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Yi-Feng Wang, Jia-Wei Li, Da-Peng Wang, Ke Jin, Jiao-Jie Hui, Hong-Yang Xu Department of Critical Care Medicine, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, People’s Republic of ChinaCorrespondence: Jiao-Jie Hui; Hong-Yang Xu, Email huijiaojie15@163.com; xhy1912@aliyun.comAbstract: Intestinal barrier injury and hyperglycemia are common in patients with sepsis. Bacteria translocation and systemic inflammatory response caused by intestinal barrier injury play a significant role in sepsis occurrence and deterioration, while hyperglycemia is linked to adverse outcomes in sepsis. Previous studies have shown that hyperglycemia is an independent risk factor for intestinal barrier injury. Concurrently, increasing evidence has indicated that some anti-hyperglycemic agents not only improve intestinal barrier function but are also beneficial in managing sepsis-induced organ dysfunction. Therefore, we assume that these agents can block or reduce the severity of sepsis by improving intestinal barrier function. Accordingly, we explicated the connection between sepsis, intestinal barrier, and hyperglycemia, overviewed the evidence on improving intestinal barrier function and alleviating sepsis-induced organ dysfunction by anti-hyperglycemic agents (eg, metformin, peroxisome proliferators activated receptor-γ agonists, berberine, and curcumin), and summarized some common characteristics of these agents to provide a new perspective in the adjuvant treatment of sepsis.Keywords: sepsis, sepsis-induced organ dysfunction, intestinal barrier, anti-hyperglycemic agents

Da-Peng Wang,1 Kai-Yan Jin,1 Peng Zhao,2 Qi Lin,3 Kai Kang,4 Jian Hai1 1Department of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, Shanghai, 200065, People’s Republic of China; 2Institute for Translational Medicine, Institute for Biomedical Engineering and Nanoscience, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, People’s Republic of China; 3Department of Pharmacy, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 4Department of Research and Surveillance Evaluation, Shanghai Center for Health Promotion, Shanghai, 200040, People’s Republic of ChinaCorrespondence: Da-Peng Wang; Jian HaiDepartment of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, No. 389, Xincun Road, Putuo District, Shanghai, 200065, People’s Republic of ChinaFax +86-21-66111093Email wdpboj@126.com; haijiandoct@zoho.com.cnIntroduction: Brain ischemia is a common neurological disorder worldwide that activates a cascade of pathophysiological events involving decreases in oxygen and glucose levels. Despite substantial efforts to explore its pathogenesis, the management of ischemic neuronal injury remains an enormous challenge. Accumulating evidence suggests that VEGF modified nanofiber (NF) materials and the fatty-acid amide hydrolase (FAAH) inhibitor URB597 exert an influence on alleviating ischemic brain damage. We aimed to further investigate their effects on primary hippocampal neurons, as well as the underlying mechanisms following oxygen–glucose deprivation (OGD).Methods: Different layers of VEGF-A loaded polycaprolactone (PCL) nanofibrous membranes were first synthesized by using layer-by-layer (LBL) self-assembly of electrospinning methods. The physicochemical and biological properties of VEGF-A NF membranes, and their morphology, hydrophilicity, and controlled-release of VEGF-A were then estimated. Furthermore, the effects of VEGF-A NF and URB597 on OGD-induced mitochondrial oxidative stress, inflammatory responses, neuronal apoptosis, and endocannabinoid signaling components were assessed.Results: The VEGF-A NF membrane and URB597 can not only promote hippocampal neuron adhesion and viability following OGD but also exhibited antioxidant/anti-inflammatory and mitochondrial membrane potential protection. The VEGF-A NF membrane and URB597 also inhibited OGD-induced cellular apoptosis through activating CB1R signaling. These results indicate that VEGF-A could be controlled-released by LBL self-assembled NF membranes.Discussion: The VEGF-A NF membrane and URB597 displayed positive synergistic neuroprotective effects through the inhibition of mitochondrial oxidative stress and activation of CB1R/PI3K/AKT/BDNF signaling, suggesting that a VEGF-A loaded NF membrane and the FAAH inhibitor URB597 could be of therapeutic value in ischemic cerebrovascular diseases.Keywords: brain ischemia, cannabinoid receptor, fatty-acid amide hydrolase, mitochondrial oxidative stress, nanofiber, VEGF-A

Ya-Qin Liu1 *,* Si-Meng Xue1 *,* Peng Zhang1 *,* Lin-Na Xu,1 De-Ping Wang,2 Guang Li,1 Ji-Min Cao1,2 1Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, Luzhou, Sichuan 646000, People’s Republic of China; 2Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, People’s Republic of China*These authors contributed equally to this work.Correspondence: Guang LiKey Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, 319 Zhongshan Road Section 3, Jiangyang District, Luzhou 646000, Sichuan Province, People’s Republic of ChinaTel +86 830-3161222Fax +86 830 3161222Email liguang@swmu.edu.cnJi-Min CaoKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Department of Physiology, Shanxi Medical University, 56 Xin Jian Nan Lu Road, Taiyuan 030001, Shanxi Province, People’s Republic of ChinaTel +86 351 4235246Fax +86 351 4135117Email caojimin@126.comBackground: The toxicity of silica nanoparticles (SiNPs) on cardiac electrophysiology has seldom been evaluated.Methods: Patch-clamp was used to investigate the acute effects of SiNP-100 (100 nm) and SiNP-20 (20 nm) on the transmembrane potentials (TMPs) and ion channels in cultured neonatal mouse ventricular myocytes. Calcium mobilization in vitro, cardiomyocyte ROS generation, and LDH leakage after exposure to SiNPs in vitro and in vivo were measured using a microplate reader. Surface electrocardiograms were recorded in adult mice to evaluate the arrhythmogenic effects of SiNPs in vivo. SiNP endocytosis was observed using transmission electron microscopy.Results: Within 30 min, both SiNPs (10− 8– 10− 6 g/mL) did not affect the resting potential and IK1 channels. SiNP-100 increased the action potential amplitude (APA) and the INa current density, but SiNP-20 decreased APA and INa density. SiNP-100 prolonged the action potential duration (APD) and decreased the Ito current density, while SiNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased Ito density. Both SiNPs (10− 6 g/mL) induced calcium mobilization but did not increase ROS and LDH levels and were not endocytosed within 10 min in cardiomyocytes in vitro. In vivo, SiNP-100 (4– 10 mg/kg) and SiNP-20 (4– 30 mg/kg) did not elevate myocardial ROS but increased LDH levels depending on dose and exposure time. The same higher dose of SiNPs (intravenously injected) induced tachyarrhythmias and lethal bradyarrhythmias within 90 min in adult mice.Conclusion: SiNPs (i) exert rapid toxic effects on the TMPs of cardiomyocytes in vitro largely owing to their direct interfering effects on the INa and Ito channels and Ca2+ homeostasis but not IK1 channels and ROS levels, and (ii) induce tachyarrhythmias and lethal bradyarrhythmias in vivo. SiNP-100 is more toxic than SiNP-20 on cardiac electrophysiology, and the toxicity mechanism is likely more complicated in vivo.Keywords: silica nanoparticle, cardiac electrophysiology, transmembrane potential, ion channel, nanotoxicology

Benzo (k) fluoranthene (BkF) has adverse effects on male reproduction, but its specific mechanism of action is still unclear. This study focused on the role of RNA reading protein YTHDF2 and its mechanism in BkF induced male reproductive injury. Mouse GC-2 spermatocytes were exposed to 0, 40, 80, 160 μM BkF. It was found that BkF significantly increased the apoptosis of GC-2 cell and decreased its survival rate. BCL2 in spermatocytes decreased significantly, while the expression of P53 and BAX exhibited a notable increase. Interestingly, the expression of RNA reading protein YTHDF2 progressively rose in tandem with the escalating BkF exposure dosage. Overexpression of YTHDF2 significantly reduced the viability of cells and increased the apoptosis rate. Meanwhile, there was a substantial increase in the expression of P53 and BAX, BCL2 was significantly down-regulated. On the contrary, interfering with YTHDF2 increased cell proliferation and reduced cell apoptosis. Furthermore, YTHDF2 overexpression exacerbated the decrease in cell viability under BkF exposure, while YTHDF2 knockdown was the opposite. The results from the RIP assay demonstrated a significant enhancement in the interaction of YTHDF2 protein with BCL2 mRNA following the overexpression of YTHDF2. In addition, animal experiments showed that there was an increase in apoptosis and a decrease in proliferation of testicular cells in mice in the high-dose (30 mg/kg) BkF group by TUNEL staining and Ki67 staining. Immunohistochemical analysis showed that BCL2 levels were significantly lower in the high-dose group than in the control group, while YTHDF2, P53 and BAX were dramatically increased. In summary, our study suggests that YTHDF2 has been implicated in BkF-induced male reproductive injury by promoting the degradation of BCL2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Among many risk factors for preeclampsia (PE), prepregnancy body mass index (BMI) is one of few controllable factors. However, there is a lack of stratified analysis based on the prepregnancy BMI. This study aimed to determine the influencing factors for PE and assess the impact of PE on obstetric outcomes in twin pregnancies by prepregnancy BMI., Methods: This was a retrospective cohort study between January 1, 2017, and December 31, 2022, in Southwest China. Impact factors and associations between PE and obstetric outcomes were analyzed separately for twin pregnancies with prepregnancy BMI < 24kg/m 2 (non-overweight group) and BMI ≥ 24kg/m 2 (overweight group)., Results: In total, 3602 twin pregnancies were included, of which, 672 women were allocated into the overweight group and 11.8% of them reported with PE; 2930 women were allocated into the non-overweight group, with a PE incidence of 5.6%. PE had a negative effect on birthweight and increased the incidence of neonatal intensive care unit admission in both the overweight and non-overweight groups (43.0% vs. 28.0%, p  = .008 ; 45.7% vs. 29.1%, p  < .001). Among overweight women, PE increased the proportion of postpartum hemorrhage (15.2% vs. 4.4%, p  < .001). After adjustments, multivariate regression analysis showed that excessive gestational weight gain (aOR = 1.103, 95% CI: 1.056-1.152; aOR = 1.094, 95% CI: 1.064-1.126) and hypoproteinemia (aOR = 2.828, 95% CI: 1.501-5.330; aOR = 6.932, 95% CI: 4.819-9.971) were the shared risk factors for PE in both overweight and non-overweight groups. In overweight group, in vitro fertilization was the other risk factor (aOR = 2.713, 95% CI: 1.183-6.878), whereas dichorionic fertilization (aOR = 0.435, 95% CI: 0.193-0.976) and aspirin use during pregnancy (aOR = 0.456, 95% CI: 0.246-0.844) were protective factors. Additionally, anemia during pregnancy (aOR = 1.542, 95% CI: 1.090-2.180) and growth discordance in twins (aOR = 2.451, 95% CI: 1.215-4.205) were connected with an increased risk of PE only in non-overweight twin pregnancies., Conclusions: Both discrepancy and similarity of impact factors on developing PE were found between overweight and non-overweight twin pregnancies in this study. However, the dosage and initiation time of aspirin, as well as twin chorionicity on the occurrence of PE in two subgroups, are still debated.

Chronic cerebral ischemia is a complex form of stress, of which the most common hemodynamic characteristic is chronic cerebral hypoperfusion (CCH). Lasting endoplasmic reticulum (ER) stress can drive neurological disorders. Targeting ER stress shows potential neuroprotective effects against stroke. However, the role of ER stress in CCH pathological processes and the effects of targeting ER stress on brain ischemia are unclear. Here, a CCH rat model was established by bilateral common carotid artery occlusion. Rats were treated with 4-PBA, URB597, or both for 4 weeks. Neuronal morphological damage was detected using hematoxylin-eosin staining. The expression levels of the ER stress-ASK1 cascade-related proteins GRP78, IRE1α, TRAF2, CHOP, Caspase-12, ASK1, p-ASK1, JNK, and p-JNK were assessed by Western blot. The mRNA levels of TNF-α, IL-1β, and iNOS were assessed by RT-PCR. For oxygen-glucose deprivation experiments, mouse hippocampal HT22 neurons were used. Apoptosis of the hippocampus and HT22 cells was detected by TUNEL staining and Annexin V-FITC analysis, respectively. CCH evoked ER stress with increased expression of GRP78, IRE1α, TRAF2, CHOP, and Caspase-12. Co-immunoprecipitation experiments confirmed the interaction between TRAF2 and ASK1. ASK1/JNK signaling, inflammatory cytokines, and neuronal apoptosis were enhanced, accompanied by persistent ER stress; these were reversed by 4-PBA and URB597. Furthermore, the ASK1 inhibitor GS4997 and 4-PBA displayed synergistic anti-apoptotic effects in cells with oxygen-glucose deprivation. In summary, ER stress-induced apoptosis in CCH is associated with the IRE1α/TRAF2/ASK1/JNK signaling pathway. Targeting the ER stress-ASK1 cascade could be a novel therapeutic approach for ischemic cerebrovascular diseases., (© 2024. The Author(s).)

Objective: To analyze the isolation rate, prevalence trends, species distribution, and drug sensitivity of non-tuberculous mycobacteria (NTM) in Anhui Province, providing a reference for diagnosis and treatment strategies., Methods: Specimens from suspected mycobacterial infection patients at Anhui Chest Hospital (including outpatients and inpatients) from January 2021 to December 2023 were cultured. Identified NTM strains were analyzed for species distribution and drug sensitivity., Results: Of 10,519 mycobacteria strains cultured, 1,589 were NTM (15.11%). The top four species were Mycobacterium intracellulare (75.36%), Mycobacterium abscessus (11.78%), Mycobacterium kansasii (7.09%), and Mycobacterium avium (2.85%). NTM strains showed high sensitivity to amikacin and clarithromycin (≥90%) and significant sensitivity to rifabutin, moxifloxacin, and rifampicin (89.03%-79.61%). They exhibited high resistance to imipenem/cilastatin, sulfamethoxazole, minocycline, and doxycycline (≥95%)., Conclusion: NTM isolation rates in Anhui have remained stable, with the predominant species being M. intracellulare, M. kansasii, M. abscessus, and M. avium. NTM strains are highly sensitive to amikacin, clarithromycin, rifabutin, moxifloxacin, and rifampicin. These findings can guide diagnosis, treatment strategies, and drug selection for NTM disease in Anhui Province., Competing Interests: None., (AJTR Copyright © 2024.)

The high-fidelity (HiFi) long-read sequencing technology developed by PacBio has greatly improved the base-level accuracy of genome assemblies. However, these assemblies still contain base-level errors, particularly within the error-prone regions of HiFi long reads. Existing genome polishing tools usually introduce overcorrections and haplotype switch errors when correcting errors in genomes assembled from HiFi long reads. Here, we describe an upgraded genome polishing tool - NextPolish2, which can fix base errors remaining in those "highly accurate" genomes assembled from HiFi long reads without introducing excessive overcorrections and haplotype switch errors. We believe that NextPolish2 has a great significance to further improve the accuracy of telomere-to-telomere (T2T) genomes. NextPolish2 is freely available at https://github.com/Nextomics/NextPolish2., (© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.)

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease and currently there is no pharmacological therapy. Sympathetic nerve overactivity plays an important role in the development of TAAD. Sympathetic innervation is mainly controlled by nerve growth factor (NGF, a key neural chemoattractant) and semaphoring 3A (Sema3A, a key neural chemorepellent), while the roles of these two factors in aortic sympathetic innervation and especially TAAD are unknown. We hypothesized that genetically manipulating the NGF/Sema3A ratio by the Ngf -driven Sema3a expression approach may reduce aortic sympathetic nerve innervation and mitigate TAAD progression. A mouse strain of Ngf gene-driven Sema3a expression (namely NgfSema3a/Sema3a mouse) was established by inserting the 2A-Sema3A expression frame to the Ngf terminating codon using CRISPR/Cas9 technology. TAAD was induced by β-aminopropionitrile monofumarate (BAPN) both in NgfSema3a/Sema3a mice and wild type (WT) littermates. Contrary to our expectation, the BAPN-induced TAAD was severer in NgfSema3a/Sema3a mice than in wild-type (WT) mice. In addition, NgfSema3a/Sema3a mice showed higher aortic sympathetic innervation, inflammation and extracellular matrix degradation than the WT mice after BAPN treatment. The aortic vascular smooth muscle cells isolated from NgfSema3a/Sema3a mice and pretreated with BAPN in vivo for two weeks showed stronger capabilities of proliferation and migration than that from the WT mice. We conclude that the strategy of Ngf -driven Sema3a expression cannot suppress but worsens the BAPN-induced TAAD. By investigating the aortic phenotype of NgfSema3a/Sema3a mouse strain, we unexpectedly find a path to exacerbate BAPN-induced TAAD which might be useful in future TAAD studies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: The P2X3 receptor, a trimeric ionotropic purinergic receptor, has emerged as a potential therapeutic target for refractory chronic cough (RCC). Nevertheless, gefapixant/AF-219, the only marketed P2X3 receptor antagonist, might lead taste disorders by modulating the human P2X2/3 (hP2X2/3) heterotrimer. Hence, in RCC drug development, compounds exhibiting strong affinity for the hP2X3 homotrimer and a weak affinity for the hP2X2/3 heterotrimer hold promise. An example of such a molecule is sivopixant/S-600918, a clinical Phase II RCC candidate with a reduced incidence of taste disturbance compared to gefapixant. Sivopixant and its analogue, (3-(4-([3-chloro-4-isopropoxyphenyl]amino)-3-(4-methylbenzyl)-2,6-dioxo-3,6-dihydro-1,3,5-triazin-1(2H)-yl)propanoic acid (DDTPA), exhibit both high affinity and high selectivity for hP2X3 homotrimers, compared with hP2X2/3 heterotrimers. The mechanism underlying the druggable site and its high selectivity remains unclear., Experimental Approach: To analyse mechanisms that distinguish this drug candidate from other inhibitors of the P2X3 receptors we used a combination of chimera construction, site covalent occupation, metadynamics, mutagenesis and whole-cell recording., Key Results: The high affinity and selectivity of sivopixant/DDTPA for hP2X3 receptors was determined by the tri-symmetric site located close to the upper vestibule. Substitution of only four amino acids inside the upper body domain of hP2X2 with those of hP2X3, enabled the hP2X2/3 heterotrimer to exhibit a similar level of apparent affinity for sivopixant/DDTPA as the hP2X3 homotrimer., Conclusion and Implications: From the receptor-ligand recognition perspective, we have elucidated the molecular basis of novel RCC clinical candidates' cough-suppressing properties and reduced side effects, offering a promising approach to the discovery of novel drugs that specifically target P2X3 receptors., (© 2023 British Pharmacological Society.)

Bacoside A (gypenoside, Gyp) is a potent bioactive compound derived from Gynostemma pentaphyllum, known to exert inhibitory effects on various malignant tumors. However, the effects of Gyp on glioma as well as the underlying mechanisms remain unclear. In the present study, we first conducted a comprehensive investigation into the anti-glioma potential of gypenosides using network pharmacology to identify potential glioma-related targets. Protein-protein interaction networks were assembled, and GO and KEGG enrichment analyses were performed for shared targets. Experimental validation involved assessing the viability of U251 and U87 cell lines using the MTS method. Furthermore, trans-well and scratch migration assays evaluated the cell migration, while flow cytometry and Hoechst 33342 staining were utilized for apoptosis assessment. The study also monitored changes in autophagy flow through fluorescence microscopy. The expression levels of proteins pertinent to migration, apoptosis, and autophagy were tested using Western blotting. Findings revealed that Gyp upregulated apoptosis-related proteins (Bax and cleaved caspase-9), downregulated anti-apoptotic protein Bcl-2, and migration-associated matrix metalloproteinases (MMP-2 and MMP-9). Furthermore, autophagy-related proteins (Beclin1 and LC3 II) were upregulated, and p62 protein expression was downregulated. Gyp displayed considerable potential in suppressing glioma progression by inhibiting cell proliferation, invasion, and migration and promoting apoptosis and autophagy. Gyp may offer potential clinical therapeutic choices in glioma management., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Augmentation of endoplasmic reticulum (ER) stress may trigger excessive oxidative stress, which induces mitochondrial dysfunction. The fatty acid amide hydrolase inhibitor, URB597, shows anti-oxidation characteristics in multiple neurological disorders. The present study aimed to determine whether inhibition of ER stress was involved in the protective effects of URB597 against chronic cerebral hypoperfusion (CCH)-induced cognitive impairment. Hippocampal HT-22 cells were exposed to oxygen-glucose deprivation. The cell viability, apoptosis, ER stress, mitochondrial ATP, and oxidative stress levels were assessed following treatment with URB597, benzenebutyric acid (4-PBA), and thapsigargin (TG). Furthermore, the effects of URB597 on ER stress and related pathways were investigated in the CCH animal model, including Morris water maze testing of cognition, western blotting analysis of ER stress signaling, and transmission electron microscopy of mitochondrial and ER ultrastructure changes. The results suggested that cerebral ischemia caused ER stress with upregulation of ER stress signaling-related proteins, mitochondrial dysfunction, neuronal apoptosis, ultrastructural injuries of mitochondria-associated ER membranes, and cognitive decline. Co-immunoprecipitation experiments confirmed the interaction between CB2 and β-Arrestin1. Inhibiting ER stress by URB597 improved these changes by activating CB2/β-Arrestin1 signaling, which was reversed by the CB2 antagonist, AM630. Together, the results identified a novel mechanism of URB597, involving CCH-induced cognitive impairment alleviation of CB2-dependent ER stress and mitochondrial dysfunction. Furthermore, this study identified CB2 as a potential target for therapy of ischemic cerebrovascular diseases., (© 2024. The Author(s).)

Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease that manifests as skin rash, arthritis, lymphadenopathy, and multiple organ lesions. Epigenetics, including DNA methylation, histone modification, and non-coding RNA regulation, mainly affect the function and characteristics of cells through the regulation of gene transcription or translation. Increasing evidence indicates that there are a variety of complex epigenetic effects in patients with SLE, which interfere with the differentiation and function of T, and B lymphocytes, monocytes, and neutrophils, and enhance the expression of SLE-associated pathogenic genes. This paper summarizes our currently knowledge regarding pathogenesis of SLE, and introduces current advances in the epigenetic regulation of SLE from three aspects: immune function, inflammatory response, and lupus complications. We propose that epigenetic changes could be used as potential biomarkers and therapeutic targets of SLE., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Inc.)

Long noncoding RNAs (lncRNAs) represent a large subgroup of RNA transcripts that lack the function of coding proteins and may be essential universal genes involved in carcinogenesis and metastasis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNAMALAT1) is overexpressed in various human tumors, including gliomas. However, the biological function and molecular mechanism of action of lncRNA-MALAT1 in gliomas have not yet been systematically elucidated. Accumulating evidence suggests that the abnormal expression of lncRNA-MALAT1 in gliomas is associated with various physical properties of the glioma, such as tumor growth, metastasis, apoptosis, drug resistance, and prognosis. Furthermore, lncRNAs, as tumor progression and prognostic markers in gliomas, may affect tumorigenesis, proliferation of glioma stem cells, and drug resistance. In this review, we summarize the knowledge on the biological functions and prognostic value of lncRNA-MALAT1 in gliomas. This mini-review aims to deepen the understanding of lncRNA-MALAT1 as a novel potential therapeutic target for the individualized precision treatment of gliomas., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In July 2022, the World Health Organization announced monkeypox as a public health emergency of international concern (PHEIC), and over 85,000 global cases have been reported currently. However, preventive and therapeutic treatments for the monkeypox virus (MPXV) remain limited. MPXV mRNA cap N7 methyltransferase (MTase) is composed of two subunits (E1 C-terminal domain (E1 CTD ) and E12) which are essential for the replication of MPXV. Here, we solved a 2.16 Å crystal structure of E12. We also docked the D1 CTD of the vaccinia virus (VACV) corresponding to the E1 CTD in MPXV with E12 and found critical residues at their interface. These residues were further used for drug screening. After virtual screening, the top 347 compounds were screened out and a list of top 20 potential MPXV E12 inhibitors were discovered, including Rutin, Quercitrin, Epigallocatechin, Rosuvastatin, 5-hydroxy-L-Tryptophan, and Deferasirox, etc., which were potential E12 inhibitors. Taking the advantage of the previously unrecognized special structure of MPXV MTase composing of E1 CTD and E12 heterodimer, we screened for inhibitors targeting MTase for the first time based on the interface between the heterodimer of MPXV MTase. Our study may provide insights into the development of anti-MPXV drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Postoperative pulmonary complications (PPCs) are an important quality indicator and are associated with significantly increased mortality in infants. The objective of this study was to identify risk factors for PPCs in neonates undergoing non-cardiothoracic surgery., Methods: In this retrospective study, all neonates who underwent non-cardiothoracic surgery in a children's hospital from October 2020 to September 2022 were included for analysis. Demographic data and perioperative variables were obtained. The primary outcome was the occurrence of PPCs. Univariate analysis and multivariable logistic regression analysis were used to investigate the effect of patient-related factors on the occurrence of PPCs., Results: Totally, 867 neonatal surgery patients met the inclusion criteria in this study, among which 35.3% (306/867) patients experienced pulmonary complications within 1 week postoperatively. The PPCs observed in this study were 51 exacerbations of pre-existing pneumonia, 198 new patchy shadows, 123 new pulmonary atelectasis, 10 new pneumothorax, and 6 new pleural effusion. Patients were divided into two groups: PPCs (n=306) and non-PPCs (n=561). The multivariate stepwise logistic regression analysis revealed five independent risk factors for PPCs: corrected gestational age (OR=0.938; 95% CI 0.890 to 0.988), preoperative pneumonia (OR=2.139; 95% CI 1.033 to 4.426), length of surgery (> 60 min) (OR=1.699; 95% CI 1.134 to 2.548), preoperative mechanical ventilation (OR=1.857; 95% CI 1.169 to 2.951), and intraoperative albumin infusion (OR=1.456; 95% CI 1.041 to 2.036) in neonates undergoing non-cardiothoracic surgery., Conclusion: Identifying risk factors for neonatal PPCs will allow for the identification of patients who are at higher risk and intervention for any modifiable risk factors identified., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Chronic cerebral hypoperfusion (CCH) can cause a series of pathophysiological processes, including neuronal autophagy and apoptosis. VEGF-A has been reported to affect angiogenesis and neurogenesis in many CNS diseases. However, its effects on neuronal autophagy and apoptosis, as well as the underlying mechanisms in CCH remain unclear., Methods: To address these issues, the CCH model was established by permanent bilateral common carotid artery occlusion (2VO). Rats were sacrificed at different stages of CCH. Hippocampal morphological and ultrastructural changes were detected using HE staining and electron microscopy. The immunoreactivities of microtubule-associated protein 1 light chain 3 (LC3) and phospho-cAMP response element binding protein (p-CREB) were examined by immunofluorescence staining. The neuronal apoptosis was detected via TUNEL staining. The levels of LC3-II, Beclin-1, Akt, p-Akt, CREB, p-CREB, Caspase-3, and Bad were accessed by Western blotting. Furthermore, mouse hippocampal HT22 neurons received the oxygen and glucose deprivation (OGD) treatment, VEGF-A treatment, and GSK690693 (an Akt inhibitor) treatment, respectively., Results: LC3-II protein started to increase at 3 days of CCH, peaked at 4 weeks of CCH, then decreased. CCH increased the levels of LC3-II, Caspase-3, and Bad, and decreased the levels of p-Akt, CREB, and p-CREB, which were reversed by VEGF-A treatment. VEGF-A also improved CCH-induced neuronal ultrastructural injuries and apoptosis in the hippocampus in vitro. In HT22, the anti-apoptosis and pro-phosphorylation of VEGF-A were reversed by GSK690693., Conclusion: Present results provide a novel neuroprotective effect of VEGF-A in CCH that is related to the inhibition of neuronal autophagy and activation of the Akt/CREB signaling, suggesting a potential therapeutic strategy for ischemic brain damage., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In recent years, aggregation-induced emission (AIE)-active materials have been emerging as a promising means for bioimaging and phototherapy. However, the majority of AIE luminogens (AIEgens) need to be encapsulated into versatile nanocomposites to improve their biocompatibility and tumor targeting. Herein, we prepared a tumor- and mitochondria-targeted protein nanocage by the fusion of human H-chain ferritin (HFtn) with a tumor homing and penetrating peptide LinTT1 using genetic engineering technology. The LinTT1-HFtn could serve as a nanocarrier to encapsulate AIEgens via a simple pH-driven disassembly/reassembly process, thereby fabricating the dual-targeting AIEgen-protein nanoparticles (NPs). The as designed NPs exhibited an improved hepatoblastoma-homing property and tumor penetrating ability, which is favorable for tumor-targeted fluorescence imaging. The NPs also presented a mitochondria-targeting ability, and efficiently generated reactive oxygen species (ROS) upon visible light irradiation, making them valuable for inducing efficient mitochondrial dysfunction and intrinsic apoptosis in cancer cells. In vivo experiments demonstrated that the NPs could provide the accurate tumor imaging and dramatic tumor growth inhibition with minimal side effects. Taken together, this study presents a facile and green approach for fabrication of tumor- and mitochondria-targeted AIEgen-protein NPs, which can serve as a promising strategy for imaging-guided photodynamic cancer therapy. STATEMENT OF SIGNIFICANCE: AIE luminogens (AIEgens) show strong fluorescence and enhanced ROS generation in the aggregate state, which would facilitate the image-guided photodynamic therapy [12-14]. However, the major obstacles that hinder biological applications are their lack of hydrophilicity and selective targeting [15]. To address this issue, this study presents a facile and green approach for the fabrication of tumor‑ and mitochondria‑targeted AIEgen-protein nanoparticles via a simple disassembly/reassembly of the LinTT1 peptide-functionalized ferritin nanocage without any harmful chemicals or chemical modification. The targeting peptide-functionalized nanocage not only restricts the intramolecular motion of AIEgens leading to enhanced fluorescence and ROS production, but also confers good targeting to AIEgens., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Aims: Intraosseous hibernomas are rarely reported tumours with brown adipocytic differentiation of unknown aetiology, with only 38 cases documented in the literature. We sought to further characterise the clinicopathologic, imaging and molecular features of these tumours., Methods and Result: Eighteen cases were identified occurring in eight females and 10 males (median age = 65 years, range = 7-75). Imaging indication was cancer surveillance/staging in 11 patients and clinical concern for a metastasis was raised in 13 patients. The innominate bone (7), sacrum (5), mobile spine (4), humerus (1) and femur (1) were involved. Median tumour size was 1.5 cm (range = 0.8-3.8). Tumours were sclerotic (11), mixed sclerotic and lytic (4) or occult (1). Microscopically, tumours were composed of large polygonal cells with distinct cell membranes, finely vacuolated cytoplasm, central or paracentral small bland nuclei with prominent scalloping. Growth around trabecular bone was observed. Tumour cells were immunoreactive for S100 protein (15/15) and adipophilin (5/5), while negative for keratin AE1/AE3(/PCK26) (0/14) and brachyury (0/2). Chromosomal microarray analysis, performed on four cases, did not show clinically significant copy number variation across the genome or on 11q, the site of AIP and MEN1., Conclusion: Analysis of 18 cases of intraosseous hibernoma, to our knowledge, the largest series to date, revealed that these tumours are most often detected in the spine and pelvis of older adults. Tumours were generally small, sclerotic and frequently found incidentally and can raise concern for metastasis. Whether or not these tumours are related to soft tissue hibernomas is uncertain., (© 2023 John Wiley & Sons Ltd.)

Objective: To investigate the mechanism of drug reversing resistance of Agaricus blazei extract FA-2-b-β on T cell acute lymphoblastic leukemia (T-ALL) cell lines., Methods: Cell proliferation was detected by CCK-8 assay; the apoptosis, cell cycle mitochondrial membrane potential, and intracellular rhodamine accumulation were detected by flow cytometry, and apoptosis-related gene and protein expression were detected by qPCR and Western blot; the membrane surface protein MDR1 was observed by immunofluorescence microscopy., Results: Different concentrations of FA-2-b-β significantly inhibited proliferation and induced apoptosis of CCRF-CEM and CEM/C1 ( P <0.05), and CCRF-CEM cell cycle were arrested at S phase, and CEM/C1 cells were arrested at G 0 /G 1 phase. Western blot and qPCR results show that FA-2-b-β inhibited ABCB1、ABCG2、CTNNB、MYC and BCL-2 expression, but upregulated Bax expression. In addition, FA-2-b-β reversed the resistance characteristics of CEM/C1 drug-resistance cells, which decreased mitochondrial membrane potential, and significantly increased the intracellular rhodamine accumulation, and weakening of the expression of the membrane surface protein MDR1. With the Wnt/β-catenin inhibitor (ICG001), the process was further intensified., Conclusion: Agaricus Blazei Extract FA-2-b-β inhibits cell proliferation, promotes apoptosis, regulates the cell cycle, reduces mitochondrial energy supply, and down-regulate MDR1 expression to reverse the resistance of CEM/C1, which all suggest it is through regulating the Wnt signaling pathway in T-ALL.

Aims: Clear roles and mechanisms in explaining gut microbial dysbiosis and microbial metabolites short-chain fatty acids (SCFAs) alterations in chronic cerebral ischemic pathogenesis have yet to be explored. In this study, we investigated chronic cerebral hypoperfusion (CCH)-induced gut microbiota and metabolic profiles of SCFAs as well as the effects and mechanisms of fecal microbiota transplantation (FMT) and SCFAs treatment on CCH-induced hippocampal neuronal injury., Methods: Bilateral common carotid artery occlusion (BCCAo) was used to establish the CCH model. Gut microbiota and SCFAs profiles in feces and hippocampus were evaluated by 16S ribosomal RNA sequencing and gas chromatography-mass spectrometry. RNA sequencing analysis was performed in hippocampal tissues. The potential molecular pathways and differential genes were verified through western blot, immunoprecipitation, immunofluorescence, and ELISA. Cognitive function was assessed via the Morris water maze test. Ultrastructures of mitochondria and synapses were tested through a transmission electron microscope., Results: Chronic cerebral hypoperfusion induced decreased fecal acetic and propionic acid and reduced hippocampal acetic acid, which were reversed after FMT and SCFAs administration by changing fecal microbial community structure and compositions. Furthermore, in the hippocampus, FMT and SCFAs replenishment exerted anti-neuroinflammatory effects through inhibiting microglial and astrocytic activation as well as switching microglial phenotype from M1 toward M2. Moreover, FMT and SCFAs treatment alleviated neuronal loss and microglia-mediated synaptic loss and maintained the normal process of synaptic vesicle fusion and release, resulting in the improvement of synaptic plasticity. In addition, FMT and SCFAs supplement prevented oxidative phosphorylation dysfunction via mitochondrial metabolic reprogramming. The above effects of FMT and SCFAs treatment led to the inhibition of CCH-induced cognitive impairment., Conclusion: Our findings highlight FMT and SCFAs replenishment would be the feasible gut microbiota-based strategy to mitigate chronic cerebral ischemia-induced neuronal injury., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Nitric oxide (NO) exhibits a crucial role in various versatile and distinct physiological functions. Hence, its real-time sensing is highly important. Herein, we developed an integrated nanoelectronic system comprising a cobalt single-atom nanozyme (Co-SAE) chip array sensor and an electronic signal processing module (IND Co-SAE ) for both in vitro and in vivo multichannel qualifying of NO in normal and tumor-bearing mice. The high atomic utilization and catalytic activity of Co-SAE endowed an ultrawide linear range for NO varying from 36 to 4.1 × 10 5 nM with a low detection limit of 12 nM. Combining in situ attenuated total reflectance surface enhanced infrared spectroscopy (ATR-SEIRAS) measurements and density function calculation revealed the activating mechanism of Co-SAE toward NO. The NO adsorption on an active Co atom forms *NO, followed by the reaction between *NO and OH - , which could help design relevant nanozymes. Further, we investigated the NO-producing behaviors of various organs of both normal and tumor-bearing mice using the proposed device. We also evaluated the NO yield produced by the wounded mouse using the designed device and found it to be approximately 15 times that of the normal mouse. This study bridges the technical gap between a biosensor and an integrated system for molecular analysis in vitro and in vivo . The as-fabricated integrated wireless nanoelectronic system with multiple test channels significantly improved the detection efficiency, which can be widely used in designing other portable sensing devices with multiplexed analysis capability.

A plant can be thought of as a colony comprising numerous growth buds, each developing to its own rhythm. Such lack of synchrony impedes efforts to describe core principles of plant morphogenesis, dissect the underlying mechanisms, and identify regulators. Here, we use the minimalist known angiosperm to overcome this challenge and provide a model system for plant morphogenesis. We present a detailed morphological description of the monocot Wolffia australiana , as well as high-quality genome information. Further, we developed the plant-on-chip culture system and demonstrate the application of advanced technologies such as single-nucleus RNA-sequencing, protein structure prediction, and gene editing. We provide proof-of-concept examples that illustrate how W. australiana can decipher the core regulatory mechanisms of plant morphogenesis., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Introduction: Flaviviruses are emerging or reemerging pathogens that have caused several outbreaks throughout the world and pose serious threats on human health and economic development. RNA-based therapeutics are developing rapidly, and hold promise in the fight against flaviviruses. However, to develop efficient and safe therapeutics for flaviviruses, many challenges remain unsolved., Areas Covered: In this review, the authors briefly introduced the biology of flaviviruses and the current advances in RNA-based therapeutics for them. Furthermore, the authors list the challenges and possible solutions in this area. Finally, the authors give their opinion on the development and future of RNA-based therapeutics for flaviviruses., Expert Opinion: With the rapid development of structural biology, the crystal structures of flavivirus proteins may lay the foundation for future rational drug design. Studies regarding the interactions between the flavivirus and the host will also be invaluable to inhibitor design. Researchers should maintain the current momentum to bring about safe and effective anti-flavivirus drugs to licensure through joint efforts of academia, government, and industry.

Objective: Thirty-day readmission is one of the common complications after lumbar surgery. More 30-day readmission increases the total hospitalization, economic burden, and physical pain of patients, delays the progress of postoperative rehabilitation, and even lead to die. Therefore, it is necessary to analyze the risk factors of 30-day readmission following lumbar surgery., Methods: We searched for all the clinical trials published from the establishment of the database to May 1, 2022 through the Cochrane Library, Web of Science, Embase, and PubMed. Data including age, American Society of Anesthesiology physical status class, preoperative hematocrit (Hct), diabetes mellitus (DM), current smoker, chronic obstructive pulmonary disease (COPD), length of hospital stay (LHS), operation time, and surgical site infection (SSI) were extracted. We used Review Manager 5.4 for data analysis., Results: Six studies with 30,989 participants were eligible for this meta-analysis. The analysis revealed that there were statistically significant differences in the age (95% confidence interval [CI]: -3.35-2.90, P < 0.001), preoperative Hct (95% CI: 0.75-1.33, P < 0.001), DM (95% CI: 0.56-0.74, P < 0.001), COPD (95% CI: 0.38-0.58, P < 0.001), operation time (95% CI: -35.54-16.18, P < 0.001), LHS (95% CI: -0.54-0.50, P < 0.001), and SSI (95% CI: 0.02-0.03, P < 0.001) between no readmission and readmission groups. In terms of the American Society of Anesthesiology physical status class and current smoker, there was no significant effect on the 30-day readmission (P = 0.16 and P = 0.35 respectively)., Conclusions: Age, preoperative Hct, DM, COPD, operation time, LHS, and SSI are the danger factors of 30-day readmission following lumbar surgery., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The JAK/STAT3 signaling pathway is aberrantly hyperactivated in many cancers, promoting cell proliferation, survival, invasiveness, and metastasis. Thus, inhibitors targeting JAK/STAT3 have enormous potential for cancer treatment. Herein, we modified aldisine derivatives by introducing the isothiouronium group, which can improve the antitumor activity of the compounds. We performed a high-throughput screen of 3157 compounds and identified compounds 11a , 11b , and 11c , which contain a pyrrole [2,3-c] azepine structure linked to an isothiouronium group through different lengths of carbon alkyl chains and significantly inhibited JAK/STAT3 activities. Further results showed that compound 11c exhibited the optimal antiproliferative activity and was a pan-JAKs inhibitor capable of inhibiting constitutive and IL-6-induced STAT3 activation. In addition, compound 11c influenced STAT3 downstream gene expression (Bcl-xl, C-Myc, and Cyclin D1) and induced the apoptosis of A549 and DU145 cells in a dose-dependent manner. The antitumor effects of 11c were further demonstrated in an in vivo subcutaneous tumor xenograft experiment with DU145 cells. Taken together, we designed and synthesized a novel small molecule JAKs inhibitor targeting the JAK/STAT3 signaling pathway, which has predicted therapeutic potential for JAK/STAT3 overactivated cancer treatment.

Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time- and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy (cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence (AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of medium-resolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery., (© 2023. The Author(s).)

Cadmium (Cd) is a well-characterized bone toxic agent and can induce bone damage via inhibiting osteogenic differentiation. Bone morphogenetic protein (BMP)/SMAD signaling pathway can mediate osteogenic differentiation, but the association between Cd and BMP/SMAD signaling pathway is yet to be illuminated. To understand what elements of BMPs and SMADs are affected by Cd to influence osteogenic differentiation and if BMPs can be the biomarkers of which Cd-induced osteoporosis, human bone marrow mesenchymal stem cells (hBMSCs) were treated with cadmium chloride (CdCl2) in vitro to detect the expression of BMPs and SMADs, and 134 subjects were enrolled to explore if the BMPs can be potential biomarkers of Cd-associated bone damage. Our results showed that Cd exposure significantly promoted the adipogenic differentiation of hBMSCs and inhibited its osteogenic differentiation by inhibiting the expression of BMP-2/4, SMAD4, and p-SMAD1/5/9 complex. And mediation analyses yielded that BMP-4 mediated 39.32% (95% confidence interval 7.47, 85.00) of the total association between the Cd and the risk of Cd-associated bone damage. Moreover, during differentiation, BMP-4 had the potential to enhance mineralization compared with CdCl2 only group. These results reveal that BMP-4 can be a diagnostic biomarker and therapeutic target for Cd-associated bone damage., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.)

We investigated the potential effects and mechanisms of vascular endothelial growth factor (VEGF)-nanofiber membranes (NFMs) treatment in a rat model of chronic cerebral hypoperfusion (CCH). VEGF-NFMs treatment promoted angiogenesis in surgical temporal cortex and hippocampus, alleviating decreased CBF in these two cerebral regions. VEGF-NFMs application improved reduced NAA/Cr ratio, preventing neuronal loss. VEGF-NFMs sticking decreased the number of TUNEL-positive cells in surgical temporal cortex, ameliorated impaired synaptic plasticity, and inhibited the release of pro-inflammatory cytokines and the activation of microglia and astrocytes in surgical temporal cortex and hippocampus. Furthermore, BDNF-TrkB/PI3K/AKT, BDNF-TrkB/ERK and HIF-1a/VEGF/ERK pathways were involved in the treatment of VEGF-NFMs against CCH-induced neuronal injury. These results showed the neuroprotective effects of VEGF-NFMs sticking may initiate from neurovascular repairing followed by inhibition of neuronal apoptosis and neuronal and synaptic damage, eventually leading to the suppression of cognitive dysfunction, which provided theoretical foundation for further clinical transformation of VEGF-NFMs., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Little is known about the association between gut microbiota and intestinal injury under a state of chronic cerebral hypoperfusion (CCH). Here, the effects of gut microbiota and short-chain fatty acids (SCFAs), as important metabolic products, on intestinal function and potential mechanisms after CCH were investigated., Methods: Rats were subjected to bilateral common carotid artery occlusion (BCCAo) to induce CCH. The gut microbiota and metabolites of SCFAs were assessed by 16S rRNA sequencing and targeted metabolomics, respectively. Transcriptomic analysis of colon tissues was also conducted. Subsequently, potential molecular pathways and differentially expressed genes were verified by western blot, immunoprecipitation, and immunofluorescence analyses. Furthermore, the integrity of the colonic barrier was evaluated by hematoxylin and eosin and mucin 2 staining and expression levels of tight junction proteins. Besides, colonic inflammation was further assessed by flow cytometry and expression levels of inflammatory cytokines. In addition, colonic mitochondrial dysfunction was analyzed via membrane potential, reactive oxygen species, electron transport chain (ETC) activities, adenosine triphosphate content, and mitochondrial ultrastructure., Results: CCH modified gut microbial composition and microbial metabolism of SCFAs, which may be associated with inhibition of mitochondrial ETC activities and oxidative phosphorylation, leading to dysregulation of mitochondrial energy metabolism. Furthermore, CCH induced differentiation of pathogenic Th17 cells, promoted the formation of complexes of interferon regulatory factor 4 and signal transducer and activator of transcription 3 (STAT3), and increased the phosphorylation of STAT3. This was associated with an impairment of colonic barrier function and chronic colonic inflammation. In contrast, FMT and SCFA replenishment ameliorated CCH-induced gut microbial dysbiosis by increasing the intestinal content of Ruminococcus&#95;sp&#95;N15&#95;MGS&#95;57 and modulating microbial metabolism of SCFAs by increasing acetic acid contents associated with an improvment of the balance between Tregs and Th17 cells, mitochondrial ETC activities, and oxidative phosphorylation to prevent colonic inflammation and dysregulation of mitochondrial energy metabolism., Conclusion: These findings indicate that FMT and SCFA replenishment present a promising therapeutic strategy against colonic dysfunction under a state of chronic cerebral ischemia., (© 2022. The Author(s).)

Objective: This study aimed to address the status, role, and mechanism of sympathetic nerve infiltration in the progression of stomach adenocarcinoma (STAD)., Methods: Sympathetic nerve and its neurotransmitter NE, β-ARs, and associated signaling molecules in the STAD tissues and the adjacent tissues from 46 STAD patients were examined using immunostaining, HPLC, and western blotting. The effects and mechanisms of β2-AR activation on the proliferation, migration and invasion of AGS and SGC-7901 gastric cancer (GC) cell lines were examined using CCK-8, transwell, and western blotting assays. Correlations between genes and STAD survival were analyzed using bioinformatics., Results: Striking sympathetic nerve infiltration, elevations of NGF, TrkA, GAP43, TH, S100, NE, β2-AR, YKL-40, syndecan-1, MMP9, CD206, and CD31 were observed in the STAD tissues compared to the adjacent tissues. Activation of β2-AR in the two GC cell lines significantly amplified the expressions of NGF, YKL-40, MMP9, syndecan-1, p-STAT3 and p-ERK, and increased GC cell proliferation, migration and invasion. Bioinformatic analyses revealed positive correlations of NGF, β2-AR, syndecan-1, and macrophage infiltration, respectively, with low survival of STAD, of β2-AR respectively with STAT3, ERK1/2 (MAPK1/3), YKL-40, MMP9, and syndecan-1, and of YKL-40 with MMP9., Conclusion: Sympathetic nerves significantly infiltrated into human STAD tissues as a result of high NGF and TrkA expressions; elevated NE led to overactivation of β2-AR-STAT3/ERK-YKL-40 signaling pathway, and finally caused cancer cell growth and invasion, M2 macrophage infiltration, angiogenesis, matrix degradation and STAD metastasis and progression., Competing Interests: The authors declare no competing interests. Additional informationSupplementary content related to this article has been published online at https://doi.org/10.1016/j.heliyon.2022.e12468., (© 2022 The Author(s).)

Coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has escalated into a global tragedy afflicting human health, life, and social governance. Through the increasing depth of research and a better understanding of this disease, it has been ascertained that, in addition to the lungs, SARS-CoV-2 can also induce injuries to other organs including the liver. Liver injury is a common clinical manifestation of COVID-19, particularly in severe cases, and is often associated with a poorer prognosis and higher severity of COVID-19. This review focuses on the general existing information on liver injury caused by COVID-19, including risk factors and subpopulations of liver injury in COVID-19, the association between preexisting liver diseases and the severity of COVID-19, and the potential mechanisms by which SARS-CoV-2 affects the liver. This review may provide some useful information for the development of therapeutic and preventive strategies for COVID-19-associated liver injury., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest for this work., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

The novel coronavirus disease (COVID-19) outbreak that emerged at the end of 2019 has now swept the world for more than 2 years, causing immeasurable damage to the lives and economies of the world. It has drawn so much attention to discovering how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated and entered the human body. The current argument revolves around two contradictory theories: a scenario of laboratory spillover events and human contact with zoonotic diseases. Here, we reviewed the transmission, pathogenesis, possible hosts, as well as the genome and protein structure of SARS-CoV-2, which play key roles in the COVID-19 pandemic. We believe the coronavirus was originally transmitted to human by animals rather than by a laboratory leak. However, there still needs more investigations to determine the source of the pandemic. Understanding how COVID-19 emerged is vital to developing global strategies for mitigating future outbreaks., (© 2022 Wiley-VCH GmbH.)

The most frequent internal modification in eukaryotic mRNA is N6-methyladenosine (m6A). However, what we know about the m6A regulators in Ankylosing spondylitis (AS) is still limited. In our study, eight distinct m6A regulators were selected utilizing Differentially Expressed Gene (DEG) analysis of the Gene Expression Omnibus GSE73754 dataset for making comparisons between AS (Ankylosing spondylitis) and non-AS patients. The random forest model and the nomogram model were used to screen the eight candidate m6A regulators and evaluate their prediction accuracy for the occurrence of AS. Furthermore, based on the selected m6A regulators, the AS patients were divided into two subgroups, and we applied principal component analysis algorithms to calculate their m6A score and evaluate the m6A patterns. Our findings revealed that patients in cluster A were linked to activated CD4 T cell immunity and activated CD8 T cell immunity. With its major contributions in the area of immunology, our research in m6A patterns may benefit the future diagnosis and treatment strategies of AS., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Cheng Zhong et al.)

Background: A significant proportion of women with preeclampsia (PE) exhibit persistent postpartum hypertension (PHTN) at 3 months postpartum associated with cardiovascular morbidity. This study aimed to screen patients with PE to identify the high-risk population with persistent PHTN., Methods: This retrospective cohort study enrolled 1,000 PE patients with complete parturient and postpartum blood pressure (BP) profiles at 3 months postpartum. The enrolled patients exhibited new-onset hypertension after 20 weeks of pregnancy, while those with PE superimposed upon chronic hypertension were excluded. Latent class cluster analysis (LCCA), a method of unsupervised learning in machine learning, was performed to ascertain maternal exposure clusters from eight variables and 35 subordinate risk factors. Logistic regression was applied to calculate odds ratios (OR) indicating the association between clusters and PHTN., Results: The 1,000 participants were classified into three exposure clusters (subpopulations with similar characteristics) according to persistent PHTN development: high-risk cluster (31.2%), medium-risk cluster (36.8%), and low-risk cluster (32.0%). Among the 1,000 PE patients, a total of 134 (13.4%) were diagnosed with persistent PHTN, while the percentages of persistent PHTN were24.68%, 10.05%, and 6.25% in the high-, medium-, and low-risk clusters, respectively. Persistent PHTN in the high-risk cluster was nearly five times higher (OR, 4.915; 95% confidence interval (CI), 2.92-8.27) and three times (OR, 2.931; 95% CI, 1.91-4.49) than in the low- and medium-risk clusters, respectively. Persistent PHTN did not differ between the medium- and low-risk clusters. Subjects in the high-risk cluster were older and showed higher BP, poorer prenatal organ function, more adverse pregnancy events, and greater medication requirement than the other two groups., Conclusion: Patients with PE can be classified into high-, medium-, and low-risk clusters according to persistent PHTN severity; each cluster has cognizable clinical features. This study's findings stress the importance of controlling persistent PHTN to prevent future cardiovascular disease., (© 2022. The Author(s).)

Multi-drug-resistant microbial pathogens are a serious global health problem. New compounds with antibacterial activity serve as good candidates for developing novel antibacterial drugs which is very urgent and important. In this work, based on the unique scaffold of indirubin, an active ingredient of traditional Chinese medicine formulation Danggui Luhui Wan, we synthesized 29 indirubin-3'-monoximes and preliminarily evaluated their antibacterial activities. The antibacterial activity results demonstrated that the synthesized indirubin-3'-monoximes 5a-5z and 5aa-5ad displayed good potency against S. aureus ATCC25923 (MIC = 0.4-25.6 μg mL -1 ). Among them, we found that the 5-F, 5-Cl and 7-CF 3 substituted indirubin-3'-monoximes 5r, 5s and 5aa also showed better antibacterial efficiency for S. aureus (MICs up to 0.4 μg mL -1 ) than the prototype natural product indirubin (MIC = 32 μg mL -1 ). More importantly, indirubin-3'-monoxime 5aa has certain synergistic effect with levofloxacin against clinic multidrug-resistant S. aureus (fractional inhibitory concentration index: 0.375). In addition, relevant experiments including electron microscopy observations, PI staining and the leakage of extracellular potassium ions and nucleic acid (260 nm) have been performed after treating S. aureus with indirubin-3'-monoxime 5aa, and the results revealed that indirubin-3'-monoximes could increase the cell membrane permeability of S. aureus . Although indirubin-3'-monoxime 5aa showed some cytotoxicity toward SH-SY5Y cells relative to compounds 5r and 5s, the skin irritation test of male mice after shaving showed that compound 5aa at a concentration of 12.8 μg mL -1 had no toxicity to mouse skin, and it could be used as a leading compound for skin antibacterial drugs., Competing Interests: All the authors declare that they have no conflict of interest., (This journal is © The Royal Society of Chemistry.)