Melastoma dodecandrum lour. Protects against cerebral ischemia-reperfusion injury by ameliorating oxidative stress and endoplasmic reticulum stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Melastoma dodecandrum Lour. (MD), a traditional Chinese medicine used by the She ethnic group, has been used to treat cerebral ischemia-reperfusion (CIR) injury due to its efficacy in promoting blood circulation and removing blood stasiss; however, the therapeutic effects and mechanisms of MD in treating CIR injury remain unclear. AIM: To investigate the protective effects of MD on CIR injury, in addition to its impact on oxidative stress, endoplasmic reticulum (ER) stress, and cell apoptosis. MATERIALS AND METHODS: The research was conducted using both cell experiments and animal experiments. The CCK-8 method, immunofluorescence staining, and flow cytometry were used to analyze the effects of MD-containing serum on oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cell viability, reactive oxygen species (ROS) clearance, anti-inflammatory, neuroprotection and inhibition of apoptosis. Furthermore, 2,3,5-Triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, Nissl staining, and immunohistochemistry were used to detect infarct size, pathological changes, Nissl corpuscula and neuronal protein expression in middle cerebral artery occlusion (MCAO) rats. Polymerase chain reaction and Western Blotting were conducted in cell and animal experiments to detect the expression levels of ER stress-related genes and proteins. RESULTS: The MD extract enhanced the viability of PC12 cells under OGD/R modeling, reduced ROS and IL-6 levels, increased MBP levels, and inhibited cell apoptosis. Furthermore, MD improved the infarct area in MCAO rats, increased the number of Nissl bodies, and regulated neuronal protein levels including Microtubule-Associated Protein 2 (MAP-2), Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament 200 (NF200). Additionally, MD could regulate the expression levels of oxidative stress proteins malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and catalase (CAT). Both cell and animal experiments demonstrated that MD could inhibit ER stress-related proteins (GRP78, ATF4, ATF6, CHOP) and reduce cell apoptosis. CONCLUSION: This study confirmed that the therapeutic mechanism of the MD extract on CIR injury was via the inhibition of oxidative stress and the ER stress pathway, in addition to the inhibition of apoptosis.

Mediating role of inflammatory biomarkers in the causal effect of body composition on glycaemic traits and type 2 diabetes.

OBJECTIVE: The aim was to investigate the mediating role of inflammatory biomarkers in the causal effect of body composition on glycaemic traits and type 2 diabetes. METHODS: A retrospective observational study and a Mendelian randomization (MR) study were used. Observational analyses were performed using data from 4717 Chinese children and adolescents aged 6-18 years who underwent dual-energy X-ray absorptiometry for body composition. MR analyses were based on summary statistics from UK Biobank, deCODE2021, Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC) and other large consortiums. Inflammatory biomarkers included leptin, adiponectin, osteocalcin, fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). RESULTS: In a retrospective observational study, increased fat mass had a positive effect on homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of pancreatic beta cell function (HOMA-ß) through FGF23, whereas fat-free mass produced the opposite effects. PTH and osteocalcin played significant roles in the association of fat mass and fat-free mass with fasting glucose, fasting insulin and HOMA-IR (all p < 0.05). Mediation MR results indicated that childhood body mass index affected glycaemic traits through leptin and adiponectin. There existed a causal effect of fat-free mass on type 2 diabetes via FGF23 (indirect effect: OR [odds ratio]: 1.14 [95% CI, confidence interval: 1.01-1.28]) and adiponectin (OR: 0.85 [95% CI: 0.77-0.93]). Leptin mediated the causal association of fat mass (indirect effect: ß: -0.05 [95% CI: -0.07, -0.02]) and fat-free mass (ß: 0.03 [95% CI: 0.01, 0.04]) with fasting glucose. CONCLUSIONS: Our findings suggest that different body compositions have differential influences on glycaemic traits and type 2 diabetes through distinct inflammatory biomarkers. The findings may be helpful in tailoring management of body composition based on inflammatory biomarkers with different glycaemic statuses.

Ternary deep eutectic solvents for esterification of 2-methylpropenoic acid with alcohols.

In this paper, a set of novel ternary deep eutectic solvents (T-DESs) is synthesized and applied in the esterification of 2-methylpropenoic acid with alcohols. T-DESs have multiple functions, serving as a catalyst, polymerization inhibitor, and solvent, and demonstrate excellent catalytic esterification reaction activity (up to 96% yield). The optimal T-DESs 1 can be recycled 14 times without any decrease in its catalytic activity, thus solving the problems of methacrylate product separation with a polymerization inhibitor, catalyst recovery, and organic solvent pollution.

The dual role of POSTN in maintaining glioblastoma stem cells and the immunosuppressive phenotype of microglia in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is an immunosuppressive, universally lethal cancer driven by glioblastoma stem cells (GSCs). The interplay between GSCs and immunosuppressive microglia plays crucial roles in promoting the malignant growth of GBM; however, the molecular mechanisms underlying this crosstalk are unclear. This study aimed to investigate the role of POSTN in maintaining GSCs and the immunosuppressive phenotype of microglia. METHODS: The expression of POSTN in GBM was identified via immunohistochemistry, quantitative real-time PCR, and immunoblotting. Tumorsphere formation assay, Cell Counting Kit-8 assay and immunofluorescence were used to determine the key role of POSTN in GSC maintenance. ChIP-seq and ChIP-PCR were conducted to confirm the binding sequences of ß-catenin in the promoter region of FOSL1. Transwell migration assays, developmental and functional analyses of CD4+ T cells, CFSE staining and analysis, enzyme-linked immunosorbent assays and apoptosis detection tests were used to determine the key role of POSTN in maintaining the immunosuppressive phenotype of microglia and thereby promoting the immunosuppressive tumor microenvironment. Furthermore, the effects of POSTN on GSC maintenance and the immunosuppressive phenotype of microglia were investigated in a patient-derived xenograft model and orthotopic glioma mouse model, respectively. RESULTS: Our findings revealed that POSTN secreted from GSCs promotes GSC self-renewal and tumor growth via activation of the αVß3/PI3K/AKT/ß-catenin/FOSL1 pathway. In addition to its intrinsic effects on GSCs, POSTN can recruit microglia and upregulate CD70 expression in microglia through the αVß3/PI3K/AKT/NFκB pathway, which in turn promotes Treg development and functionality and supports the formation of an immunosuppressive tumor microenvironment. In both in vitro models and orthotopic mouse models of GBM, POSTN depletion disrupted GSC maintenance, decreased the recruitment of immunosuppressive microglia and suppressed GBM growth. CONCLUSION: Our findings reveal that POSTN plays critical roles in maintaining GSCs and the immunosuppressive phenotype of microglia and provide a new therapeutic target for treating GBM.

Association of Serum Tsukushi Levels with Urinary Albumin-Creatinine Ratio in Type 2 Diabetes Patients.

Objective: Tsukushi is a newly identified hepatokine. Recent studies have shown that it relates to diabetes, lipid metabolism and fibrosis, but there is currently no investigation about whether Tsukushi is associated with diabetic kidney disease. Therefore, this study aimed to investigate the relationship between Tsukushi and diabetic kidney disease by characterizing Tsukushi levels in healthy subjects and type 2 diabetes with urinary albumin-creatinine ratio. Methods: Serum Tsukushi level was quantified by enzyme-linked immunosorbent assay in 167 normoalbuminuria, 80 microalbuminuria, and 31 macroalbuminuria patients with type 2 diabetes as compared with 53 healthy subjects. The correlation analysis was used to investigate the relationship between urinary albumin-creatinine ratio or Tsukushi level and other metabolic parameters. Multiple linear regression and logistic regression analysis were used to analyze the independent factors for urinary albumin-creatinine ratio and estimated glomerular filtration rate. Results: The Tsukushi level in the macroalbuminuria group was significantly higher than that in the normoalbuminuria or the microalbuminuria group. Multiple linear regression showed that the significantly independent factors for UACR included high Tsukushi quartile, systolic blood pressure, creatinine, homeostasis model assessment of insulin resistance, low 2-h post-oral glucose tolerance test c-peptide and female. Logistic regression demonstrated that the odds ratio of Tsukushi for glomerular filtration rate ≤90(mL/min/1.73m2) was 1.636 (95% CI 1.091-2.452, P=0.017). Conclusion: The circulating Tsukushi increased in type 2 diabetes patients with albuminuria and was associated with urinary albumin-creatinine ratio, implying that Tsukushi may be involved in the pathogenesis of diabetic kidney disease, which deserves future studies.

High-yield production of 5-keto-D-gluconic acid via regulated fermentation strategy of Gluconobacter oxydans and its conversion to L-(+)-tartaric acid.

Herein, we propose the production of 5-keto-D-gluconic acid (5KGA) by fermentation using Gluconobacter oxydans (G. oxydans) as the starting strain, from an initial concentration of 100 g/L glucose as substrate and the chemical conversion of 5KGA to L-(+)-tartaric acid (L-TA). The results show the efficacy and feasibility of two-stage pH (5.50→natural) linkage ventilation (0.5 vvm and 1.0 vvm, L/L/min) control of batch fermentation for 5KGA production. The final 5KGA yield of 100.2 g/L of 1.0 vvm is much higher than 0.5 vvm with an average productivity of 1.95 g/L/h. Changing the method of fermentation from batch to fed-batch can efficently prolong the high activity of G. oxydans for 5KGA production with an increased average productivity of 3.10 g/L/h, and the conversion rate of glucose to 5KGA is 92.50 %. The chemical conversion of 5KGA to L-TA catalyzed by metal ions in vitro indicates that the optimal catalyst is Cu2+ with a conversion rate of 35.09 % of 5KGA to L-TA. Our method can provide a practical and effective alternative for the industrial production of 5KGA and its conversion to L-TA.

Effects of the FHL2 gene on the development of subcutaneous and intramuscular adipocytes in goats.

BACKGROUND: Adipose tissue affects not only the meat quality of domestic animals, but also human health. Adipocyte differentiation is regulated by a series of regulatory genes and cyclins. Four and half-LIM protein (FHL2) is positively correlated with the hypertrophy of adipocytes and can cause symptoms such as obesity and diabetes. RESULT: In the transcriptome sequencing analysis of intramuscular adipocytes after three days of differentiation, the differentially expressed gene FHL2 was found. To further explore the biological significance of the differentially expressed gene FHL2, which was downregulated in the mature adipocytes. We revealed the function of FHL2 in adipogenesis through the acquisition and loss of function of FHL2. The results showed that the overexpression of FHL2 significantly increased the expression of adipogenic genes (PPARγ, C/EBPß) and the differentiation of intramuscular and subcutaneous adipocytes. However, silencing FHL2 significantly inhibited adipocyte differentiation. The overexpression of FHL2 increased the number of adipocytes stained with crystal violet and increased the mRNA expression of proliferation marker genes such as CCNE, PCNA, CCND and CDK2. In addition, it significantly increased the rate of EdU positive cells. In terms of apoptosis, overexpression of FHL2 significantly inhibited the expression of P53 and BAX in both intramuscular and subcutaneous adipocytes, which are involved in cell apoptosis. However, overexpression of FHL2 promoted the expression of BCL, but was rescued by the silencing of FHL2. CONCLUSIONS: In summary, FHL2 may be a positive regulator of intramuscular and subcutaneous adipocyte differentiation and proliferation, and acts as a negative regulator of intramuscular and subcutaneous adipocyte apoptosis. These findings provide a theoretical basis for the subsequent elucidation of FHL2 in adipocytes.

Associations between adherence to 24-Hour Movement Guidelines with continuous metabolic syndrome score among Chinese children and adolescents.

OBJECTIVES: The objective of this study was to evaluate the associations between adherence to 24-Hour Movement Guidelines (24-HMG) with continuous metabolic syndrome score (cMetS) among Chinese children. STUDY DESIGN: Cross-sectional study. METHODS: We conducted a cross-sectional study among 4604 children aged 6-17 years from Shenzhen, China. The 24-HMG was constructed using the self-report information on moderate-to-vigorous physical activity (MVPA), screen time (ST), and sleep duration. The cMetS was calculated based on waist circumference, homoeostatic model assessment for insulin resistance, mean arterial blood pressure, high-density lipoprotein cholesterol, and triglyceride. Multivariate linear regression models were used to assess the associations between adherence to recommendations of 24-HMG and cMetS. RESULTS: Among the participants, 563 (12.23%) students adhered to 3 recommendations of the 24-HMG. We found that adhering to more recommendations was negatively associated with cMetS (P for trend: <0.001). For specific combinations, meeting the ST + MVPA recommendations was negatively associated with cMetS (coefficients [ß]: -0.686; 95% confidence interval [CI]: -1.148, -0.223). Individuals who adhered to all recommendations had a lower cMetS (ß: -0.693; 95% CI: -1.147, -0.238) than those who met none of the recommendations. CONCLUSIONS: Our study showed that adherence to more recommendations of the 24-HMG was associated with lower levels of cMetS in Chinese children and adolescents.

Interfacial Self-Assembly Nanostructures: Constructions and Applications.

Interfacial self-assembly nanoarrays refer to the spontaneously organized nanostructures at interfaces, relying on the intrinsic properties of involved materials, such as surface energy, molecular structure, and interactions. In recent years, the exponential growth of self-assembly nanotechnology has substantially expanded the utility of nanomaterials. Particularly, non-covalent interactions-based interfacial self-assembly represents a viable and promising approach for the synthesis of novel nanostructure. This review introduces the significance and current development status of interfacial self-assembly technology, focusing on the driving mode, application, and prospects of interfacial self-assembly nanoarrays over the past few years.

Molecular Characterizations of FAM13A and Its Functional Role in Inhibiting the Differentiation of Goat Intramuscular Adipocytes through RIG-I Receptor Signaling Pathway.

The aim of this study was to elucidate the effect of FAM13A on the differentiation of goat intramuscular precursor adipocytes and its mechanism of action. Here, we cloned the CDS region 2094 bp of the goat FAM13A gene, encoding a total of 697 amino acid residues. Functionally, overexpression of FAM13A inhibited the differentiation of goat intramuscular adipocytes with a concomitant reduction in lipid droplets, whereas interference with FAM13A expression promoted the differentiation of goat intramuscular adipocytes. To further investigate the mechanism of FAM13A inhibiting adipocyte differentiation, 104 differentially expressed genes were screened by RNA-seq, including 95 up-regulated genes and 9 down-regulated genes. KEGG analysis found that the RIG-I receptor signaling pathway, NOD receptor signaling pathway and toll-like receptor signaling pathway may affect adipogenesis. We selected the RIG-I receptor signaling pathway enriched with more differential genes as a potential adipocyte differentiation signaling pathway for verification. Convincingly, the RIG-I like receptor signaling pathway inhibitor (HY-P1934A) blocked this pathway to save the phenotype observed in intramuscular adipocyte with FAM13A overexpression. Finally, the upstream miRNA of FAM13A was predicted, and the targeted inhibition of miR-21-5p on the expression of FAM13A gene was confirmed. In this study, it was found that FAM13A inhibited the differentiation of goat intramuscular adipocytes through the RIG-I receptor signaling pathway, and the upstream miRNA of FAM13A (miR-21-5p) promoted the differentiation of goat intramuscular adipocytes. This work extends the genetic regulatory network of IMF deposits and provides theoretical support for improving human health and meat quality from the perspective of IMF deposits.

Switch-like Gene Expression Modulates Disease Susceptibility.

A fundamental challenge in biomedicine is understanding the mechanisms predisposing individuals to disease. While previous research has suggested that switch-like gene expression is crucial in driving biological variation and disease susceptibility, a systematic analysis across multiple tissues is still lacking. By analyzing transcriptomes from 943 individuals across 27 tissues, we identified 1,013 switch-like genes. We found that only 31 (3.1%) of these genes exhibit switch-like behavior across all tissues. These universally switch-like genes appear to be genetically driven, with large exonic genomic structural variants explaining five (~18%) of them. The remaining switch-like genes exhibit tissue-specific expression patterns. Notably, tissue-specific switch-like genes tend to be switched on or off in unison within individuals, likely under the influence of tissue-specific master regulators, including hormonal signals. Among our most significant findings, we identified hundreds of concordantly switched-off genes in the stomach and vagina that are linked to gastric cancer (41-fold, p<10-4) and vaginal atrophy (44-fold, p<10-4), respectively. Experimental analysis of vaginal tissues revealed that low systemic levels of estrogen lead to a significant reduction in both the epithelial thickness and the expression of the switch-like gene ALOX12. We propose a model wherein the switching off of driver genes in basal and parabasal epithelium suppresses cell proliferation therein, leading to epithelial thinning and, therefore, vaginal atrophy. Our findings underscore the significant biomedical implications of switch-like gene expression and lay the groundwork for potential diagnostic and therapeutic applications.

LC-MS based metabolomics identification of natural metabolites against Fusarium oxysporum.

Fusarium is a soil-borne pathogen that poses a serious threat to the quality and yield of hundreds of crops worldwide, particularly tobacco production. Using metabolomics technology, we investigated natural metabolites from disease-conducting soil (DCS) and disease-suppressing soil (DSS) of tobacco rhizosphere as fungicides to control tobacco Fusarium wilt (TFW), which is mainly caused by Fusarium oxysporum. Furthermore, the antifungal mechanisms of these natural metabolites were preliminarily elucidated through various assessments, including antifungal activity determination, chemotaxis effect tests, PI staining experiments, and measurements of extracellular conductivity and protein content. Metabolomics results showed that the DCS with three different disease grades (G1, G5 and G9 groups) had significantly higher levels of 15, 14 and 233 differential rhizosphere metabolites (DRMs) and significantly lower levels of 72, 152 and 170 DRMs compared to the DSS (G0 group). According to KEGG pathway analysis, these DRMs were found to be enriched in the caffeine metabolism, biosynthesis of phenylpropanoids, galactose metabolism and tyrosine metabolism, etc. Linustatin, scopoletin and phenylpropiolic acid were picked out from these DRMs and found to have suppressive activity against F. oxysporum through correlation analysis and antifungal experiments. The three DRMs showed strong inhibitory effects on the growth and spore germination of F. oxysporum at concentrations of 0.5 mM or higher in each test period. Furthermore, F. oxysporum showed a phobotaxis effect against these three DRMs at concentrations as low as 0.25 mM. Finally, we found that the three DRMs had an inhibitory effect on F. oxysporum by destroying the integrity of the cell membrane and increasing the membrane permeability of F. oxysporum. This study firstly reports the inhibition activity of phenylpropiolic acid and linustatin on F. oxysporum, providing a practical and environmentally friendly method for biocontrol of TFW by using natural fungicides.

Asymmetric association between meteorological factors and human infections with hemorrhagic fever with renal syndrome: A 16-year ecological trend study in Shaanxi, China.

Objective: Hemorrhagic fever with renal syndrome (HFRS) continues to pose a significant threat to global health. This study aimed to investigate both the long- and short-term asymmetric impacts of variations in meteorological variables on HFRS. Methods: The reported monthly HFRS incidence data from Shaanxi between 2004 and 2019, along with corresponding meteorological data, were collected to conduct an ecological trend analysis. Subsequently, the autoregressive distributed lag (ARDL) and nonlinear ARDL (NARDL) models were used to examine the long- and short-term asymmetric effects of climate variables on HFRS incidence. Results: Overall, a reduction in HFRS incidence was observed in Shaanxi from 2004 to 2019, with an average annual percentage change of -0.498 % (95 %CI -13.247 % to 12.602 %). HFRS incidence peaked in December and reached its lowest point in March each year. A 1 mm increase in aggregate precipitation (AP) was associated with a 4.3 % rise in HFRS incidence, while a 1 mm decrease contributed to a 3.7 % increase, indicating a long-term asymmetric impact (Wald long-term asymmetry test [WLT] = 9.072, P = 0.003). In the short term, a 1 % decrease in mean relative humidity (MRH) led to a 5.7 % decline in HFRS incidence (Wald short-term asymmetry test [WSR] = 5.978, P = 0.015). Additionally, changes in meteorological variables showed varied effects: ΔMWV(+) at a 1-month lag had a significant positive short-term effect on HFRS; ΔMRH(+) at a 3-month lag, ΔAP(+) at a 2-month lag, ΔAP(-) at a 1-month lag, ΔASH(+) at a 1-month lag, and ΔASH(-) at a 3-month lag all exhibited strong negative short-term impacts on HFRS incidence. Conclusions: Weather variability plays a significant role in influencing HFRS incidence, with both long- and short-term asymmetric and/or symmetric effects. Utilizing the NARDL model through a One Health lens offers promising opportunities for enhancing HFRS control measures.

Weight-Specific Grip Strength as a Novel Indicator Associated with Cardiometabolic Risk in Children: The EMSNGS Study.

CONTEXT: Handgrip strength (HGS) is an important indicator of sarcopenia and adverse health outcomes. However, evaluating HGS in children presents challenges, and its association with metabolism remains incompletely understood. OBJECTIVE: To establish grip strength reference values for Chinese children and adolescents, as well as to evaluate the relationship between HGS and cardiometabolic risk. METHODS: Data were collected from 4 072 participants aged 6-18 as part of the Evaluation and Monitoring on School-based Nutrition and Growth in Shenzhen (EMSNGS) study. HGS was measured, and relative HGS (RHGS) was normalized by body mass index. Age- or weight-specific HGS and RHGS were derived using the generalized additive model of location, scale, and shape (GAMLSS) model, and participants' values were categorized into quartiles, defining low strength as the lowest quartile. The cardiometabolic risk index (CMRI) z-score was calculated, with high risk defined as a z-score of ≥ 1. RESULTS: Both boys and girls exhibited similar increases in age- and weight-specific grip strength. Low grip strength, classified by weight-specific HGS and RHGS, was linked to higher CMRI z-scores compared to classifications based on age-specific references in both sexes. A dose-dependent relationship was observed between weight-specific grip strength and cardiometabolic risk, particularly in boys. Compared to the middle category (P25th-P75th), the odds ratios for high cardiometabolic risks associated with low grip strength increased in both sexes. CONCLUSION: This study established grip strength reference values for Chinese youth, introduced the concept of weight-specific HGS and RHGS, and demonstrated a dose-dependent relationship between weight-specific grip strength and cardiometabolic risk. These findings highlighted the association between low muscle strength and increased cardiometabolic risk.

The superior value of radiomics to sonographic assessment for ultrasound-based evaluation of extrathyroidal extension in papillary thyroid carcinoma: a retrospective study.

BACKGROUND: Extrathyroidal extension was related with worse survival for patients with papillary thyroid carcinoma. For its preoperative evaluation, we measured and compared the predicting value of sonographic method and ultrasonic radiomics method in nodules of papillary thyroid carcinoma. PATIENTS AND METHODS: Data from 337 nodules were included and divided into training group and validation group. For ultrasonic radiomics method, a best model was constructed based on clinical characteristics and ultrasonic radiomic features. The predicting value was calculated then. For sonographic method, the results were calculated using all samples. RESULTS: For ultrasonic radiomics method, we constructed 9 models and selected the extreme gradient boosting model for its highest accuracy (0.77) and area under curve (0.813) in validation group. The accuracy and area under curve of sonographic method was 0.70 and 0.569. Meanwhile. We found that the top-6 important features of xgboost model included no clinical characteristics, all of whom were high-dimensional radiomic features. CONCLUSIONS: The study showed the superior value of ultrasonic radiomics method to sonographic method for preoperative detection of extrathyroidal extension in papillary thyroid carcinoma. Furthermore, high-dimensional radiomic features were more important than clinical characteristics.

Evaluation of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in preterm infants with brain injury.

BACKGROUND: Prematurity-related brain injury is a common and serious complication that has long-term effects on the survival and development of affected infants. Currently, the roles of certain biomarkers such as the protein hydrolysis product SBDP145, melatonin, soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), high mobility group box 1 protein (HMGB1), and hypoxia-inducible factor 1-alpha (HIF-1α) in prematurity-related brain injury remain not fully elucidated. Our study aims to assess the significance of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in preterm infants with brain injury. METHODS: 135 preterm infants admitted to our hospital from January 2020 to February 2022 were selected and divided into 78 cases in a prematurity-associated brain injury group, and 57 cases in another group of preterm infants without brain injury or other diseases according to the magnetic resonance imaging results. The levels of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in the two groups were analyzed. The serum concentrations of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in newborns with different severity of ventricular hemorrhage were observed, and the levels of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in those with different severity of white matter brain injury were compared. RESULTS: The levels of SBDP145, sLOX-1, HMGB1 and HIF-1α were significantly higher in the preterm combined brain injury group than in the preterm group, and melatonin levels were significantly lower than in the preterm group(P < 0.05). The levels of SBDP145, sLOX-1, HMGB1 and HIF-1α were higher in the moderate to severe group and melatonin levels were lower in the mild group of newborns with ventricular hemorrhage (P < 0.05). The levels of SBDP145, sLOX-1, HMGB1 and HIF-1α were higher in the moderate-severe group and melatonin levels were lower in the mild group in newborns with cerebral white matter injury (P < 0.05). The independent variables were SBDP145, melatonin, sLOX-1, HMGB1, HIF-1α, and the dependent variable was the prognosis of neonates with brain injury. Univariate logistic regression analysis and multivariate logistic regression analysis were performed. The results showed that the influencing factors of newborns with brain injury were SBDP145, melatonin, sLOX-1, HMGB1, HIF-1α. CONCLUSION: The levels of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α were highly expressed in preterm newborns with brain injury, and the levels were higher when the condition of the newborns was more severe. These findings suggest the potential clinical utility of these biomarkers in predicting and monitoring brain injury in preterm infants, which could aid in early intervention and improve long-term outcomes.

Mendelian randomization analysis reveals no causal relationship between thyroid function and sarcopenia-related traits.

Background: Recent research has indicated a potential association between thyroid function and sarcopenia, but the specific mechanisms and a definitive causal relationship have yet to be established. Therefore, the objective of this study is to examine the potential causal connection between thyroid function and sarcopenia-related traits, including hand-grip strength, appendicular lean mass (ALM), and walking pace. Methods: The study used a bi-directional two-sample MR design, with thyroid function examined as the exposure and sarcopenia-related traits as the outcome in the first stage, and then reversed in the second stage. The genetic instruments for thyroid function were obtained from a comprehensive meta-analysis involving 271,040 participants. Data on sarcopenia-related traits based on GWASs were collected from the UK Biobank, which includes up to 461,026 European participants. The estimates for MR were calculated using the inverse-variance weighted (IVW) method, and several sensitivity analyses were performed. Results: After applying the Bonferroni correction for multiple testing, our MR analyses revealed no significant impact of thyroid function liability on sarcopenia-related traits. Similarly, our reverse MR analysis did not provide evidence supporting the influence of liability to sarcopenia-related traits on thyroid function. The results of the primary IVW MR analyses were largely in line with those obtained from our sensitivity MR analyses. Conclusion: Our research findings do not suggest a link between thyroid function and sarcopenia-related traits. The associations identified in epidemiological studies may be influenced, at least in part, by shared biological mechanisms or environmental confounders.

Unraveling the role of lactate-related genes in myocardial infarction.

Background: Lactate is a crucial intermediary, facilitating communication between myocardial energy metabolism and microenvironmental regulation. The present study aimed to investigate the relationship between lactate-related genes (LRGs) and myocardial infarction (MI). Methods: A total of 23 LRGs exhibited differential expression between individuals with MI and healthy controls. Lasso regression analysis and validation with the GSE61144 dataset identified three hub genes: COX20, AGK, and PDHX. Single-gene GSEA of these genes revealed strong enrichment in pathways related to amino acid metabolism, cell cycle, and immune functions. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was utilized to validate the expression levels of the hub genes. Results: Immune infiltration analysis revealed differences in CD4+ T and CD8+ T cells between the MI and control groups. Additionally, 67 candidate drugs targeting the three hub LRGs were identified, and a ceRNA network was constructed to explore the intricate interactions among these genes. Conclusions: These findings enhance the understanding of MI and have potential therapeutic implications.

Dysregulated gene expression of SUMO machinery components induces the resistance to anti-PD-1 immunotherapy in lung cancer by upregulating the death of peripheral blood lymphocytes.

Background: The majority of patients with lung cancer exhibit drug resistance after anti-PD-1 immunotherapy, leading to shortened patient survival time. Previous studies have suggested an association between epigenetic abnormalities such as methylation and clinical response to anti-PD-1 immunotherapy, while the role of SUMOylation in resistance to anti-PD-1 antibody immunotherapy is still unclear. Methods: Here, the mRNA expression of 15 SUMO machinery components in PBMC from lung cancer patients receiving anti-PD-1 immunotherapy were analyzed using real-time PCR. Base on the percentage change in mRNA levels, the relationship between the expression of SUMO machinery components and outcomes of anti-PD-1 immunotherapy, and the influencing factors of SUMOylation were evaluated. PBMC was treated with different concentrations of 2-D08 (a specific inhibitor of SUMOylation) in vitro, and analyzed the activation and the death rates of lymphocyte subsets by flow cytometry analysis. Results: A predictive method, base on the gene expression of three SUMO machinery components (SUMO1, SUMO3 and UBE2I), were developed to distinguish non-responders to PD-1 inhibitors. Furthermore, the number of lymphocytes in peripheral blood significantly reduced in the dysregulated SUMOylation groups (the percentage change >100 or -50 ~ -100 groups). In vitro studies confirmed that lightly low SUMOylation level improved the activation status of T and NK lymphocytes, but extremely low SUMOylation level lead to the increased death rates of lymphocytes. Conclusion: Our findings implied that dysregulated gene expression of SUMO machinery components could induce the resistance of anti-PD-1 immunotherapy in lung cancer by upregulating the death of peripheral blood lymphocytes. These data might provide effective circulating biomarkers for predicting the efficacy of anti-PD-1 immunotherapy, and uncovered a novel regulatory mechanism of resistance to anti-PD-1 immunotherapy.

Structural analysis of the human C5a-C5aR1 complex using cryo-electron microscopy.

The complement system is a complex network of proteins that plays a crucial role in the innate immune response. One important component of this system is the C5a-C5aR1 complex, which is critical in the recruitment and activation of immune cells. In-depth investigation of the activation mechanism as well as biased signaling of the C5a-C5aR1 system will facilitate the elucidation of C5a-mediated pathophysiology. In this study, we determined the structure of C5a-C5aR1-Gi complex at a high resolution of 3 Å using cryo-electron microscopy (Cryo-EM). Our results revealed the binding site of C5a, which consists of a polar recognition region on the extracellular side and an amphipathic pocket within the transmembrane domain. Furthermore, we found that C5a binding induces conformational changes of C5aR1, which subsequently leads to the activation of G protein signaling pathways. Notably, a key residue (M265) located on transmembrane helix 6 (TM6) was identified to play a crucial role in regulating the recruitment of ß-arrestin driven by C5a. This study provides more information about the structure and function of the human C5a-C5aR1 complex, which is essential for the proper functioning of the complement system. The findings of this study can also provide a foundation for the design of new pharmaceuticals targeting this receptor with bias or specificity.