H2S inhibits LiCl/pilocarpine-induced seizures and promotes neuroprotection by regulating TRPV2 expression via the AC3/cAMP/PKA pathway.

It is widely acknowledged that epilepsy is a neurological disorder characterized by recurrent and atypical neuronal discharges, resulting in transient dysfunction within the brain. The protective role of hydrogen sulfide (H2S) in epilepsy has been elucidated by recent studies, but the underlying mechanisms remain poorly understood. To investigate this, the concentration of H2S was measured by spectrophotometry and a fluorescent probe in LiCl/Pilocarpine (LiCl/Pilo)-induced seizures in rats. The localization of proteins was examined using immunofluorescence. Electroencephalogram and behavioral tests were employed to evaluate the occurrence of seizures. Neuropathological changes in the hippocampus were examined by hematoxylin-eosin staining, Nissl staining, and transmission electron microscopy. Through proteomics and bioinformatics analysis, we identified the differential proteins in the hippocampus of rats following H2S intervention. Protein changes were detected through western blotting. The results showed that H2S treatment significantly alleviated seizures and minimized post-seizures neurological damage in rats. Proteomics analysis revealed adenylate cyclase 3 (AC3) as a protein potentially targeted by H2S. Moreover, the AC3 activator forskolin reversed the downregulation effect of H2S on the AC3/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/transient receptor potential vanilloid 2 (TRPV2) signaling pathway. In conclusion, H2S targets and downregulates the expression of AC3, thereby modulating the AC3/cAMP/PKA signaling pathway to regulate the expression of TRPV2 in LiCl/Pilo-induced seizures, ultimately leading to seizure inhibition and neuroprotection.

Reusable Solid-form Phase-Selective Organogelators for Rapid and Efficient Remediation of Crude Oil Spill.

Phase-selective organogelators (PSOGs) are considered as a prospective tool for their application in oil spill remediation. However, the number of reports on the PSOGs that can be used in powder form for prompt phase-selective gelation of crude oils is still limited. In this study, a series of compounds with l-mandelic acid as the scaffold bearing different amino acid fragments have been prepared. Also, the gelation behaviors and properties of these derivatives toward organic liquids, product oils, and a type of Chinese crude oil were investigated via heating-and-cooling process, stirring, or resting operation. Besides, the micromorphologies of the resulting gels and the driving forces for the gel formation have been studied by scanning electron microscopy, Fourier transform infrared, UV spectroscopy, concentration-dependent 1H NMR, and X-ray diffraction. Particularly, gelator C15-Phe-Mac-Nap was shown to have the capability of congealing the Chinese crude oil selectively from water in powder form with a relatively lower gelator dosage, as compared with the other gelators we reported in the current and previous works. Moreover, gelator C15-Phe-Mac-Nap displayed some advantageous behaviors such as the reusability of gelator, excellent mechanical and chemical stability of the crude oil gels, and nontoxicity of the gelator in the aquatic environment, indicating its great potential application value for marine oil spill remediation.

YB-1 Recruits Drosha to Promote Splicing of pri-miR-192 to Mediate the Proangiogenic Effects of H2S.

Aims: The genes targeted by miRNAs have been well studied. However, little is known about the feedback mechanisms to control the biosynthesis of miRNAs that are essential for the miRNA feedback networks in the cells. In this present study, we aimed at examining how hydrogen sulfide (H2S) promotes angiogenesis by regulating miR-192 biosynthesis. Results: H2S promoted in vitro angiogenesis and angiogenesis in Matrigel plugs embedded in mice by upregulating miR-192. Knockdown of the H2S-generating enzyme cystathionine γ-lyase (CSE) suppressed in vitro angiogenesis, and this suppression was rescued by exogenous H2S donor NaHS. Plakophilin 4 (PKP4) served as a target gene of miR-192. H2S up-regulated miR-192 via the VEGFR2/Akt pathway to promote the splicing of primary miR-192 (pri-miR-192), and it resulted in an increase in both the precursor- and mature forms of miR-192. H2S translocated YB-1 into the nuclei to recruit Drosha to bind with pri-miR-192 and promoted its splicing. NaHS treatment promoted angiogenesis in the hindlimb ischemia mouse model and the skin-wound-healing model in diabetic mice, with upregulated miR-192 and downregulated PKP4 on NaHS treatment. In human atherosclerotic plaques, miR-192 levels were positively correlated with the plasma H2S concentrations. Innovation and Conclusion: Our data reveal a role of YB-1 in recruiting Drosha to splice pri-miR-192 to mediate the proangiogenic effect of H2S. CSE/H2S/YB-1/Drosha/miR-192 is a potential therapeutic target pathway for treating diseases, including organ ischemia and diabetic complications. Antioxid. Redox Signal. 36, 760-783. The Clinical Trial Registration number is 2016-224.

Trans-anethole attenuates diet-induced nonalcoholic steatohepatitis through suppressing TGF-ß-mediated fibrosis.

BACKGROUND: Nonalcoholic Steatohepatitis (NASH) is the most severe type of non-alcoholic fatty liver disease (NAFLD) and one of the most common chronic liver diseases, leading to the increased risk of liver failure, cirrhosis and hepatocellular carcinoma. Trans-anethole was reported to have anti-inflammatory, anti-obesity and anti-diabetic activities. However, its role in NASH remains unknown. Therefore, we aimed to explore the effect of Trans-anethole on NASH. METHODS: Eight-week-old C57BL/6 mice were fed on a methionine- and choline-deficient (MCD) diet for 8 weeks to induce NASH in mice, and on the meanwhile, mice were also orally administrated with or without 100 mg/kg Trans-anethole daily to evaluate the effect of Trans-anethole on NASH. RESULTS: Trans-anethole dose-dependently ameliorated liver injury in MCD diet-fed mice, then the most effective dose of Trans-anethole 100 mg/kg was chosen. Trans-anethole significantly attenuated hepatic steatosis, inflammation and hepatic fibrosis in MCD diet-induced NASH mice. Moreover, Trans-anethole reduced hepatic fibrosis by inhibiting transforming growth factor-beta signaling pathway both in vivo and in vitro. CONCLUSION: Trans-anethole effectively ameliorated NASH in MCD diet-fed mice, which suggested that Trans-anethole might serve as a therapeutic strategy for NASH.

Photoreaction-driven two-dimensional periodic polyrotaxane-type supramolecular nanoarchitecture.

A 2D polypseudorotaxane-type assembly was constructed using cucurbit[8]uril and styrylpyridinium-bearing triphenylamine. In addition, tunable non-covalent to covalent transition was achieved by [2+2] photodimerization of styrylpyridinium units. Thus, a more stable 2D polyrotaxane-type nanoarchitecture was obtained, which could capture [60]fullerene and further exhibit an excellent photodynamic therapy effect.

Flexible quantum dot light-emitting devices for targeted photomedical applications.

Quantum dot light-emitting devices (QLEDs), originally developed for displays, were recently demonstrated to be promising light sources for various photomedical applications, including photodynamic therapy cancer cell treatment and photobimodulation cell metabolism enhancement. With exceptional emission wavelength tunability and potential flexibility, QLEDs could enable wearable, targeted photomedicine with maximized absorption of different medical photosensitizers. In this paper, we report, for the first time, the in vitro study to demonstrate that QLEDs-based photodynamic therapy can effectively kill Methicillin-resistant Staphylococcus aureus, an antibiotic-resistant bacterium. We then present successful synthesis of highly efficient quantum dots with narrow spectra and specific peak wavelengths to match the absorption peaks of different photosensitizers for targeted photomedicine. Flexible QLEDs with a peak external quantum efficiency of 8.2% and a luminance of over 20,000 cd/m2 at a low driving voltage of 6 V were achieved. The tunable, flexible QLEDs could be employed for oral cancer treatment or diabetic wound repairs in the near future. These results represent one fresh stride toward realizing QLEDs' long-term goal to enable the wide clinical adoption of photomedicine.

Hydrotreatment of bio-oil distillates produced from pyrolysis and hydrothermal liquefaction of duckweed: A comparison study.

A comprehensive comparison of hydrothermal liquefaction (HTL) to the pyrolysis of duckweed was conducted to determine the yields and components of the crude bio-oils and their distillates. The upgrading behaviors of the distillates were thoroughly investigated with the use of used engine oil as a solvent. With all other variables fixed, HTL produced crude bio-oil with a lower H/C ratio (1.28 ±â€¯0.03) than pyrolysis did (1.45 ±â€¯0.04). However, its distillates had a higher H/C ratio (1.60 ±â€¯0.05) and total yield (66.1 ±â€¯2.0 wt%) than pyrolysis (1.46 ±â€¯0.04 and 47.2 ±â€¯1.4 wt%, respectively). Phenolics and nitrogenous heterocycles constituted relatively major proportions of the two crude bio-oils and most of their distillates. Obvious differences in molecular composition between the two crude bio-oils and their distillates were ascribed to the distinct impacts of HTL and pyrolysis and were affected by the distillate temperature. Co-hydrotreating with used engine oil (UEO) provided the upgraded bio-oils much higher H/C ratios (~1.78 ±â€¯0.05) and higher heating values (~45.5 ±â€¯1.4 MJ·kg-1), as well as much lower contents of N, O and S compared to their initial distillates. Aromatics and alkanes constituted a large proportion in most of upgraded bio-oils. N removal from the pyrolysis distillates was easier than from the HTL distillates. Distinct differences in yields and molecular compositions for the upgraded bio-oils were also attributed to the different influences associated with the two conversion routes.

Hydrogen sulfide promotes angiogenesis by downregulating miR-640 via the VEGFR2/mTOR pathway.

We previously found hydrogen sulfide (H2S) to be a new proangiogenic factor. However, the mechanisms underlying the cardiovascular effect of this small gas molecule remain largely unknown. The aim of the present study was to identify the essential microRNAs (miRNAs) involved in the transduction of H2S signals in vascular endothelial cells (ECs). The expression of miR-640 and its signaling elements, vascular endothelial growth factor receptor 2 (VEGFR2), hypoxia inducible factor 1-α (HIF1A), and mammalian target of rapamycin (mTOR), was measured using quantitative PCR and Western blotting. Overexpression and inhibition of miR-640 were performed to clarify their roles in mediating the effect of H2S. In addition, knockdown of VEGFR2, HIF1A, and mTOR was performed using siRNAs, dominant negative mutants, or inhibitors to examine their roles in the transduction of the H2S signals. miR-640 levels decreased in vascular ECs that were treated with H2S, whereas overexpression of miR-640 blunted the proangiogenic effect of H2S. Knockdown of either VEGFR2 or mTOR blunted the downregulation of miR-640 and the proangiogenic effect induced by H2S. In addition, miR-640 bound to the 3'-UTR of HIF1A mRNA and then inhibited the expression of HIF1A. The inhibition could be recovered by treating cells with H2S. Thus we concluded that miR-640 plays a pivotal role in mediating the proangiogenic effect of H2S; H2S acts through downregulation of the expression of miR-640 and increasing the levels of HIF1A through the VEGFR2-mTOR pathway.

VEGFR2 functions as an H2S-targeting receptor protein kinase with its novel Cys1045-Cys1024 disulfide bond serving as a specific molecular switch for hydrogen sulfide actions in vascular endothelial cells.

AIMS: The potential receptor for hydrogen sulfide (H2S) remains unknown. RESULTS: H2S could directly activate vascular endothelial growth factor receptor 2 (VEGFR2) and that a small interfering RNA (siRNA)-mediated knockdown of VEGFR2 inhibited H2S-induced migration of human vascular endothelial cells. H2S promoted angiogenesis in Matrigel plug assay in mice and this effect was attenuated by a VEGF receptor inhibitor. Using tandem mass spectrometry (MS), we identified a new disulfide complex located between Cys1045 and Cys1024 within VEGFR2 that was labile to H2S-mediated modification. Kinase activity of the mutant VEGFR2 (C1045A) devoid of the Cys1045-Cys1024 disulfide bond was significantly higher than wild-type VEGFR2. Transfection with vectors expressing VEGFR2 (C1045A) caused a significant increase in cell migration, while the migration-promoting effect of H2S disappeared in the cells transfected with VEGFR2 (C1045A). Therefore, the Cys1045-Cys1024 disulfide bond serves as an intrinsic inhibitory motif and functions as a molecular switch for H2S. The formation of the Cys1045-Cys1024 disulfide bond disrupted the integrity of the active conformation of VEGFR2. Breaking the Cys1045-Cys1024 disulfide bond recovered the active conformation of VEGFR2. This motif was prone to a nucleophilic attack by H2S via an interaction of their frontier molecular orbitals. siRNA-mediated knockdown of cystathionine γ-lyase attenuated migration of vascular endothelial cells induced by VEGF or moderate hypoxia. INNOVATION AND CONCLUSION: The study provides the first piece of evidence of a molecular switch in H2S-targeting receptor protein kinase in H2S-induced angiogenesis and that may be applicable to additional kinases containing functionally important disulfide bonds in mediating various H2S actions.