Search Results (4)

Human Ca_v1.3 (hCa_v1.3) is of great interest as a potential target for Parkinson’s disease. However, common medications like dihydropyridines (DHPs), a kind of classic calcium channel blocker, have poor selectivity to hCa_v1.3 in clinical treatment, mainly due to being implicated in cardiovascular side-effects mediated by human Ca_v1.2 (hCa_v1.2). Recently, pyrimidine-2,4,6-triones (PYTs) have received extensive attention as prominent selective inhibitors to hCa_v1.3. In this study, we describe the selectivity mechanism of PYTs for hCa_v1.2 and hCa_v1.3 based on molecular dynamic simulation methods. Our results reveal that the van der Waals (vdW) interaction was the most important force affecting selectivity. Moreover, the hydrophobic interaction was more conducive to the combination. The highly hydrophobic amino acid residues on hCa_v1.3, such as V162 (IR1), L303 (IR2), M481 (IR3), and F484 (IR3), provided the greatest contributions in the binding free energy. On the other hand, the substituents of a halogen-substituted aromatic ring, cycloalkyl and norbornyl on PYTs, which are pertinent to the steric hindrance of the compounds, played core roles in the selectivity and affinity for hCa_v1.3, whereas strong polar substituents needed to be avoided. The findings could provide valuable information for designing more effective and safe medicines for Parkinson’s disease. Full article

Heat stress (HS), a nonspecific response to environmental heat, can seriously affect dairy cow health. Feed additives may alleviate HS in dairy cows by improving rumen fermentation efficacy, stimulating feed consumption, enhancing vasodilation, and/or improving antioxidant capacity. The temperature–humidity index (THI) indicates that spring is a non-HS season, and summer is an HS season. HS results in the decrease in dairy cow antioxidant capacities. Our results indicated the decrease in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidation (T-AOC) levels and the increase in malondialdehyde (MDA) level during HS season. Meanwhile, antioxidant indexes (SOD, GSH-Px, and T-AOC) were positively correlated with milk yield (p < 0.01), whereas MDA exhibited a significant negative correlation with milk yield (p < 0.05). In addition, the effects of dihydropyridine (DHP) on antioxidant capacity and ruminal microbial communities in dairy cows under HS were investigated. During summer, dairy cows were randomly assigned into two groups under HS, including a standard diet (S-ND) group and standard diet with 3 g/day/cow DHP (S-D) group. DHP treatment significantly restored SOD and GSH-Px levels under HS. Denaturing gradient gel electrophoresis results indicated that the DHP altered ruminal bacterial community mainly composed Proteobacteria and Firmicutes in dairy cows under HS. Our results suggest that DHP can enhance the antioxidant abilities of dairy cows with favorable effects on ruminal microbial communities under HS, further alleviating HS on dairy cows. Full article

Amongst nitrogen heterocycles of different ring sizes and oxidation statuses, dihydropyridines (DHP) occupy a prominent role due to their synthetic versatility and occurrence in medicinally relevant compounds. One of the most straightforward synthetic approaches to polysubstituted DHP derivatives is provided by nucleophilic dearomatization of readily assembled pyridines. In this article, we collect and summarize nucleophilic dearomatization reactions of pyridines reported in the literature between 2010 and mid-2018, complementing and updating previous reviews published in the early 2010s dedicated to various aspects of pyridine chemistry. Since functionalization of the pyridine nitrogen, rendering a (transient) pyridinium ion, is usually required to render the pyridine nucleus sufficiently electrophilic to suffer the attack of a nucleophile, the material is organized according to the type of N-functionalization. A variety of nucleophilic species (organometallic reagents, enolates, heteroaromatics, umpoled aldehydes) can be productively engaged in pyridine dearomatization reactions, including catalytic asymmetric implementations, providing useful and efficient synthetic platforms to (enantioenriched) DHPs. Conversely, pyridine nitrogen functionalization can also lead to pyridinium ylides. These dipolar species can undergo a variety of dipolar cycloaddition reactions with electron-poor dipolarophiles, affording polycyclic frameworks and embedding a DHP moiety in their structures. Full article

Oxidative stress has been implicated in pathophysiology of different human stress- and age-associated disorders, including osteoporosis for which antioxidants could be considered as therapeutic remedies as was suggested recently. The 1,4-dihydropyridine (DHP) derivatives are known for their pleiotropic activity, with some also acting as antioxidants. To find compounds with potential antioxidative activity, a group of 27 structurally diverse DHPs, as well as one pyridine compound, were studied. A group of 11 DHPs with 10-fold higher antioxidative potential than of uric acid, were further tested in cell model of human osteoblast-like cells. Short-term combined effects of DHPs and 50 µM H₂O₂ (1-h each), revealed better antioxidative potential of DHPs if administered before a stressor. Indirect 24-h effect of DHPs was evaluated in cells further exposed to mild oxidative stress conditions induced either by H₂O₂ or tert-butyl hydroperoxide (both 50 µM). Cell growth (viability and proliferation), generation of ROS and intracellular glutathione concentration were evaluated. The promotion of cell growth was highly dependent on the concentrations of DHPs used, type of stressor applied and treatment set-up. Thiocarbatone III-1, E2-134-1 III-4, Carbatone II-1, AV-153 IV-1, and Diethone I could be considered as therapeutic agents for osteoporosis although further research is needed to elucidate their bioactivity mechanisms, in particular in respect to signaling pathways involving 4-hydroxynoneal and related second messengers of free radicals. Full article