Structure-based design of non-hypertrophic apelin receptor modulator.

Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.

Simulated microgravity-induced oxidative stress and loss of osteogenic potential of osteoblasts can be prevented by protection of primary cilia.

Oxidative stress has been considered to be closely related to spaceflight-induced bone loss; however, mechanism is elusive and there are no effective countermeasures. Using cultured rat calvarial osteoblasts exposed to microgravity simulated by a random positioning machine, this study addressed the hypotheses that microgravity-induced shortening of primary cilia leads to oxidative stress and that primary cilium protection prevents oxidative stress and osteogenesis loss. Microgravity was found to induce oxidative stress (as represented by increased levels of reactive oxygen species (ROS) and malondialdehyde production, and decreased activities of antioxidant enzymes), which was perfectly replicated in osteoblasts growing in NG with abrogated primary cilia (created by transfection of an interfering RNA), suggesting the possibility that shortening of primary cilia leads to oxidative stress. Oxidative stress was accompanied by mitochondrial dysfunction (represented by increased mitochondrial ROS and decreased mitochondrial membrane potential) and intracellular Ca2+ overload, and the latter was found to be caused by increased activity of Ca2+ channel transient receptor potential vanilloid 4 (TRPV4), as also evidenced by TRPV4 agonist GSK1016790A-elicited Ca2+ influx. Supplementation of HC-067047, a specific antagonist of TRPV4, attenuated microgravity-induced mitochondrial dysfunction, oxidative stress, and osteogenesis loss. Although TRPV4 was found localized in primary cilia and expressed at low levels in NG, microgravity-induced shortening of primary cilia led to increased TRPV4 levels and Ca2+ influx. When primary cilia were protected by miR-129-3p overexpression or supplementation with a natural flavonoid moslosooflavone, microgravity-induced increased TRPV4 expression, mitochondrial dysfunction, oxidative stress, and osteogenesis loss were all prevented. Our data revealed a new mechanism that primary cilia function as a controller for TRPV4 expression. Microgravity-induced injury on primary cilia leads to increased expression and overactive channel of TRPV4, causing intracellular Ca2+ overload and oxidative stress, and primary cilium protection could be an effective countermeasure against microgravity-induced oxidative stress and loss of osteogenic potential of osteoblasts.

Nanoarchitectonics of heteroatom-doped hierarchical porous carbon derived from carboxymethyl cellulose carbon aerogel and metal-organic framework for capacitive deionization.

Capacitive deionization (CDI) using porous materials offers a sustainable solution for providing affordable freshwater, but the low salt adsorption rate of benchmark carbon materials significantly limit the practical implementation. Herein, we utilized carboxymethyl cellulose sodium (CMC) as the carbon skeleton to produce a composite carbon aerogel loaded with ZIF-8 (ZIF-8/CMC-CA). The presence of ZIF-8 nanoparticles improved the pore structure of the material and provides a certain pseudo capacitance by introducing N. Compared with ZIF-8 derived carbons (ZIF-8-C), the CMC provided a good three-dimensional structure for the dispersion of ZIF-8 nanoparticles, reduced the agglomeration of particles. Furthermore, numerous carboxyl and hydroxyl groups on CMC enhanced the hydrophilicity of materials. Due to the interconnected structure, ZIF-8/CMC-CA exhibited excellent conductivity, a high specific surface area, and offered suitable channels for the rapid entry and exit of ions. In a three-electrode system, the total specific capacitance of the ZIF-8/CMC-CA electrode was 357.14 F g-1. The adsorption rate of ZIF-8/CMC-CA was 2.02 mg g-1 min-1 in a 500 mg L-1 NaCl solution. This study may provide new insight for modifying and fabricating electrode materials for practical CDI applications.

Selectivity adsorption of sulfate by amino-modified activated carbon during capacitive deionization.

ABSTRACTCapacitive deionization (CDI) is an environmentally friendly desalination technique with low energy consumption. However, unmodified carbon electrode materials have poor sulfate selectivity and adsorption capacity. In this work, to improve sulfate selectivity, we prepared activated carbon materials loaded with different amino contents by grafting amino groups via acid treatment for different times. In the competitive ion adsorption experiments, the sulfate selectivity of AC was only 0.64 and the amino-modified AC increased by 1.98-2.52 times due to the formation of stronger hydrogen bonds between the amino group and sulfate. AC-NH2-4 had the best selectivity and the sulfate selective coefficient was 2.25. The desorption of sulfate was 92.46% within one hour. In addition, the surface of the amino-modified activated carbon showed significantly improved electrochemical properties and better capacitance. The specific capacitance of amino-modified AC in different electrolyte solutions was consistent with the competitive adsorption results. The specific capacitance of amino-modified AC in Na2SO4 electrolyte solution was the highest. The modified electrode material also had the advantages of a higher adsorption capacity and excellent regeneration performance after continuous electric adsorption-desorption cycles. Therefore, it may have development potential to selectively adsorb sulfate in practical applications.

Selective adsorption of phosphate by carboxyl-modified activated carbon electrodes for capacitive deionization.

Capacitive deionization (CDI) has been considered as a promising technology for removing phosphate from water but suffer inferior selectivity and electrosorption performances for phosphate of current carbon electrodes in CDI. Herein, we achieved highly selective phosphate removal from a ternary effluent of Cl-, PO43-, and SO42- by using nitric acid-treated activated carbon (AC) with various modification times and pure AC as the anode and cathode, a novel phosphate selective asymmetric CDI reactor. The results showed that carboxyl groups greatly grafted on the materials after modification (varying from 0.00084 to 0.0012 mol g-1). The phosphate selectivity of the present research was higher than that of unmodified CDI, and it increased with the increase of carboxyl groups content. The highest phosphate selectivity (2.01) in modified materials is almost six times higher than that of pure AC. Moreover, the modified electrodes exhibited good regenerative ability with a phosphate desorption efficiency of around 72.12% during the adsorption/desorption process and great stability during the cycling experiment. These results demonstrated that the innovative application of nitric acid-modified AC can effectively selectively remove phosphate from mixed anion solution, opening a hopeful window to selective adsorption in water treatment by CDI.

Protective effects of 7-hydroxyethyl chrysin on rats with exercise-induced fatigue in hypobaric hypoxia environment.

: To investigate the protective effect of 7-hydroxyethyl chrysin (7-HEC) on rats with exercise-induced fatigue in hypobaric hypoxic condition.Forty healthy male Wistar rats were randomly divided into four groups with 10 rats in each group: control group, model group, chrysin group and 7-HEC group. The rats in control group were raised at local altitude but other three groups were raised in a simulating altitude of for hypobaric hypoxia treatment. The chrysin group and 7-HEC group were given chrysin or 7-HEC by gavage for respectively; while the control group and model group were given the same amount of sterilized water. The weight-bearing swimming tests were performed 3 d later, and the weight-bearing swimming time was documented. After rats were sacrificed, the liver and skeletal muscle tissue samples were taken for pathological examination and determination of lactate, malondialdehyde (MDA), total superoxide dismutase (T-SOD) and glycogen levels. Blood urea nitrogen was also determined. Compared with the model group, weight-bearing swimming times were significantly prolonged in 7-HEC group [ vs. (4.04±1.30) min, <0.01]; pathological changes in liver and skeletal muscle tissue were attenuated; generation rate of blood urea nitrogen vs. 0.60) mmol·L·min, <0.05], lactate [liver: (0.14±0.05) vs. (0.10±0.03) mg·g·min, skeletal muscle: vs. (0.18±] and MDA [liver: (0.48) vs. (0.78±0.28) nmol·mg·min, skeletal muscle: (0.87±0.19) vs. (0.63±0.11) nmol·mg·min] were significantly reduced (all < 0.05); glycogen content [liver: (15.16±2.69) vs. skeletal muscle: (1.46±0.49) vs.0.48) mg/g] and T-SOD [liver: (1.87±0.01) vs. (2.68±0.12) U/mL, skeletal muscle: 0.42) vs. 0.96) U/mL] were significantly improved (all <0.05). 7-HEC has significant protective effect on the rats with exercise-induced fatigue in hypobaric hypoxia condition.