Acute renal failure induced by a toxic dose of acetaminophen (also known as paracetamol, or APAP) is common in both humans and experimental animal models. Glomerular ultrastructural alterations induced by APAP overdose associated with the suppression of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic antioxidants and anti-inflammatory compounds, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced nephrotoxicity. Rats either received a single dose of APAP (2 g/kg) before being sacrificed after 24 hours or were pretreated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP and then sacrificed 24 hours post APAP ingestion. APAP significantly (p < 0.05) increased blood levels of urea, creatinine, malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), which were effectively reduced by RES + QUR. In addition, APAP overdose induced the tissue expression of the apoptotic biomarker, p53, and caused profound kidney damage as demonstrated by substantial alterations to the glomerular basement membrane, podocytes, endothelial cells, widening of Bowman’s space, and vacuolation of the cells lining the parietal layer, which were substantially protected by RES + QUR. Furthermore, a significant (p < 0.0001) positive correlation was observed between either glomerular basement membrane or podocyte foot processes and these parameters, urea, creatinine, MDA, and TNF-α. Thus, we conclude that APAP induces alterations to the glomerulus ultrastructure, which is protected by resveratrol plus quercetin, which also reduces blood levels of urea and creatinine, and biomarkers of oxidative stress and inflammation.

Progress in the study of Covid‐19 disease in rodents has been hampered by the lack of angiotensin‐converting enzyme 2 (ACE2; virus entry route to the target cell) affinities for the virus spike proteins across species. Therefore, we sought to determine whether a modified protocol of lipopolysaccharide (LPS)‐induced acute respiratory distress syndrome in rats can mimic both cell signalling pathways as well as severe disease phenotypes of Covid‐19 disease. Rats were injected via intratracheal (IT) instillation with either 15 mg/kg of LPS (model group) or saline (control group) before being killed after 3 days. A severe acute respiratory syndrome (SARS)‐like effect was observed in the model group as demonstrated by the development of a “cytokine storm” (>2.7 fold increase in blood levels of IL‐6, IL‐17A, GM‐CSF, and TNF‐α), high blood ferritin, demonstrable coagulopathy, including elevated D‐dimer (approximately 10‐fold increase), PAI‐1, PT, and APTT (p < 0.0001). In addition, LPS increased the expression of lung angiotensin II type I receptor (AT1R)‐JAK‐STAT axis (>4 fold increase). Chest imaging revealed bilateral small patchy opacities of the lungs. Severe lung injury was noted by the presence of both, alveolar collapse and haemorrhage, desquamation of epithelial cells in the airway lumen, infiltration of inflammatory cells (CD45+ leukocytes), widespread thickening of the interalveolar septa, and ultrastructural alterations similar to Covid‐19. Thus, these findings demonstrate that IT injection of 15 mg/kg LPS into rats, induced an AT1R/JAK/STAT‐mediated cytokine storm with resultant pneumonia and coagulopathy that was commensurate with moderate and severe Covid‐19 disease noted in humans.

Metformin treatment reduces the efficacy of mesenchymal stem cell therapy for cardiac repair during diabetic cardiomyopathy. Stem cell therapy in diabetics may be more effective in combination with AMPK inhibitors.