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Increased gut permeability is implicated in the initiation and extent of the cytokine inflammatory response associated with exertional heat stroke (EHS). The primary objective of this study was to determine if a five amino acid oral rehydration solution (5AAS), specifically designed for the protection of the gastrointestinal lining, would prolong time to EHS, maintain gut function and dampen the systemic inflammatory response (SIR) measured during EHS recovery. Male C57/BL6J mice instrumented with radiotelemetry were gavaged with 150 μL of 5AAS or H2O, and ≈12 h later were either exposed to an EHS protocol where mice exercised in a 37.5°C environmental chamber to a self‐limiting maximum core temperature (Tc,max) or performed the exercise control (EXC) protocol (25°C). 5AAS pretreatment attenuated hypothermia depth and length (p < 0.005), which are indicators of EHS severity during recovery, without any effect on physical performance or thermoregulatory responses in the heat as determined by percent body weight lost (≈9%), max speed (≈6 m/min), distance (≈700 m), time to Tc,max (≈160 min), thermal area (≈550°C∙min), and Tc,max (42.2°C). EHS groups treated with 5AAS showed a significant decrease in gut transepithelial conductance, decreased paracellular permeability, increased villus height, increased electrolyte absorption and changes in tight junction protein expression pattern suggestive of improved barrier integrity (p < 0.05). No differences were witnessed between EHS groups in acute phase response markers of liver, circulating SIR markers, or indicators of organ damage during recovery. These results suggest that a 5AAS improves Tc regulation during EHS recovery through maintaining mucosal function and integrity. [ABSTRACT FROM AUTHOR]

In specific, miR-186-5p is enriched in exosomes of activated CD8 T cells and preferentially enters renal tubular cells where it directly binds endosomal TLR7/8 and initiates renal inflammation. CD8 T Cell-Derived Exosomal miR-186-5p Elicits Renal Inflammation via Activating Tubular TLR7/8 Signal Axis (Adv. Sci. 25/2023) In article number 2301492, Ke Zen, Zhihong Liu, and co-workers identify exosomal miR-186-5p from activated CD8 T cells as such circulating pathogenic factor that causes renal dysfunction. [Extracted from the article]

Abstract: Aim: Fibrinogen (Fg) is reported to participate in inflammation through Toll‐like receptor 4 (TLR4). However, it remains unknown whether Fg might induce podocyte damage through TLR4 and be related to disease activity in patients with focal segmental glomerulosclerosis (FSGS). Methods: We observed Fg‐induced alterations in actin and apoptosis in cultured human podocytes transfected with or without TLR4 siRNA. Expression of TLR4, phospho‐p38 MAPK and phospho‐NF‐κB p65 was evaluated by quantitative reverse transcription polymerase chain reaction (qRT‐PCR) or western blotting, and we analysed urinary Fg levels in adriamycin‐treated mice and double immunofluorescence staining for TLR4, Fg and podocin. Urinary Fg changes were also analyzed in FSGS patients under prednisone treatment. Results: First, Fg dose‐dependently induced actin damage and apoptosis in cultured human podocytes, with an Fg‐induced increase in TLR4 expression, and TLR4 siRNA transfection prevented these effects. TLR4 knockdown inhibited activation of p38 MAPK and NF‐κB p65 in podocytes. Elevated urinary Fg levels were positively correlated with albuminuria in adriamycin‐treated mice, in which Fg and TLR4 colocalized and exhibited increased expression in podocytes. Additionally, elevated urinary Fg levels were positively correlated with 24‐h proteinuria and foot process width in FSGS patients. Urinary Fg levels were significantly decreased in patients with complete remission but not in those without remission. Conclusions: Fg induced podocytes injury via the TLR4‐p38 MAPK‐NF‐κB p65 pathway. In FSGS patients, urinary Fg levels reflect therapeutic response to prednisone and disease activity. [ABSTRACT FROM AUTHOR]