Dexmedetomidine mitigates lidocaine-induced spinal cord injury by repressing ferritinophagy-mediated ferroptosis by increasing CISD2 expression in rat models.

Dexmedetomidine (DEX) has been confirmed to exert neuroprotective effects in various nerve injury models by regulating ferroptosis, including spinal cord injury (SCI). Although it has been established that CDGSH iron sulfur domain 2 (CISD2) can regulate ferroptosis, whether DEX can regulate ferroptosis by CISD2 in SCI remains unclear. Lidocaine was used to induce PC12 cells and stimulate rats to establish SCI models in vitro and in vivo. MTT assays were performed to analyze cell viability. Ferroptosis was assessed by determining the levels of cellular reactive axygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and Fe2+. Ferritinophagy was analyzed by LysoTracker staining, FerroOrange staining, and immunofluorescence. Western blotting was carried out to quantify the levels of several proteins. Fluorescence microscopy was also used to observe cell autophagy. The morphology of mitochondria within the tissue was observed under transmission electron microscopy (TEM). DEX treatment weakened lidocaine-induced elevation of ROS, Fe2+, and MDA and reduced GSH in PC12 cells, indicating that DEX treatment weakened lidocaine-induced ferroptosis in PC12 cells. Similarly, lidocaine promoted autophagy, Fe2+, and microtubule-associated protein 1 light chain 3 (LC3) in PC12 cells and suppressed ferritin and p62 protein levels, indicating that DEX could weaken lidocaine-induced ferritinophagy in PC12 cells. DEX treatment improved the BBB score, reduced tissue damage, increased the number of neurons, and alleviated mitochondrial damage by inhibiting ferroptosis and ferritinophagy in lidocaine-induced SCI rat models. The decreased CISD2, ferritin heavy chain 1 (FTH1), solute carrier family 7-member 11-glutathione (SLC7A11), and glutathione peroxidase 4 (GPX4) protein levels and the elevated nuclear receptor coactivator 4 (NCOA4) protein levels in rat models in the lidocaine group were weakened by DEX treatment. Moreover, CISD2 inhibition reversed the inhibitory effects of DEX treatment on lidocaine-induced ferroptosis and ferritinophagy in PC12 cells significantly. Taken together, DEX treatment could impair lidocaine-induced SCI by inhibiting ferroptosis and ferritinophagy by upregulating CISD2 in rat models.

CLEC5A Promotes Neuronal Pyroptosis in Rat Spinal Cord Injury Models by Interacting with TREM1 and Elevating NLRC4 Expression.

Pyroptosis, an inflammatory Programmed cell death, has recently been found to play an important role in spinal cord injury (SCI). C-type lectin domain family 5 member A (CLEC5A), triggering receptor expressed on myeloid cells 1 (TREM1), and NLR-family CARD-containing protein 4 (NLRC4) have been reported to be associated with neuronal pyroptosis, but few studies have clarified their functions and regulatory mechanisms in SCI. In this study, CLEC5A, TREM1, and NLRC4 were highly expressed in lidocaine-induced SCI rat models, and their knockdown alleviated lidocaine-induced SCI. The elevation of proptosis related indicators LDH, ASC, GSDMD-N, IL-18, caspase-1, and IL-1ß levels in SCI rats was attenuated after silencing of CLEC5A, TREM1, or NLRC4. Lidocaine-induced the decrease in cell viability and the elevation in cell death were partly reversed after CLEC5A, TREM1, or NLRC4 silencing. Lidocaine-mediated effects on the levels of LDH, ASC, GSDMD-N, IL-18, caspase-1, and IL-1ß in lidocaine-induced PC-12 cells were weakened by downregulating CLEC5A, TREM1, or NLRC4. CLEC5A could interact with TREM1 to mediate NLRC4 expression, thus accelerating neuronal pyroptosis, ultimately leading to SCI exacerbation. In conclusions, CLEC5A interacted with TREM1 to increase NLRC4 expression, thus promoting neuronal pyroptosis in rat SCI models, providing new insights into the role of neuronal pyroptosis in SCI.Significance statement Pyroptosis has been reported to be involved in SCI. Higher levels of CLEC5A, TREM1, and NLRC4 associated with neuronal pyroptosis. However, the role and regulatory mechanism of CLEC5A, TREM1, and NLRC4 in SCI were not clear. Here, high expression of CLEC5A, TREM1, and NLRC4 was observed in lidocaine-induced SCI rat models. CLEC5A could interact with TREM1 to enhance the expression of NLRC4, thus accelerating neuronal pyroptosis in rat SCI models. These findings identify CLEC5A, TREM1, and NLRC4 as potential therapeutic targets for SCI.

Enhanced Recognition of a Herbal Compound Epiberberine by a DNA Quadruplex-Duplex Structure.

The small molecule epiberberine (EPI) is a natural alkaloid with versatile bioactivities against several diseases including cancer and bacterial infection. EPI can induce the formation of a unique binding pocket at the 5' side of a human telomeric G-quadruplex (HTG) sequence with four telomeric repeats (Q4), resulting in a nanomolar binding affinity (KD approximately 26 nM) with significant fluorescence enhancement upon binding. It is important to understand (1) how EPI binding affects HTG structural stability and (2) how enhanced EPI binding may be achieved through the engineering of the DNA binding pocket. In this work, the EPI-binding-induced HTG structure stabilization effect was probed by a peptide nucleic acid (PNA) invasion assay in combination with a series of biophysical techniques. We show that the PNA invasion-based method may be useful for the characterization of compounds binding to DNA (and RNA) structures under physiological conditions without the need to vary the solution temperature or buffer components, which are typically needed for structural stability characterization. Importantly, the combination of theoretical modeling and experimental quantification allows us to successfully engineer Q4 derivative Q4-ds-A by a simple extension of a duplex structure to Q4 at the 5' end. Q4-ds-A is an excellent EPI binder with a KD of 8 nM, with the binding enhancement achieved through the preformation of a binding pocket and a reduced dissociation rate. The tight binding of Q4 and Q4-ds-A with EPI allows us to develop a novel magnetic bead-based affinity purification system to effectively extract EPI from Rhizoma coptidis (Huang Lian) extracts.

Fibroblast growth factor 3 contributes to neuropathic pain through Akt/mTOR signaling in mouse primary sensory neurons.

Neuropathic pain (NP), a severe chronic pain condition, remains a substantial clinical challenge due to its complex pathophysiology and limited effective treatments. An association between the members of the Fibroblast Growth Factors (FGFs), particularly Fgf3, and the development of NP has become evident. In this study, utilizing a mouse model of NP, we observed a time-dependent increase in Fgf3 expression at both mRNA and protein levels within the dorsal root ganglia (DRG). Functional studies revealed that blocking Fgf3 expression mitigated nerve injury induced nociceptive hypersensitivity, suggesting its pivotal role in pain modulation. Moreover, our findings elucidate that Fgf3 contributes to pain hypersensitivity through the activation of the Akt/mTOR signaling in injured DRG neurons. These results not only shed light on the involvement of Fgf3 in nerve injury-induced NP but also highlight its potential as a promising therapeutic target for pain management. This study thereby advances our understanding of the molecular mechanisms underlying NP and opens new avenues for the development of effective treatment strategies.

PD1+CD4+ T cells promote receptor editing and suppress autoreactivity of CD19+CD21low B cells within the lower respiratory airways in adenovirus pneumonia.

Human adenovirus (HAdV) pneumonia poses a major health burden for young children, however, factors that contribute to disease severity remain elusive. We analyzed immune cells from bronchoalveolar lavage (BAL) of children with HAdV pneumonia and found that CD19+CD21low B cells were significantly enriched in the BAL and were associated with increased autoantibody concentrations and disease severity. Myeloid cells, PD-1+CD4+ T helper cells and CD21low B cells formed tertiary lymphoid structures within the respiratory tracts. Myeloid cells promoted autoantibody production by expressing high amounts of B cell activating factor (BAFF). In contrast, PD-1+CD4+ T helper cells induced production of IgG1 and IgG3 antibodies but suppressed autoreactive IgGs by initiating B cell receptor editing. In summary, this study reveals cellular components involved in protective versus autoreactive immune pathways in the respiratory tract, and these findings provide potential therapeutic targets for severe HAdV lower respiratory tract infections.

Gene polymorphisms of METTL5 and METTL16 are related to epithelial ovarian cancer risk in South China: A three-center case-control study.

Background: The potential relation of methyltransferase-like gene polymorphisms and epithelial ovarian cancer (EOC) remains unclear. Methods: Five SNPs (METTL5 rs3769767 A>G, METTL16 rs1056321 T>C, METTL5 rs10190853 G>A, METTL5 rs3769768 G>A and METTL16 rs11869256 A>G) of methyltransferase-like genes was selected trough NCBI dbSNP database. Two hundred and eighty-eight cases and 361 controls were enrolled from three hospitals in South China to conduct the case-control study. Genomic DNA was abstracted from peripheral blood and genotyped through a TapMan assay. Stratified analysis was conducted to explore the association of rs10190853, rs3769768, rs11869256 genotype and EOC susceptibility. The combination analysis was adopted to evaluate the relation between inferred haplotypes of the METTL5, METTL16 genes and EOC risk. Multifactor dimensionality reduction (MDR) analysis was performed to verify the interaction of SNPs. Results: Among the five analyzed SNPs, METTL5 rs3769768 AA exhibited a significant association with increased EOC risk, while METTL5 rs10190853 GA, METTL16 rs11869256 GA was certified to decrease the susceptibility of EOC. The stratified analysis further revealed the harmful effect of METTL5 rs3769768 AA in EOC patients. On the contrary, METTL16 rs11869256 AG/GG and METTL5 rs10190853 AA showed the reduced risk of EOC in patients of specific subgroups. Combination analysis identified that haplotypes AAA highly connected with reduced risk of EOC. MDR analysis revealed that these SNPs existed no specific interactions. Conclusion: METTL5 rs3769768 was related to increased risk of EOC. METTL5 rs10190853 and METTL16 rs11869256 decreased the susceptibility in EOC. METTL5 and METTL16 could be potential target of molecular therapy and prognosis markers.

METTL3-Mediated LINC00475 Alternative Splicing Promotes Glioma Progression by Inducing Mitochondrial Fission.

Mitochondrial fission promotes glioma progression. The function and regulation mechanisms of lncRNAs in glioma mitochondrial fission are unclear. The expression of LINC00475 and its correlation with clinical parameters in glioma were analyzed using bioinformatics. Then, in vitro and in vivo assays were performed to explore the function of spliced variant LINC00475 (LINC00475-S) in gliomas. To explore the mechanisms, RNA-seq, MeRIP, RIP, pulldown-IP, dCas9-ALKBH5 editing system, LC/MS, and Western blotting were utilized. LINC00475 was confirmed to be overexpressed and with higher frequencies of AS events in gliomas compared to normal brain tissue and was associated with worse prognosis. In vitro and animal tumor formation experiments demonstrated that the effect of LINC00475-S on proliferation, metastasis, autophagy, and mitochondrial fission of glioma cells was significantly stronger than that of LINC00475. Mechanistically, METTL3 induced the generation of LINC00475-S by splicing LINC00475 through m6A modification and subsequently promotes mitochondrial fission in glioma cells by inhibiting the expression of MIF. Pull-down combined LC/MS and RIP assays identified that the m6A recognition protein HNRNPH1 bound to LINC00475 within GYR and GY domains and promoted LINC00475 splicing. METTL3 facilitated HNRNPH1 binding to LINC00475 in an m6A-dependent manner, thereby inducing generation of LINC00475-S. METTL3 facilitated HNRNPH1-mediated AS of LINC00475, which promoted glioma progression by inducing mitochondrial fission. Targeting AS of LINC00475 and m6A editing could serve as a therapeutic strategy against gliomas.

Purification effect and microbial community structure of bio filter on rural dispersed sewage.

Taking rural dispersed sewage for research objects, the treatment effect and microbial community structure characteristics of a bio filter (BF) reactor was studied. At fixed time and location, the removal efficiencies of common pollutants were investigated. By using high-throughput sequencing method, the heterogeneities of microbial community structure in fillers and plant roots were analyzed. The results showed that the average annual removal rates of CODCr, NH3-N, TN, and TP by the BF were 83.10 %, 65.67 %, 60.25 %, and 80.32 % respectively, and the effluent could reach the first grade of the water pollutant discharge standard of rural sewage treatment facility (DB51/2626-2019). During the sewage treatment process, Scindapsus could effectively establish complex and stable microbial communities, and could better degrade pollutants, especially nitrogen removal. The dominant microbial communities were more than 11 phyla and 19 classes. At the genus level, the dominant bacteria included Nitrospira, Arthrobacter, Rhodoplanes, etc.

Optimization pilot scale study on ammonia nitrogen removal by bio filter.

In order to obtain the optimal conditions for ammonia nitrogen (AN) wastewater treatment by bio filter (BF), the effects of ratio of carbon to nitrogen (C/N), pH, and hydraulic load (HL) on the AN degradation were studied by Response Surface Methodology (RSM). Central Composite Design (CCD) experiments were conducted, and the response of the AN removal rates were fitted to a second-order polynomial model. The analysis of variance showed that the model was accurate and reliable. Through model fitting, the optimal condition for AN removal was: C/N of 18.95, pH of 7.78, and HL of 1.04 d-1. The maximum AN removal rate predicted by the model was 91.90%, accorded with the experimental verification value of 91.37% under the optimal condition. The research provided valuable demonstration for optimizing process parameters on AN removal in BF.

Comparison of the postoperative in-hospital versus at-home recovery quality and circadian rhythm status in preschool kids after adenotonsillectomy: a cohort and observational study.

Background: At present, minimally invasive surgery is often used in paediatric patients as a day surgery to promote rapid post-operative recovery. Obstructive Sleep Apnea Syndrome (OSAS) Patients recovery in the hospital or at home after surgery may differ in terms of recovery quality and circadian rhythm status because of sleep disruption; however, this remains unknown. Pediatric patients usually unable to explain their feelings effectively, and objective indicators to measure recovery situation in different environments are promising. This study was conducted to compare the impact of in-hospital and at-home postoperative recovery quality (primary outcome) and circadian rhythm (as measured via the salivary melatonin level) (secondary outcome) in preschool-age patients. Methods: This was a cohort, non-randomized and exploratory observational study. A total of 61 children aged 4 to 6 years who were scheduled to receive adenotonsillectomy were recruited and assigned to recover either in the hospital (Hospital group) or at home (Home group) after surgery. There were no differences in the patient characteristics and perioperative variables between the Hospital and Home groups at baseline. They received the treatment and anesthesia in the same way. The patients' preoperative and up to 28 days post-surgery OSA-18 questionnaires were harvested. Moreover, their pre- and post-surgery salivary melatonin concentrations, body temperature, three-night postoperative sleep diaries, pain scales, emergence agitation, and other adverse effects were recorded. Results: There were no significant differences in the postoperative recovery quality, as assessed by the OSA-18 questionnaire, body temperature, sleep quality, pain scales, and other adverse events (such as respiratory depression, sinus bradycardia, sinus tachycardia, hypertension, hypotension, nausea, and vomiting) between the two groups. The preoperative morning saliva melatonin secretion was decreased in both groups on the first postoperative morning (P<0.05), while a significantly greater decrease was found in the Home group on postoperative day 1 (P<0.05) and day 2 (P<0.05). Conclusions: The postoperative recovery quality of preschool kids in the hospital is as good as at home based on OSA-18 evaluation scale. However, the clinical importance of the significant decrease in morning saliva melatonin levels with at-home postoperative recovery remains unknown and warrants further study.

Genome-Scale Analysis of the Grapevine KCS Genes Reveals Its Potential Role in Male Sterility.

Very long-chain fatty acid (VLCFA) synthesis in plants, is primarily rate-limited by the enzyme 3-ketoacyl CoA synthase (KCS), which also controls the rate and carbon chain length of VLCFA synthesis. Disruption of VLCFA during pollen development, may affect the pollen wall formation and ultimately lead to male sterility. Our study identified 24 grapevine KCS (VvKCS) genes and provided new names based on their relative chromosome distribution. Based on sequence alignment and phylogenetic investigation, these genes were grouped into seven subgroups, members of the same subgroup having similar motif structures. Synteny analysis of VvKCS genes, showed that the segmental duplication events played an important role in expanding this gene family. Expression profiles obtained from the transcriptome data showed different expression patterns of VvKCS genes in different tissues. Comparison of transcriptome and RT-qPCR data of the male sterile grape 'Y-14' and its fertile parent 'Shine Muscat', revealed that 10 VvKCS genes were significantly differentially expressed at the meiosis stage, which is a critical period of pollen wall formation. Further, joint analysis by weighted gene co-expression network analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG), revealed that five of these VvKCS (VvKCS6/15/19/20/24) genes were involved in the fatty acid elongation pathway, which may ultimately affect the structural integrity of the pollen wall in 'Y-14'. This systematic analysis provided a foundation for further functional characterization of VvKCS genes, with the aim of grapevine precision breeding improvement.

Mitochondria-associated gene expression perturbation predicts clinical outcomes and shows potential for targeted therapy in neuroblastoma.

Background: Mitochondria have long been considered a potential target in cancer therapy because malignant cells are known for their altered energy production. However, there is a lack of comprehensive research on the involvement of mitochondria-associated proteins (MAPs) in neuroblastoma (NB), and their potential as therapeutic targets is yet to be fully explored. Methods: MAP genes were defined based on the protein-coding genes with mitochondrial localization. The mRNA expression patterns and dynamics of MAP genes associated with NB were investigated by integrating publicly available transcriptional profiles at the cellular and tissue levels. Multivariate Cox regression analysis was conducted to reveal the association of MAP genes with the overall survival (OS) and clinical subgroups of NB patients. The single-cell RNA-seq dataset and gene dependency screening datasets were analyzed to reveal the therapeutic potential of targeting MAP genes. Results: We compiled a total of 1,712 MAP genes. We found the global and cell type-specific mRNA expression changes of the MAP genes associated with NB status and survival. Our analyses revealed a group of MAP gene signatures independent of MYCN-amplification status associated with NB outcome. We provided computational evidence with selected MAP genes showing good performance in predicting long-term prognosis. By analyzing gene dependency of the MAP genes in NB cell lines and ex vivo human primary T cells, we demonstrated the therapeutic potential of targeting several MAP genes in NB tumors. Conclusions: Collectively, our study provides evidence for the MAP genes as extended candidates in NB tumor stratification and staging, prognostic prediction, and targeted drug development.

The Role of the miR-548au-3p/CA12 Axis in Tracheal Chondrogenesis in Congenital Pulmonary Airway Malformations.

Background: Literature has identified differentially expressed miRNAs in congenital pulmonary airway malformation (CPAM). However, the functional role of these miRNAs in CPAM remains unclear. Methods: We obtained diseased lung tissues as well as adjacent normal lung tissue from CPAM patients attending the centre. Hematoxylin and eosin (H&E) and Alcian blue staining were performed. Differentially expressed mRNA expression profile was CPAM tissue, and matched normal tissue specimens were examined by high-throughput RNA sequencing. CCK-8 assay, EdU staining, TUNEL staining, flow cytometry, and the Transwell assay were performed to investigate the effect of miR-548au-3p/CA12 axis on proliferation, apoptosis, and chondrogenic differentiation in rat tracheal chondrocytes. mRNA and protein expression levels were determined using reverse transcription-quantitative PCR and western blot analysis, respectively. The relationship between miR-548au-3p and CA12 was evaluated using the luciferase reporter assay. Results: The expression level of miR-548au-3p was significantly increased in diseased tissues compared with normal adjacent tissues from patients with CPAM. Our results indicate that miR-548au-3p functions as a positive regulator in rat tracheal chondrocyte proliferation and chondrogenic differentiation. At molecular level, miR-548au-3p promoted N-cadherin, MMP13, and ADAMTS4 expressions and reduced E-cadherin, aggrecan, and Col2A1 expressions. CA12 has been previously reported as a predicted target of miR-548au-3p, and here, we show that overexpression of CA12 in rat tracheal chondrocyte mimics the effects of inhibition of miR-548au-3p. On the other hand, CA12 knockdown reversed the effects of miR-548au-3p on cell proliferation, apoptosis, and chondrogenic differentiation. Conclusions: In conclusion, the miR-548au-3p/CA12 axis plays a role in the pathogenesis of CPAM and may lead to identification of new approaches for CPAM treatment.

Risk factors of intraoperative blood loss and transfusion for pediatric patients undergoing brain tumor removal: a retrospective cohort study.

OBJECTIVE: Intraoperative blood loss is a major challenge in pediatric brain tumor removal. Several clinical and surgical factors may influence the occurrence of intraoperative blood loss and blood transfusion. This study aimed to identify the risk factors of intraoperative blood loss and intraoperative red blood cell (RBC) transfusion for pediatric patients undergoing brain tumor removal. METHODS: A total of 297 pediatric patients undergoing brain tumor removal were selected in this retrospective, singlecenter study. Demographic data, laboratory data, imaging data, and surgical records were collected, and then independent risk factors for intraoperative blood loss and transfusion were identified using multivariate stepwise regression analysis. RESULTS: The median intraoperative blood loss in our cohort was 23.1 ml/kg (IQR 10.0-60.0 ml/kg). In total, 284 (95.6%) patients received intraoperative RBC transfusion, with a median amount of 0.2 U/kg (IQR 0.0-2.6 U/kg). Age (ß = -0.189; 95% CI [-1.359, -0.473]; p < 0.001); preoperative hemoglobin level (ß = -0.141; 95% CI [-1.528, -0.332]; p = 0.003); anesthesia time (ß = 0.189; 95% CI [0.098, 0.302]; p < 0.001); unclear tumor boundary (ß = 0.100; 95% CI [2.067, 41.053]; p = 0.031); tumor size (ß = 0.390; 95% CI [14.706, 24.342]; p < 0.001); and intraoperative continuous infusion of vasopressor (ß = 0.155; 95% CI [13.364, 52.400]; p = 0.001) were independent predictors of intraoperative blood loss. Independent predictors of the need for RBC transfusion included age (ß = -0.268; 95% CI [-0.007, -0.004]; p < 0.001); preoperative hemoglobin level (ß = -0.117; 95% CI [-0.005, -0.001]; p = 0.003); anesthesia time (ß = 0.221; 95% CI [0.001, 0.001]; p < 0.001); unclear tumor boundary (ß = 0.110; 95% CI [0.024, 0.167]; p = 0.010); tumor size (ß = 0.370; 95% CI [0.056, 0.092]; p < 0.001); intraoperative continuous infusion of vasopressor (ß = 0.157; 95% CI [0.062, 0.205]; p < 0.001); and tumor grade (ß = 0.107; 95% CI [0.007, 0.062]; p = 0.014). CONCLUSIONS: Overall, age, preoperative hemoglobin, tumor size, anesthesia time, continuous infusion of vasopressors, and unclear tumor boundary were the main determinants for intraoperative blood loss and RBC transfusion in pediatric patients undergoing brain tumor removal. Clinical trial registration no.: ChiCTR1900024803 (ChiCTR.org).

Sevoflurane Induces Ferroptosis of Glioma Cells Through Activating the ATF4-CHAC1 Pathway.

Objective: To clarify the function and mechanisms of sevoflurane (Sev) on ferroptosis in glioma cells. Methods: Different concentrations of Sev were used to treat glioma cells U87 and U251. Ferroptosis inducer Erastin was used to incubate glioma cells combined with Sev and ATF4 siRNA transfection treatment. CCK-8 assay and colorimetric assay were performed to analyze cell viability and Fe+ concentration, respectively. The releases of reactive oxygen species (ROS) were determined by flow cytometry analysis. Transcriptional sequencing was used to screen the differential genes affected by Sev in U251 cells. The mRNA and protein expression of ferroptosis-associated genes was detected by qRT-PCR and Western blotting. Results: Sev could suppress cell viability, increase ROS levels and Fe+ concentration, downregulate the protein expression levels of GPX4, and upregulate transferrin, ferritin, and Beclin-1 in a dose-dependent manner in U87 and U251 cells. The expression of ferroptosis and mitophagy-related gene activating transcription factor 4 (ATF4) was identified to be enhanced by Sev analyzed by transcriptional sequencing. ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1), which is involved in ferroptosis, is a downstream gene of ATF4. Inhibition of ATF4 could interrupt the expression of CHAC1 induced by Sev in U87 and U251 cells. Ferroptosis inducer Erastin treatment obviously inhibited the cell viability, elevated the Fe2+ concentration, and promoted ROS generation in U87 and U251 cells. The protein level of ATF4 and CHAC1 was increased in Erastin-treated U87 and U251 cells. Moreover, the interruption of Sev-induced ferroptosis and CHAC1 activating induced by ATF4 suppression could be reversed by Erastin. Conclusions: In summary, this study suggested that Sev exposure-induced ferroptosis by the ATF4-CHAC1 pathway in glioma cells.

Electron Transfer Flavoprotein (ETF) α Controls Blood Vessel Development by Regulating Endothelial Mitochondrial Bioenergetics and Oxygen Consumption.

While impairment of vascular homeostasis induced by hypercholesterolemia is the first step of cardiovascular diseases, the molecular mechanism behind such impairment is not well known. Here, we reported that high-cholesterol diet (HCD) induced defective vessel sprouting in zebrafish larvae. Electron transfer flavoprotein subunit α (ETFα) (encoded by the ETFA gene), a protein that mediates transfer of electrons from a series of mitochondrial flavoenzymes to the respiratory chain, was downregulated in HCD-fed zebrafish and in endothelial cells treated with oxidized low-density lipoprotein. Knockdown of ETFα with morpholino antisense oligonucleotides reproduced vascular sprouting defects in zebrafish larvae, while replenishing with exogeneous ETFA mRNA could successfully rescue these defects. ETFA knockdown in endothelial cells reduces cell migration, proliferation, and tube formation in vitro. Finally, knockdown of ETFA in endothelial cells also reduced fatty acid oxidation, oxygen consumption rate, and hypoxia-inducible factor-1α (HIF1α) protein levels. Taken together, we demonstrate that downregulation of ETFα is involved in hypercholesterolemia-induced defective vessel sprouting in zebrafish larvae via inhibition of endothelial proliferation and migration. The molecular mechanism behind this phenomenon is the decrease of HIF1α induced by downregulation of ETFα in endothelial cells. This work suggests that disturbance of ETFα-mediated oxygen homeostasis is one of the mechanisms behind hypercholesterolemia-induced vascular dysfunction.

Diagnosis and treatment of traumatic duodenal rupture in children.

BACKGROUND: The purpose of this study was to investigate the diagnosis and treatment experience of traumatic duodenal ruptures in children. METHODS: Clinical data were collected from four children suffering from a traumatic duodenal rupture who were admitted to and treated by our hospital from January 2012 to December 2020. The early diagnosis and treatment, surgical plan, postoperative management, complications, and prognosis of each child were analyzed. The key points and difficulties of the diagnosis and treatment for this type of injury are summarized. RESULTS: One child had an extreme infection caused by drug-resistant bacteria, which resulted in severe complications, including wound infection, dehiscence, and an intestinal fistula. One child developed an anastomotic stenosis after the duodenostomy, which improved following an endoscopic balloon dilatation. The other two children had no relevant complications after their operations. All four patients were cured and discharged from hospital. The average hospital stay was 48.25 ± 26.89 days. The follow-up period was 0.5 to 1 year. No other complications occurred, and all children had a positive prognosis. CONCLUSIONS: The early identification of a duodenal rupture is essential, and surgical exploration should be carried out proactively. The principles of damage-control surgery should be followed as much as possible during the operation. Multidisciplinary cooperation and management are both important to reduce the occurrence of postoperative complications and improve cure rates.

miR-340-5p Mediates Cardiomyocyte Oxidative Stress in Diabetes-Induced Cardiac Dysfunction by Targeting Mcl-1.

Diabetic cardiomyopathy (DCM) is initially characterized by early diastolic dysfunction, left ventricular remodeling, hypertrophy, and myocardial fibrosis, and it is eventually characterized by clinical heart failure. MicroRNAs (miRNAs), endogenous small noncoding RNAs, play significant roles in diabetes mellitus (DM). However, it is still largely unknown about the mechanism that links miRNAs and the development of DCM. Here, we aimed to elucidate the mechanism underlying the potential role of microRNA-340-5p in DCM in db/db mouse, which is a commonly used model of type 2 DM and diabetic complications that lead to heart failure. We first demonstrated that miR-340-5p expression was dramatically increased in heart tissues of mice and cardiomyocytes under diabetic conditions. Overexpression of miR-340-5p exacerbated DCM, which was reflected by extensive myocardial fibrosis and more serious dysfunction in db/db mice as represented by increased apoptotic cardiomyocytes, elevated ROS production, and impaired mitochondrial function. Inhibition of miR-340-5p by a tough decoy (TUD) vector was beneficial for preventing ROS production and apoptosis, thus rescuing diabetic cardiomyopathy. We identified myeloid cell leukemia 1 (Mcl-1) as a major target gene for miR-340-5p and showed that the inhibition of Mcl-1 was responsible for increased functional loss of mitochondria, oxidative stress, and cardiomyocyte apoptosis, thereby caused cardiac dysfunction in diabetic mice. In conclusion, our results showed that miR-340-5p plays a crucial role in the development of DCM and can be targeted for therapeutic intervention.

Inositol Alleviates Pulmonary Fibrosis by Promoting Autophagy via Inhibiting the HIF-1α-SLUG Axis in Acute Respiratory Distress Syndrome.

The effective remission of acute respiratory distress syndrome- (ARDS-) caused pulmonary fibrosis determines the recovery of lung function. Inositol can relieve lung injuries induced by ARDS. However, the mechanism of myo-inositol in the development of ARDS is unclear, which limits its use in the clinic. We explored the role and mechanism of myo-inositol in the development of ARDS by using an in vitro lipopolysaccharide- (LPS-) established alveolar epithelial cell inflammation model and an in vivo ARDS mouse model. Our results showed that inositol can alleviate the progression of pulmonary fibrosis. More significantly, we found that inositol can induce autophagy to inhibit the progression pulmonary fibrosis caused by ARDS. In order to explore the core regulators of ARDS affected by inositol, mRNA-seq sequencing was performed. Those results showed that transcription factor HIF-1α can regulate the expression of SLUG, which in turn can regulate the key gene E-Cadherin involved in cell epithelial-mesenchymal transition (EMT) as well as N-cadherin expression, and both were regulated by inositol. Our results suggest that inositol activates autophagy to inhibit EMT progression induced by the HIF-1α/SLUG signaling pathway in ARDS, and thereby alleviates pulmonary fibrosis.

The correlation between polymorphisms in the XPC gene and glioma susceptibility in a Chinese pediatric population.

BACKGROUND: A previous study revealed that single nucleotide polymorphisms (SNPs) in coding genes play a key role in tumorigenesis, genetic disorders, and drug resistance. Xeroderma pigmentosum group C (XPC) protein is a key DNA damage recognition factor that is required for maintaining the genomic stability. However, the correlation between XPC polymorphisms and glioma susceptibility is still unclear. Hence, this study aimed to investigate the correlation between XPC polymorphisms and pediatric glioma susceptibility. METHODS: A total of 399 participants (171 glioma patients and 228 controls) were enrolled to evaluate the correlation between XPC polymorphism and pediatric glioma susceptibility. The count data of two groups was analyzed by chi-squared (χ2) test. Moreover, logistic regression was used to assess the strength of XPC polymorphisms associated with glioma susceptibility. RESULTS: We identified that XPC rs1870134 G>C reduced pediatric glioma susceptibility. Compared to participants with rs1870134 GG/GC genotypes, those with rs1870134 CC genotype had a significantly lower risk for glioma [adjusted odds ratio (AOR) =0.10, 95% confidence interval (CI): 0.01 to 0.78, P=0.028]. Patients with 4-5 genotypes have higher risk of glioma than those with 0-3 genotypes (AOR =1.59, 95% CI: 1.04 to 2.43, P=0.031). The stratified analysis showed that the risky effects of rs2228000 CT/TT genotypes and rs2229090 GC/CC genotypes were more predominant among children aged ≥60 months, astrocytic tumors, and clinical stage I. CONCLUSIONS: We found for the first time that XPC polymorphisms had a statistically significant correlation with pediatric glioma susceptibility in a Chinese population. The XPC rs2228000 CT/TT and rs2229090 GC/CC genotypes could both increase the risk of pediatric glioma in subgroups with females, astrocytic tumors, and clinical stage I. The XPC polymorphism has potential to be a useful adjunct method to screen pediatric glioma.