Ca²⁺-sensing receptors (CaSRs) are G protein-coupled receptors activated by elevated concentrations of extracellular Ca²⁺. In our previous works, we showed protein and functional expression of CaSR in mouse cerebral endothelial cell (EC) (bEND.3); the CaSR response (high Ca²⁺-elicited cytosolic [Ca²⁺] elevation) was unaffected by suppression of phospholipase C but in part involved Ca²⁺ influx through transient receptor potential V1 (TRPV1) channels. In this work, we investigated if extracellular acidity affected CaSR-mediated Ca²⁺ influx triggered by high (3 mM) Ca²⁺ (CaSR agonist), 3 mM spermine (CaSR agonist), and 10 mM cinacalcet (positive allosteric modulator of CaSR). Extracellular acidosis (pH 6.8 and pH 6.0) strongly suppressed cytosolic [Ca²⁺] elevation triggered by high Ca²⁺, spermine, and cinacalcet; acidosis also inhibited Mn²⁺ influx stimulated by high Ca²⁺ and cinacalcet. Purinoceptor-triggered Ca²⁺ response, however, was not suppressed by acidosis. Extracellular acidity also did not affect membrane potential, suggesting suppressed CaSR-mediated Ca²⁺ influx in acidity did not result from the reduced electrical driving force for Ca²⁺. Our results suggest Ca²⁺ influx through a putative CaSR-TRP complex in bEND.3 EC was sensitive to extracellular pH.

Spinal cord injury (SCI) is a common central nervous system disease. It is reported that long non-coding RNA LINC00158 is involved in the process of SCI. The purpose of this study was to explore the biological role of LINC00158 in the SCI. First, we established a rat SCI model by surgical method and evaluated the motor function of rats by the Basso-Beattie-Bresnahan locomotor rating scale. The results showed that the expression of LINC00158 decreased and apoptotic cells increased in the SCI model rats. Meanwhile, we found the upregulated LC3-II/LC3-I, Beclin-1, and p62 in the SCI rats. Then, primary rat spinal cord neurons were exposed to oxygen/glucose deprivation (OGD) as an in vitro cell model of SCI. After OGD treatment, the expression of LINC00158 decreased significantly and the apoptosis of spinal cord neurons increased. OGD treatment resulted in upregulation of LC3-II/LC3-I and Beclin-1 and downregulation of p62 in primary spinal cord neurons, which could be eliminated by overexpression of LINC00158. 3-Methyladenine and chloroquine (autophagy inhibitor) reversed the inhibitory effect of LINC00158 overexpression on apoptosis of primary spinal cord neurons. In conclusion, this study demonstrated that LINC00158 overexpression repressed neuronal apoptosis by promoting autophagy, suggesting that LINC00158 may be a potential therapeutic target in the SCI.

The effect of different duration of exercise preconditioning (EP) on protecting from exhaustive exercise-induced cardiac injury (EECI) has been optimized in rats. Male Sprague-Dawley rats were divided into six groups: the control group, exhaustive exercise (EE) group, EP 20-min + EE group, EP 40-min + EE group, EP 60-min + EE group and EP 80-min + EE group. The EP groups were subjected to treadmill running at the intensity of 74.0% V̇O_{2 max}. Changes of exercise capacity, cardiac pathology, myocardial enzymology, electrocardiogram (ECG), cardiac function, and mitochondrial respiratory function were compared. Compared to the C group, the EE group has shown significant decrease of exercise capacity, elevation of serum N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin-I (cTn-I) levels, cardiac morphology change, ECG disturbance, cardiac dysfunction and reduction of myocardial mitochondrial respiration function. Compared to the EE group, the EP groups have shown significant elevation of exercise capacity, decrease of serum NT-proBNP and cTn-I, improvement of cardiac function and myocardial mitochondrial electron transfer pathway complex I, II and IV activity. The correlation analyses showed protection of EP was proportional to EP duration from 20-min to 60-min. EE caused cardiac injury. EP could protect from EECI by alleviating myocardial damage, improving cardiac function and mitochondrial ETP complex I, II and IV activity. EP protection was positively correlated to EP duration from 20-min to 60-min with EP intensity fixed at 74.0% V̇O_{2 max}.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is often caused by obesity. Currently, moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) are two effective treatments for reducing fat mass in patients with obesity and NAFLD. However, the comparative fat-reducing effects and underlying molecular mechanisms of MICT and HIIT remain unclear. This comprehensive study was performed on male Wistar rats treated with standard diet, high-fat diet, MICT, and HIIT to explore their comparative fat-reducing effects and corresponding molecular mechanisms. HIIT had a greater effect on hepatic vacuolation density and lipid content reduction than MICT, and triglyceride and total cholesterol levels in the serum and the liver demonstrated different sensitivities to different exercise training programs. At the molecular level, both MICT and HIIT altered the processes of fatty acid synthesis, fatty acid transport, fatty acid β-oxidation, and cholesterol synthesis, wherein the transcriptional and translational levels of signaling molecules peroxisome proliferator-activated receptors (PPARs) regulating fatty acid and cholesterol synthesis were strongly changed. Moreover, the metabolic pathways of amino acids, bile acids, and carbohydrates were also affected according to transcriptome analysis, and the changes in the above-mentioned processes in the HIIT group were greater than those in the MICT group. In combination with the search tool for the retrieval of interacting genes/proteins (STRING) analysis and the role of PPARs in lipid metabolism, as well as the expression pattern of PPARs in the MICT and HIIT groups, the MICT-and HIIT-induced fat loss was mediated by the PPAR pathway, causing feedback responses in fatty acid, steroid, amino acid, bile acid, and carbohydrate metabolism, and HIIT had a better fat-reducing effect, which may be initiated by PPAR-α. This study provides a theoretical basis for targeted therapy of patients with obesity and NAFLD.

LncRNAs are associated with tumorigenesis of liver cancer. LncRNA Colorectal Neoplasia Differentially Expressed (CRNDE) was identified as an oncogenic lncRNA and involved in tumor growth and metastasis. The role of CRNDE in liver cancer was investigated. CRNDE was elevated in liver cancer cells. Knockdown of CRNDE decreased cell viability and inhibited proliferation of liver cancer. Moreover, knockdown of CRNDE reduced levels of extracellular acidification rate, glucose consumption, and lactate production to repress glycolysis of liver cancer. Silence of CRNDE enhanced the expression of miR-142 and reduced enhancer of zeste homolog 2 (EZH2) and hypoxia-inducible factor 1α (HIF-1α). Over-expression of HIF-1α attenuated CRNDE silence-induced decrease of glucose consumption and lactate production. Injection with sh-CRNDE virus reduced in vivo tumor growth of liver cancer through up-regulation of miR-142 and down-regulation of EZH2 and HIF-1α. In conclusion, knockdown of CRNDE suppressed cell proliferation, glycolysis, and tumor growth of liver cancer through EZH2/miR-142/HIF-1α.

Prostate cancer is a leading cause of cancer-associated death in males. Leonurine (Leo) is a pleiotropic anti-tumor agent isolated from traditional Chinese herb that was used in gynecologic treatments. However, its pharmacological effect against prostate cancer progression remains unclear. Here, we showed that Leo dose dependently inhibited prostate cancer cell proliferation, promoted cell apoptosis, and induced cell cycle arrest. Moreover, we noticed that miR-18a-5p was downregulated and the solute carrier family 40 member 1 (SLC40A1) is upregulated by Leo treatment. SLC40A1 knockdown by siRNA abrogated the inhibitory effect of Leo on prostate cancer progression. Notably, Leo also significantly inhibited prostate cancer progression in a subcutaneous xenograft tumor mouse model in vivo. This study further unveiled the mechanism by which Leo inhibited prostate cancer progression, which provides a promising potential for its future clinical application.