N6-methyladenosine demethylase ALKBH5 homologous protein protects against cerebral I/R injury though suppressing SNHG3-mediated neural PANoptosis: Involvement of m6A-related macromolecules in the diseases of nervous system.

In order to address this gap in knowledge, the present study utilized both in vivo and in vitro models to investigate the role of the m6A demethylase ALKBH5 in protecting against cerebral I/R injury by inhibiting PANoptosis (Pytoptosis, Ppoptosis, and Necroptosis) in an m6A-dependent manner. They observed that ALKBH5, the predominant m6A demethylase, was downregulated in these models, while SNHG3 and PANoptosis-related proteins (ZBP1, AIM2, Cappase-3, Caspase-8, cleaved Caspase-1, GSDMD-N, and p-MLKL) were elevated. Additionally, both ALKBH5 overexpression and SNHG3-deficiency were found to ameliorate PANoptosis and injury induced by OGD/reperfusion and OGD/RX in both mice tissues and astrocyte cells. Further experiments demonstrated that ALKBH5 induced m6A-demethylation in SNHG3, leading to its degradation. Low expression of SNHG3, on the other hand, prevented the formation of the SNHG3-ELAVL1-ZBP1/AIM2 complex, which in turn destabilized ZBP1 and AIM2 mRNA, resulting in the downregulation of these PANoptosis-related genes. Ultimately, the rescue experiments provided evidence that ALKBH5 protected against PANoptosis in cerebral I/R injury models through the inhibition of SNHG3.This study sheds light on the intricate molecular mechanisms involved in the pathogenesis of cerebral I/R injury and highlights the potential of m6A-related genes as therapeutic targets in this condition.

Optimal Oxophilicity at the Fe-Nx Interface Enhances the Generation of Singlet Oxygen for Efficient Fenton-Like Catalysis.

In the pursuit of efficient singlet oxygen generation in Fenton-like catalysis, the utilization of single-atom catalysts (SACs) emerges as a highly desired strategy. Here, a discovery is reported that the single-atom Fe coordinated with five N-atoms on N-doped porous carbon, denoted as Fe-N5/NC, outperform its counterparts, those coordinated with four (Fe-N4/NC) or six N-atoms (Fe-N6/NC), as well as state-of-the-art SACs comprising other transition metals. Thus, Fe-N5/NC exhibits exceptional efficacy in activating peroxymonosulfate for the degradation of organic pollutants. The coordination number of N-atoms can be readily adjusted by pyrolysis of pre-assembly structures consisting of Fe3+ and various isomers of phenylenediamine. Fe-N5/NC displayed outstanding tolerance to environmental disturbances and minimal iron leaching when incorporated into a membrane reactor. A mechanistic study reveals that the axial ligand N reduces the contribution of Fe-3d orbitals in LUMO and increases the LUMO energy of Fe-N5/NC. This, in turn, reduces the oxophilicity of the Fe center, promoting the reactivity of *OO intermediate-a pivotal step for yielding singlet oxygen and the rate-determining step. These findings unveil the significance of manipulating the oxophilicity of metal atoms in single-atom catalysis and highlight the potential to augment Fenton-like catalysis performance using Fe-SACs.

METTL3-deficiency Suppresses Neural Apoptosis to Induce Protective Effects in Cerebral I/R Injury via Inhibiting RNA m6A Modifications: A Pre-clinical and Pilot Study.

N6-Methyladenosine (m6A) RNA methylation involves in regulating the initiation, progression and aggravation of cerebral ischemia-reperfusion (I/R) injury, however, the detailed functions and mechanisms by which m6A drives cerebral I/R injury are not fully understood. This study found that methyltransferase-like 3 (METTL3) m6A-dependently regulated cerebral I/R injury trough regulating a novel LncRNA ABHD11-AS1/miR-1301-3p/HIF1AN/HIF-1α axis. Specifically, the middle cerebral artery occlusion (MCAO)/reperfusion mice models and glucose deprivation (OGD)/reoxygenation (RX) astrocyte cell models were respectively established, and we verified that METTL3, ABHD11-AS1 and HIF1AN were upregulated, whereas miR-1301-3p and HIF-1α were downregulated in both MCAO/reperfusion mice tissues and OGD/RX astrocytes. Mechanical experiments confirmed that METTL3 m6A dependently increased stability and expression levels of ABHD11-AS1, and elevated ABHD11-AS1 sponged miR-1301-3p to upregulate HIF1AN, resulting in the downregulation of HIF-1α. Moreover, silencing of METTL3 rescued MCAO/reperfusion and OGD/RX-induced oxidative stress-associated cell apoptosis and cell cycle arrest in both mice brain tissues in vivo and the mouse primary astrocytes in vitro, which were abrogated by overexpressing ABHD11-AS1 and downregulating miR-1301-3p. Taken together, our study firstly reported a novel METTL3/m6A/ ABHD11-AS1/miR-1301-3p/HIF1AN/HIF-1α signaling cascade in regulating the progression of cerebral I/R injury, and future work will focus on investigating whether the above genes can be used as biomarkers for the treatment of cerebral I/R injury by performing clinical studies.

Accumulation of Ag(0) Single Atoms at Water/Mineral Interfaces during Sunlight-Induced Reduction of Ionic Ag by Phenolic DOM.

Silver (Ag) undergoes a complex and dynamic Ag+/Ag0 cycle under environmental conditions. The Ag+ → Ag nanoparticles (AgNPs) transformation due to the combined actions of sunlight, O2, and dissolved organic matter has been a well-known environmental phenomenon. In this study, we indicate that this process may be accompanied by a pronounced accumulation of Ag(0) single atoms (Ag-SAs) on the minerals' surfaces. According to spherical aberration-corrected scanning transmission electron microscopy and high-energy-resolution X-ray adsorption fine structure analyses, humic acid (HA) and phenol (PhOH) can induce Ag-SAs accumulation, whereas oxalic acid causes only AgNPs deposition. Ag-SAs account for more than 20 wt % of total Ag(0) on the γ-Al2O3 surfaces during HA- and PhOH-mediated photolysis processes. HA also causes Ag-SAs to accumulate on two other prevalent soil minerals, SiO2 and Fe2O3, and the fractions of Ag-SAs are about 15 wt %. Our mechanism studies suggest that a phenolic molecule acts as a reducing agent of Ag+ and a stabilizer of Ag-SAs, protecting Ag-SAs against autocatalytic nucleation.

Abrading-Induced Breakdown of Ag Nanoparticles into Atomically Dispersed Ag for Enhancing Antimicrobial Performance.

Silver is among the most essential antimicrobial agents. Increasing the efficacy of silver-based antimicrobial materials will reduce operating costs. Herein, we show that mechanical abrading causes atomization of Ag nanoparticles (AgNPs) into atomically dispersed Ag (AgSAs) on the surfaces of an oxide-mineral support, which eventually boosts the antibacterial efficacy considerably. This approach is straightforward, scalable, and applicable to a wide range of oxide-mineral supports; additionally, it does not require any chemical additives and operates under ambient conditions. The obtained AgSAs-loaded γ-Al2O3 inactivated Escherichia coli (E. coli) five times as fast as the original AgNPs-loaded γ-Al2O3. It can be utilized over 10 runs with minimal efficiency loss. The structural characterizations indicate that AgSAs exhibit a nominal charge of 0 and are anchored at the doubly bridging OH on the γ-Al2O3 surfaces. Mechanism studies demonstrate that AgSAs, like AgNPs, damage bacterial cell wall integrity, but they release Ag+ and superoxide substantially faster. This work not only provides a simple method for manufacturing AgSAs-based materials but also shows that AgSAs have better antibacterial properties than the AgNPs counterpart.

Chaihu-Shugan-San inhibits neuroinflammation in the treatment of post-stroke depression through the JAK/STAT3-GSK3ß/PTEN/Akt pathway.

Post-stroke depression (PSD) is one of the most common neuropsychiatric consequence of stroke, affecting cognitive function, recovery of somatic function, and patient survival. The aim of this study was to evaluate whether Chaihu-Shugan-San, a traditional Chinese medicine formula used clinically to treat depression, could improve symptoms in a rat model for PSD, to investigate the potential mechanisms, and to validate the findings in an in vitro oxygen and glucose deprivation (OGD) model. Male rats were subjected to middle cerebral artery occlusion (MCAO) and to chronic unpredictable mild stress (CUMS). The rats were then allocated to experimental groups (n = 15) that were treated with Chaihu-Shugan-San, a JAK-STAT3 inhibitor, a GSK3ß overexpressing virus, or an empty virus (control). The subjects allocated to each group, as well as those that received no treatment and rats that did not undergo MCAO/CUMS, were then subjected to forced swimming, tail suspension, and sugar water preference tests, and their neurological deficit score was determined. Inflammatory factor levels and the expression of proteins related to the JAK/STAT3-GSK3ß/PTEN/Akt pathway were measured, and the synaptic ultrastructure was observed using transmission electron microscopy. Flow cytometry showed microglia polarization towards the M1 phenotype in an in vitro PSD model, which was reversed after treatment with a GSK3ß overexpression virus, Chaihu-Shugan-San, or a JAK-STAT3 inhibitor. The results showed that Chaihu-Shugan-San has a therapeutic effect on an in vivo model for PSD and can regulate microglia polarization through the activation of the JAK/STAT3-GSK3ß/PTEN/Akt pathway, suggesting that it exerts its effect via the inhibition of neuroinflammation.

Selective Hydrogenation of Furfural over the Co-Based Catalyst: A Subtle Synergy with Ni and Zn Dopants.

A multimetal doping strategy has aroused extensive attention in promoting a non-noble catalyst for selective hydrogenation reaction. Herein, a multimetallic catalyst (NiCoZn@CN) with excellent catalytic performance for hydrogenation of furfural (FAL) to furfuryl alcohol (FOL) is prepared through a facile, inexpensive, and efficient pyrolysis method. Using H2 as a H donor, extremely high selectivity (>99%) with 100% conversion is attained over the optimal NiCoZn@CN-600 catalyst. The subtle synergy between Co and Ni, Zn dopants, which remarkably promotes the performance of the Co-based catalyst, is revealed. In the NiCoZn@CN system, Co0 is proven to be the main active site, whose content is greatly improved by Ni and Co dopants. Additionally, the Ni dopant could also benefit activation of H2 and the Zn dopant could enhance metal nanoparticle dispersion and the porous structure of the catalyst. In situ FTIR indicates that the vertical adsorption mode of FAL with the Oaldehyde terminal on NiCoZn@CN-600 ensures a selective hydrogenation process. With a N-doped carbon matrix, NiCoZn@CN-600 shows good cycling stability in five times run. NiCoZn@CN-600 is also competent in the catalytic transfer hydrogenation (CTH) of FOL, affording >99% yield with 2-propanol as a H donor. This study opens an avenue toward rational design of multimetallic doping catalysts with high selectivity for challenging reactions in the conversion of biomass-derived compounds.

Nosiheptide analogues as potential antibacterial agents via dehydroalanine region modifications: Semi-synthesis, antimicrobial activity and molecular docking study.

The frequent and inappropriate use of antibiotics aggravate the variation and evolution of multidrug-resistant bacteria, posing a serious threat to public health. Nosiheptide (NOS) has excellent lethality against a variety of Gram-positive bacteria, however the physical and chemical drawbacks hamper its routine application in clinical practice. In this study, by using NOS as the starting material, a total of 15 NOS analogues (2a-4e) were semi-synthesized via its dehydroalanine residue reacting with monosubstituted anilines. In vitro antimicrobial susceptibilities of NOS and its analogues against two methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) clinical isolates were determined by broth microdilution assay to determine the minimum inhibitory concentration (MIC). Antimicrobial susceptibility testing data shown that most of the NOS analogues had a better antibacterial effect than the parent compound, with compound 3c exhibiting the highest antibacterial activity against VRE (MIC = 0.0078 mg/L) and MRSA (MIC < 0.0039 mg/L). Molecular docking of synthetic compounds was also performed to verify the binding interactions of NOS analogues with the target. Our data indicated that compound 3c possesses stronger and more complex intermolecular force than other analogues, which is consistent with the results of the biological activity evaluation. Overall, this study identified a number of potential antibacterial NOS analogues that could act as potent therapeutic agents for multidrug-resistant bacterial infections.

Tuning the synthesis of polymetallic-doped ZIF derived materials for efficient hydrogenation of furfural to furfuryl alcohol.

Cu, Co and Zn modified N-doped porous carbons (CuCo/Zn@NPC) are prepared using a polymetallic homogeneous doping and self-templating method as high performance non-noble metal catalysts for the hydrogenation of furfural (FF) to furfuryl alcohol (FAL). The CuCo/Zn@NPC-600 catalyst after treatment at 600 °C shows a superior catalytic activity with nearly 100% conversion of FF and an almost 100% selectivity of FAL using H2 at 140 °C. Meanwhile in the catalytic transfer hydrogenation (CTH) using 2-propanol as a H-donor, the conversion of FF reaches 95.8% and the selectivity of FAL is 99.1%. The results show that the Zn dopant leads to 37.3 times higher yield on the CuCo/Zn@NPC-600 catalyst than that on CuCo@NPC-600, and 2.3 times higher than that on Co/Zn@NPC-600 with Cu dopants. The efficient activity of the CuCo/Zn@NPC-600 catalyst is mainly due to the highly dispersed metal nanoparticles, the advanced porous structure resulting from Zn escape from the precursor template, and the synergistic effect between Cu and Co. Furthermore, the CuCo/Zn@NPC-600 catalyst exhibits good recyclability in FF hydrogenation in four cycle tests. The advanced synthesis method using a homogeneous doping and self-templating strategy sheds light on preparing effective catalysts for hydrogenation of biomass-based compounds.

Mutational biosynthesis to generate novel analogs of nosiheptide featuring a fluorinated indolic acid moiety.

Nosiheptide (NOS) is a member of bicyclic thiopeptides possessing a biologically important indolic acid (IA) moiety appended onto the family-characteristic core system. The IA formation relies primarily on NosL, a radical S-adenosylmethionine (SAM) protein that catalyzes a complex rearrangement of the carbon side chain of l-tryptophan, leading to the generation of 3-methyl-2-indolic acid (MIA). Here, we establish an efficient mutational biosynthesis strategy for the structural expansion of the side-ring system of NOS. The nosL-deficient mutant Streptomyces actuosus SL4005 complemented by chemically feeding 6-fluoro-MIA is capable of accumulating two new products. The target product 6'-fluoro-NOS contains an additional fluorine atom at C6 of the IA moiety, in contrast with an unexpected product 6'-fluoro-NOSint that features an open side ring and a bis-dehydroalanine (Dha) tail. The newly obtained 6'-fluoro-NOS displayed equivalent or slightly reduced activities against the tested drug-resistant pathogens compared with NOS, but dramatically decreased water solubility compared with NOS. Our results indicate that the modification of the IA moiety of NOS not only affects its biological activity but also affects its activity which will be key considerations for further modification.

Atypical antipsychotics for Parkinson's disease psychosis: a systematic review and meta-analysis.

PURPOSE: To assess the present evidence regarding the efficiency, safety, and potential risks of pharmacotherapy used for Parkinson's disease psychosis (PDPsy) treatment. PATIENTS AND METHODS: We searched the following databases: PubMed, the Cochrane Library, ISI Web of Science, and Embase using the following terms: atypical antipsychotics, pimavanserin, olanzapine, quetiapine, clozapine, Parkinson's disease and psychosis. We systematically reviewed all randomized placebo-controlled trials comparing an atypical antipsychotic with a placebo. RESULTS: A total of 13 randomized placebo-controlled trials for a total 1142 cases were identified involving pimavanserin (n=4), clozapine (n=2), olanzapine (n=3), and quetiapine (n=4). For each atypical antipsychotic, a descriptive synthesis and meta-analyses was presented. Pimavanserin was associated with a significant improvement in psychotic symptoms compared to a placebo without worsening motor function. Clozapine was efficacious in alleviating psychotic symptoms and did not exacerbate motor function either. Quetiapine and Olanzapine did not demonstrate significant differences in reducing psychotic symptoms but may aggravate motor function. CONCLUSIONS: There is strong evidence that pimavanserin is effective for the treatment of PDPsy. Clozapine is also recommended but should be used with caution due to its side effects. In the future, more well-designed randomized controlled trials (RCTs) are needed to confirm and update the findings reported in this meta-analysis.

Co-expression of SpSOS1 and SpAHA1 in transgenic Arabidopsis plants improves salinity tolerance.

BACKGROUND: Na+ extrusion from cells is important for plant growth in high saline environments. SOS1 (salt overly sensitive 1), an Na+/H+ antiporter located in the plasma membrane (PM), functions in toxic Na+ extrusion from cells using energy from an electrochemical proton gradient produced by a PM-localized H+-ATPase (AHA). Therefore, SOS1 and AHA are involved in plant adaption to salt stress. RESULTS: In this study, the genes encoding SOS1 and AHA from the halophyte Sesuvium portulacastrum (SpSOS1 and SpAHA1, respectively) were introduced together or singly into Arabidopsis plants. The results indicated that either SpSOS1 or SpAHA1 conferred salt tolerance to transgenic plants and, as expected, Arabidopsis plants expressing both SpSOS1 and SpAHA1 grew better under salt stress than plants expressing only SpSOS1 or SpAHA1. In response to NaCl treatment, Na+ and H+ in the roots of plants transformed with SpSOS1 or SpAHA1 effluxed faster than wild-type (WT) plant roots. Furthermore, roots co-expressing SpSOS1 and SpAHA1 had higher Na+ and H+ efflux rates than single SpSOS1/SpAHA1-expressing transgenic plants, resulting in the former amassing less Na+ than the latter. As seen from comparative analyses of plants exposed to salinity stress, the malondialdehyde (MDA) content was lowest in the co-transgenic SpSOS1 and SpAHA1 plants, but the K+ level was the highest. CONCLUSION: These results suggest SpSOS1 and SpAHA1 coordinate to alleviate salt toxicity by increasing the efficiency of Na+ extrusion to maintain K+ homeostasis and protect the PM from oxidative damage induced by salt stress.

The Ag-promoted α-C-H arylation of alcohols.

We herein report the functionalization of α-C-H in alcohols through cross-dehydrogenative coupling reactions. Selectfluor was used as a mild oxidant. In situ-generated HF participated in the reaction and no external strong acid was necessary. A variety of heteroaryl-substituted alcohols were achieved with good yields and with good functional group tolerance.

Over-expression of a plasma membrane H+-ATPase SpAHA1 conferred salt tolerance to transgenic Arabidopsis.

The SpAHA1 gene, encoding a plasma membrane (PM) H+-ATPase (AHA) in Sesuvium portulacastrum, was transformed into Arabidopsis plants, and its expression increased salinity tolerance of transgenic Arabidopsis plants: seed germination ratio, root growth, and biomass of transgenic plants were greater compared to wild-type plants under NaCl treatment condition. Upon salinity stress, both Na+ and H+ effluxes in the roots of SpAHA1 expressing plants were faster than those of untransformed plants. Transformed plants with SpAHA1 had lower Na+ and higher K+ contents relative to wild-type plants when treated with NaCl, resulting in greater K+/Na+ ratio in transgenic plants than in wild-type plants under salt stress. Extent of oxidative stress increased in both transgenic and wild-type plants exposed to salinity stress, but overexpression of SpAHA1 could alleviate the accumulation of hydrogen peroxide (H2O2) induced by NaCl treatment in transgenic plants relative to wild-type plants; the content of malondialdehyde (MDA) was lower in transgenic plants than that in wild-type plants under salinity stress. These results suggest that the higher H+-pumping activity generated by SpAHA1 improved the growth of transgenic plants via regulating ion and reactive oxygen species (ROS) homeostasis in plant cells under salinity stress.

Sea-Sponge-like Structure of Nano-Fe3O4 on Skeleton-C with Long Cycle Life under High Rate for Li-Ion Batteries.

To meet the demands of long cycle life under high rate for lithium-ion batteries, the advancement of anode materials with stable structural properties is necessarily demanded. Such promotion needs to design reasonable structure to facilitate the transportation of electron and lithium ions (Li+). Herein, a novel C/Fe3O4 sea-sponge-like structure was synthesized by ultrasonic spray pyrolysis following thermal decomposition process. On the basis of sea-sponge carbon (SSC) excellences in electronic conductivity and short Li+ diffusion pathway, nano-Fe3O4 anchored on stable SSC skeleton can deliver high electrochemical performance with long cycle life under high rate. During electrochemical cycling, well-dispersed nano-Fe3O4 in ∼6 nm not only averts excessive pulverization and is enveloped by solid electrolyte interphase film, but also increases Li+ diffusion efficiency. The much improved electrochemical properties showed a capacity of around 460 mAh g-1 at a high rate of 1.5C with a retention rate of 93%, which is maintained without degradation up to 1000 cycles (1C = 1000 mA g-1).

A meta-analysis of effects of selective serotonin reuptake inhibitors on blood pressure in depression treatment: outcomes from placebo and serotonin and noradrenaline reuptake inhibitor controlled trials.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) have been commonly prescribed for depression treatment. However, their effects on blood pressure are unclear. MATERIALS AND METHODS: Effects on blood pressure of depressive patients in two groups (SSRIs versus placebo and SSRIs versus SNRIs) were evaluated. A search was conducted for double-blind, randomized controlled trials (RCTs) in PubMed, EMBASE, ISI Web of Science, PsycNET, CCRCT, and DARE (up to March 2017). The outcomes were systolic blood pressure (SBP) changes and diastolic blood pressure (DBP) changes from baseline to endpoint or to a certain period of treatment duration. Weighted mean differences (WMDs) and 95% CIs were calculated and pooled using random effects models. The χ2 test and I2 statistics were used to assess heterogeneity. Funnel plots, Begg's test, and Egger's test were used to estimate publication bias. RESULTS: A total of 23 RCTs involving 13,285 participants were included. Patients on SSRIs showed no significant differences in blood pressure changes compared with placebo. In the group of SSRIs versus SNRIs, overall SBP changes and DBP changes revealed statistical significances (WMD 1.5 mmHg, 95% CI -2.15, -0.84, Z=4.46, P<0.00001 and WMD 1.34 mmHg, 95% CI -1.92, -0.75, Z=6.18, P<0.00001). Subgroup analyses on treatment duration and age further evidenced these findings. CONCLUSION: It was established that SSRIs did not affect blood pressure, while SNRIs led to a modest increase in SBP and DBP with statistical significance compared with SSRIs.