Melt-quenched glass formation of a family of metal-carboxylate frameworks.

Metal-organic framework (MOF) glasses are an emerging class of glasses which complement traditional inorganic, organic and metallic counterparts due to their hybrid nature. Although a few zeolitic imidazolate frameworks have been made into glasses, how to melt and quench the largest subclass of MOFs, metal carboxylate frameworks, into glasses remains challenging. Here, we develop a strategy by grafting the zwitterions on the carboxylate ligands and incorporating organic acids in the framework channels to enable the glass formation. The charge delocalization of zwitterion-acid subsystem and the densely filled channels facilitate the coordination bonding mismatch and thus reduce the melting temperature. Following melt-quenching realizes the glass formation of a family of carboxylate MOFs (UiO-67, UiO-68 and DUT-5), which are usually believed to be un-meltable. Our work opens up an avenue for melt-quenching porous molecular solids into glasses.

Hydrogen sulfide functions as a micro-modulator bound at the copper active site of Cu/Zn-SOD to regulate the catalytic activity of the enzyme.

The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas molecule, hydrogen sulfide (H2S), was found to bind at active-site copper of Cu/Zn-SOD using a series of methods including radiolabeled binding assay, X-ray absorption near-edge structure (XANES), and crystallography. Such an H2S binding enhanced the electrostatic forces to guide the negatively charged substrate superoxide radicals to the catalytic copper ion, changed the geometry and energy of the frontier molecular orbitals of the active site, and subsequently facilitated the transfer of an electron from the superoxide radical to the catalytic copper ion and the breakage of the copper-His61 bridge. The physiological relevance of such an H2S effect was also examined in both in vitro and in vivo models where the cardioprotective effects of H2S were dependent on Cu/Zn-SOD.

Modulating Liquid-Liquid Transitions and Glass Formation in Zeolitic Imidazolate Frameworks by Decoration with Electron-Withdrawing Cyano Groups.

The liquid phase of metal-organic frameworks (MOFs) is key for the preparation of melt-quenched bulk glasses as well as the shaping of these materials for various applications; however, only very few MOFs can be melted and transformed into stable glasses. Here, the solvothermal and mechanochemical preparation of a new series of functionalized derivatives of ZIF-4 (Zn(im)2, where im- = imidazolate and ZIF = zeolitic imidazolate framework) containing the cyano-functionalized imidazolate linkers CNim- (4-cynanoimidazolate) and dCNim- (4,5-dicyanoimidazolate) is reported. The strongly electron-withdrawing nature of the CN groups facilitates low-temperature melting of the materials (below 310 °C for some derivatives) and the formation of microporous ZIF glasses with remarkably low glass-transition temperatures (down to only about 250 °C) and strong resistance against recrystallization. Besides conventional ZIF-4, the CN-functionalized ZIFs are so far the only MOFs to show an exothermic framework collapse to a low-density liquid phase and a subsequent transition to a high-density liquid phase. By systematic adjustment of the fraction of cyano-functionalized linkers in the ZIFs, we derive fundamental insights into the thermodynamics of the unique polyamorphic nature of these glass formers as well as further design rules for the porosity of the ZIF glasses and the viscosity of their corresponding liquids. The results provide new insights into the unusual phenomenon of liquid-liquid transitions as well as a guide for the chemical diversification of meltable MOFs, likely with implications beyond the archetypal ZIF glass formers.

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.

Histone deacetylase 6 promotes skin wound healing by regulating fibroblast migration and differentiation in aged mice.

Skin wound healing tends to slow down with aging, which is detrimental to both minor wound recovery in daily life and the recovery after surgery. The aim of current study was to explore the effect of histone deacetylase 6 (HDAC6) on wound healing during aging. Cultured human dermal fibroblasts (HDFs) and mouse full-thickness skin wound model were used to explore the functional changes of replicative senescent dermal fibroblasts and the effect of aging on skin wound healing. Scratch wound healing assay revealed significantly decreased migration speed of senescent HDFs, and BrdU incorporation assay indicated their considerably retardant proliferation. The protein expression levels of collagen and HDAC6 were significantly decreased in both senescent HDFs and skin tissues from aged mice. HDAC6 activity inhibition with highly selective inhibitor tubastatin A (TsA) or HDAC6 knockdown with siRNA decreased the migration speed of HDFs and considerably suppressed fibroblast differentiation induced by transforming growth factor-ß1 (TGF-ß1), which suggests the involvement of HDAC6 in regulating fundamental physiological activities of dermal fibroblasts. In vivo full-thickness skin wound healing was significantly delayed in young HDAC6 knockout mice when compared with young wild type mice. In addition, the wound healing was significantly slower in aged wild type mice than that in young wild type mice, and became even worse in aged HDAC6 knockout aged mice. Compared to the aged wild type mice, aged HDAC6 knockout mice exhibited delayed angiogenesis, reduced collagen synthesis, and decreased collagen deposition in skin wounds. Together, these results suggest that delayed skin wound healing in aged mice is associated with impaired fibroblast function. Adequate expression and activity of HDAC6 are required for fibroblasts migration and differentiation.

MOF-Directed Synthesis of Crystalline Ionic Liquids with Enhanced Proton Conduction.

Arranging ionic liquids (ILs) with long-range order can not only enhance their performance in a desired application, but can also help elucidate the vital between structure and properties. However, this is still a challenge and no example has been reported to date. Herein, we report a feasible strategy to achieve a crystalline IL via coordination self-assembly based reticular chemistry. IL1 MOF, was prepared by designing an IL bridging ligand and then connecting them with metal clusters. IL1 MOF has a unique structure, where the IL ligands are arranged on a long-range ordered framework but have a labile ionic center. This structure enables IL1 MOF to break through the typical limitation where the solid ILs have lower proton conductivity than their counterpart bulk ILs. IL1 MOF shows 2-4 orders of magnitude higher proton conductivity than its counterpart IL monomer across a wide temperature range. Moreover, by confining the IL within ultramicropores (<1 nm), IL1 MOF suppresses the liquid-solid phase transition temperatures to lower than -150 °C, allowing it to function with high conductivity in a subzero temperature range.

Hydrogen sulfide rescues high glucose-induced migration dysfunction in HUVECs by upregulating miR-126-3p.

Diabetes (especially Type II) is one of the primary threats to cardiovascular health. Wound healing defects and vascular dysfunction are common in diabetic patients, and the primary cause of deterioration is sustained high plasma glucose. microRNA, a noncoding RNA, has regulatory functions that are critical to maintaining homeostasis. MicroRNA (miR)-126-3p is a potential diabetes biomarker and a proangiogenic factor, and its plasma level decreases in diabetic patients. Previous studies have revealed the proangiogenic character of the gasotransmitter hydrogen sulfide (H2S). However, little is known about the relationship between H2S and miR-126-3p when the extracellular glucose level is high, let alone their influences on deteriorated endothelial cell migration, a key component of angiogenesis, which is crucial for wound healing. Human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33.3 mmol/L) or normal glucose (5.5 mmol/L) for 48 h. Affymetrix miRNA profiling and real-time PCR were used to validate the miRNA expression. An H2S probe (HSip-1) was used to detect endogenous H2S. Scratch wound-healing assays were used to evaluate HUVEC migration. The protein levels were quantified by Western blot. Both exogenous and endogenous H2S could upregulate the miR-126-3p levels in HUVECs or muscle tissue. High glucose decreased the H2S level and the protein expression of the H2S-producing enzyme cystathionine γ-lyase (CSE) in HUVECs; however, the DNA methyltransferase 1 (DNMT1) protein level was upregulated. CSE overexpression not only increased the miR-126-3p level by decreasing the DNMT1 protein level but also rescued the deteriorated cell migration in HUVECs treated with high glucose. DNMT1 overexpression decreased the miR-126-3p level and inhibited the migration of HUVECs, whereas silencing DNMT1 improved cell migration. High glucose decreased the endogenous H2S and miR-126-3p levels and increased the DNMT1 expression, thus inducing the migration dysfunction of HUVECs. Treatment with exogenous H2S or the overexpression of the endogenously produced enzyme CSE would rescue this migration dysfunction through H2S-DNMT1-miR-126-3p.

H2S regulates endothelial nitric oxide synthase protein stability by promoting microRNA-455-3p expression.

The aims of the present study are to determine whether hydrogen sulfide (H2S) is involved in the expression of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production, and to identify the role of microRNA-455-3p (miR-455-3p) during those processes. In cultured human umbilical vein endothelial cells (HUVECs), the expression of miR-455-3p, eNOS protein and the NO production was detected after administration with 50 µM NaHS. The results indicated that H2S could augment the expression of miR-455-3p and eNOS protein, leading to the increase of NO level. We also found that overexpression of miR-455-3p in HUVECs increased the protein levels of eNOS whereas inhibition of miR-455-3p decreased it. Moreover, H2S and miR-455-3p could no longer increase the protein level of eNOS in the presence of proteasome inhibitor, MG-132. In vivo, miR-455-3p and eNOS expression were considerably increased in C57BL/6 mouse aorta, muscle and heart after administration with 50 µmol/kg/day NaHS for 7 days. We also identified that H2S levels and miR-455-3p expression increased in human atherosclerosis plaque while H2S levels decreased in plasma of atherosclerosis patients. Our data suggest that the stability of eNOS protein and the NO production could be regulated by H2S through miR-455-3p.

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.