Heat stress induces calcium dyshomeostasis to subsequent cognitive impairment through ERS-mediated apoptosis via SERCA/PERK/eIF2α pathway.

Heat exposure is an environmental stressor that has been associated with cognitive impairment. However, the neural mechanisms that underlie this phenomenon have yet to be extensively investigated. The Morris water maze test was utilized to assess cognitive performance. RNA sequencing was employed to discover the primary regulators and pathological pathways involved in cognitive impairment caused by heat. Before heat exposure in vivo and in vitro, activation of the sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) was achieved by CDN1163. Hematoxylin-Eosin, Nissl staining, calcium imaging, transmission electron microscopy, western blot, and immunofluorescence were utilized to visualize histological changes, intracellular calcium levels, endoplasmic reticulum stress (ERS) markers, apoptosis, and synaptic proteins alterations. Heat stress (HS) significantly induced cognitive decline and neuronal damage in mice. By the transcriptome sequencing between control (n = 5) and heat stress (n = 5) mice in hippocampal tissues, we identified a reduction in the expression of the atp2a gene encoding SERCA, accompanied by a corresponding decrease in its protein level. Consequently, this dysregulation resulted in an excessive accumulation of intracellular calcium ions. Furthermore, HS exposure also activated ERS and apoptosis, as evidenced by the upregulation of p-PERK, p-eIF2α, CHOP, and caspase-3. Consistently, a reduction in postsynaptic density protein 95 (PSD95) and synaptophysin (SYN) expressions indicated modifications in synaptic function. Notably, the impacts on neurons caused by HS were found to be mitigated by CDN1163 treatment both in vivo and in vitro. Additionally, SERCA-mediated ERS-induced apoptosis was attenuated by GSK2606414 treatment via inhibiting PERK-eIF2α-CHOP axis that not only curtailed the level of caspase-3 but also elevated the levels of PSD95 and SYN. These findings highlight the significant impact of heat stress on cognitive impairment, and further elucidate the underlying mechanism involving SERCA/PERK/eIF2α pathway.

Nutritional supplements formulated to prevent cognitive impairment in animals.

Heat stress will cause a series of response in the living system and the most significant impact is on brain functions. The aim of this article is to develop nutritional supplements that can alleviate cognitive decline caused by heat stress. In this article, we screen functional food factors which can prevent or relieve effects on heat stress injury based on bioinformatics. 129 function factors related to the crossover targets were obtained, and a food database related to the prevention of high-temperature impairment was constructed. After a series of scoring standards combined with food classification, two formulas-nutrition fortifier formula (tyrosine and multivitamin B) and plant compound formula (quercetin, proanthocyanidin, and naringin) were investigated using animal experiments to determine their ability to prevent cognitive impairment of heat-stressed animals. Our results demonstrated that certain functional food factors and our two designed formulations significantly prevent cognitive impairment of heat-stressed animals. Further mechanism was carried out by cell viability assay, reactive oxygen species assay, real-time quantitative PCR and Western blot. The results showed that the plant compound formula diluted 4000 times had the best relieving effect on HT22 after heat stress, and this concentration formula can significantly alleviate the elevated levels of reactive oxygen species caused by heat stress. This formula also can significantly down-regulate IL-1ß, IL-6, TNF-α, IL-10, iNOS and COX-2 expression. Likewise, Western blot results showed that the formula could activate the cAMP pathway and increase the expression of phosphorylated PKA and BDNF in hippocampal cells.

The combination of HT-ac and HBET improves the cognitive and learning abilities of heat-stressed mice by maintaining mitochondrial function through the PKA-CREB-BDNF pathway.

The aim was to investigate whether the combination of hydroxytyrosol acetate (HT-ac) and ethyl ß-hydroxybutyrate (HBET) can improve the cognition of heat-stressed mice, meanwhile exploring the mechanism of action. Mice were divided into 5 groups: control, heat-stressed, HT-ac, HBET, and HT-ac + HBET. Mice were gavaged for 21 days and exposed to heat (42.5 ± 0.5 °C, RH 60 ± 10%, 1 h day-1) on days 15-21, except for the control group. Results showed that the combination of HT-ac + HBET improved the cognitive and learning abilities of heat-stressed mice, which were tested by Morris water maze, shuttle box, and jumping stage tests. The combination of HT-ac + HBET maintained the integrity of neurons and mitochondria of heat-stressed mice. Likewise, this combination increased the mitochondrial membrane potential, the ATP content, the expression of phosphorylated PKA, BDNF, phosphorylated CREB and Bcl-2, and decreased the expression of Bax, caspase-3, and intracytoplasmic Cyt C in heat-stressed mice.

[METTL14 as a predictor of postoperative survival outcomes of patients with hepatocellular carcinoma].

OBJECTIVE: To investigate the expression of RNA methyltransferase METTL14 in hepatocellular carcinoma (HCC) and its clinical significance. METHODS: Immunohistochemical staining was used to detect the expression of METTL14 in 147 pairs of HCC and adjacent hepatic tissues. According to the scores rated by pathologists, the 147 cases of HCC were divided into high and low METTL14 expression groups. The correlation between the expression of METTL14 and clinicopathological parameters was analyzed, and Kaplan-Meier method was used to analyze the relationship between the expression of METTL14 and the prognosis and survival (including the overall survival and disease-free survival) of the patients with HCC after operation. Univariate analysis and multivariate analysis were carried out to assess the impact of METTL14 expression level on the overall survival and tumor-free survival of the patients after operation using a COX regression model and explore whether METTL14 expression level is an independent prognostic risk factor of the postoperative patients. RESULTS: The expression of METTL14 was significantly lower in HCC tissues than in the adjacent tissues (P < 0.001). METTL14 expression in HCC tissues was significantly correlated with the tumor size (P=0.044) and TNM stage (P=0.046). A low expression of METTL14 in HCC tissues was significantly correlated with a poor prognosis and a significantly shortened overall survival time and disease-free survival time of the patients (P < 0.05), and was an independent risk factor affecting the overall survival and disease-free survival of HCC patients. CONCLUSIONS: METTL14 may be a new prognostic marker for patients with HCC after hepatectomy.