ARC-64176

This study aimed to investigate the role and molecular mechanism of L-type calcium channel (LTCC) on fluoride exposure-induced kidney injury. Subchronic and chronic fluoride exposures were included in the experiment. Each part contained 140 ICR male mice. They were randomly divided into 7 groups: control group, high-fluoride group (NaF 30 mg/L), low-fluoride group (NaF 5 mg/L), high/low-fluoride + agonist (FPL64176) group, high/low-fluoride + inhibitor (nifedipine) group. One week before the end of fluoride exposure, each mouse in the fluoride exposure group was injected intraperitoneally with LTCC agonist (FPL64176) or inhibitor (nifedipine) (5 mg/kg day). The apoptosis of kidney cell was observed by TUNEL, and the protein expression levels of Cav1.2 and CaM, CaMKII, Bcl-2, and Bax were detected by Western blot. Compared with the control group, the protein expression levels of Cav1.2, CaM, and Bax significantly increased, and those of CaMKII and Bcl-2 significantly decreased, the ratio of Bax/Bcl-2 also significantly increased, and the number of apoptotic kidney cells significantly increased in the high/low-fluoride group and in the high/low-fluoride + agonist group. The above indicators and fluoride exposure concentrations showed in time- and dose-dependent changes. Compared with the high/low-fluoride + agonist group, the protein expression level of the molecular in the kidney cells above mentioned was significantly opposite and the number of apoptotic kidney cells significantly decreased in the high/low-fluoride + inhibitor group. In conclusion, LTCC mediates the kidney injury induced by fluoride exposure in mice. Fluoride exposure induced abnormal expression of the Cav1.2 protein, Ca²⁺ signal transduction pathway, and apoptosis-regulated proteins, which is one of the molecular mechanisms. Nifedipine may be a new and effective anti-fluoride drug.

Published studies have shown that the transient receptor potential vanilloid 1 (TRPV1) receptor agonist, resiniferatoxin (RTX), has pro and antiemetic effects. RTX can suppress vomiting evoked by a variety of nonselective emetogens such as copper sulfate and cisplatin in several vomit-competent species. In the least shrew, we have already demonstrated that combinations of ultra-low doses of RTX and low doses of the cannabinoid CB1/2 receptor agonist delta-9-tetrahydrocannabinol (Δ9-THC) produce additive antiemetic effects against cisplatin-evoked vomiting. In the current study, we investigated the broad-spectrum antiemetic potential of very low nonemetic doses of RTX against a diverse group of specific emetogens including selective and nonselective agonists of serotonergic 5-hydroxytrptamine (5-HT3) receptor (5-HT and 2-Me-5-HT), dopaminergic D2 receptor (apomorphine and quinpirole), cholinergic M1 receptor (pilocarpine and McN-A-343), as well as the selective substance P neurokinin NK1 receptor agonist GR73632, the selective L-Type calcium channel agonist FPL64176, and the sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA) inhibitor thapsigargin. When administered subcutaneously, ultra-low (0.01 µg/kg) to low (5.0 µg/kg) doses of RTX suppressed vomiting induced by the aforementioned emetogens in a dose-dependent fashion with 50% inhibitory dose values ranging from 0.01 to 1.26 µg/kg. This study is the first to demonstrate that low nanomolar nonemetic doses of RTX have the capacity to completely abolish vomiting caused by diverse receptor specific emetogens in the least shrew model of emesis.