Multimodal deep transfer learning to predict retinal vein occlusion macular edema recurrence after anti-VEGF therapy.

Purpose: To develop a multimodal deep transfer learning (DTL) fusion model using optical coherence tomography angiography (OCTA) images to predict the recurrence of retinal vein occlusion (RVO) and macular edema (ME) after three consecutive anti-VEGF therapies. Methods: This retrospective cross-sectional study consisted of 2800 B-scan OCTA macular images collected from 140 patients with RVO-ME. The central macular thickness (CMT) > 250 µm was used as a criterion for recurrence in the three-month follow-up after three injections of anti-VEGF therapy. The qualified OCTA image preprocessing and the lesion area segmentation were performed by senior ophthalmologists. We developed and validated the clinical, DTL, and multimodal fusion models based on clinical and extracted OCTA imaging features. The performance of the models and experts predictions were evaluated using several performance metrics, including the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. Results: The DTL models exhibited higher prediction efficacy than the clinical models and experts' predictions. Among the DTL models, the Vgg19 performed better than that of the other models, with an AUC of 0.968 (95 % CI, 0.943-0.994), accuracy of 0.913, sensitivity of 0.922, and specificity of 0.902 in the validation cohort. Moreover, the fusion Vgg19 model showed the highest prediction efficacy among all the models, with an AUC of 0.972 (95 % CI, 0.946-0.997), accuracy of 0.935, sensitivity of 0.935, and specificity of 0.934 in the validation cohort. Conclusions: Multimodal fusion DTL models showed robust performance in predicting RVO-ME recurrence and may be applied to assist clinicians in determining patients' follow-up time after anti-VEGF therapy.

Understanding, diagnosing, and treating pancreatic cancer from the perspective of telomeres and telomerase.

Telomerase is associated with cellular aging, and its presence limits cellular lifespan. Telomerase by preventing telomere shortening can extend the number of cell divisions for cancer cells. In adult pancreatic cells, telomeres gradually shorten, while in precancerous lesions of cancer, telomeres in cells are usually significantly shortened. At this time, telomerase is still in an inactive state, and it is not until before and after the onset of cancer that telomerase is reactivated, causing cancer cells to proliferate. Methylation of the telomerase reverse transcriptase (TERT) promoter and regulation of telomerase by lactate dehydrogenase B (LDHB) is the mechanism of telomerase reactivation in pancreatic cancer. Understanding the role of telomeres and telomerase in pancreatic cancer will help to diagnose and initiate targeted therapy as early as possible. This article reviews the role of telomeres and telomerase as biomarkers in the development of pancreatic cancer and the progress of research on telomeres and telomerase as targets for therapeutic intervention.

Unveiling Synergistic Potency: Exploring Butyrolactone I to Enhance Gentamicin Efficacy against Methicillin-Resistant Staphylococcus aureus (MRSA) Strain USA300.

Staphylococcus aureus, including MRSA strains, poses significant health risks, imposing a significant disease burden and mortality. We investigate butyrolactone I (BL-1), a marine-derived metabolite from Aspergillus terreus, enhancing aminoglycoside efficacy against MRSA. A promising synergy is observed with BL-1 and various aminoglycosides, marked by low fractional inhibitory concentration indexes (FICIs < 0.5). Comprehensive studies utilizing USA300 MRSA and gentamicin reveal a remarkable one-fourth reduction in minimum inhibitory concentration (MIC) with 20 µg/mL BL-1. A relative abundance assay indicates that BL-1 enhances gentamicin uptake while restraining extracellular presence, involving intricate transmembrane signaling and molecular interactions. RNA-Seq analysis yielded an unexpected revelation, unveiling a distinctive gene expression profile and distinguishing it from other treatment approaches. Furthermore, meticulous analyses validated the extensive perturbations induced by BL-1 exposure, affecting diverse biological functions, encompassing glycolysis, amino acid metabolisms, substance transmembrane transport, and virulence generation. These valuable insights inspired further confirmation of bacterial virulence and the modulation of membrane permeability resulting from BL-1 treatment. Phenotypic validations corroborated our observations, revealing reduced membrane permeability and hemolytic toxicity, albeit demanding a deeper comprehension of the intricate interplay underlying these actions. Our study contributes crucial mechanistic insights to the development of therapeutic strategies against this notorious pathogen and the judicious employment of aminoglycosides. Additionally, it elucidates marine-derived metabolites' ecological and functional roles, exemplified by fungal quorum sensing signals. These compounds could give producers a competitive edge, inhibiting microorganism proliferation and suggesting novel approaches for combating resistant pathogens.

Causal relationship between Helicobacter pylori antibodies and gastroesophageal reflux disease (GERD): A mendelian study.

BACKGROUND: Observational studies have indicated that both Helicobacter pylori infection and the presence of Helicobacter pylori antibodies may increase the risk of gastroesophageal reflux disease (GERD). However, the exact association between Helicobacter pylori antibodies and the occurrence of GERD remains largely unresolved. Therefore, this two-sample Mendelian randomization (MR) study aims to investigate the causal relationship between Helicobacter pylori infection and GERD. METHODS: This study encompassed seven different specific protein antibodies targeting Helicobacter pylori and utilized a genome-wide association study (GWAS) on GERD. MR analysis was conducted to assess the causal relationship between Helicobacter pylori antibodies and the development of GERD. RESULTS: Genetically predicted serum levels of Helicobacter pylori IgG antibodies were positively associated with an increased risk of GERD (odds ratio [OR] = 1.001, 95% CI 1.000-1.003, P = 0.043). No causal relationship was found between other Helicobacter pylori antibodies and gastroesophageal reflux disease. CONCLUSION: The outcomes derived from our two-sample Mendelian randomization analysis demonstrate a discernible link between the levels of Helicobacter pylori IgG antibodies and an augmented susceptibility to GERD. However, it is imperative to expand the sample size further in order to corroborate the correlation between Helicobacter pylori infection and GERD.

Association Between Dysmenorrhea and Risk of Epilepsy in East Asian Populations: A Bidirectional Two-Sample Mendelian Randomization Study.

Dysmenorrhea is associated with epilepsy. Existing evidence is mostly limited to observational studies, which are liable to confounding and bias. This study investigated the causal relevance of dysmenorrhea on epilepsy using Mendelian randomization (MR). We extracted instrumental variants for dysmenorrhea and epilepsy from published genomewide association study data, focusing on individuals of East Asian descent. A comprehensive suite of MR estimations and sensitivity analyses was performed to ensure the robustness of the findings. Each outcome database was analyzed separately in both directions. For dysmenorrhea and epilepsy, 7 and 3 genetic variants respectively were selectively extracted as instrumental variants. The results suggest that dysmenorrhea is causally associated with an elevated risk of epilepsy (inverse variance weighted [IVW]: OR = 1.26; 95% CI [1.07, 1.47]; p = 4.42 × 10-3); conversely, no strong evidence was found to corroborate that epilepsy exerts a causal effect on the incidence of dysmenorrhea (IVW: OR = 1.04; 95% CI [0.82, 1.33]; p = .72). These findings provide novel insights into the causal relationship between dysmenorrhea and epilepsy, which may have implications for clinical decision-making in patients with epilepsy and dysmenorrhea.

Peptic ulcer disease burden, trends, and inequalities in 204 countries and territories, 1990-2019: a population-based study.

Background: Peptic ulcer disease has been a major threat to the world's population, which remains a significant cause of hospitalization worldwide and healthcare resource utilization. Objectives: We aimed to describe the global burden, trends, and inequalities of peptic ulcer disease. Design: An observational study was conducted. Methods: In this secondary analysis of the Global Burden of Disease, Injuries, and Risk Factors Study 2019, we extracted data for age-standardized incidence rates (ASIRs), disability-adjusted life year rates (ASDRs), and mortality rates (ASMRs); then, we stratified by age, level of regionals, and country; subsequently, we calculated estimated annual percentage changes (EAPC) of ASIR, ASDR, ASMR, and quantified cross-country inequalities in peptic ulcer disease mortality. Results: Globally, ASIR showed a continuous downward trend, from 63.84 in 1990 to 44.26 per 100,000 population in 2019, with an annual decrease of 1.42% [EAPC = -1.42 (95% CI: -1.55 to -1.29)]. ASDR showed a continuing downward trend, and the EAPC was -3.47% (-3.58 to -3.37). ASMR showed a persistent decline, declining by nearly half in 2019 compared to 1990 (3.0 versus 7.39 per 100,000 population), with an annual decrease of 2.55% [EAPC = -3.36 (95% CI: -3.47 to -3.25)]. A significant reduction in sociodemographic index (SDI)-related inequality, from an excess of 190.43 disability-adjusted life years (DALY) per 100,000 (95% CI: -190.83 to -190.02) between the poorest and richest countries in 1990 to 62.85 DALY per 100,000 (95% CI -62.81 to -62.35) in 2019. Conclusion: Global peptic ulcer disease morbidity and mortality rates decreased significantly from 1990 to 2019. These health gains were in accordance with a substantial reduction in the magnitude of SDI-related inequalities across countries, which is paired with overall socioeconomic and health improvements observed in the region.

A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis.

BACKGROUND: CPUL1, a phenazine analog, has demonstrated potent antitumor properties against hepatocellular carcinoma (HCC) and indicates a promising prospect in pharmaceutical development. However, the underlying mechanisms remain largely obscure. METHODS: Multiple HCC cell lines were used to investigate the in vitro effects of CPUL1. The antineoplastic properties of CPUL1 were assessed in vivo by establishing a xenograft nude mice model. After that, metabolomics, transcriptomics, and bioinformatics were integrated to elucidate the mechanisms underlying the therapeutic efficacy of CPUL1, highlighting an unanticipated involvement of autophagy dysregulation. RESULTS: CPUL1 suppressed HCC cell proliferation in vitro and in vivo, thereby endorsing the potential as a leading agent for HCC therapy. Integrative omics characterized a deteriorating scenario of metabolic debilitation with CPUL1, presenting an issue in the autophagy contribution of autophagy. Subsequent observations indicated that CPUL1 treatment could impede autophagic flow by suppressing autophagosome degradation rather than its formation, which supposedly exacerbated cellular damage triggered by metabolic impairment. Moreover, the observed late autophagosome degradation may be attributed to lysosome dysfunction, which is essential for the final stage of autophagy and cargo disposal. CONCLUSIONS: Our study comprehensively profiled the anti-hepatoma characteristics and molecular mechanisms of CPUL1, highlighting the implications of progressive metabolic failure. This could partially be ascribed to autophagy blockage, which supposedly conveyed nutritional deprivation and intensified cellular vulnerability to stress.

Dietary inflammatory index and risk of non-alcoholic fatty liver disease and advanced hepatic fibrosis in US adults.

Background and aims: This study aims to investigate whether the Dietary Inflammatory Index (DII) is associated with non-alcoholic fatty liver disease (NAFLD) and advanced hepatic fibrosis (AHF) among non-institutionalized adults in the United States. Methods: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2016, a total of 10,052 adults aged ≥18 years were included in the analysis. We used multivariable analysis, controlling for demographic variables, to evaluate the association between DII and NAFLD and AHF, a restricted cubic spline (RCS) was used to model the non-linear relationship between DII and NAFLD. Results: For 10,052 participants, DII ranges from -4.63 to 5.47. Compared with quartile 1, higher DII group were associated with higher levels of female, separated/divorced, lower education level, heavy alcohol use, current smoke status, BMI, poverty income ratio, and waist circumference. DII also showed a significantly positive correlation with ALT, AST. In the fully adjusted multivariable model, DII was positively associated with the presence of NAFLD (OR 1.09, 1.06-1.13 CI, p trend <0.0001), and AHF (OR 1.15, 1.07-1.23 CI, p trend <0.001). The association remained statistically significant after stratified by gender in terms of NAFLD, but in case of AHF only in males (Q4 vs. Q1: OR 2.68, 1.63-4.41 CI, p trend <0.0001) was statistically significant. In the RCS models, the relation of DII and NAFLD started increase rapidly until around 1.80 and then started relatively flat afterward. Conclusion: Higher pro-inflammatory level was associated with higher risk of NAFLD in males and females, and with higher risk of AHF in males but not in females. Therefore, strategies to promote an Zhang anti-inflammatory diet should be considered to prevent and ameliorate NAFLD and AHF in adults.

Subacute oral toxicology and toxicokinetics of pterostilbene, a novel Top1/Tdp1 inhibiting anti-tumor reagent.

This study evaluated the subacute toxicity and toxicokinetics of a potential anti-cancer drug candidate, pterostilbene, in rats. Animals were orally administered at two repeated doses of 200 and 500 mg/kg for 28 days. No mortality was observed during the 28 days of continuous administration of pterostilbene. Body weight and food consumption in each group increased steadily, while no significant difference was found. Liver weight in the 500 mg/kg female, but not male group increased with mild cytoplasmic vacuoles observed in histopathological study. Toxicokinetics was assessed by measuring plasma concentrations of pterostilbene on the first and 28th day of administration using UPLC-MS/MS. Toxicokinetic parameters showed that AUC0-t significantly increased in all animals, while the increase in females was greater than males. System exposure of pterostilbene appeared to be linear within the administrated dose range. In conclusion, our findings suggested a minimal subacute toxicity profile of pterostilbene, which could strongly support further development of this compound as a novel anti-cancer agent.

Association between secondhand smoke and cancers in adults in the US population.

BACKGROUND: Tobacco use is the leading preventable cause of cancer and premature death, smoking has a clear causal relationship with a variety of cancers. However, the relationship between exposure to secondhand smoke (SHS) and other cancers besides lung cancer is not clear. In this study, we intend to investigate the cancers mortality risks especially other cancers besides lung cancer associated with exposure to SHS. METHODS: The National Health and Nutrition Examination Survey is a longitudinal population-based, nationally representative health survey and mortality rates linked to the National Death Index (NDI) database. In this study, the participants completed a questionnaire assessing sociodemographic data, anthropometry, and lifestyle information, including smoking and alcohol consumption, meanwhile, all the participants were screened for serum cotinine. First, Spearman correlation analysis was performed to confirm the correlation between serum cotinine level and exposure status. And then, exposure to SHS was divided into two groups: low exposure group (serum cotinine level between 0.015 and 10) and high exposure group (serum cotinine level ≥ 10), Cox proportional hazards regression modeling was used to evaluate the association between exposure to SHS and eight different types of smoke-related cancer. RESULTS: In this study, we evaluated a cohort of 25,794 US residents older than 19 years from 2005 to 2016 and were followed for mortality through the February 2019. We conducted Spearman correlation analysis to confirm the correlation between serum cotinine level and exposure status (including smoking and exposure to SHS), it demonstrated the correlation coefficient between serum cotinine level and exposure to smoke was 0.976, p < 0.00001. By Cox proportional hazards regression modeling, high exposure group were found to be positively associated with all neoplasms with a total Hazard Ratio (HR) of 1.748 (95% Confidence Interval (CI), 1.415-2.159), had higher all-cause mortality risks than non-exposure to tobacco smoke. Regarding the specific types, we found the following associations: cancer of the lung (HR, 1.484; 95% CI, 1.191-1.849), stomach (HR, 1.491; 95% CI, 1.199-1.854), bladder (HR, 1.487; 95% CI, 1.198,1.846), esophageal (HR, 1.487; 95% CI 1.194-1.852), kidney (HR, 1.497; 95% CI, 1.201-1.865), pancreatic (HR, 1.479; 95% CI 1.189-1.841), leukemia (HR, 1.479; 95% CI 1.190-1.839), cervical (HR, 1.490; 95% CI 1.198-1.853). However, low exposure group were non-existent statistically significant with a Hazard Ratio (HR) of 1.062 (95% Confidence Interval (CI), 0.953-1.183). CONCLUSIONS: The research demonstrated that serum cotinine has a significant correlation with smoke exposure status, which confirmed serum cotinine can be used as an indicator to reflect human smoke exposure. What's more, our results confirmed high exposure of SHS (serum cotinine level ≥ 10) has a significant effect on lung, stomach, bladder, esophagus, kidney, pancreatic, leukemia, cervical cancer.

Prediction model for elevated intraocular pressure risk after silicone oil filling based on clinical features.

Background: To evaluate risk factors and further develop prediction models for intraocular pressure elevation (IOP) after vitreoretinal surgery with silicone oil tamponade to support clinical management. Methods: A retrospective study analyzed 1,061 eyes of 1,061 consecutive patients that presented to the Jiangsu Province Hospital between December 2015 and December 2020, the IOP was measured from the preoperative visit and at the 1-week, 1-month, 3-month, and 6-month visits, and the final postoperative visit before silicone oil removal. Four machine learning methods were used to carried out the prediction of IOP elevation: Decision Tree, Logistic Regression, Random Forest, and Gradient-Boosted Decision Trees (GBDT) based on features including demographic and clinical characteristics, preoperative factors and surgical factors. Predictors were selected based on the p-value of the univariate analysis. Results: Elevated intraocular pressure developed in 26.01% of the eyes postoperatively. Elevated intraocular pressure primarily occurred within 1-2 weeks after surgery. Additionally, the majority of IOP values were distributed around 25-40 mmHg. GBDT utilizing features with p-values less than 0.5 from the hypothesis testing demonstrated the best predictive performance for 0.7944 in accuracy. The analysis revealed that age, sex, hypertension, diabetes, myopia, retinal detachment, lens status and biological parameters have predictive value. Conclusion: Age, sex, hypertension, diabetes, myopia, retinal detachment, lens status and biological parameters have influence on postoperative intraocular pressure elevation for patients with silicone oil tamponade after pars plana vitrectomy. The prediction model showed promising accuracy for the occurrence of IOP elevation. This may have some reference significance for reducing the incidence of high intraocular pressure after pars plana vitrectomy combined with silicone oil filling.

[Effects of different swimming exercises on alcoholic fatty liver formation in mice].

Objective: To investigate the effects of 7-week swimming exercise with different loads on the improvement of liver lipid metabolism in mice with alcoholic fatty liver disease (AFLD) and its relationship with the regulation of miR-34a/PPARα. Methods: Fifty male KM mice were randomly divided into control group (K, n=10) and alcoholic fatty liver group (AFLD, n=40). The AFLD model was constructed after feeding with 50% alcohol for 7 weeks with 1 d rest per week. After successful model construction, the mice were divided into a model group (M), a 30-min swimming exercise group (LE), a 60-min swimming exercise group (ME), and a 90-min loaded swimming exercise group (HE, 5% of body mass as tail lead load), with 10 mice in each group, for a total of 7 weeks of intervention. After completion, the serum and liver tissues were collected, the liver index, visceral fat ratio, hepatocyte injury indicators, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GT), total cholesterol (TC), triglyceride (TG), and high/low density lipoprotein cholesterol (H/LDL-C) content were measured; HE staining was used to observe the changes in liver structure, Western blot was used to detect the protein levels of PPARα, FAS and TNF-α in liver tissues, and mRNA expression profiles were analyzed by sequencing After RT-PCR, the mRNA expressions of miR-34a, PPARα, FAS, TNF-α and CPT-1 were verified. Results: Compared with K group, the hepatic cord disorder, focal lipid vacuum, obvious lipid droplet vacuolation, abnormal ectopic nucleus were observed in AFLD group ; liver function was decreased significantly. Compared with the M group, the liver functions of the ME and HE groups were improved significantly, the serum levels of TG, TC and LDL-C were decreased, while the HDL-C level was increased (P<0.01 or P<0.05), and the liver index and visceral fat ratio were decreased (P< 0.01 or P<0.05), the focal lipid droplet degeneration of hepatocytes was decreased, and the structure of the hepatic cord was clearer; and the ME group showed a more significant intervention effect. Compared with the M group, the expression levels of PPARα protein in the liver tissues of the LE, ME, and HE groups were increased, while the protein expression levels of FAS and TNF-α were decreased (P<0.01 or P<0.05). Based on Illumina high-throughput sequencing and mRNA differential expression analysis, there are 38 differentially expressed genes in the PPARα pathway, including 9 up-regulated genes and 29 down-regulated genes, which are involved in liver fatty acid oxidation, lipid metabolism, and apoptosis inhibition. Compared with group M, the gene levels of miR-34a, FAS, and TNF-α in LE, ME, and HE groups were decreased, and the gene levels of PPARα and CPT-1 were increased (P<0.01 or P<0.05). Conclusion: Swimming with different loads can improve liver functions in AFLD mice, promote lipid droplet degradation, and regulate liver lipid metabolism. The mechanism may be related to the activation of miR-34a/PPARα, and the intervention effect of moderate-load swimming is better.

Development and validation of a liquid chromatography-tandem mass spectrometry method for CPUL1, a novel antitumor candidate compound, and its application to pharmacokinetic studies.

An active substance of pyrano[3,2-a]phenazine, also called CPUL1, is a synthesized phenazine derivative and displays broad-spectrum anticancer activities. Quantitative assessment of CPUL1 in biological samples has not been well established, hindering pharmaceutical development and application. According to international guidelines, a sensitive and selective liquid chromatography-tandem mass spectrometry method in negative ion mode was developed and validated for quantification of CPUL1 in human plasma, colorectal cancer cell lines, and rat plasma, whereby linearity and accuracy were demonstrated for the range of 1-1000 ng/ml. The validated liquid chromatography-tandem mass spectrometry method was successfully employed in pharmacokinetic studies of CPUL1 in vitro and in vivo. Notably, the cellular pharmacokinetic behavior of CPUL1 varies in colorectal cancer cell lines. Regarding the pharmacokinetic processes in vivo, oral absorption was less effective than an injection, with a bioavailability of 23.66%. CPUL1 was linearly eliminated after a single administration; however, it could accumulate in tissues (heart, liver, spleen, lung, and kidney) after multiple injections. In summary, this study established a capable bioanalytical method for CPUL1 and provided exploratory pharmacokinetic data, paving the way for use of this promising derivative in disease models.

Physical Exercise Repairs Obstructive Jaundice-Induced Damage to Intestinal Mucosal Barrier Function via H2S-Mediated Regulation of the HMGB1/Toll Like Receptors 4/Nuclear Factor Kappa B Pathway.

The present study aimed to determine the effect of aerobic exercise on improving damage to intestinal mucosal barrier function caused by obstructive jaundice (OJ) and explore the mechanism. Fifty male KM mice were divided into five groups: sham operation group (S), model group (M), exercise group (TM), DL-propargylglycine + exercise (PT) group, and sodium hydrosulfide + exercise (NT) group. Additionally, mice in S group underwent common bile duct ligation for 48 h to establish a murine obstructive jaundice model. In PT group, propargylglycine (40 mg/kg) was intraperitoneally injected 7 days after surgery. NaHS (50 µmol/kg) was intraperitoneally injected into mice in the NT group 7 days after surgery. The TM group, NT group and PT group exercised on a slope of 0% at a speed of 10 m/min without weight training (30 min/day). HE staining showed that the intestinal mucosa of group M was atrophied and that the villi were broken. The intestinal mucosal structure of mice in the TM group was improved. Serum assays showed that H2S levels were higher in the TM group than in the M group; compared with the levels in the TM group, the PT group levels were decreased and the NT group levels were increased. In addition, aerobic exercise inhibits the HMGB1/TLR4/NF-κB signaling pathway by promoting endogenous H2S production, thereby exerting a protective effect on the intestinal mucosal barrier.

[Aerobic exercise combined with huwentoxin-I upregulates phase-â ¡ detoxification enzymes to alleviate obstructive jaundice-induced central nervous system injury in mice].

OBJECTIVE: To explore the effects of aerobic exercise combined with huwentoxin-I (HWTX-I)-mediated Keap1-Nrf2-ARE pathway on phase II detoxification enzymes HO-1 and NQO1 and their protective effects against obstructive jaundice (OJ)-induced central nervous system injury in mice. METHODS: 50 male KM mice were randomly divided into blank group (GO), model group (M), aerobic exercise group (T), HWTX-I group (H), and aerobic exercise combined with HWTX-I group (TH). Mouse models of OJ were established with surgical suture for 72 h in the mice in all the groups except for the blank control group. The mice received interventions by aerobic exercise and tail vein injection of HWTX-I (0.05 µg/g) and were assessed by behavioral observation, Clark's neurological function scores, enzyme-linked immunosorbent assay (ELISA), brain tissue Nissl staining, hippocampal tissue Western blotting, and liver tissue mRNA expression profiling and sequencing. RESULTS: The mice in group M had obvious jaundice symptoms after the operation with significantly increased Clark's neurological score (P < 0.01). Compared with those in group M, the mice in group T, group H, and group TH showed significantly decreased serum levels of ALT, AST, TBIL, and TBA (P < 0.01) with increased contents of 5-HT and BDNF and decreased contents of S100B and NSE in the hippocampus (P < 0.01). Synergistic effects between aerobic exercise and HWTX-I were noted on the above parameters except for the liver function indicators. Interventions with aerobic exercise and HWTX-I, alone or in combination, obviously lessened pathologies in the brain tissue induced by OJ, and the combined treatment produced the strongest effect. The treatment also increased the expression levels of Nrf2, HO-1, and NQO1 mRNA and protein in brain tissues (P < 0.01 or 0.05) with a synergistic effect between aerobic exercise and HWTX-I. Illumina high-throughput sequencing showed that the differentially expressed factors participated mainly in such neural regulatory pathways as neuroactive ligand-receptor interaction, GABAergic synapses, dopaminergic synapses, synaptic vesicle circulation, and axon guidance, involving tissue cell neuronal signal transduction, apoptosis inhibition, immune response, and toxicity. Aerobic exercise and HWTX-I synergistically increased the accumulation of the signal pathways related with neuron damage repair and proliferation. CONCLUSIONS: Aerobic exercise combined with HWTX-I can up-regulate the expression of phase Ⅱ detoxification enzymes HO-1 and NQO1 through the Keap1-Nrf2-ARE pathway to protect the central nervous system against OJ-induced damage in mice.

Aerobic Exercise Inhibits CUMS-Depressed Mice Hippocampal Inflammatory Response via Activating Hippocampal miR-223/TLR4/MyD88-NF-κB Pathway.

Objective: To investigate the role of aerobic exercise in inhibiting chronic unpredictable mild stress (CUMS) depressed mice hippocampal inflammatory response and its potential mechanisms. Methods: Fifty-four male eight-week-old C57BL/6 mice were divided as control group (CG) (18 mice) and model group (36 mice). Model group mice were treated with 13 chronic stimulating factors for 28 days to set up the CUMS depression model. Neurobehavioral assessment was performed after modeling. The mice in the model group were randomly divided into the control model group (MG) and the aerobic exercise group (EG), with 18mice in each group. The EG group carried out the adaptive training of the running platform: 10 m/min, 0° slope, and increased by 10 minutes per day for 6 days. The formal training was carried for 8 weeks with 10 m/min speed, 0° slope, 60 min/d, 6 d/Week. After the training, a neurobehavioral assessment was performed, and hippocampus IL-1ß and IL-10 protein levels were detected by ELISA. RT-PCR was used to detect the expression of miR-223 and TLR4, MyD88, and NF-κB in the hippocampus. Western blot was used to detect the expression of TLR4 and phosphorylated NF-κBp65 protein in the hippocampus. Results: The hippocampus function of CUMS depression model mice was impaired. The forced swimming and forced tail suspension time were significantly prolonged, and inflammatory factors IL-1ß were significantly increased in the hippocampus. Aerobic exercise significantly improves CUMS-depressed mice hippocampal function, effectively reducing depressive behavior and IL-1ß levels, and increasing IL-10 levels. Besides, aerobic exercise significantly upregulates the expression level of miR-223 and inhibits the high expression of TLR4, MyD88, and NF-κB. Conclusion: Aerobic exercise significantly increases the CUMS-depressed mice hippocampus expression of miR-223, and inhibits the downstream TLR4/MyD88-NF-κB signaling pathway and the hippocampal inflammatory response, which contributes to the improvement of the hippocampal function.

Differential gene expression in HaCaT cells may account for the various clinical presentation caused by anthropophilic and geophilic dermatophytes infections.

BACKGROUND: Despite the worldwide prevalence of dermatophyte infections, only a few genes are reported to be related to dermatophyte infections. In addition, the mechanism by which different ecological dermatophytes infection leads to varying intensity of inflammation remains unclear. OBJECTIVES: To investigate the mechanism of varying intensity of skin inflammation caused by different ecological dermatophytes infection. METHODS: We infected HaCaT cells with anthropophilic and geophilic dermatophytes to mimic various ecological dermatophyte infections. RNA-sequencing (RNA-seq) was employed to identify the change in the gene expression of HaCaT cells. To verify the expression of differentially expressed genes (DEGs), we selected 18 HaCaT cells genes to conduct qPCR experiments. In addition, immunoblotting was conducted to validate key genes from the MAPK signalling pathway. RESULTS: After HaCaT cells were infected with the anthropophilic Trichophyton rubrum (T rubrum) and the geophilic Microsporum gypseum (M gypseum), 118 and 619 differentially expressed genes were identified in HaCaT cells, respectively. These genes may provide a clue as to how keratinocytes respond to anthropophilic and geophilic dermatophytes. We also found that JUN may play a critical role in keratinocytes infected with M gypseum. CONCLUSIONS: Differential gene expression in HaCaT cells may account for the various clinical presentation caused by anthropophilic and geophilic dermatophytes infections. In addition, the intense inflammatory reaction of M gypseum infection may be triggered by activating the JNK-JUN signalling pathway.

Mitochondrial OXPHOS is involved in the protective effects of L-arginine against heat-induced low sperm motility of boar.

The present study aimed to analyze the time- and temperature-responses of boar sperm and clarify the mechanism underlying the protective effects of L-arginine on heat-induced low sperm motility. Mature boar sperm was used to evaluate the effects of temperature, exposure time, L-arginine level and their interactions on sperm motility, respectively. Results showed increasing exposure time resulted in the decreased total motility and rate of rapid progressive sperm, and the increased rates of the immotile sperm and the sperm shaking in place at 38 and 39 °C, respectively (P < 0.05). L-arginine supplementation at the dose of 1.0 mM increased total motility and decreased rate of immotile sperm (P < 0.05). Heat at 39 °C decreased total motile and rate of rapid progressive sperm (P < 0.05), increased the level of sperm reactive oxygen species (ROS) (P < 0.05), reduced mitochondrial membrane potential (ΔΨm), ATP content and the activities of mitochondrial respiratory chain complexes (MRCC) ΙΙΙ and V (P < 0.05), which were attenuated by L-arginine supplementation. There were significant increases in the relative mRNA expression of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha in heat-exposed group without L-arginine supplementation. In conclusion, the rising temperatures impacted boar sperm motility in a time-dependent manner. In vitro addition of L-arginine to boar semen had a dose-dependent effect on sperm motility and sperm incubated with 1.0 mM L-arginine showed elevated motility. L-arginine supplementation can ameliorate heat-induced increase in ROS level and decreases in MRCC activities, which further maintain mitochondrial oxidative phosphorylation function, ATP synthesis and boar sperm motility.

Effect of the valine-to-lysine ratio on the performance of sows and piglets in a hot, humid environment.

To determine the effect of the valine-to-lysine (Val: Lys) ratio on the performance of sows and piglets in a hot, humid environment, eleven Large White × Landrace sows (parity 2 or 3) were selected and randomly assigned to 3 groups. The diets contained total dietary Val: Lys ratios of 0.72, 0.87, or 1.01:1. Sows were fed from d 29 prepartum to d 21 postpartum in a hot, humid environment (temperature: 22-31 ℃, relative humidity: 69-96%). The results showed that dietary valine improved the average daily feed intake (ADFI) of the sows in wk3 of the lactation and the average daily gain (ADG) of the piglets from day 7-14 after farrowing. Dietary valine increased the concentrations of lactose in colostrum and immunoglobulin M (IgM) in piglet serum. Additionally, dietary valine affected metabolite and metabolic hormone concentrations. The increase in the ratio of dietary Val: Lys decreased the blood urea nitrogen and increased serum glucose in the sows and increased serum albumin in the piglets. In addition, increasing dietary Val: Lys increased the serum concentration of estradiol-17ß in the sows. In conclusion, in a hot, humid environment, dietary valine could improve the performance of sows and piglets by increasing colostrum lactose and serum immunoglobulin concentration in piglets and by influencing serum glucose in sows.

The complete mitochondrial genome of a medicinal insect, Hydrillodes repugnalis (Lepidoptera: Noctuoidea: Erebidae), and related phylogenetic analysis.

The complete mitochondrial genome (mitogenome) of an important medicinal insect Hydrillodes repugnalis (Lepidoptera: Noctuoidea) was sequenced and analyzed. The mitogenome is circular with 15,570 bp long, and shows typical gene content and arrangement. Nucleotide composition is highly biased toward A + T nucleotides (81.1%). All protein-coding genes (PCGs) initiate with canonical start codon ATN, except for cox1 being CGA. The typical stop codon TAA is used for most PCGs, while the nad4l uses the TAG, and cox1 and cox2 use incomplete termination codon T. All tRNAs have a typical clover-leaf structure, except for trnS1 (AGN) lacking the dihydrouridine arm. Comparative mitogenome analysis showed that the motif "ATGATAA" between atp8 and atp6, and the motif "ATACTAA" between trnS2 and nad1 are commonly present in noctuoid mitogenomes. In A + T-rich regions, the motif "ATAGA" and subsequent poly-T structure, the motif "ATTTA" and followed macrosatellite (AT)n element and an "A"-rich 3' end upstream of the trnM gene can be recognized across noctuoid mitogenomes. Phylogenetic analyses showed that H. repugnalis is nested into the Erebidae clade, consistently being sister to the Aganainae. Within Noctuoidea, the (Notodontidae + (Erebidae + (Nolidae + (Euteliidae + Noctuidae)))) was consistently recovered firstly based on multiple mitochondrial datasets.