Exogenous hydrogen sulfide ameliorates diabetes-associated cognitive dysfunction by regulating the nrf-2/HO-1 axis and the NLRP3 inflammasome pathway in diabetic rats.

Diabetes-associated cognitive dysfunction (DACD) is a complication of diabetes mellitus that leads to an increased risk of cognitive impairment and dementia. However, the molecular mechanism underlying DACD has not been elucidated, and a promising therapy for this disease remains to be established. Hydrogen sulfide (H2S), a significant antioxidative and anti-inflammatory gasotransmitter, has emerged as a neuroprotective agent. In this study, we investigated the protective effects of H2S on DACD in a streptozotocin (STZ)-induced diabetic rat model. We applied the Morris water maze to evaluate spatial learning and memory abilities. We used Western blotting and immunohistochemical staining to investigate the expression of the Nrf-2/HO-1 axis and the NLRP3 inflammasome. After NaHS (H2S donor) administration, diabetic rats exhibited improved spatial learning and memory retrieval abilities in the Morris water maze. In STZ-induced diabetic rats, the protein expression levels of the Nrf-2/HO-1 axis, the NLRP3 inflammasome and subsequent inflammatory cytokines in the hippocampal region were elevated compared to those in control rats. Exogenous H2S triggered Nrf-2/HO-1 antioxidant activity and inhibited NLRP3 inflammasome activation and proinflammatory cytokine expression. These findings suggested that exogenous H2S has neuroprotective effects by modulating the Nrf-2/HO-1 axis and the NLRP3 inflammasome pathway, which were found to be associated with DACD. H2S treatment may be a promising therapeutic strategy for preventing the progression of tissue damage caused by DACD.

Micro-ribonucleic acid-23a-3p prevents the onset of type 2 diabetes mellitus by suppressing the activation of nucleotide-binding oligomerization-like receptor family pyrin domain containing 3 inflammatory bodies-caused pyroptosis through negatively regulating NIMA-related kinase 7.

AIMS/INTRODUCTION: Micro-ribonucleic acids (miRNAs) possess crucial functions in governing metabolisms associated with type 2 diabetes mellitus. This study aimed to investigate the role of miR-23a-3p in pyroptosis caused by nucleotide-binding oligomerization-like receptor family pyrin domain containing 3 (NLRP3) inflammatory body activation, thereby reducing the occurrence of type 2 diabetes mellitus. MATERIALS AND METHODS: miR-23a-3p and NIMA-related kinase 7 (NEK7) expression in type 2 diabetes mellitus patients and rat models was examined. Dual-luciferase reporter gene experiments were used to verify the targeting relationship between miR-23a-3p and NEK7. Bone marrow-derived macrophages were transfected with miR-23a-3p mimic, miR-23a-3p inhibitor or short hairpin NEK7 and were treated with a specific activator of NLRP3 inflammatory body (lipopolysaccharide + adenosine-5'-triphosphate) to evaluate expression of NEK7, miR-23a-3p, gasdermin D p30, pro-caspase-1 and caspase-1 in cells, and interleukin-1ß and tumor necrosis factor-α in supernatant. Type 2 diabetes mellitus rat models were used to observe the influences of miR-23a-3p, NEK7 and NLRP3 inflammatory body on pyroptosis and type 2 diabetes mellitus in vivo. RESULTS: NEK7 was overexpressed, whereas miR-23a-3p was underexpressed in patients and rat models with type 2 diabetes mellitus. NEK7 was a target gene of miR-23a-3p. After the addition of lipopolysaccharide + adenosine-5'-triphosphate in bone marrow-derived macrophages, the expression of miR-23a-3p subsequently declined. Furthermore, the addition of lipopolysaccharide + adenosine-5'-triphosphate elevated NEK7, NLRP3, pro-caspase-1, cle-caspase-1 and gasdermin D p30 expressions in bone marrow-derived macrophages, and enhanced levels of interleukin-1ß and tumor necrosis factor-α in the supernatant, accompanied with conspicuous cell pyroptosis, which was reversed after miR-23a-3p overexpression and NEK7 silencing. miR-23a-3p overexpression alleviated liver and kidney damage in type 2 diabetes mellitus rats, and reduced NLRP3-induced pyroptosis. CONCLUSIONS: Targeting NEK7 by miR-23a-3p could reduce NLRP3-induced pyroptosis, and assuage liver and kidney injuries in type 2 diabetes mellitus rats.