Toll-like receptor 4 mutation protects obese mice against endothelial dysfunction by decreasing NADPH oxidase isoforms 1 and 4.

OBJECTIVE: To analyze the role of toll-like receptor 4 in modulating metabolism and endothelial function. APPROACH AND RESULTS: Type 2 diabetic mice with mutated toll-like receptor 4 (DWM) were protected from hyperglycemia and hypertension, despite an increased body weight. Isometric tension was measured in arterial rings with endothelium. Relaxations to acetylcholine were blunted in aortae and mesenteric arteries of Lepr(db/db) mice, but not in DWM mice; the endothelial NO synthase dimer/monomer ratio and endothelial NO synthase phosphorylation levels were higher in DWM preparations. These differences were abolished by apocynin. Contractions to acetylcholine (in the presence of L-NAME) were larger in carotid arteries from Lepr(db/db) mice than from DWM mice and were inhibited by indomethacin and SC560, demonstrating involvement of cyclooxygenase-1. The release of 6-ketoprostaglandin F1α was lower in DWM mice arteries, implying lower cyclooxygenase-1 activity. Apocynin, manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin, catalase, and diethyldithiocarbamate inhibited endothelium-dependent contractions. The mRNA and protein levels of NADPH oxidase isoforms NOX1 and NOX4 were downregulated in DWM mice arteries. The in vivo and in vitro administration of lipopolysaccharide caused endothelial dysfunction in the arteries of wild-type, but not toll-like receptor 4-mutated mice. CONCLUSIONS: Toll-like receptor 4 plays a key role in obesity and diabetes-associated endothelial dysfunction by increasing oxidative stress.

Pentafluoro(phenoxy)cyclotriphosphazene Stabilizes Electrode/Electrolyte Interfaces for Sodium-Ion Pouch Cells of 145 Wh Kg-1.

Sodium-ion batteries are competitive candidates for large-scale energy storage batteries due to the abundant sodium resource. However, the electrode interface in the conventional electrolyte is unstable, deteriorating the cycle life of the cells. Introducing functional electrolyte additives can generate stable electrode interfaces. Here, pentafluoro(phenoxy)cyclotriphosphazene (FPPN) serves as a functional electrolyte additive to stabilize the interfaces of the layered oxide cathode and the hard carbon anode. The fluorine substituting groups and the π-π conjugated ─PN─ structure decrease the lowest unoccupied molecular orbital and increase the highest occupied molecular orbital of FPPN, respectively, realizing the preferential reduction and oxidization of FPPN on the anode and cathode simultaneously, which results in the formation of a uniform, ultrathin, and inorganic-rich solid electrolyte interlayer and cathode electrolyte interphase. The sodium-ion pouch cells of 5 Ah capacity rather than coin cells are assembled to evaluate the effect of FPPN. It can retain a high capacity of 4.46 Ah after 1000 cycles, corresponding to a low decay ratio of 0.01% per cycle. The pouch cell also achieves a high energy density of 145 Wh kg-1 and a wide operating temperature of -20-60 °C. This work can attract more attention to the rational electrolyte design for practical applications.

Demystifying the Salt-Induced Li Loss: A Universal Procedure for the Electrolyte Design of Lithium-Metal Batteries.

Lithium (Li) metal electrodes show significantly different reversibility in the electrolytes with different salts. However, the understanding on how the salts impact on the Li loss remains unclear. Herein, using the electrolytes with different salts (e.g., lithium hexafluorophosphate (LiPF6), lithium difluoro(oxalato)borate (LiDFOB), and lithium bis(fluorosulfonyl)amide (LiFSI)) as examples, we decouple the irreversible Li loss (SEI Li+ and "dead" Li) during cycling. It is found that the accumulation of both SEI Li+ and "dead" Li may be responsible to the irreversible Li loss for the Li metal in the electrolyte with LiPF6 salt. While for the electrolytes with LiDFOB and LiFSI salts, the accumulation of "dead" Li predominates the Li loss. We also demonstrate that lithium nitrate and fluoroethylene carbonate additives could, respectively, function as the "dead" Li and SEI Li+ inhibitors. Inspired by the above understandings, we propose a universal procedure for the electrolyte design of Li metal batteries (LMBs): (i) decouple and find the main reason for the irreversible Li loss; (ii) add the corresponding electrolyte additive. With such a Li-loss-targeted strategy, the Li reversibility was significantly enhanced in the electrolytes with 1,2-dimethoxyethane, triethyl phosphate, and tetrahydrofuran solvents. Our strategy may broaden the scope of electrolyte design toward practical LMBs.

A prospective study to evaluate the efficacy and safety of oral acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy.

The present study aimed to evaluate the efficacy and safety of acetyl-L-carnitine (ALC) for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). The study was carried out as a prospective, randomized, double-blind, placebo-controlled and paralleled clinical study. A total of 239 patients with CIPN were selected as the study subjects. Of the 239 subjects, 118 subjects received 3 g/day ALC orally for 8 weeks and 121 received a placebo. The primary endpoint was improvement of peripheral neuropathy by at least one grade. Patient status was assessed at week 4, 8 and 12 after enrollment into the study. In both the full analysis set (FAS) and the per-protocol set (PPS), peripheral sensory neuropathy was significantly ameliorated in the ALC group with 50.5 and 51.6% patients meeting the primary endpoint at week 8, compared with 24.1 and 23.1% of patients in the placebo group (P<0.001 in both sets). Secondary endpoints, such as the nerve electrophysiological examination and the Karnofsky physical score were also significantly improved in patients receiving ALC treatment, as compared with the placebo group (FAS, P=0.0463 and P=0.022; PPS, P=0.0076 and P=0.0064, respectively). Cancer-associated fatigue was significantly alleviated following ALC treatment in the PPS (P=0.0135). In the safety analysis set, the difference in adverse events incidence between the two groups was not statistically significant (P=0.3903). There were only two severe adverse events in the ALC group, which were not associated with the effect of ALC. In conclusion, the results of the present study demonstrated that in Chinese patients with cancer, oral administration of ALC is effective at ameliorating peripheral sensory neuropathy induced by chemotherapy, as well as reducing of cancer-associated fatigue and improving physical conditions.

Anfibatide, a novel GPIb complex antagonist, inhibits platelet adhesion and thrombus formation in vitro and in vivo in murine models of thrombosis.

Platelet adhesion and aggregation at the sites of vascular injury are key events for thrombosis and haemostasis. It has been well demonstrated that interaction between glycoprotein (GP) Ibα and von Willebrand factor (VWF) initiates platelet adhesion and contributes to platelet aggregation, particularly at high shear. GPIb has long been suggested as a desirable antithrombotic target, but anti-GPIb therapy has never been successfully developed. Here, we evaluated the antithrombotic potential of Anfibatide, a novel snake venom-derived GPIb antagonist.We found Anfibatide inhibited washed murine platelet aggregation induced by ristocetin and recombinant murine VWF. It also blocked botrocetin-induced binding of murine plasma VWF to recombinant human GPIbα. Interestingly, Anfibatide did not inhibit botrocetin-induced aggregation of platelet-rich plasma, indicating that its binding site may differ from other snake venom-derived GPIb antagonists. Anfibatide strongly inhibited platelet adhesion, aggregation, and thrombus formation in perfusion chambers at high shear conditions and efficiently dissolved preformed thrombi. Anfibatide also inhibited thrombus growth at low shear conditions, though less than at high shear. Using intravital microscopy, we found that Anfibatide markedly inhibited thrombosis in laser-injured cremaster vessels and prevented vessel occlusion in FeCl3-injured mesenteric vessels. Importantly, Anfibatide further inhibited residual thrombosis in VWF-deficient mice, suggesting that Anfibatide has additional antithrombotic effect beyond its inhibitory role in GPIb-VWF interaction. Anfibatide did not significantly cause platelet activation, prolong tail bleeding time, or cause bleeding diathesis in mice. Thus, consistent with the data from an ongoing clinical trial, the data from this study suggests that Anfibatide is a potent and safe antithrombotic agent.