The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a crucial role in the prognosis of subarachnoid hemorrhage (SAH). WNK1 kinase negatively regulates NLRP3 in various inflammatory conditions, but its role in early brain injury (EBI) after SAH remains unclear. In this study, we used an in vivo SAH model in rats/mice and AAV-WNK1 intraventricular injection to investigate its neuroprotective mechanisms. WNK1 expression was significantly reduced in SAH patient blood and SAH model brain tissue, correlating negatively with microglial activation. AAV-WNK1 alleviated brain edema, neuronal necrosis, behavioral deficits, and inflammation by inhibiting NLRP3 inflammasome activation. In hemin-stimulated BV-2 cells, WNK1 overexpression reduced NLRP3 activation and inflammatory cytokines. Chloride counteracted WNK1's inhibitory effects, and WNK1 suppressed P2X7R-induced NLRP3 activation. Mechanistically, WNK1 functioned via the OXSR1/STK39 pathway. These findings highlight WNK1 as a key regulator of intracellular chloride balance and neuroinflammation, presenting a potential therapeutic target for SAH treatment.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Subarachnoid Hemorrhage/complications* ; Inflammasomes/metabolism* ; Rats ; Mice ; Neuroinflammatory Diseases/metabolism* ; WNK Lysine-Deficient Protein Kinase 1/genetics* ; Male ; Humans ; Chlorides/metabolism* ; Mice, Inbred C57BL ; Rats, Sprague-Dawley ; Brain Injuries/metabolism* ; Microglia/metabolism* ; Protein Serine-Threonine Kinases

Objective:To investigate the expressions and clinical significances of breast cancer susceptibility gene 1 (BRCA1) and tubulin β3 (TUBB3) in patients with gastric cancer, so as to provide a basis for accurate diagnosis and treatment of gastric cancer.Methods:The data of 46 hospitalized patients with gastric cancer who underwent gastroscopebiopsy or operation in Maanshan People's Hospital in Anhui Province from December 2018 to May 2020 were collected. The expressions of BRCA1 and TUBB3 in tumor tissues and peritumoral tissues were determined by immunohistochemistry. Real-time fluorescent quantitative polymerase chain reaction (qRT-PCR) was used to detect BRCA1 and TUBB3 mRNA expressions in tumor tissues and peritumoral tissues. The correlations between expressions of BRCA1 and TUBB3 in gastric cancer tissues and clinicopathologic features were analyzed.Results:The positive rates of BRCA1 and TUBB3 proteins in gastric cancer tissues were higher than those in peritumoral tissues [43.5% (20/46) vs. 16.7% (5/30), 65.2% (30/46) vs. 6.7% (2/30), both P < 0.05]. qRT-PCR showed that the relative expression of BRCA1 mRNA in gastric cancer tissues was higher than that in peritumoral tissues (15.5±6.8 vs. 5.0±1.6, t = 9.41, P < 0.01); the relative expression of TUBB3 mRNA in gastric cancer tissues was higher than that in peritumoral tissues (22.1±6.3 vs. 5.7±1.9, t = 3.51, P < 0.01). The positive rate of TUBB3 protein in female patients was lower than that in male patients [15.4% (2/13) vs. 84.8% (28/33)], the positive rate of BRCA1 protein in patients with positive human epidermal growth factor receptor 2 (HER2) was higher than that in patients with negative HER2 [87.5% (7/8) vs. 47.4% (18/38)], the positive rate of BRCA1 protein in patients with family history was higher than that in patients without family history [85.7% (6/7) vs. 35.9% (14/39)], and the differences were statistically significant (all P < 0.05). The positive expressions of BRCA1 and TUBB3 proteins in gastric cancer tissues were both correlated with tumor stage and differentiation (all P < 0.05), and the expressions of BRCA1 and TUBB3 proteins were correlated ( χ2 = 33.52, P < 0.01). Conclusions:BRCA1 and TUBB3 may be related to the occurrence and development of gastric cancer, and there may be a certain relationship between BRCA1 and TUBB3, BRCA1 and HER2. BRCA1 and TUBB3 may have significances in the diagnosis and treatment of gastric cancer.

The human tissue kallikrein(KLK)gene family consists of 15 highly conservative serine pro-teases,which is the largest uninterrupted cluster of protease genes in the human genome. Several members of the family are expected to be markers for tumor diagnosis and prognosis. Studies find that the expressions of KLK2-11 and KLK13-15 are abnormal,and the majority of KLKs have potential diagnostic and prognostic values.