Increased oxidative stress and advanced glycation end-product (AGE) formation are major contributors to the development of type 2 diabetes. Here plasma proteins e.g. albumin can undergo glycoxidation and play a key role in diabetes onset and related pathologies. However, despite recent progress linking albumin-AGE to increased oxidative stress and downstream effects, its action in metabolic organs such as the liver remains to be elucidated. The current study therefore investigated links between oxidative perturbations and biochemical/structural modifications of plasma albumin, and subsequent downstream effects in transgenic db/db mouse livers and HepG2 cells, respectively. Our data reveal increased oxidative stress biomarkers and lipid accumulation in plasma and livers of diabetic mice, together with albumin glycoxidation. Purified mouse albumin modifications resembled those typically found in diabetic patients, i.e. degree of glycation, carbonylation, AGE levels and in terms of chemical composition. Receptor for AGE expression and reactive oxygen species production were upregulated in db/db mouse livers, together with impaired proteolytic, antioxidant and mitochondrial respiratory activities. In parallel, acute exposure of HepG2 cells to glycated albumin also elicited intracellular free radical formation. Together this study demonstrates that AGE-modified albumin can trigger damaging effects on the liver, i.e. by increasing oxidative stress, attenuating antioxidant capacity, and by impairment of hepatic proteolytic and respiratory chain enzyme activities.
Both cellular and humoral immunities are critically important to control COVID19 infection but little is known about the kinetics of those responses and, in particular, in patients who will go on to develop a severe form of the disease over several weeks. We herein report the first set of data of our prospective cohort study of 90 hospitalized cases. Serological surveys were thoroughly performed over 2 month period by assessing IgG and IgM responses by immunofluorescence, immunoblot, Western blot and conventional ELISA using clinical RUN isolates of SARS-CoV-2 immobilized on 96 well plates. While the IgM and, unexpectedly, the IgG responses were readily detected early during the course of the disease (5-7 days post-first symptoms), our results (n=3-5 and over the full dilution set of the plasma 1/200 to 1/12800) demonstrated a significant decrease (over 2.5-fold) of IgG levels in severe (ICU) hospitalized patients (exemplified in patient 1) by WB and ELISA. In contrast, mild non-ICU patients had a steady and yet robust rise in their specific IgG levels against the virus. Interestingly, both responses (IgM and IgG) were initially against the nucleocapsid (50kDa band on the WB) and spreading to other major viral protein S and domains (S1 and S2. In conclusion, serological testing may be helpful for the diagnosis of patients with negative RT-PCR results and for the identification of asymptomatic cases. Moreover, medical care and protections should be maintained particularly for recovered patients (severe cases) who may remain at risk of relapsing or reinfection. Experiments to ascertain T cell responses but although their kinetics overtime are now highly warranted. All in all, these studies will help to delineate the best routes for vaccination.
Humoral immunity is critically important to control COVID-19. Long-term antibody responses remain to be fully characterized in hospitalized patients who have a high risk of death. We compared specific Immunoglobulin responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between two groups, intensive care unit (ICU) and non-ICU hospitalized patients over several weeks. Plasma specific IgG, IgM, and IgA levels were assessed using a commercial ELISA and compared to an in-house cell-based ELISA. Among the patients analyzed (mean (SD) of age, 64.4 (15.9) years, 19.2% female), 12 (46.2%) were hospitalized in ICU. IgG levels increased in non-ICU cases from the second to the eighth week after symptom onset. By contrast, IgG response was blunted in ICU patients over the same period. ICU patients with hematological malignancies had very weak or even undetectable IgG levels. While both groups had comparable levels of specific IgM antibodies, we found much lower levels of specific IgA in ICU versus non-ICU patients. In conclusion, COVID-19 ICU patients may be at risk of reinfection as their specific IgG response is declining in a matter of weeks. Antibody neutralizing assays and studies on specific cellular immunity will have to be performed.
Alphaviruses are a group of arboviruses that generate chronic inflammatory rheumatisms in humans. Currently, no approved vaccines or antiviral therapies are available to prevent or treat alphavirus-induced diseases. The aim of this study was to evaluate the repositioning of the anti-cancer molecule irinotecan as a potential modulator of the antiviral and inflammatory responses of primary human synovial fibroblasts (HSF), the main stromal cells of the joint synovium. HSF were exposed to O’nyong-nyong virus (ONNV) and polyinosinic-polycytidylic acid (PIC) to mimic, respectively, acute and chronic infectious settings. The cytokine IL-1β was used as a major pro-inflammatory cytokine to stimulate HSF. Quantitative RT-PCR analysis revealed that irinotecan at 15 µM was able to amplify the antiviral response (i.e., interferon-stimulated gene expression) of HSF exposed to PIC and reduce the expression of pro-inflammatory genes (CXCL8, IL-6 and COX-2) upon IL-1β treatment. These results were associated with the regulation of the expression of several genes, including those encoding for STAT1, STAT2, p53 and NF-κB. Irinotecan did not modulate these responses in both untreated cells and cells stimulated with ONNV. This suggests that this drug could be therapeutically useful for the treatment of chronic and severe (rather than acute) arthritis due to viruses.
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