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Wei Wang, Ni Yang, Yu-Hang Yang, Ri Wen, Chun-Feng Liu, Tie-Ning Zhang Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Chun-Feng Liu; Tie-Ning ZhangDepartment of Pediatrics, Shengjing Hospital of China Medical University, No. 36 SanHao Street, Shenyang City, Liaoning Province, 110004, People’s Republic of ChinaTel +86-18940251826; +86-18940253339Email zhliu258@hotmail.com; cmuztn@vip.qq.comAbstract: Emerging data indicates that non-coding RNAs (ncRNAs) represent more than just “junk sequences” of the genome and have been found to be involved in multiple diseases by regulating various biological process, including the activation of inflammasomes. As an important aspect of innate immunity, inflammasomes are large immune multiprotein complexes that tightly regulate the production of pro-inflammatory cytokines and mediate pyroptosis; the activation of the inflammasomes is a vital biological process in inflammatory diseases. Recent studies have emphasized the function of ncRNAs in the fine control of inflammasomes activation either by directly targeting components of the inflammasomes or by controlling the activity of various factors that control the activation of inflammasomes; consequently, ncRNAs may represent potential therapeutic targets for inflammatory diseases. Understanding the precise role of ncRNAs in controlling the activation of inflammasomes will help us to design targeted therapies for multiple inflammatory diseases. In this review, we summarize the regulatory role and therapeutic potential of ncRNAs in the activation of inflammasomes by focusing on a range of inflammatory diseases, including microbial infection, sterile inflammatory diseases, and fibrosis-related diseases. Our goal is to provide new ideas and perspectives for future research.Keywords: ncRNAs, inflammasomes, infection, immune, inflammation, fibrosis

Histone deacetylases (HDACs) are zinc-dependent deacetylases that remove acetyl groups from lysine residues of histones or form protein complexes with other proteins for transcriptional repression, changing chromatin structure tightness, and inhibiting gene expression. Recent in vivo and in vitro studies have amply demonstrated the critical role of HDACs in the cell biology of the nervous system during both physiological and pathological processes and have provided new insights into the conduct of research on neurological disease targets. In addition, in vitro and in vivo studies on HDAC inhibitors show promise for the treatment of various diseases. This review summarizes the regulatory mechanisms of HDAC and the important role of its downstream targets in nervous system diseases, and summarizes the therapeutic mechanisms and efficacy of HDAC inhibitors in various nervous system diseases. Additionally, the current pharmacological situation, problems, and developmental prospects of HDAC inhibitors are described. A better understanding of the pathogenic mechanisms of HDACs in the nervous system may reveal new targets for therapeutic interventions in diseases and help to relieve healthcare pressure through preventive measures., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite considerable research efforts, inflammatory diseases remain a heavy burden on human health, causing significant economic losses annually. Histone deacetylases (HDACs) play a significant role in regulating inflammation (via histone and non-histone protein deacetylation) and chromatin structure and gene expression regulation. Herein, we present a detailed description of the different HDACs and their functions and analyze the role of HDACs in inflammatory diseases, including pro-inflammatory cytokine production reduction, immune cell function modulation, and anti-inflammatory cell activity enhancement. Although HDAC inhibitors have shown broad inflammatory disease treatment potentials, their clinical applicability remains limited because of their non-specific effects, adverse effects, and drug resistance. With further research and insight, these inhibitors are expected to become important tools for the treatment of a wide range of inflammatory diseases. This review aims to explore the mechanisms and application prospects of HDACs and their inhibitors in multiple inflammatory diseases., 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis causes a high mortality rate and current treatment focuses on supportive therapies but lacks specific therapeutic targets. Notably, sirtuins (SIRTs) shows potential clinical application in the treatment of sepsis. It has been demonstrated that SIRTs, the nicotinamide adenine dinucleotide + (NAD + )-dependent deacetylases that regulate key signaling pathways in eukaryotes and prokaryotes, are involved in a variety of biological processes. To date, seven mammalian yeast Sir2 homologs have been identified. SIRTs can regulate inflammation, oxidative stress, apoptosis, autophagy, and other pathways that play important roles in sepsis-induced organ dysfunction. However, the existing studies on SIRTs in sepsis are too scattered, and there is no relevant literature to integrate them. This review innovatively summarizes the different mechanisms of SIRTs in sepsis organ dysfunction according to the different systems, and focuses on SIRT agonists, inhibitors, and targeted drugs that have been proved to be effective in the treatment of sepsis, so as to integrate the clinical research and basic research closely. We searched PubMed for all literature related to SIRTs and sepsis since its inception using the following medical subject headings: sirtuins, SIRTs, and sepsis. Data on the mechanisms of SIRTs in sepsis-induced organ damage and their potential as targets for disease treatment were extracted., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

With the emergence of new variant strains resulting from high mutation rates and genome recombination, avian infectious bronchitis virus (IBV) has caused significant economic losses to the poultry industry worldwide. Little is known about the underlying mechanisms of IBV-host interactions, particularly how IBV utilizes host metabolic pathways for efficient viral replication and transmission. In the present study, the effects of the cell membrane, viral envelope membrane, and viperin-mediated cholesterol synthesis on IBV replication were explored. Our results revealed significant increase in cholesterol levels and the expression of viperin after IBV infection. Acute cholesterol depletion in the cell membrane and viral envelope membrane by treating cells with methyl-β-cyclodextrin (MβCD) obviously inhibited IBV replication; thereafter, replenishment of the cell membrane with cholesterol successfully restored viral replication, and direct addition of exogenous cholesterol to the cell membrane significantly promoted IBV infection during the early stages of infection. In addition, overexpression of viperin effectively suppressed cholesterol synthesis, as well as IBV replication, whereas knockdown of viperin (gene silencing with siRNA targeting viperin, siViperin) significantly increased IBV replication and cholesterol levels, whereas supplementation with exogenous cholesterol to viperin-transfected cells markedly restored viral replication. In conclusion, the increase in viperin induced by IBV infection plays an important role in IBV replication by affecting cholesterol production, providing a theoretical basis for understanding the pathogenesis of IBV and discovering new potential antiviral targets., (© 2024. The Author(s).)

Sepsis-induced myocardial depression (SIMD), a common complication of sepsis, is one of the main causes of death in patients with sepsis. The pathogenesis of SIMD is complicated, and the process of SIMD remains incompletely understood, with no single or definitive mechanism fully elucidated. Notably, pyroptosis, as a pro-inflammatory programmed cell death, is characterized by Gasdermin-mediated formation of pores on the cell membrane, cell swelling, and cell rupture accompanied by the release of large amounts of inflammatory factors and other cellular contents. Mechanistically, pyroptosis is mainly divided into the canonical pathway mediated by caspase-1 and the non-canonical pathway mediated by caspase-4/5/11. Pyroptosis has been confirmed to participate in various inflammation-associated diseases. In recent years, more and more studies have shown that pyroptosis is also involved in the occurrence and development of SIMD. This article reviews the molecular mechanisms of pyroptosis and its research progress in SIMD, aiming to provide novel strategies and targets for the treatment of SIMD.

In order to explore the evolution law and driving mechanism of aerobic denitrification bacteria in Baiyangdian Lake under different hydrological scenarios, based on water quality survey and high-throughput sequencing technology, this study conducted a water quality factor analysis and aerobic denitrification bacteria α -diversity analysis, species composition, and network analysis. The results showed that the water body of Baiyangdian Lake was weakly alkaline, with the highest T and the lowest DO in the rainy season and the lowest T and the highest DO in the freezing season. There were significant differences between NH 4 + -N, NO 2 -N, TN, permanganate index, Fe, and Mn in Baiyangdian water under different hydrological scenarios ( - -N, NO 3 - -N, TN, permanganate index, Fe, and Mn in Baiyangdian water under different hydrological scenarios ( P < 0.01), and there was no significant difference in TP under different hydrological scenarios ( P > 0.05). The largest category in water bodies under different hydrological scenarios was Proteobacteria, and the genera with a higher relative abundance were Magnetospirillum , Aeromonas , Pseudomonas , Azospirillum , and Bradyrhizobium . In addition, within the aerobic denitrifying bacteria community, there were significant differences in α -diversity ( P < 0.001), with the highest abundance of microbial communities occurring during the freezing period, and the highest diversity and evenness of microbial communities during the dry and freezing periods. According to the RDA and Mantel analyses, the water quality driving factors of flora were different under different hydrological scenarios. The water quality driving factors of flora in the dry season were pH, NO 3 - -N, NO 2 - -N, and permanganate index; the driving factors of flora in the rainy season were pH, T , DO, NO 2 - -N, and TP; the driving factors of flora in the normal season were NO 2 - -N, Fe, and permanganate index; and the driving factors of flora in the freezing season were NO 3 - -N and NONO 2 - -N. Network analysis showed that there were temporal differences in species related to water quality driving factors. The genera related to water quality driving factors during the dry season were Magnetospirillum , Aeromonas , and Azoarcus , whereas the genera related to the rainy season were Magnetospirillum , Pseudomonas , and Aeromonas . The genera related to the normal season were Magnetospirillum , Pseudomonas , and Limnohabitans , and the genera related to the freezing period were Magnetospirillum , Azoarcus , and Pseudomonas . The relationship between key water quality factors (mainly T , DO, NO 3 - -N, and permanganate index) and aerobic denitrification flora in different hydrological scenarios was gradually changing with time. In conclusion, the study on the evolution characteristics of aerobic denitrification bacteria in Baiyangdian Lake under different hydrological scenarios and the driving mechanism of environmental factors could provide a basis for understanding the evolution mechanism of aerobic denitrification bacteria in the natural environment.

Objective: Sepsis is considered a major cause of health loss in children and had high mortality and morbidity. Currently, there is no reliable model for predicting the prognosis of pediatric patients with sepsis. This study aimed to analyze the clinical characteristics of sepsis in children and assess the risk factors associated with poor prognosis in pediatric sepsis patients to identify timely interventions and improve their outcomes., Methods: This study analyzed the clinical indicators and laboratory results of septic patients hospitalized in the Pediatric Intensive Care Unit of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China, from January 1, 2019, to December 31, 2021. Risk factors for sepsis were identified by logistic regression analyses., Results: A total of 355 children with sepsis were enrolled, with 333 children (93.8%) in the good prognosis group, and 22 children (6.2%) in the poor prognosis group. Among them, there were 255 patients (71.8%) in the sepsis group, and 100 patients (28.2%) in the severe sepsis group. The length of hospital stay in the poor prognosis group was longer than that in the good prognosis group (P<0.01). The levels of interleukin 1β (IL-1β) in the poor prognosis group were higher than those in the good prognosis group (P>0.05), and the platelet (PLT), albumin (ALB), and hemoglobin (Hb) levels were lower in the poor prognosis group (P<0.01). The IL-8 levels in the severe sepsis group were higher than those in the sepsis group (P<0.05). Multiple logistic regression analysis suggested that lower Hb levels, ALB levels, peak PLT counts, and higher IL-1β levels were independent risk factors for poor prognosis in children with sepsis., Conclusion: Lower Hb, ALB, and PLT counts and elevated IL-1β are independent risk factors for poor prognosis in children with sepsis., (© 2024. Huazhong University of Science and Technology.)

Inflammatory diseases, including infectious diseases, diabetes-related diseases, arthritis-related diseases, neurological diseases, digestive diseases, and tumor, continue to threaten human health and impose a significant financial burden despite advancements in clinical treatment. Pyroptosis, a pro-inflammatory programmed cell death pathway, plays an important role in the regulation of inflammation. Moderate pyroptosis contributes to the activation of native immunity, whereas excessive pyroptosis is associated with the occurrence and progression of inflammation. Pyroptosis is complicated and tightly controlled by various factors. Accumulating evidence has confirmed that epigenetic modifications and post-translational modifications (PTMs) play vital roles in the regulation of pyroptosis. Epigenetic modifications, which include DNA methylation and histone modifications (such as methylation and acetylation), and post-translational modifications (such as ubiquitination, phosphorylation, and acetylation) precisely manipulate gene expression and protein functions at the transcriptional and post-translational levels, respectively. In this review, we summarize the major pathways of pyroptosis and focus on the regulatory roles and mechanisms of epigenetic and post-translational modifications of pyroptotic components. We also illustrate these within pyroptosis-associated inflammatory diseases. In addition, we discuss the effects of novel therapeutic strategies targeting epigenetic and post-translational modifications on pyroptosis, and provide prospective insight into the regulation of pyroptosis for the treatment of inflammatory diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Potassium Channel Tetramerization Domain Containing 15 (KCTD15) participates in the carcinogenesis of several solid malignancies; however, its role in colorectal cancer (CRC) remains unclear. Here we find that KCTD15 exhibits lower expression in CRC tissues as compared to para-carcinoma tissues. Tetracycline (tet)-induced overexpression and knockdown of KCTD15 confirms KCTD15 as an anti-proliferative and pro-apoptotic factor in CRC both in vitro and in xenografted tumors. N6-methyladenosine (m6A) is known to affect the expression, stabilization, and degradation of RNAs with this modification. We demonstrate that upregulation of fat mass and obesity-associated protein (FTO), a classical m6A eraser, prevents KCTD15 mRNA degradation in CRC cells. Less KCTD15 RNA is recognized by m6A 'reader' YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) in FTO-overexpressed cells. Moreover, KCTD15 overexpression decreases protein expression of histone deacetylase 1 (HDAC1) but increases acetylation of critical tumor suppressor p53 at Lys373 and Lys382. Degradation of p53 is delayed in CRC cells post-KCTD15 overexpression. We further show that the regulatory effects of KCTD15 on p53 are HDAC1-dependent. Collectively, we conclude that KCTD15 functions as an anti-growth factor in CRC cells, and its expression is orchestrated by the FTO-YTHDF2 axis. Enhanced p53 protein stabilization may contribute to KCTD15's actions in CRC cells., (© 2024. The Author(s).)

Objective: Placenta-derived inflammation plays a vital role in the pathophysiology of gestational diabetes mellitus (GDM). IL-32 is a novel pro-inflammatory cytokine and metabolic regulator involved in the development of metabolic disease. We investigated the effect of IL-32 in GDM., Materials and Methods: First-trimester C-reactive protein (CRP) level was monitored in a case-control study of 186 women with GDM and 186 women without. Placental tissue was lysed and analyzed by high-resolution liquid chromatography-tandem mass spectrometry. Circulating level of inflammatory cytokines IL-32, IL-6, and TNF-α were measured by ELISA kits. The expression of placenta-derived macrophages, inflammatory cytokines, and related pathway proteins were assessed by reverse transcriptase-quantitative PCR, western blot, immunohistochemistry, or immunofluorescence., Results: First-trimester CRP level in peripheral blood was closely associated with glucose and insulin resistance index and was an independent correlation with the development of GDM. High-resolution liquid chromatography-tandem mass spectrometry revealed that placenta-derived CRP expression was dramatically elevated in women with GDM. Interestingly, the expression of placenta-derived IL-32 was also increased and located in the macrophages of placental tissue. Meanwhile, the expression of IL-6, TNF-α, and p-p38 were up-regulated in the placental tissues with GDM. Either IL-6 or TNF-α was colocated with IL-32 in the placental tissue. Importantly, circulating IL-32 throughout pregnancy was increased in GDM and was related to placental-derived IL-32 expression, circulating IL-6, and TNF-α, glucose and insulin resistance index., Conclusion: Increased circulating IL-32 throughout pregnancy was closely associated with placenta macrophage-derived IL-32 expression and GDM. First trimester IL-32 level in peripheral blood may serve to predict the development of GDM., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Recent evidence has shown that the long non-coding RNA (lncRNA) rPvt1 is elevated in septic myocardial tissues and that its knockdown attenuates sepsis-induced myocardial injury. However, the mechanism underlying the role of rPvt1 in septic myocardial dysfunction has not been elucidated. Methods: In this study, we performed transcriptomic, proteomic, and metabolomic assays and conducted an integrated multi-omics analysis to explore the association between rPvt1 and lipopolysaccharide (Lipopolysaccharide)-induced H9C2 cardiomyocyte injury. LncRNA rPvt1 silencing was achieved using a lentiviral transduction system. Results: Compared to those with the negative control, rPvt1 knockdown led to large changes in the transcriptome, proteome, and metabolome. Specifically, 2,385 differentially expressed genes (DEGs), 272 differentially abundant proteins and 75 differentially expressed metabolites (DEMs) were identified through each omics analysis, respectively. Gene Ontology functional annotation, Kyoto Encyclopedia of Genes and Genomes, Nr, eukaryotic orthologous groups, and Clusters of Orthologous Groups of Proteins pathway analyses were performed on these differentially expressed/abundant factors. The results suggested that mitochondrial energy metabolism might be closely related to the mechanism through which Pvt1 functions. Conclusion: These genes, proteins, metabolites, and their related dysregulated pathways could thus be promising targets for studies investigating the rPvt1-regluatory mechanisms involved in septic myocardial dysfunction, which is important for formulating novel strategies for the prevention, diagnosis and treatment of septic myocardial injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Wen, Yang, Yang and Liu.)

Sirtuins (SIRTs) are a nicotinic adenine dinucleotide (+) -dependent histone deacetylase that regulates critical signaling pathways in prokaryotes and eukaryotes. Studies have identified seven mammalian homologs of the yeast SIRT silencing message regulator 2, namely, SIRT1-SIRT7. Recent in vivo and in vitro studies have successfully demonstrated the involvement of SIRTs in key pathways for cell biological function in physiological and pathological processes of the cardiovascular system, including processes including cellular senescence, oxidative stress, apoptosis, DNA damage, and cellular metabolism. Emerging evidence has stimulated a significant evolution in preventing and treating cardiovascular disease (CVD). Here, we review the important roles of SIRTs for the regulatory pathways involved in the pathogenesis of cardiovascular diseases and their molecular targets, including novel protein post-translational modifications of succinylation. In addition, we summarize the agonists and inhibitors currently identified to target novel specific small molecules of SIRTs. A better understanding of the role of SIRTs in the biology of CVD opens new avenues for therapeutic intervention with great potential for preventing and treating CVD., Competing Interests: Competing interests The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Sepsis-induced myocardial depression (SIMD) is common in pediatric intensive care units and seriously threatens children's health. Recently, long noncoding RNAs (lncRNAs) have been showed to play important roles in various diseases; however, its role in SIMD is unclear. In this study, we used lipopolysaccharide (LPS)-treated rats and H9c2 cardiomyocytes to mimic SIMD in vivo and in vitro. We found that the expression of a novel lncRNA, we named lncRNA-AABR07066529.3, was elevated in LPS-induced rat heart tissue and H9c2 cardiomyocytes. In addition, LPS-induced inflammation, apoptosis, and pyroptosis were significantly exacerbated after lncRNA-AABR07066529.3 knockdown. Moreover, we found that myeloid differentiation factor 88 (MyD88) was upregulated in LPS-treated groups and was inhibited by lncRNA-AABR07066529.3. Besides, MyD88 knockdown abolished lncRNA-AABR07066529.3 silencing effects on inflammation, apoptosis, and pyroptosis induced by LPS in H9c2 cardiomyocytes. In our study, we found lncRNA-AABR07066529.3 exerted protective effects on LPS-induced cardiomyocytes by regulating MyD88 and might serve as a potential treatment target for SIMD., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: The association between gut microbes and short-chain fatty acids (SCFAs) and therapeutic responses of patients with lung cancer (LC) receiving therapy remains unknown., Methods: Fecal and serum samples were prospectively collected from patients with LC, classified as responders, if they presented durable clinical benefits, and non-responders, if not. The composition of gut microbes was analyzed using 16S ribosomal DNA sequencing. Serum SCFA concentrations were detected using gas chromatography. Cell proliferation, migration, invasion, cell cycle, and apoptosis assays were performed on isobutyric acid-treated A549 cells. Reverse transcription-quantitative PCR, Western blotting, immunocytochemistry, and immunofluorescence staining experiments have been performed to investigate the expression of associated genes or proteins., Results: Non-responders harbored higher microbiome α-diversity but lower β-diversity compared with responders. Compared to the patients with low α-diversity, those with high α-diversity showed significantly shorter progression-free survival. Additionally, β-diversity has also been observed between these two groups. Specifically, Parasutterella, Clostridiaceae , and Prevotella&#95;7 were more abundant among responders, whereas Bacteroides&#95;stercoris and Christensenellaceae&#95;R-7&#95;group were more abundant in non-responders. The serum SCFA (especially acetate and isobutyrate) levels tended to be higher in responders. Isobutyric acid inhibited the proliferation, migration, and invasion of A549 cells by inducing apoptosis and G1/S arrest while upregulating the expression of GPR41, GPR43, and GPR5C and downregulating that of PAR1, and increasing the activity of histone acetyltransferases., Conclusion: We revealed the influence of gut microbiota and SCFAs on the therapeutic responses in patients with LC and the anti-tumor effect of isobutyric acid, indicating their potential use as therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Wu, Zhang and Zhao.)

The metabolism of glucose and lipids is essential for energy production in the body, and dysregulation of the metabolic pathways of these molecules is implicated in various acute and chronic diseases, such as type 2 diabetes, Alzheimer's disease, atherosclerosis (AS), obesity, tumor, and sepsis. Post-translational modifications (PTMs) of proteins, which involve the addition or removal of covalent functional groups, play a crucial role in regulating protein structure, localization function, and activity. Common PTMs include phosphorylation, acetylation, ubiquitination, methylation, and glycosylation. Emerging evidence indicates that PTMs are significant in modulating glucose and lipid metabolism by modifying key enzymes or proteins. In this review, we summarize the current understanding of the role and regulatory mechanisms of PTMs in glucose and lipid metabolism, with a focus on their involvement in disease progression associated with aberrant metabolism. Furthermore, we discuss the future prospects of PTMs, highlighting their potential for gaining deeper insights into glucose and lipid metabolism and related diseases., (© 2023. The Author(s).)

Purpose: Myocardial injury is a common complication in patients with endotoxaemia/sepsis, especially in children. Moreover, it develops through an unclear pathophysiological mechanism, and effective therapies are lacking. Recently, RNA modification, particularly N 6 -methyladenosine (m 6 A) modification, has been found to be involved in various physiological processes and to play important roles in many diseases. However, the role of m 6 A modification in endotoxaemia/sepsis-induced myocardial injury is still in its infancy. Therefore, we attempted to construct the m 6 A modification map of myocardial injury in a rat model treated by lipopolysaccharide (LPS) and explore the role of m 6 A modification in LPS-induced myocardial injury., Method: Myocardial injury adolescent rat model was constructed by intraperitoneal injection of LPS. m 6 A RNA Methylation Quantification Kit was used to detect overall level of m 6 A modification in rat cardiac tissue. m 6 A-specific methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were conducted to identify the altered m 6 A-modified genes and differentially expressed genes in cardiac tissue of rats treated by LPS and control rats (6 versus. 6). Bioinformatics was used to analyze the functions of differentially m 6 A modified genes, differentially expressed genes, and genes with both differential m 6 A modification and differential expression. qPCR was used to detect expression of m 6 A modification related enzymes., Result: We found that the overall level of m 6 A modification in cardiac tissue of the LPS group was up-regulated compared with that of the control group. MeRIP-seq and RNA-seq results showed that genes with differential m 6 A modification, genes with differential expression and genes with both differential m 6 A modification and differential expression were closely associated with inflammatory responses and apoptosis. In addition, we found that m 6 A-related enzymes (Mettl16, Rbm15, Fto, Ythdc2 and Hnrnpg) were differentially expressed in the LPS group versus. the control group., Conclusion: m 6 A modification is involved in the pathogenesis process of LPS-induced myocardial injury, possibly through the regulation of inflammatory response and apoptosis-related pathways. These results provide valuable information regarding the potential pathogenic mechanisms underlying LPS-induced myocardial injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Zhang, Yang, Wen, Wang, Zhang, Yang and Liu.)

Introduction: The influence of reduced functional status has become increasingly relevant because of the gradual decline in mortality rate over the recent years. Nonetheless, only a few studies investigating the functional status of patients with trauma at hospital discharge have been conducted. This study aimed to identify the risk factors influencing the mortality rate in pediatric trauma survivors at a pediatric intensive care unit and analyze their functional status using the Functional Status Scale (FSS)., Methods: A retrospective analysis was conducted at Shengjing Hospital of China Medical University. Children admitted to the pediatric intensive care unit between January 2015 and January 2020 who met the trauma diagnostic criteria were included. The FSS score and the Injury Severity Score (ISS) were recorded upon admission and discharge, respectively. Clinical data were compared between the survival and non-survival groups to identify the risk factors for poor prognosis. The risk factors for mortality were identified using multivariate and univariate analyses., Results: A total of 246 children {59.8%, male; median [interquartile range (IQR)] age: 3 [1-7] years} were diagnosed with trauma (including head trauma, chest trauma, abdominal trauma, and extremity trauma). Of these patients, 207 were discharged, 11 dropped out mid-treatment, and 39 died (hospital mortality rate, 15.9%). Upon admission, the median FSS and trauma scores were 14 (IQR, 11-18) and 22 (IQR, 14-33) points, respectively. At discharge, the FSS score was 8 (IQR, 6-10) points. The patient clinical status improved with a ΔFSS score of -4 (IQR, -7, 0) points. At hospital discharge, 119 (48.3%), 47 (19.1%), 27 (11.0%), 12 (4.8%), and 2 (0.9%) survivors had good, mildly abnormal, moderately abnormal, severely abnormal, and very severely abnormal function, respectively. Reduced functional status in patients was categorized as follows: motor, 46.4%; feeding, 26.1%; sensory, 23.2%; mental, 18.4%; and communication, 17.9%. In the univariate analysis, ISS >25 points, shock, respiratory failure, and coma were independently associated with the mortality rate. Multivariate analysis revealed that the ISS was an independent risk factor for mortality., Conclusion: The mortality rate of patients with trauma was high. ISS was an independent risk factor for mortality. Mildly reduced functional status remained at discharge and was reported in nearly half of the discharged patients. Motor and feeding functions were the most severely impacted domains., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Yang, Zhang, Yang, Xu, Wang, Gao and Liu.)

Background: Research on coagulation dysfunction following burns is controversial. This study aimed to describe the coagulation changes in severe burn patients by examining coagulation parameters., Methods: Patients with third-degree total body surface area (TBSA) burns of ≥30% were enrolled between 2017 and 2020. Platelet (PLT) count and coagulation indexes (including APTT, INR, FIB, DD, and AT Ⅲ) were measured at admission and once weekly for 8 weeks, and statistical analysis was performed. The patient medical profiles were reviewed to extract demographic and clinical data, including TBSA, third-degree TBSA, and inhalation injury. The total intravenous fluids and transfusions of crystalloids, fresh frozen plasma (FFP), and red blood cells (RBC) were calculated during the forty-eight-hour period. The number of sepsis cases was recorded., Results: We enrolled 104 patients , and while the overall coagulation trend fluctuated, inflection points appeared around one week and demonstrated hypercoagulability. INR was significantly higher in the non-survival group than in the survivors' group from admission to three weeks after burn (all p<0.01). From post-injury week 1 to post-injury week 3, the APTT in the non-survival group was greater than in the survival group, but the non-survival group's PLT count was lower than that in the survival group (all p<0.05). At two and three weeks after burns, the FIB levels in the non-survival group were significantly lower than those of the survival group (both p<0.01). The prevalence of inhalation injury and the proportion of sepsis cases were significantly higher in the non-survival group than in the survival group ( p ＜ 0.05, p ＜ 0.001, respectively). At the time of death, APTT, INR, and FDP levels were significantly higher in the non-survival group in the survivor group, and FIB, ATIII, and PLT were significantly lower than in the survivor group (all p<0.01). On the day of death, nine of the 12 dead patients had disseminated intravascular coagulation (DIC)., Conclusions: Coagulation dysfunction was most prominent in severe burn patients 1 week after injury and presented as hypercoagulability. Large-area burn injury, large amounts of fluid resuscitation, inhalation injury, and sepsis may all contribute to coagulation dysfunction, which can further develop into DIC and even death in severe burns patients., Competing Interests: Conflict of interest All authors have no conflict to declare., (Copyright © 2022 Elsevier Ltd and ISBI. All rights reserved.)

Purpose: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China., Methods: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed., Results: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel., Conclusion: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi., (© 2023. The Author(s).)

Sarcomas, comprising approximately 1% of human malignancies, show a poor response to treatment and easy recurrence. Metabolic reprogramming play an important role in tumor development in sarcomas. Accumulating evidence shows that non-coding RNAs (ncRNAs) participate in regulating the cellular metabolism of sarcomas, which improves the understanding of the development of therapy-resistant tumors. This review addresses the regulatory roles of metabolism-related ncRNAs and their implications for sarcoma initiation and progression. Dysregulation of metabolism-related ncRNAs is common in sarcomas and is associated with poor survival. Emerging studies show that abnormal expression of metabolism-related ncRNAs affects cellular metabolism, including glucose, lipid, and mitochondrial metabolism, and leads to the development of aggressive sarcomas. This review summarizes recent advances in the roles of dysregulated metabolism-related ncRNAs in sarcoma development and stemness and describes their potential to serve as biological biomarkers for disease diagnosis and prognosis prediction, as well as therapeutic targets for treating refractory sarcomas., Competing Interests: Conflict of interest statement The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Uncontrolled diabetes causes a catabolic state with multi-organic complications, of which impairment on skeletal muscle contributes to the damaged mobility. Kcnma1 gene encodes the pore-forming α-subunit of Ca 2+ - and voltage-gated K + channels of large conductance (BK channels), and loss-of-function mutations in Kcnma1 are in regards to impaired myogenesis. Herein, we observed a time-course reduction of Kcnma1 expression in the tibialis anterior muscles of leptin receptor-deficient (db/db) diabetic mice. To investigate the role of Kcnma1 in diabetic muscle atrophy, muscle-specific knockdown of Kcnma1 was achieved by mice receiving intravenous injection of adeno-associated virus-9 (AAV9)-encoding shRNA against Kcnma1 under the muscle creatine kinase (MCK) promoter. Impairment on muscle mass and myogenesis were observed in m/m mice with AAV9-shKcnma1 intervention, while this impairment was more obvious in diabetic db/db mice. Simultaneously, damaged mitochondrial dynamics and biogenesis showed much severer in db/db mice with AAV9-shKcnma1 intervention. RNA sequencing revealed the large transcriptomic changes resulted by Kcnma1 knockdown, and changes in mitochondrial homeostasis-related genes were validated. Besides, the artificial alteration of Kcnma1 in mouse C2C12 myoblasts was achieved with an adenovirus vector. Consistent results were demonstrated by Kcnma1 knockdown in palmitate-treated cells, whereas opposite results were exhibited by Kcnma1 overexpression. Collectively, we document Kcnma1 as a potential keeper of mitochondrial homeostasis, and the loss of Kcnma1 is a critical event in priming skeletal muscle loss in diabetes., (© 2023 Federation of American Societies for Experimental Biology.)

Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies., (© 2022. The Author(s).)

Background: Septic shock is associated with increased mortality. Predicting mortality, including early prediction for septic shock patients in intensive care units (ICUs), remains an important challenge., Method: We searched the Medical Information Mart for Intensive Care IV database. Odds ratios (ORs) with 95% confidence intervals (CIs) of the relationships between shock index (SI), modified SI (MSI), and diastolic SI (DSI) of patients with septic shock requiring vasopressors and 3-day/in-hospital mortality were calculated using logistic regression models. The time-course changes of these parameters were compared between survivors and non-survivors. The performance of the different parameters was described by the area under the receiver operating characteristic (ROC) curve (AUC) and compared with DeLong analysis., Results: A total of 1266 patients with septic shock requiring vasopressors were identified. The 3-day mortality rate and in-hospital mortality rate were 8.7% and 23.5%, respectively. Multivariable logistic regression analysis showed significant associations between pre-vasopressor SI/MSI/DSI and 3-day mortality in patients with septic shock requiring vasopressors in fully adjusted models (Ps for trend < 0.01). The AUCs of pre-vasopressor SI, MSI, and DSI were 0.746, 0.710, and 0.732 for 3-day mortality, respectively. There were significant differences in the time-course of SI, MSI, and DSI between survivors and non-survivors at 3-day/in-hospital mortality among patients with septic shock requiring vasopressors (repeated-measures ANOVA, inter-subjects difference P < 0.001)., Conclusion: Pre-vasopressor SI, MSI, and DSI values identified patients with septic shock requiring vasopressors who are at increased risk of early death. Of these easy-to-acquire values, SI and MSI show a comparatively better performance., (© 2022. The Author(s).)

Background: Sarcomas comprise approximately 1% of all human malignancies; treatment resistance is one of the major reasons for the poor prognosis of sarcomas. Accumulating evidence suggests that non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs, and circular RNAs, are important molecules involved in the crosstalk between resistance to chemotherapy, targeted therapy, and radiotherapy via various pathways., Methods: We searched the PubMed (MEDLINE) database for articles regarding sarcoma-associated ncRNAs from inception to August 17, 2022. Studies investigating the roles of host-derived miRNAs, long ncRNAs, and circular RNAs in sarcoma were included. Data relating to the roles of ncRNAs in therapeutic regulation and their applicability as biomarkers for predicting the therapeutic response of sarcomas were extracted. Two independent researchers assessed the quality of the studies using the Würzburg Methodological Quality Score (W-MeQS)., Results: Observational studies revealed the ectopic expression of ncRNAs in sarcoma patients who had different responses to antitumor treatments. Experimental studies have confirmed crosstalk between cellular pathways pertinent to chemotherapy, targeted therapy, and radiotherapy resistance. Of the included studies, W-MeQS scores ranged from 3 to 10 (average score = 5.42). Of the 12 articles that investigated ncRNAs as biomarkers, none included a validation cohort. Selective reporting of the sensitivity, specificity, and receiver operating curves was common., Conclusions: Although ncRNAs appear to be good candidates as biomarkers for predicting treatment response and therapeutics for sarcoma, their differential expression across tissues complicates their application. Further research regarding their potential for inhibiting or activating these regulatory molecules to reverse treatment resistance may be useful., Funding: This study's literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang)., Competing Interests: HC, TZ, FZ, TZ No competing interests declared, (© 2022, Chen et al.)

Abstract: Background: The exact molecular mechanisms underlying sepsis remain unclear. Accumulating evidence has shown that noncoding RNAs (ncRNAs) are involved in sepsis and sepsis-associated organ dysfunction (SAOD). Methods: We performed this updated systematic review focusing mainly on research conducted in the last 5 years regarding ncRNAs associated with sepsis and SAOD. The following medical subject headings were used in the PubMed database from October 1, 2016, to March 31, 2022: "microRNA," "long noncoding RNA," "circular RNA," "sepsis," and/or "septic shock." Studies investigating the role of ncRNAs in the pathogenesis of sepsis and as biomarkers or therapeutic targets in the disease were included. Data were extracted in terms of the role of ncRNAs in the pathogenesis of sepsis and their applicability for use as biomarkers or therapeutic targets in sepsis. The quality of the studies was assessed using a modified guideline from the Systematic Review Center for Laboratory Animal Experimentation. Results: A total of 537 original studies investigated the potential roles of ncRNAs in sepsis and SAOD. Experimental studies in the last 5 years confirmed that long ncRNAs have important regulatory roles in sepsis and SAOD. However, studies on circular RNAs and sepsis remain limited, and more studies should be conducted to elucidate this relationship. Among the included studies, the Systematic Review Center for Laboratory Animal Experimentation scores ranged from 3 to 7 (an average score of 3.78). Notably, 94 ncRNAs were evaluated as potential biomarkers for sepsis, and selective reporting of the sensitivity, specificity, and receiver operating characteristic curve was common. A total of 117 studies demonstrated the use of ncRNAs as potential therapeutic targets in sepsis and SAOD. At a molecular level, inflammation-related pathways, mitochondrial dysfunction, cell apoptosis, and/or oxidative stress were the most extensively studied. Conclusion: This review suggests that ncRNAs could be good biomarkers and therapeutic candidates for sepsis and SAOD. Prospective, large-scale, and multicenter cohort studies should be performed to evaluate specific ncRNAs as biomarkers and test the organ-specific delivery of these regulatory molecules when used as therapeutic targets., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by the Shock Society.)

Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death in intensive care units. The development of sepsis-associated organ dysfunction (SAOD) poses a threat to the survival of patients with sepsis. Unfortunately, the pathogenesis of sepsis and SAOD is complicated, multifactorial, and has not been completely clarified. Recently, numerous studies have demonstrated that pyroptosis, which is characterized by inflammasome and caspase activation and cell membrane pore formation, is involved in sepsis. Unlike apoptosis, pyroptosis is a pro-inflammatory form of programmed cell death that participates in the regulation of immunity and inflammation. Related studies have shown that in sepsis, moderate pyroptosis promotes the clearance of pathogens, whereas the excessive activation of pyroptosis leads to host immune response disorders and SAOD. Additionally, transcription factors, non-coding RNAs, epigenetic modifications and post-translational modifications can directly or indirectly regulate pyroptosis-related molecules. Pyroptosis also interacts with autophagy, apoptosis, NETosis, and necroptosis. This review summarizes the roles and regulatory mechanisms of pyroptosis in sepsis and SAOD. As our understanding of the functions of pyroptosis improves, the development of new diagnostic biomarkers and targeted therapies associated with pyroptosis to improve clinical outcomes appears promising in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wen, Liu, Tong, Zhang and Yang.)

Cardiovascular disease (CVD) has become a leading cause of mortality and morbidity globally, making it an urgent concern. Although some studies have been performed on CVD, its molecular mechanism remains largely unknown for all types of CVD. However, recent in vivo and in vitro studies have successfully identified the important roles of posttranslational modifications (PTMs) in various diseases, including CVD. Protein modification, also known as PTMs, refers to the chemical modification of specific amino acid residues after protein biosynthesis, which is a key process that can influence the activity or expression level of proteins. Studies on PTMs have contributed directly to improving the therapeutic strategies for CVD. In this review, we examined recent progress on PTMs and highlighted their importance in both physiological and pathological conditions of the cardiovascular system. Overall, the findings of this review contribute to the understanding of PTMs and their potential roles in the treatment of CVD., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Yong-Ping Liu et al.)

Sepsis-induced myocardial depression is common among patients in the intensive care unit; however, the exact mechanisms underlying this condition remain unclear. We investigated differences in the expression of specific proteins and determined the potential functions of the proteins in a rat model of lipopolysaccharide-induced septic shock. Left ventricular tissue was excised from 16 rats (sepsis group, 8; control group, 8) and analysed. Quantitative analysis of the global proteome was performed using 4D label-free technique. Bioinformatic analyses were conducted based on differentially expressed (DE) proteins. Parallel reaction monitoring (PRM) validation for selected proteins and western blotting for selected global protein modifications in heart tissues were also performed. As a result, out of 3653 proteins identified, 108 were expressed differentially between the two groups. The bioinformatic analyses revealed that DE proteins play important roles in metabolism- and immune-related pathways. PRM results supported the plausibility and reliability of the proteomics data. Modification of heart tissue acetyllysine, succinyllysine, 2-hydroxyisobutyryllysine, and lactyllysine revealed clear differences between the two groups, indicating the effects of protein modification. Our study suggested that expression patterns of global proteins in heart tissue were different between the two groups. These results provide new valuable information on the possible mechanisms underlying sepsis-induced myocardial depression. SIGNIFICANCE: The expression patterns of global proteins in the heart tissues of patients with sepsis and control groups remain unknown. In this study, we used the 4D label-free proteomics technique to compare differentially expressed (DE) proteins between the sepsis and control groups. We identified 3653 proteins, 108 of which were expressed differentially between the sepsis and control groups. Further bioinformatic analyses revealed that DE proteins play critical roles in metabolism- and immune-related processes and pathways. Interestingly, modification of heart tissue acetyllysine, succinyllysine, 2-hydroxyisobutyryllysine, and lactyllysine revealed clear differences between the sepsis and control groups. The findings of this study improve our understanding of the basic molecular mechanisms underlying sepsis-induced myocardial depression., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The potential association between maternal exposure to PM 10 ranging from 3 months prior to conception to the end of the early trimester and the risk of anorectal atresia/stenosis in offspring has not been established. Thus, we determined the association between maternal exposure to PM 10 and risk of anorectal atresia/stenosis in offspring in this study. We recruited 713 patients including 480 male and 233 female with anorectal atresia/stenosis and 7950 randomly selected healthy offspring from the Maternal and Child Health Certificate Registry of Liaoning Province and delivered between 1 January 2010 and 31 December 2015. Monthly PM 10 concentrations were retrieved from the Environment Protection Bureau of each city in Liaoning Province. We established a multivariable logistic regression model to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Maternal exposure to PM 10 was associated with an increased risk for anorectal atresia/stenosis in offspring during the 3 months prior to conception (per 10 μg/m 3 increment: OR = 1.15, 95% CI = 1.03-1.20; per SD [27 μg/m 3 ] increment: OR = 1.33, 95% CI = 1.09-1.63) and the first trimester (per 10 μg/m 3 increment: OR = 1.08, 95% CI = 1.00-1.17; per SD [28 μg/m 3 ] increment: OR = 1.26, 95% CI = 1.01-1.57). Evaluation of the association with a shorter exposure window (1 month) revealed a positive association between anorectal atresia/stenosis and PM 10 from the 3rd month prior to pregnancy to each month of the 1st trimester. Maternal exposure to PM 10 3 months prior to conception and during the 1st trimester was associated with an increased risk of anorectal atresia/stenosis in the offspring. Future perspective cohort studies are needed to confirm our findings., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Landscape water is an important part of urban water systems, and excessive nitrogen affects its ecological functions. This study aimed to investigate the temporal and spatial distribution characteristics and driving factors of the community structure of denitrifying bacteria from landscape water. The functional gene nirS was used as a functional marker to explore the community of denitrifying bacteria in the water and sediment of landscape water. Based on parameters of the water and sediment, the temporal and spatial distribution characteristics and driving factors of the community of denitrifying bacteria were studied. The results showed significant seasonal differences in water parameters and spatial differences in sediment nitrogen ( P <0.001). No significant difference ( P >0.05) was observed in α-diversity; the EC and SOEF-NH 4 + -N were important factors affecting the α -diversity of the water and sediment. Denitrifying bacteria mainly belonged to the phylum Proteobacteria and the genera Dechloromonas, Rhodocyclaceae, Pseudomonas, Rhodobacter , and Thauera . Principal coordinate analysis revealed that the community of denitrifying bacteria in the water and sediment exhibited significant spatial differences ( P <0.001); keystone denitrifying bacteria in the water also exhibited significant spatial differences ( P <0.001). RDA and RF analysis showed that the permanganate index and TP were the main environmental factors affecting the total and keystone denitrifying bacteria in the water; SOEF-NH 4 + -N, IEF-NH 4 + -N, and WAEF-NO 3 - -N were the main environmental factors affecting the total and keystone denitrifying bacteria in the sediment. These findings could serve as a reference to understand the interaction mechanism between nitrogen and denitrification bacterial communities in landscape water.

Background: Pre-gestational diabetes mellitus (PGDM) has been known to be a risk factor for congenital heart defects (CHDs) for decades. However, the associations between maternal PGDM and gestational diabetes mellitus (GDM) and the risk of specific types of CHDs and congenital anomalies (CAs) in other systems remain under debate. We aimed to investigate type-specific CAs in offspring of women with diabetes and to examine the extent to which types of maternal diabetes are associated with increased risk of CAs in offspring., Methods and Findings: We searched PubMed and Embase from database inception to 15 October 2021 for population-based studies reporting on type-specific CAs in offspring born to women with PGDM (combined type 1 and 2) or GDM, with no limitation on language. Reviewers extracted data for relevant outcomes and performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. Risk of bias appraisal was performed using the Cochrane Risk of Bias Tool. This study was registered in PROSPERO (CRD42021229217). Primary outcomes were overall CAs and CHDs. Secondary outcomes were type-specific CAs. Overall, 59 population-based studies published from 1990 to 2021 with 80,437,056 participants met the inclusion criteria. Of the participants, 2,407,862 (3.0%) women had PGDM and 2,353,205 (2.9%) women had GDM. The meta-analyses showed increased risks of overall CAs/CHDs in offspring born to women with PGDM (for overall CAs, relative risk [RR] = 1.99, 95% CI 1.82 to 2.17, P < 0.001; for CHDs, RR = 3.46, 95% CI 2.77 to 4.32, P < 0.001) or GDM (for overall CAs, RR = 1.18, 95% CI 1.13 to 1.23, P < 0.001; for CHDs, RR = 1.50, 95% CI 1.38 to 1.64, P < 0.001). The results of the meta-regression analyses showed significant differences in RRs of CAs/CHDs in PGDM versus GDM (all P < 0.001). Of the 23 CA categories, excluding CHD-related categories, in offspring, maternal PGDM was associated with a significantly increased risk of CAs in 21 categories; the corresponding RRs ranged from 1.57 (for hypospadias, 95% CI 1.22 to 2.02) to 18.18 (for holoprosencephaly, 95% CI 4.03 to 82.06). Maternal GDM was associated with a small but significant increase in the risk of CAs in 9 categories; the corresponding RRs ranged from 1.14 (for limb reduction, 95% CI 1.06 to 1.23) to 5.70 (for heterotaxia, 95% CI 1.09 to 29.92). The main limitation of our analysis is that some high significant heterogeneity still persisted in both subgroup and sensitivity analyses., Conclusions: In this study, we observed an increased rate of CAs in offspring of women with diabetes and noted the differences for PGDM versus GDM. The RRs of overall CAs and CHDs in offspring of women with PGDM were higher than those in offspring of women with GDM. Screening for diabetes in pregnant women may enable better glycemic control, and may enable identification of offspring at risk for CAs., Competing Interests: The authors have declared that no competing interests exist.

Accumulating studies have highlighted the biologic significances of ferroptosis modification in tumor progression, but little is known whether ferroptosis modification patterns have potential roles in tumor microenvironment (TME) immune cell infiltration of hepatocellular carcinoma (HCC). In this study, we evaluated 51 ferroptosis regulators and performed consensus clustering algorithm to determine ferroptosis modification patterns and the ferroptosis related gene signature in HCC. Gene set variation analysis (GSVA) was employed to explore biological molecular variations in distinct ferroptosis modification patterns. Single sample gene set enrichment analysis (ssGSEA) algorithm was performed to quantify the relative infiltration levels of various immune cell subsets. Principal component analysis (PCA) algorithm was used to construct the ferroptosisSig score to quantify ferroptosis modification patterns of individual tumors with immune responses. Three distinct ferroptosis modification patterns were identified. GSVA enrichment analysis indicated that three ferroptosis modification subgroups were enriched in different metabolic pathways. ssGSEA analysis determined that 19 of 24 immune infiltrating cells had significant differences in three distinct ferroptosis patterns. A 91-ferroptosis gene signature was constructed to stratify patients into two ferroptosisSig score groups. Patients in the higher ferroptosisSig score were characterized by significantly prolonged survival time compared with patients in the lower ferroptosisSig score group ( p < .0001). An immunotherapy cohort confirmed patients with higher ferroptosisSig score determined significant therapeutic advantages and clinical benefits. Receiver operating characteristic (ROC) curve analysis confirmed the predictive capacity of anti-PD/L1 immunotherapy by ferroptosisSig score. Our study indicated the ferroptosis modification played a significant role in TME heterogeneity and complexity. Evaluating the ferroptosis modification pattern of individual tumor could strengthen our cognition of TME infiltration characteristics and guide more effective clinic immunotherapy strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Wu, Zhang and Wang.)

In order to study the spatial and temporal distribution characteristics of aerobic denitrification bacteria in the sediments of Gangnan Reservoir, the aerobic denitrification bacterial community was analyzed using a MiSeq high-throughput sequencing technique based on the napA gene. Moreover, the composition, diversity, difference, and network analysis of the aerobic denitrification bacterial community were investigated. The results showed higher α -diversity (Chao1 index, Observed species index, and Shannon index) in autumn and winter than that in spring and summer; that is, the richness and diversity of sampling sites in autumn and winter were higher. In terms of spatial distribution, the Chao1 index, Observed species index, Shannon index, and Simpson index of the bacterial community in the sampling sites in the transition zone were higher than those in the sampling sites in the inflow area and the main reservoir area, indicating that the richness and diversity of the bacterial community in the sampling sites in the transition zone were the highest. The aerobic denitrifying bacteria in the sediments of Gangnan Reservoir mainly belong to Protebacteria. The first dominant class was β -Proteobacteria, and the first dominant genus was Thauera . A Venn diagram analysis indicated that the community of aerobic denitrification bacteria exhibited significant spatial and temporal differences. At the spatial level, there were higher numbers of different species based on LEfSe analysis than that at the seasonal level. Among the marker species screened by random forest analysis, Comamonas had the highest contribution in all spatial sampling sites, whereas Pectobacterium had the highest contribution in all seasonal sampling sites. Network analysis showed that there were nine modules, including 565 edges of 297 nodes; 47 keystone species were obtained based on the indicator OTUs analysis and network analysis. The principal co-ordinates analysis revealed that keystone species in the spatial distribution exhibited significant differences (Adonis, P <0.001). The results of this study provide scientific basis for the separation and identification of efficient aerobic denitrifying bacteria.

Context: The immune system plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). Monocytes, the main innate immune cells, are especially important in the maintenance of a normal pregnancy., Objective: Here, we investigated the potential effect of monocytes in GDM., Methods: Monocyte count was monitored throughout pregnancy in 214 women with GDM and 926 women without in a case-control and cohort study. Circulating levels of inflammatory cytokines, placenta-derived macrophages, and their products were measured., Results: Throughout pregnancy, monocyte count was significantly decreased in women with GDM, and was closely associated with glucose level, insulin resistance, and newborn weight. First-trimester monocyte count outperformed that of the second and third trimester as a risk factor and diagnostic predictor of GDM and macrosomia both in the case-control and cohort study. In addition, our cohort study showed that as first-trimester monocyte count decreased, GDM and macrosomia incidence, glucose level, and newborn weight increased in a stepwise manner. Risk of GDM started to decrease rapidly when first-trimester monocyte count exceeded 0.48 × 109/L. Notably, CD206 and interleukin 10 (IL-10) were significantly lower, whereas CD80, CD86, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) were higher both in GDM placental tissue and peripheral blood. First-trimester monocyte count was positively related to IL-10 and CD206, but negatively related to CD80, CD86, TNF-α, and IL-6., Conclusion: Decreased monocyte count throughout pregnancy was closely associated with the development of GDM, macrosomia, and the chronic inflammatory state of GDM. First-trimester monocyte count has great potential as an early diagnostic marker of GDM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dissolved organic matter(DOM) is an important component of the organic matter in the environment. This study explored the characteristics of DOM. The components and spectral characteristics of rainwater DOM were measured using Ultraviolet-visible absorption spectrum(UV-vis) and three-dimensional fluorescence spectrum in the Hebei province. The results showed significant differences for DOM molecular weight in the northern, central, and southern region; the DOM of the northern region exhibited the lowest molecular weight. Two humic-like(C1 and C4), one protein-like(C2) and one fulvic-like(C3) components were identified by parallel factor(PARAFAC) analysis. Component C2 had a significant positive correlation with components C3 and C4( P <0.001), which may have similar sources. The C2(protein-like substances) accounted for the major proportion of DOM with the average abundance 40.59%. The DOM components based on PARAFAC exhibited significantly difference between city and country regions without spatial difference, which was consistent with the result of fluorescence regional integration(FRI). The protein-like substances based on FRI were the main components, which accounted for 61.59%-89.01%. Redundancy analysis(RDA) showed that total nitrogen, nitrate, and ammonia were the main environmental factors determining the distribution of DOM. Spectral indices presented a significant difference between city and country regions. High fluorescence(FI) and biological(BIX) and low humification(HIX) values showed that summer rain exhibited the strong autochthonous and low humification characteristics, and country region have stronger autochthonous characteristics than city region. The regression analysis demonstrates that the prediction accuracy of rainwater quality parameters in city region is high. From all the results, rainwater DOM, showing strong autogenous characteristics, exhibited significant differences between city and country regions without spatial difference in Hebei. Meanwhile, it can also provide technical support for rainwater nitrogen concentration prediction based on DOM components.

Ovarian cancer (OC) is one of the most common gynecologic malignancies with poor survival rate, and Iberin is a member of isothiocyanate family with anti-tumor activity. However, the role of Iberin in OC development has not been reported yet. In this study, A2780 and OVCAR-3 cells were treated with gradient concentrations of Iberin to investigate the effect of Iberin on OC in vitro. Meanwhile, the in vivo tumorgenesis experiment was performed using female BALB/c nude mice treated with Iberin. Iberin inhibited cell proliferation, induced G2 cell cycle arrest and promoted cell apoptosis in OC cells. Besides, Iberin reduced GSH/GSSG level, enhanced ROS accumulation, and activated MAPK signaling in OC cells. More interestingly, ROS scavenger (NAC) compensated the anti-proliferative and pro-apoptotic effects of Iberin on OC cells, suggesting the involvement of ROS in the regulation of Iberin on OC cell growth. Notably, Iberin induced down-regulation of glutathione peroxidase-1 (GPX1), and over-expression of GPX1 reversed Iberin-mediated alterations in the proliferation, apoptosis and ROS accumulation of OC cells. The in vivo tumorgenesis study further evidenced the protection of Iberin against OC development. Besides, Iberin displayed a synergistic effect on the enhancement of chemo-sensitivity in OC cells. In summary, our study demonstrates the anti-tumor effect of Iberin on OC and its potential as a therapeutic agent against OC in the future., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Dissolved organic matter (DOM) plays an important role in the evolution of microbial communities. Meanwhile, ecological water delivery is an important feature of Baiyangdian Lake. To explore how the structure of the aerobic denitrification bacteria community responds to DOM during the water delivery period, the DOM components of water were examined and high-throughput sequencing of aerobic denitrification bacteria was performed. The results showed significant differences in DOM concentration in Baiyangdian Lake, with the estuary area exhibiting lower DOM concentrations. The water exhibited strong autogenous source, while DOM in the estuary area had a higher molecular weight and degree of humification. Three protein-like substances (C1, C2, and C4) and one humic-like substance (C3) were identified through PARAFAC. The protein-like substances accounted for the major proportion of DOM, which was consistent with the results of fluorescence regional integration (FRI). The genera of the water body were mainly in the Protebacterice phylum, including Cupriavidus , Aeromonas , Thauera , Shewanella , and Pseudomonas . Meanwhile, Cupriavidus , Thauera , Shewanella , Agrobacterium , and Pseudomonas were the main indicator species, according to random forest (RF) analysis. Through network analysis, 35 key nodes of the network were obtained, belonging to Thauera , Cupriavidus, and Unclassified&#95;bacteria, respectively. Redundancy analysis (RDA) showed that a humic-like substance was the main environmental factor regulating the whole structure of the aerobic denitrification bacterial community, while protein-like substances played important roles in changes to the indicator species and key nodes of the community. Overall, protein-like substances could provide an important reference for selecting carbon sources during the screening of efficient and cold resistance aerobic denitrification bacteria that are adapted to actual water bodies.

The sources and distribution of dissolved organic matter (DOM) in the interstitial water of Baiyangdian Lake sediments were analyzed using the ultraviolet-visible absorption spectrum (UV-vis) method and three-dimensional excitation emission matrix fluorescence spectroscopy-parallel factor analysis (EEM-PARAFAC). Results showed that the DOM concentrations and molecular weight were significantly higher in summer than in spring and autumn, based on a 254 and E2/E3 values. Three protein-like substance (C1, C2, and C3) and two humic-like substances (C4, C5) were identified with the PARAFAC model. Moreover, protein-like substances accounted for the majority of DOM, reaching (63.56±16.07)%. Total DOM fluorescence intensity, the fluorescence intensity of each component, and the relative abundance exhibited significant spatial variation among the different functional zones in Baiyangdian Lake. Protein-like substances were mainly found in the breeding area, whereas humic-like substances mainly occurred in the natural area. The high BIX, FI, β : α , and low HIX indicated that DOM in sediment interstitial water exhibited low humification and highly autochthonous characteristics. Moreover, the perfect regression equations between water quality and the fluorescent components could provide a useful reference for managers aiming to protect the ecosystem of Baiyangdian Lake.

In order to reveal the interaction of overlying water-interstitial water nitrogen and phosphorus nutrient salt in summer at the entrance region of Baiyangdian Lake, this study sampled six main rivers in the region during July 2019. An analysis of the overlying water and interstitial water quality characteristics and the diffusion flux of applied nutrients at the sediment-water interface revealed the effects of nutrient diffusion on sediments and overlying water. The overlying water analysis showed that the water quality was slightly alkaline in the Baiyangdian Lake. The content of dissolved oxygen (DO) was lower, which provided an anaerobic environment for the release of endogenous pollutants from sediments. The ammonia nitrogen (NH 4 + -N) ranged from 0.35 to 1.76 mg·L -1 , and the content of ammonia nitrogen was the highest in the Zhulong River, which was the main source of water supply. The nitrate nitrogen (NO 3 - -N) content ranged from 0.75 to 1.97 mg·L -1 . The total dissolved nitrogen (TDN) ranged from 0.99 to 2.70 mg·L -1 , and the content of TDN was the highest in Puhe River. The content of total dissolved phosphorus (TDP) was 0.03 to 0.15 mg·L -1 , and the content of TDP was the highest was Baigouyin River, which is near the residential area. The results indicated that the content of ammonia nitrogen in the interstitial water was between 5.24 and 10.64 mg·L -1 , which was 10 times that of the overlying water, and endogenous pollution in the former was severe. The nitrate nitrogen content ranged from 0.36 to 0.79 mg·L -1 . The total dissolved nitrogen content was between 5.36 and 12.02 mg·L -1 , which was 5 times higher than that of the overlying water. The total dissolved phosphorus was between 0.03 and 0.3 mg·L -1 . According to integrated pollution index, the degree of interstitial water pollution was much higher than that of overlying water, and the sampling points are seriously polluted. The exchange flux analysis of NH 4 + -N, TDN, and TDP demonstrated that the diffusion flux of NH 4 + -N was between 1.71 and 7.43 mg·(m 2 ·d) -1 , and the diffusion rate of endogenous ammonia nitrogen to the overlying water was fastest in Fu River, the absorbing river in Baoding. The diffusion flux of total dissolved nitrogen was lower in the Baigouyin River, and the other five sample points averaged 9.11 mg·(m 2 ·d) -1 . In summer, the dissolved oxygen was lower and the water-sediment had a larger concentration difference, which led to massive nitrogen nutrient of sediment in anaerobic conditions released to the overlying water in great quantities that caused the serious pollution. The diffusion flux of dissolved total phosphorus showed that the sediment of Pinghe River acted as a "sink" of phosphorus nutrients, and the other sampling points ranged from 0.03 to 0.16 mg·(m 2 ·d) -1 , showing the state of phosphorus nutrient released upward to the overlying water. Finally, diffusion flux indicated that endogenous pollutants are crucial sources of overlying water pollutants. In order to effectively control the water quality in the entrance area, desilting the nitrogen and phosphorus nutrient salt of sediment is urgently required.

Globally, lung cancer is the most commonly diagnosed cancer and carries with it the greatest mortality rate, with 5-year survival rates varying from 4-17% depending on stage and geographical differences. For decades, researchers have studied disease mechanisms, occurrence rates and disease development, however, the mechanisms underlying disease progression are not yet fully elucidated, thus an increased understanding of disease pathogenesis is key to developing new strategies towards specific disease diagnoses and targeted treatments. Circular RNAs (circRNAs) are a class of non-coding RNA widely expressed in eukaryotic cells, and participate in various biological processes implicated in human disease. Recent studies have indicated that circRNAs both positively and negatively regulate lung cancer cell proliferation, migration, invasion and apoptosis. Additionally, circRNAs could be promising biomarkers and targets for lung cancer therapies. This review systematically highlights recent advances in circRNA regulatory roles in lung cancer, and sheds light on their use as potential biomarkers and treatment targets for this disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Zhang, Wu, Huang and Zhao.)

Background: The global incidence of metabolic syndrome (MetS) is continuously increasing, making it a potential worldwide public health concern. Research on dietary factors related to MetS has attracted considerable attention in the recent decades. However, the research hotspots, knowledge structure, and theme trends for the dietary factors associated with MetS remain unknown, and have not yet been systematically mapped. This study aimed to review the research status of diet as a risk factor for MetS through bibliometric methods. Bibliometric analysis was conducted using the Web of Science database. Research hotspots were identified using biclustering analysis with the gCLUTO software, and knowledge structure was explored via social network analysis using the Ucinet software. Theme trends were investigated using evolutionary analysis with the SciMAT software. In total, 1,305 papers were analyzed. The research output on the dietary factors associated with MetS increased steadily. The research scope was gradually expanding and diverse. Overall, eight research hot spots, four key dietary nodes, and four motor themes on the dietary factors associated with MetS were identified. Fatty acids, dietary fiber, and polyphenols have been the focus of research in this field over the years. Evolutionary analysis showed that fish oil and vitamin C were well-developed research foci recently. Prebiotics was recognized as an emerging theme with certain developmental potential. These findings provide a better understanding of the research status of the dietary factors associated with MetS and a reference for future investigations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cao, Wu, Chang, Zhang, Li, Chen and Zhao.)

Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition in the second or third trimester of pregnancy. GDM has a considerable impact on health outcomes of the mother and offspring during pregnancy, delivery, and beyond. Although the exact mechanism regarding GDM remains unclear, numerous studies have suggested that non-coding RNAs, including long non-coding (lnc)RNAs, microRNAs, and circular RNAs, were involved in the pathogenesis of GDM in which they played vital regulatory roles. Additionally, several studies have revealed that extracellular vehicles also participated in the pathogenesis of GDM, highlighting their important role in this disease. Considering the lack of effective biomarkers for the early identification of and specific treatment for GDM, non-coding RNAs and extracellular vehicles may be promising biomarkers and even targets for GDM therapies. This review provides an update on our understanding of the role of non-coding RNAs and extracellular vehicles in GDM. As our understanding of the function of lncRNAs and extracellular vehicles improves, the future appears promising for their use as potential biomarkers and treatment targets for GDM in clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Wang, Huang and Gao.)

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and is characterized by a hyperinflammatory state accompanied by immunosuppression. Long noncoding RNAs (lncRNAs) are noncoding RNAs longer than 200 nucleotides and have important roles in mediating various biological processes. Recently, lncRNAs were found to exert both promotive and inhibitory immune functions in sepsis, thus participating in sepsis regulation. Additionally, several studies have revealed that lncRNAs are involved in sepsis-induced organ dysfunctions, including cardiovascular dysfunction, acute lung injury, and acute kidney injury. Considering the lack of effective biomarkers for early identification and specific treatment for sepsis, lncRNAs may be promising biomarkers and even targets for sepsis therapies. This review systematically highlights the recent advances regarding the roles of lncRNAs in sepsis and sheds light on their use as potential biomarkers and treatment targets for sepsis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Yang, Wen, Liu and Zhang.)

Background: Septic shock with myocardial depression is very common in intensive care units. However, the exact molecular mechanisms underlying sepsis-induced myocardial depression remain unclear. Whether the profiles of transcripts of uncertain coding potential (TUCPs) differ between patients with and without myocardial depression is also unknown. Our study aimed to find expression differences between groups of TUCPs and determine their potential functions in a preclinical model., Methods: We generated rat models of hypodynamic septic shock induced by lipopolysaccharide. A total of 12 rats were established and left ventricular tissue from each was collected. We performed RNA-seq to identify TUCPs in each sample. Transcripts with an corrected P value of < 0.05 were defined as differentially expressed (DE). We also performed GO terms and KEGG analysis to identify the potential functions of DE TUCPs., Results: A total of 4,851 TUCPs were identified in heart samples, 85 of which were expressed differently between the sepsis and control groups. Further bioinformatic analyses suggested that TUCPs play important roles in myocardial contraction, energy regulation, and metabolic processes, and are also involved in the regulation of several pathways., Conclusion: Our results demonstrate that TUCPs both participate in and mediate the pathological process of myocardial depression. Our study improves the understanding of the basic molecular mechanisms underlying myocardial depression from a novel perspective.

Trimethylated histone H3 lysine 27 (H3K27me3) is a repressive histone marker that regulates a variety of developmental processes, including those that determine flowering time. However, relatively little is known about the mechanism of how H3K27me3 is recognized to regulate transcription. Here, we identified BAH domain-containing transcriptional regulator 1 (BDT1) as an H3K27me3 reader. BDT1 is responsible for preventing flowering by suppressing the expression of flowering genes. Mutation of the H3K27me3 recognition sites in the BAH domain disrupted the binding of BDT1 to H3K27me3, leading to de-repression of H3K27me3-enriched flowering genes and an early-flowering phenotype. We also found that BDT1 interacts with a family of PHD finger-containing proteins, which we named PHD1-6, and with CPL2, a Pol II carboxyl terminal domain (CTD) phosphatase responsible for transcriptional repression. Pull-down assays showed that the PHD finger-containing proteins can enhance the binding of BDT1 to the H3K27me3 peptide. Mutations in all of the PHD genes caused increased expression of flowering genes and an early-flowering phenotype. This study suggests that the binding of BDT1 to the H3K27me3 peptide, which is enhanced by PHD proteins, is critical for preventing early flowering., (© 2021 Institute of Botany, Chinese Academy of Sciences.)

Sigma-1 (σ-1) receptor agonists are considered as potential treatment for stroke. TS-157 is an alkoxyisoxazole-based σ-1 receptor agonist previously discovered in our group. The present study describes TS-157 profile in a battery of tests for cerebral ischemia. Initial evaluation demonstrated the compound's safety profile and blood-brain barrier permeability, as well as its ability to induce neurite outgrowth in vitro. The neurite outgrowth was shown to be mediated via σ-1 receptor agonism and involves upregulation of ERK phosphorylation (pERK). In particular, TS-157 also significantly accelerated the recovery of motor function in rats with transient middle cerebral artery occlusion (tMCAO). Overall, the results herein support the notion that σ-1 receptor agonists are potential therapeutics for stroke and further animal efficacy studies are warranted.

Mitochondrial damage is considered one of the main pathogenetic mechanisms in septic cardiomyopathy. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) is critical for maintaining energy homeostasis in different organs and in various physiological and pathological states. It is also a key regulator gene in mitochondrial metabolism. In this study, we investigated whether regulation of the PGC-1α gene had protective effects on septic cardiomyopathy. We developed a rat model of septic cardiomyopathy. H9c2 myocardiocytes were treated with lipopolysaccharide (LPS) and PGC-1α expression measured. PGC-1α-overexpressing lentivirus was used to transfect H9c2 cells. ZLN005 was used to activate PGC-1α. The effect of the inhibition of PGC-1α expression on myocardial cell injury and its underlying mechanisms were also explored. Cell viability was measured by CCK-8 assay. Mitochondrial damage was determined by measuring cellular ATP, reactive oxygen species, and the mitochondrial membrane potential. An apoptosis analysis kit was used to measure cellular apoptosis. Mitochondrial DNA was extracted and real-time PCR performed. LC3B, mitochondrial transcription factor A (TFA), P62, Bcl2, and Bax were determined by immunofluorescence. LC3B, TFA, P62, Parkin, PTEN-induced putative kinase 1, and PGC-1α proteins were determined by Western blotting. We found mitochondrial damage and apoptotic cells in the myocardial tissue of rats with septic cardiomyopathy and in LPS-treated cardiomyocytes. PGC-1α expression was decreased in the late phase of septic cardiomyopathy and in LPS-treated cardiomyocytes. PGC-1α activation by ZLN005 and PGC-1α overexpression reduced apoptosis in myocardiocytes after LPS incubation. PGC-1α gene overexpression alleviated LPS-induced cardiomyocyte mitochondrial damage by activating mitochondrial biogenesis and autophagy functions. Our study indicated that mitochondrial damage and apoptosis occurred in septic cardiomyopathy and LPS-treated cardiomyocytes. The low expression level of PGC-1α protein may have contributed to this damage. By activating the expression of PGC-1α, apoptosis was reduced in cardiomyocytes. The underlying mechanism may be that PGC-1α can activate mitochondrial biogenesis and autophagy functions, reducing mitochondrial damage and thereby reducing apoptosis.

Sepsis-induced myocardial depression has high mortality and is very common in intensive care units. Previous studies have found that microRNAs play an important role in regulating sepsis-induced myocardial depression. miR-150-5p is involved in many biological processes; however, the mechanism underlying its role in sepsis-induced myocardial depression is still unclear. In this study, we generated rat models of septic shock induced by lipopolysaccharide. Whole genomic RNA sequencing was performed on 12 left ventricles collected after LPS treatment to identify miRNAs. Most of the target genes of the differently expressed microRNAs were involved in apoptosis, according to Gene Ontology. We also observed apoptosis in the heart tissue and in H9C2 cardiomyocytes stimulated with lipopolysaccharide, indicating that cell apoptosis may be an important mechanism in sepsis-induced myocardial depression. Furthermore, the expression of miR-150-5p was reduced, and overexpression of miR-150-5p with mimics resulted in a decrease in apoptosis, decreased expression of cleaved caspase3 and Bax, and increased expression of Bcl-2. Additionally, after H9C2 cells were transfected with miR-150-5p mimics or an inhibitor, the expression of Akt2 decreased or increased, respectively. These findings suggest that miR-150-5p can alleviate apoptosis and may be a novel therapeutic target for sepsis-induced myocardial depression., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 Xiao Geng Zhu et al.)