Activity

(±)VK4-40 dose-dependently reduced cocaine self-administration and cocaine-primed reinstatement of drug-seeking behaviour. (±)VK4-40 also inhibited cocaine-enhanced brain-stimulation reward caused by optogenetic stimulation of dopamine neurons in the ventral tegmental area. (±)VK4-40 alone decreased brain-stimulation reward but produced neither conditioned place preference nor place aversion. This new D

partial agonist also failed to alter oral sucrose self-administration.

The novel D

partial agonist, (±)VK4-40 attenuates cocaine reward and relapse in rodents, without significant unwanted effects. These findings support further investigation of D

partial agonists as putative treatments for cocaine use disorder.

The novel D3 partial agonist, (±)VK4-40 attenuates cocaine reward and relapse in rodents, without significant unwanted effects. These findings support further investigation of D3 partial agonists as putative treatments for cocaine use disorder.

With an increasing aging population, postmenopausal osteoporosis has become a global public health problem. Previous evidence has shown that postmenopausal osteoporosis is a skeletal disease mainly caused by estrogen deficiency, generally accompanied by inflammation, and dietary isoflavones may ameliorate postmenopausal osteoporosis by anti-inflammatory activity. We have generated isoflavone-enriched soybean leaves (IESLs), but their anti-inflammatory activity and effect on attenuating osteoporosis are still obscure. Here, we determined the isoflavone profiles of IESLs and evaluated their anti-inflammatory activity in lipopolysaccharide-stimulated RAW 264.7 cells and anti-osteoporotic effects on ovariectomy-induced osteoporosis in rats.

IESLs had a high content of total isoflavone. Hydrolysate of IESLs (HIESLs) was rich with the aglycones daidzein and genistein, and HIESLs can significantly inhibit lipopolysaccharide-induced inflammation by reducing messenger RNA expression of iNOS, COX-2, IL6, and IL1β. Moreover, ovariectomized rats receiving aqueous extracts of IESLs (HIESLs) orally maintained more bone mass than control rats did, which was attributed to inhibition of osteoclastogenesis by downregulating the messenger RNA expression of the bone-specific genes RANKL/OPG, OC, and cathepsin K, and the inflammation-related genes IL6, NFκB, and COX-2.

IESLs may attenuate postmenopausal osteoporosis by suppressing osteoclastogenesis with anti-inflammatory activity and be a potential source of functional food ingredients for the prevention of osteoporosis. © 2020 Society of Chemical Industry.

IESLs may attenuate postmenopausal osteoporosis by suppressing osteoclastogenesis with anti-inflammatory activity and be a potential source of functional food ingredients for the prevention of osteoporosis. © 2020 Society of Chemical Industry.

Temporal lobe epilepsy is a complex neurological disease caused by imbalance of excitation and inhibition in the brain. Growing literature implicates altered Ca

signalling in many aspects of epilepsy but the diversity of Ca

channels that regulate this syndrome are not well-understood. Here, we report that mice lacking the store-operated Ca

channel, Orai1, in the brain show markedly stronger seizures in response to the chemoconvulsants, kainic acid and pilocarpine. Electrophysiological analysis reveals that selective deletion of Orai1 channels in inhibitory neurons disables chemoconvulsant-induced excitation of GABAergic neurons in the CA1 hippocampus. Likewise, deletion of Orai1 in GABAergic neurons abrogates the chemoconvulsant-induced burst of spontaneous inhibitory postsynaptic currents (sIPSCs) on CA1 pyramidal neurons in the hippocampus. This loss of chemoconvulsant inhibition likely aggravates status epilepticus in Orai1 KO mice. These results identify Orai1 channels as regulators of hippocampalr seizures to KA (P = 0.001) and pilocarpine (P less then 0.00001) and loss of chemoconvulsant-induced increases in sIPSC responses compared with WT controls. We conclude that Orai1 channels regulate chemoconvulsant-induced excitation in GABAergic neurons and that destabilization of the excitatory/inhibitory balance in Orai1 KO mice aggravates chemoconvulsant-mediated seizures. These results identify Orai1 channels as novel molecular regulators of hippocampal neuronal excitability and seizures.In recent years, phase separation has been increasingly reported to play a pivotal role in a wide range of biological processes. Due to the close relationships between cancer and disorders in intracellular physiological function, the identification of new mechanisms involved in intracellular regulation has been regarded as a new direction for cancer therapy. Introducing the concept of phase separation into complex descriptions of disease mechanisms may provide many different insights. Here, we review the recent findings on the phase separation of cancer-related proteins, describing the possible relationships between phase separation and key proteins associated with cancer and indicate possible regulatory modalities, especially drug candidates for phase separation, which may provide more effective strategies for cancer therapy.Training volume is one of the critical variables required to promote resistance training benefits (e. g., hypertrophy, muscular strength). Thus, strategies to improve training volume are required. We tested the hypothesis that there is an increase in performance and reduction in the rate of perceived exertion in strength training with caffeine supplementation, carbohydrate mouth rinse, and a synergistic effect of caffeine supplementation plus carbohydrate mouth rinse. We recruited 29 physically active women 24±4 years, 60.0±7.9 kg, 161.0±6.0 cm. PF-04691502 This study was a double-blind, randomized, placebo-controlled, and crossover one. The subjects performed all sessions of strength training under different conditions caffeine (6.5 mg·kg-1 body mass); carbohydrate (6 g of maltodextrin rinsed for 10 s); caffeine plus carbohydrate; or placebo. We applied the ANOVA for repeated measures through the null-hypothesis statistical test, and the Bayes factors analyses approach. The subjects showed significant improvement in the total repetitions (P0.