 5%-18% of patients diagnosed with severe acute respiratory syndrome coronavirus 2 may progress rapidly to a severe form of the illness and subsequent death. We examined the relationship between sociodemographic, clinical, and laboratory findings with mortality among patients. In this study, 112 patients were evaluated from February to May 2020 and 80 patients met the inclusion criteria. Tocilizumab was administered, followed by methylprednisolone to patients with pneumonia severity index score ≤130 and computerized tomography scan changes. Demographic data and clinical outcomes were collected. Laboratory biomarkers were monitored during hospitalization. Statistical analyses were performed with significance p ≤ .05. A total of 80 patients: 45 males (56.25%) and 35 females (43.75%) met the study inclusion criteria. A total of 7 patients (8.75%) were deceased. An increase in mortality outcome was statistically significantly associated with higher average levels of interleukin-6 (IL-6) with p value (.050), and d-dimer with p value (.024). Bivariate logistics regression demonstrated a significant increased odds for mortality for patients with bacterial lung infections (odds ratio [OR]: 10.83; 95% confidence interval [CI]: 2.05-57.40; p = .005) and multiorgan damage (OR: 103.50; 95% CI: 9.92-1079.55; p = .001). Multivariate logistics regression showed a statistically significant association for multiorgan damage (adjusted odds ratio [AOR]: 94.17; 95% CI: 7.39-1200.78; p = .001). We identified three main predictors for high mortality. These include IL-6, d-dimer, and multiorgan damage. The latter was the highest potential risk for in-hospital deaths. This warrants aggressive health measures for early recognition of the problem and initiation of treatment to reverse injuries.

Integrative Modeling of Quantitative Plasma Lipoprotein, Metabolic, and Amino Acid Data Reveals a Multiorgan Pathological Signature of SARS-CoV-2 Infection.

The metabolic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on human blood plasma were characterized using multiplatform metabolic phenotyping with nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Quantitative measurements of lipoprotein subfractions, α-1-acid glycoprotein, glucose, and biogenic amines were made on samples from symptomatic coronavirus disease 19 (COVID-19) patients who had tested positive for the SARS-CoV-2 virus (n = 17) and from age- and gender-matched controls (n = 25). Data were analyzed using an orthogonal-projections to latent structures (OPLS) method and used to construct an exceptionally strong (AUROC = 1) hybrid NMR-MS model that enabled detailed metabolic discrimination between the groups and their biochemical relationships. Key discriminant metabolites included markers of inflammation including elevated α-1-acid glycoprotein and an increased kynurenine/tryptophan ratio. There was also an abnormal lipoprotein, glucose, and amino acid signature consistent with diabetes and coronary artery disease (low total and HDL Apolipoprotein A1, low HDL triglycerides, high LDL and VLDL triglycerides), plus multiple highly significant amino acid markers of liver dysfunction (including the elevated glutamine/glutamate and Fischer's ratios) that present themselves as part of a distinct SARS-CoV-2 infection pattern. A multivariate training-test set model was validated using independent samples from additional SARS-CoV-2 positive patients and controls. The predictive model showed a sensitivity of 100% for SARS-CoV-2 positivity. The breadth of the disturbed pathways indicates a systemic signature of SARS-CoV-2 positivity that includes elements of liver dysfunction, dyslipidemia, diabetes, and coronary heart disease risk that are consistent with recent reports that COVID-19 is a systemic disease affecting multiple organs and systems. Metabolights study reference: MTBLS2014.

Network Pharmacological Analysis Combined with Experimental Verification to Explore the Effect of Ginseng Polypeptide on the Improvement of Diabetes Symptoms in db/db Mice.

Diabetes mellitus is a typical metabolic disease that has become a major threat to human health worldwide. Ginseng polypeptide (GP), a small molecule active substance isolated from ginseng, has shown positive hypoglycemic effects in preliminary studies. However, its mechanism in ameliorating multiorgan damage in db/db mice is unclear. In this study, we utilized network pharmacology, molecular docking, and animal experiments to explore the targets and biological mechanisms of GP to ameliorate multiorgan damage in T2DM. The results showed that GP improves T2DM by inhibiting inflammation and oxidative damage, thereby alleviating hyperglycemia, insulin resistance, and multiorgan damage in db/db mice. These effects are potentially mediated through the PI3K-Akt signaling pathway and the MAPK signaling pathway. This study establishes GP's efficacy in alleviating T2DM and provides a robust theoretical basis for the development of new drugs or functional foods for treating this disease.

Understanding on the possible routes for SARS CoV-2 invasion via ACE2 in the host linked with multiple organs damage.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accountable for causing the coronavirus diseases 2019 (COVID-19), is already declared as a pandemic disease globally. Like previously reported SARS-CoV strain, the novel SARS-CoV-2 also initiates the viral pathogenesis via docking viral spike-protein with the membranal angiotensin-converting enzyme 2 (ACE2) - a receptor on variety of cells in the human body. Therefore, COVID-19 is broadly characterized as a disease that targets multiple organs, particularly causing acute complications via organ-specific pathogenesis accompanied by destruction of ACE2+ cells, including alveolus, cardiac microvasculature, endothelium, and glomerulus. Under such circumstances, the high expression of ACE2 in predisposing individuals associated with anomalous production of the renin-angiotensin system (RAS) may promote enhanced viral load in COVID-19, which comparatively triggers excessive apoptosis. Furthermore, multi-organ injuries were found linked to altered ACE2 expression and inequality between the ACE2/angiotensin-(1-7)/mitochondrial Ang system (MAS) and renin-angiotensin-system (RAS) in COVID-19 patients. However, the exact pathogenesis of multi-organ damage in COVID-19 is still obscure, but several perspectives have been postulated, involving altered ACE2 expression linked with direct/indirect damages by the virus-induced immune responses, such as cytokinin storm. Thus, insights into the invasion of a virus with respect to ACE2 expression site can be helpful to simulate or understand the possible complications in the targeted organ during viral infection. Hence, this review summarizes the multiple organs invasion by SARS CoV-2 linked with ACE2 expression and their consequences, which can be helpful in the management of the COVID-19 pathogenesis under life-threatening conditions.

Is Ferroptosis a Key Component of the Process Leading to Multiorgan Damage in COVID-19?

Even though COVID-19 is mostly well-known for affecting respiratory pathology, it can also result in several extrapulmonary manifestations, leading to multiorgan damage. A recent reported case of SARS-CoV-2 myocarditis with cardiogenic shock showed a signature of myocardial and kidney ferroptosis, a novel, iron-dependent programmed cell death. The term ferroptosis was coined in the last decade to describe the form of cell death induced by the small molecule erastin. As a specific inducer of ferroptosis, erastin inhibits cystine-glutamate antiporter system Xc-, blocking transportation into the cytoplasm of cystine, a precursor of glutathione (GSH) in exchange with glutamate and the consequent malfunction of GPX4. Ferroptosis is also promoted by intracellular iron overload and by the iron-dependent accumulation of polyunsaturated fatty acids (PUFA)-derived lipid peroxides. Since depletion of GSH, inactivation of GPX4, altered iron metabolism, and upregulation of PUFA peroxidation by reactive oxygen species are peculiar signs of COVID-19, there is the possibility that SARS-CoV-2 may trigger ferroptosis in the cells of multiple organs, thus contributing to multiorgan damage. Here, we review the molecular mechanisms of ferroptosis and its possible relationship with SARS-CoV-2 infection and multiorgan damage. Finally, we analyze the potential interventions that may combat ferroptosis and, therefore, reduce multiorgan damage.

Protein-driven mechanism of multiorgan damage in COVID-19.

We propose a new plausible mechanism by mean of which SARS-CoV-2 produces extrapulmonary damages in severe COVID-19 patients. The mechanism consist on the existence of vulnerable proteins (VPs), which are (i) mainly expressed outside the lungs; (ii) their perturbations is known to produce human diseases; and (iii) can be perturbed directly or indirectly by SARS-CoV-2 proteins. These VPs are perturbed by other proteins, which are: (i) mainly expressed in the lungs, (ii) are targeted directly by SARS-CoV-2 proteins, (iii) can navigate outside the lungs as cargo of extracellular vesicles (EVs); and (iv) can activate VPs via subdiffusive processes inside the target organ. Using bioinformatic tools and mathematical modeling we identifies 26 VPs and their 38 perturbators, which predict extracellular damages in the immunologic endocrine, cardiovascular, circulatory, lymphatic, musculoskeletal, neurologic, dermatologic, hepatic, gastrointestinal, and metabolic systems, as well as in the eyes. The identification of these VPs and their perturbators allow us to identify 27 existing drugs which are candidates to be repurposed for treating extrapulmonary damage in severe COVID-19 patients. After removal of drugs having undesirable drug-drug interactions we select 7 drugs and one natural product: apabetalone, romidepsin, silmitasertib, ozanezumab, procaine, azacitidine, amlexanox, volociximab, and ellagic acid, whose combinations can palliate the organs and systems found to be damaged by COVID-19. We found that at least 4 drugs are needed to treat all the multiorgan damages, for instance: the combination of romidepsin, silmitasertib, apabetalone and azacitidine.