The coronavirus disease 2019 (COVID-19) pandemics is a challenge without precedent for the modern science. Acute Respiratory Discomfort Syndrome (ARDS) is the most common immunopathological event in SARS-CoV-2, SARS-CoV, and MERS-CoV infections. Fast lung deterioration results of cytokine storm determined by a robust immunological response leading to ARDS and multiple organ failure. Here, we show cysteine protease Cathepsin L (CatL) involvement with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 from different points of view. CatL is a lysosomal enzyme that participates in numerous physiological processes, including apoptosis, antigen processing, and extracellular matrix remodeling. CatL is implicated in pathological conditions like invasion and metastasis of tumors, inflammatory status, atherosclerosis, renal disease, diabetes, bone diseases, viral infection, and other diseases. CatL expression is up-regulated during chronic inflammation and is involved in degrading extracellular matrix, an important process for SARS-CoV-2 to enter host cells. In addition, CatL is probably involved in processing SARS-CoV-2 spike protein. As its inhibition is detrimental to SARS-CoV-2 infection and possibly exit from cells during late stages of infection, CatL could have been considered a valuable therapeutic target. Therefore, we describe here some drugs already in the market with potential CatL inhibiting capacity that could be used to treat COVID-19 patients. In addition, we discuss the possible role of host genetics in the etiology and spreading of the disease.
Os autores apresentam uma revisão de alguns pontos de vista com relação à anorexia nervosa. Alinham-se aspectos classificatórios, históricos, clínicos e terapêuticos. Reconhecida como a base para ocorrências místicas na Idade Média, foi entendida como uma apresentação histérica no século XVII, para tornar-se, logo em seguida, objeto das indagações freudianas. Discute-se a anorexia como uma apresentação da estrutura histérica, aqui abordada a partir dos conceitos freudianos sobre histeria, Édipo e feminino, e considerando-se o corpo físico como um mero suporte para articulações simbólicas. Para Freud, a anorexia nervosa seria um quadro pelo qual a histérica exprime sua aversão à sexualidade.
<b><i>Background:</i></b> Fabry disease (FD) is a rare X-linked storage disorder resulting from the deficient activity of the lysosomal hydrolase α-galactosidase A (α-Gal A). Here we describe a 23-year-old man with FD possessing a novel mutation in the <i>GLA</i> gene, the evaluation of his family, and the functional characterization of the novel variant. <b><i>Methods:</i></b> Two generations of a family were screened for FD by clinical symptoms and low enzymatic activity. This step was followed by DNA sequencing that showed a novel <i>GLA</i> missense mutation. To confirm the pathogenicity potential of the mutation, we employed site-directed polymerase chain reaction mutagenesis. <i>GLA</i> wild-type and mutant plasmids were transfected into mammalian cells; RNA and proteins were extracted for expression and analysis of enzymatic activity. <b><i>Results:</i></b> The patient presents the variant p.Asn34Asp in the <i>GLA</i> and had several manifestations of FD since adolescence. The investigation of the deficiency of α-Gal A was initiated due to stage 4 of chronic kidney disease. All family members carrying the novel mutation presented early symptoms, including index case’s mother, who received a renal transplant when she was 35 years old. <i>In silico</i> and in vitro analysis confirmed the pathogenic potential of the mutation p.Asn34Asp showing that the enzyme had only 4% of residual activity due to protein misfolding. The ability of the pharmacological chaperone 1-deoxygalactonojirimycin to recover the mutant was confirmed, producing 37.5% of residual activity. <b><i>Conclusion:</i></b> In this work, we present a novel missense mutation in <i>GLA</i> that leads to the production of a catalytically competent α-Gal A, which is degraded before its delivery to the lysosome, promoting severe manifestations of FD, with a very similar disease course in affected men and women.
Inflammation is closely related to renal diseases. This is particularly true for renal diseases caused by infections as in viral diseases. In this review, we highlight the inflammatory mechanisms that underlie kidney dysfunction in SARS-CoV-2, human immunodeficiency (HIV), hepatitis C (HCV), and hepatitis B (HBV) infections. The pathophysiology of renal involvement in COVID-19 is complex, but kidney damage is frequent, and the prognosis is worse when it happens. Virus-like particles were demonstrated mostly in renal tubular epithelial cells and podocytes, which suggest that SARS-CoV-2 directly affects the kidneys. SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor, which is found in endothelial cells, to infect the human host cells. Critical patients with SARS-CoV-2-associated acute kidney injury (AKI) show an increase in inflammatory cytokines (IL-1β, IL-8, IFN-γ, TNF-α), known as cytokine storm that favors renal dysfunction by causing intrarenal inflammation, increased vascular permeability, volume depletion, thromboembolic events in microvasculature and persistent local inflammation. Besides AKI, SARS-CoV-2 can also cause glomerular disease, as other viral infections such as in HIV, HBV and HCV. HIV-infected patients present chronic inflammation that can lead to a number of renal diseases. Proinflammatory cytokines and TNF-induced apoptosis are some of the underlying mechanisms that may explain the virus-induced renal diseases that are here reviewed.
Aim Focal segmental glomerulosclerosis recurs in up to 30% and up to 80% of adult and pediatric kidney transplant recipients, respectively. There is no standard of care treatment. The purpose of this study was to evaluate clinical characteristics, treatments and outcomes of patients with focal segmental glomerulosclerosis recurrence (FSGSr). Methods This was a retrospective single‐center cohort study including FSGSr patients treated with plasmapheresis (PP) and combinations of high dose steroids, cyclosporine and rituximab. Results Among 61 patients included in this analysis the median time to diagnosis was 19 days. The incidence of first biopsy‐confirmed FSGSr was 18% reaching 52.4% with follow‐up biopsies. During PP treatment 54% of the patients developed infectious complications. PP was discontinued in 37% of patients due to treatment failure (no remission or graft loss) and in 26% due to an adverse event. All patients who discontinued PP due to adverse event did not show clinical response or lost the allograft. The incidence of acute rejection was 34.4%. The incidences of partial and complete remissions were 16.4% and 27.8%, respectively. Overall 6‐years patient and graft survivals were 90.7% and 64.5%, respectively. Conclusion This analysis confirms the low, variable and unpredictable rate of FSGSr remission, inconsistencies among available therapeutic options and its high rate of adverse events, and the negative impact on graft survival.
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