Superoxide dismutases: marker in predicting reduced left ventricular ejection fraction in patients with type 2 diabetes and acute coronary syndrome.

AIM: To examine the prognostic value of superoxide dismutase (SOD) activity for monitoring reduced left ventricular ejection fraction(LVEF)in the patients with type 2 diabetes and acute coronary syndrome (ACS). METHODS: The population of this cross-sectional study included 2377 inpatients with type 2 diabetes who had an ACS admitted to the Shandong Provincial Hospital Affiliated to Shandong First Medical University from January 2016 to January 2021. RESULTS: Diabetic patients with ACS were divided into 2 subgroups based on LVEF. The mean SOD activity was significantly lower in patients with an LVEF ≤ 45% than in those with an LVEF > 45% (149.1 (146.4, 151.9) versus 161.9 (160.8, 163.0)). Using ROC statistic, a cut-off value of 148.8 U/ml indicated an LVEF ≤ 45% with a sensitivity of 51.6% and a specificity of 73.7%. SODs activity were found to be correlated with the levels of NT-proBNP, hs-cTnT, the inflammatory marker CRP and fibrinogen. Despite taking the lowest quartile as a reference (OR 0.368, 95% CI 0.493-0.825, P = 0.001) or examining 1 normalized unit increase (OR 0.651, 95% CI 0.482-0.880, P = 0.005), SOD activity was found to be a stronger predictor of reduced LVEF than CRP and fibrinogen, independent of confounding factors. CONCLUSIONS: Our cross-sectional study suggests that SOD activity might be a valuable and easily accessible tool for assessing and monitoring reduced LVEF in the diabetic patients with ACS.

Shank3 deficiency elicits autistic-like behaviors by activating p38α in hypothalamic AgRP neurons.

BACKGROUND: SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38α, a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38α are involved in the development of autism caused by Shank3 mutations or deficiency. METHODS: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3-/-) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38α in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38α. T180A and Y182F mutations expressed inactive p38α. RESULTS: We found that Shank3 controls stereotypic behavior and sociability by regulating p38α activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3-/- mice. Consistently, overexpression of p38α in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38α in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. In contrast, activated p38α in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. LIMITATIONS: We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38α in AgRP neurons significantly ameliorates autistic behaviors of Shank3-/- mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38α in AgRP neurons. CONCLUSIONS: These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38α signaling in AgRP neurons, suggesting that p38α signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism.

Characterization of novel PHEX variants in X-linked hypophosphatemic rickets and genotype-PHEX activity correlation.

BACKGROUND: X-linked hypophosphatemia (XLHR) is the most common genetic form of hypophosphatemic rickets (HR), which is caused by phosphate regulating endopeptidase homolog X-linked (PHEX) gene mutation. At present, the genotype-phenotype relationship of XLHR and the pathogenic role of PHEX have not been fully understood. METHODS: In this study, we summarized clinical features in a new cohort of 49 HR patients and detected 16 novel PHEX and 5 novel non-PHEX variants. Subsequently, we studied the pathogenesis of new variants by protein expression, glycosylation analysis, subcellular localization and endopeptidase activity. RESULTS: The results showed that missense variants (Q189H and X750R) slightly reduced protein expression without obviously altering protein length and localization, whereas truncating variants significantly impaired the synthesis of PHEX and produced a shorter immature protein in cells. Interestingly, no evident correlation was observed between mutation types and clinical phenotypes. However, when we analyzed the relationship between PHEX activity and serum phosphorus level, we found that patients with low PHEX activity tended to have severe hypophosphatemia and high rickets severity score (RSS). Following this observation, we established two new knock-in XLHR mouse models with two novel Phex variants (c.T1349C and c.C426G, respectively) using CRISPR/Cas9 technology. Both mouse models demonstrated clinical manifestations of XLHR seen in patients and PhexC426G mice showed more severe phenotype than PhexT1349C mice, which further confirmed the rationality of genotype-PHEX enzymatic activity correlation analysis. CONCLUSION: Therefore, our findings demonstrated that novel PHEX variants could disrupt protein function via affecting protein synthesis, post-translational modification, cellular trafficking and catalytic activity. Our study facilitates a better understanding of XLHR pathogenic mechanism and PHEX activity-phenotype correlation, which is of crucial importance for future diagnosis and treatment of XLHR.

Combined association of abdominal obesity and depressive symptoms with risk of type 2 diabetes: A cohort study.

OBJECTIVE: To explore the combined effect of abdominal obesity and depressive symptoms on the risk to type 2 diabetes, while also assessing the potential influence of various glycemic states and gender on this combined relationship. METHODS: Data is acquired from the China Health and Retirement Longitudinal Study, and 5949 participants were included for analysis. Participants were divided into four groups: neither have abdominal obesity nor depressive symptoms (AO-/DS-), only have depressive symptoms (AO-/DS+), only have abdominal obesity (AO+/DS-), and have both abdominal obesity and depressive symptoms (AO+/DS+). Stratified analyses differentiating the glycemic statuses and sex of the participants were also carried out. RESULTS: After adjusting for the confounders, the AO-/DS+, AO+/DS- and AO+/DS+ phenotypes were all discovered to be risk factors for type 2 diabetes (OR = 1.38, 95%CI: 1.06-1.79; OR = 2.07, 95%CI: 1.63-2.63; OR = 2.38, 95%CI: 1.83-3.11, respectively) compared with the AO-/DS- phenotype in the overall population. In further stratified analyses, we arrived at the same conclusion for normoglycemic individuals, especially in females. For prediabetes and males, the AO+/DS- and AO+/DS+ phenotypes are risk factors for type 2 diabetes compared with the AO-/DS- phenotype, but not with AO-/DS+. CONCLUSION: Regardless of glycemic status and sex, the coexistence of abdominal obesity and depressive symptoms were associated with an increased risk of type 2 diabetes. Depressive symptoms were independent risk factors for type 2 diabetes only in normoglycemic individuals and females.

Energy deficiency promotes rhythmic foraging behavior by activating neurons in paraventricular hypothalamic nucleus.

Background: Dysregulation of feeding behavior leads to a variety of pathological manifestations ranging from obesity to anorexia. The foraging behavior of animals affected by food deficiency is not fully understood. Methods: Home-Cage system was used to monitor the behaviors. Immunohistochemical staining was used to monitor the trend of neuronal activity. Chemogenetic approach was used to modify neuronal activity. Results: We described here a unique mouse model of foraging behavior and unveiled that food deprivation significantly increases the general activities of mice with a daily rhythmic pattern, particularly foraging behavior. The increased foraging behavior is potentiated by food cues (mouthfeel, odor, size, and shape) and energy deficit, rather than macronutrient protein, carbohydrate, and fat. Notably, energy deficiency increases nocturnal neuronal activity in paraventricular hypothalamic nucleus (PVH), accompanying a similar change in rhythmic foraging behavior. Activating neuronal activity in PVH enhances the amplitude of foraging behavior in mice. Conversely, inactivating neuronal activity in PVH decreases the amplitude of foraging behavior and impairs the rhythm of foraging behavior. Discussion: These results illustrate that energy status and food cues regulate the rhythmic foraging behavior via PVH neuronal activity. Understanding foraging behavior provides insights into the underlying mechanism of eating-related disorders.

The Fatty Liver Index, the Strongest Risk Factor for Low Testosterone Level.

INTRODUCTION: The study aimed to determine if hepatic steatosis assessed by fatty liver index (FLI) was an independent risk factor for male low testosterone level and whether the FLI was the strongest risk factor for low testosterone level in two different age groups. METHODS: Two cross-sectional studies were performed. A total of 3,443 male participants (aged 46-75) were recruited into study A (part of lONgitudinal study (REACTION)). Then a total of 267 male participants (aged 25-45) were recruited into study B. Serum total testosterone (TT) and sex hormone-binding globulin (SHBG) levels, indicators for assessing hepatic steatosis were measured. The Pearson correlation and regression analysis were performed to investigate the risk factors for low testosterone level. RESULTS: The FLI had the strongest negative correlation with serum testosterone in the study A (r = -0.436) and B (r = -0.542). Compared with patients with a FLI lower than 30, the risk for low testosterone level increased by 3.48-fold in subjects with a FLI higher than 60 adjusted for potential risk factors in study A. In study B, the odds ratio of low testosterone level in patients with potential hepatic steatosis was 4.26 (1.57-11.60) after adjusted for age and homeostasis model assessment of insulin resistance (HOMA-IR) and 0.59 (0.14-2.60) after adjusted for age, HOMA-IR, waist circumference, body mass index, and SHBG. CONCLUSIONS: FLI was the strongest risk factor for male low testosterone level independent of insulin resistance in male populations of different ages; however, the association can be modulated by SHBG levels in the young. SIGNIFICANCE STATEMENT: In the study, FLI was the strongest negative risk factor for low testosterone level in the Chinese adult male population. The results suggested that hepatic steatosis assessed by the FLI was the main risk factor for male low testosterone level, independent of age, insulin resistance, smoking, and drinking status; however, the association of FLI and TT levels can be modulated by SHBG levels. Taken together these findings indicate that clinical physicians should pay more attention to the FLI index and hepatic steatosis, so that they can take advantage of them for assessing the risk of developing of low testosterone level in the male population.

Metformin inhibits inflammatory response and endoplasmic reticulum stress to improve hypothalamic aging in obese mice.

The hypothalamus, as a vital brain region for endocrine and metabolism regulation, undergoes functional disruption during obesity.The anti-aging effect of metformin has come into focus. However, whether it has the potential to ameliorate hypothalamic aging and dysfunction in the obese state remains unclear. In this study, obese mice were utilized to investigate the effects of metformin on the hypothalamus of obese mice. According to the results, metformin treatment resulted in improved insulin sensitivity, reduced blood glucose and lipid levels, as well as attenuation of hypothalamic aging, demonstrated by decreased SA-ß-gal staining and downregulation of senescence markers. Additionally, metformin decreased the expression of endoplasmic reticulum stress-related proteins in neurons and reduced the inflammatory response triggered by microglia activation. Further mechanistic analysis revealed that metformin inhibited the expression and activation of STING and NLRP3 in microglia. These results reveal a possible mechanism by which metformin ameliorates hypothalamic aging.

High cholesterol diet-induced testicular dysfunction in rats.

PURPOSE: Hypercholesterolemia due to a high-cholesterol diet is linked to numerous diseases and may lead to male infertility. However, the underlying mechanism remains unknown. The maintenance of male fertility requires intact testicular structures (including seminiferous tubules and mesenchyme) and functioning cells (Leydig cells, Sertoli cells and germ cells, etc.), production of appropriate concentrations of sex hormones, and cooperation among testicular cells. Thus, we considered whether male fertility declined as the structure and function of testicular cells were altered in rats on a high-cholesterol diet. METHODS: Male Sprague Dawley rats were fed either a standard or a high-cholesterol diet for 16 weeks. Serum sex hormones, lipid components, semen quality, and fertility rate were assayed in the rats. The 3ß-hydroxysteroid dehydrogenase (3ß-HSD), Wilms tumor 1 (WT-1), and deleted in azoospermia-like (DAZL) were regarded as specific markers of Leydig, Sertoli, and germ cells in rats. In addition, the ultrastructure of the testis and expression levels of particular marker molecules of testicular cells were further investigated. RESULTS: Compared to rats fed on a regular diet, the serum testosterone levels and sperm progressive motility decreased in rats fed high cholesterol. Moreover, we observed a deformed nucleus, dilated smooth endoplasmic reticulum, and swollen mitochondria of Leydig cells and a schizolytic nucleus of Sertoli cells in rats on a high-cholesterol diet. The 3ß-HSD, WT-1, and DAZL protein expression levels were significantly reduced in rats on a high-cholesterol diet. CONCLUSIONS: Our results showed that a high-cholesterol diet adversely affected testosterone production and sperm progressive motility, possibly due to Leydig, Sertoli, and germ cell abnormalities.

Switching from high-fat diet to normal diet ameliorate BTB integrity and improve fertility potential in obese male mice.

Obesity is a prominent risk factor for male infertility, and a high-fat diet is an important cause of obesity. Therefore, diet control can reduce body weight and regulate blood glucose and lipids, but it remains unclear whether it can improve male fertility and its mechanism. This study explores the effects of switching from a high-fat diet (HFD) to a normal diet (ND) on the fertility potential of obese male mice and its related mechanisms. In our study, male mice were separated into three groups: normal diet group (NN), continuous high-fat diet group (HH), and return to normal diet group (HN). The reproductive potential of mice was tested through cohabitation. Enzymatic methods and ELISA assays were used to measure metabolic indicators, follicle-stimulating hormone (FSH) levels and intratesticular testosterone levels. Transmission electron microscopy and immunofluorescence with biotin tracers assessed the integrity of the blood-testis barrier (BTB). Malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) were inspected for the assessment of oxidative stress. The expression and localization of BTB-related proteins were detected through the immunoblot and immunofluorescence. The mice in the high-fat diet group indicated increased body weight and epididymal fat weight, elevated serum TC, HDL, LDL, and glucose, decreased serum FSH, and dramatic lipid deposition in the testicular interstitium. Analysis of fertility potential revealed that the fertility rate of female mice and the number of pups per litter in the HH group were significantly reduced. After the fat intake was controlled by switching to a normal diet, body weight and epididymal fat weight were significantly reduced, serum glucose and lipid levels were lowered, serum FSH level was elevated and the deposition of interstitial lipids in the testicles was also decreased. Most significantly, the number of offspring of male mice returning to a normal diet was significantly increased. Following further mechanistic analysis, the mice in the sustained high-fat diet group had disrupted testicular BTB integrity, elevated levels of oxidative stress, and abnormal expression of BTB-related proteins, whereas the restoration of the normal diet significantly ameliorated the above indicators in the mice. Our study confirms diet control by switching from a high-fat diet to a normal diet can effectively reduce body weight, ameliorate testicular lipotoxicity and BTB integrity in male mice, and improve fertility potential, providing an effective treatment option for obese male infertility.

The association between total bile acid and bone mineral density among patients with type 2 diabetes.

Objective: Bile acids have underlying protective effects on bones structure. Long-term diabetes also causes skeletal disorders including osteoporosis, Charcot arthropathy and renal osteodystrophy. Nevertheless, few studies have reported whether bile acid is associated with bone metabolism in diabetics. This study aimed to explore the relationship between total bile acid (TBA) and bone mineral density (BMD) among patients with type 2 diabetes mellitus (T2DM). Methods: We retrospectively included 1,701 T2DM patients who were hospitalized in Taian City Central Hospital (TCCH), Shandong Province, China between January 2017 to December 2019. The participants were classified into the osteopenia (n = 573), osteoporosis (n= 331) and control groups (n= 797) according to BMD in the lumbar spine and femoral. The clinical parameters, including TBA, bilirubin, vitamin D, calcium, phosphorus and alkaline phosphatase were compared between groups. Multiple linear regression was used to analyze the relationship between TBA and BMD in lumbar spine, femoral, trochiter, ward's triangle region. A logistic regression was conducted to develop a TBA-based diagnostic model for differentiating abnormal bone metabolism from those with normal BMD. We evaluated the performance of model using ROC curves. Results: The TBA level was significantly higher in patients with osteoporosis (Median[M]= 3.300 µmol/L, interquartile range [IQR] = 1.725 to 5.250 µmol/L) compared to the osteopenia group (M = 3.200 µmol/L, IQR = 2.100 to 5.400 µmol/L) and control group (M = 2.750 µmol/L, IQR = 1.800 to 4.600 µmol/L) (P <0.05). Overall and subgroup analyses indicated that TBA was negatively associated with BMD after adjusted for the co-variates (i.e., age, gender, diabetes duration, BMI, total bilirubin, direct bilirubin, indirect bilirubin) (P <0.05). Logistic regression revealed that higher TBA level was associated with increased risk for abnormal bone metabolism (OR = 1.044, 95% CI = 1.005 to 1.083). A TBA-based diagnostic model was established to identify individuals with abnormal bone metabolism (T-score ≤ -1.0). The area under ROC curve (AUC) of 0.767 (95% CI = 0.730 to 0.804). Conclusion: Our findings demonstrated the potential role of bile acids in bone metabolism among T2DM patients. The circulating TBA might be employed as an indicator of abnormal bone metabolism.

A clinical observation study on the effect of needle-free insulin syringe on blood glucose control and well-being index in patients with early-onset type 2 diabetes mellitus.

Objective: To explore the effect of using needle-free insulin syringe on blood sugar control and well-being index in patients with early-onset type 2 diabetes mellitus. Methods: A total of 42 patients with early-onset type 2 diabetes mellitus treated with insulin aspart 30 injection in a stable condition in the Endocrinology Department of a tertiary hospital from January 2020 to July 2021 were randomly divided into two groups, one group received insulin pen injections followed by needle-free injections, and the other group received needle-free injections followed by insulin pen injections. Transient scanning glucose monitoring was performed during the last two weeks of each injection modality phase. Comparison of the two injection methods in terms of test indicators and differences in injection site pain scores, the number of red spots on the skin at the injection site and the number of bleeding spots on the skin at the injection site. Results: The FBG of the needle-free injection group was lower than that of the Novo Pen group (p<0.05); the 2-hour postprandial blood glucose of the needle-free injection group was lower than that of the Novo Pen group, but there was no statistical significant difference. The amount of Insulin in the needle-free injector group was lower than that in the Novo pen group, but there was no statistical significant difference between the two groups. The WHO-5 score of the needle-free injector group was higher than that of the Novo Pen group(p<0.05); the pain score at the injection site was lower than that of the Novo Pen group (p<0.05). The number of skin red spots using the needle-free syringe was more than that of the Novo pen group(p<0.05); the number of skin bleeding at the site of injection was similar between the two injection methods. Conclusion: Compared to traditional insulin pens, subcutaneous injection of premixed insulin using a needle-free syringe is effective in controlling fasting blood glucose in patients with early onset type 2 diabetes and is less painful at the injection site. In addition, blood glucose monitoring should be strengthened and insulin dosage should be adjusted in a timely manner.

Involvement of p38 MAPK in Leydig cell aging and age-related decline in testosterone.

Introduction: Age-related decline in testosterone is associated with Leydig cell aging with impaired testosterone synthesis in aging. Obesity accelerates the age-related decline in testosterone. However, the mechanisms underlying the Leydig cell aging and the effects of obesity on Leydig cell aging remain unclear. Method: Natural aging mice and diet-induced obese mice were used to assess the process of testicular Leydig cell senescence with age or obesity. Bioinformatic analysis of the young and aged human testes was used to explore key genes related Leydig cell aging. Leydig cell-specific p38 MAPK knockout (p38LCKO) mice were used to further analyze the roles of p38 MAPK in Leydig cell aging. The levels of testosterone and steroidogenic enzymes, activity of p38 MAPK, aging status of Leydig cells, and oxidative stress and inflammation of testes or Leydig cells were detected by ELISA, immunoblotting, immunofluorescence, and senescence-associated ß-galactosidase (SA-ß-Gal) staining analysis, respectively. Result: The serum testosterone level was significantly reduced in aged mice compared with young mice. In the testis of aged mice, the reduced mRNA and protein levels of LHCGR, SRB1, StAR, CYP11A1, and CYP17A1 and the elevated oxidative stress and inflammation were observed. KEGG analysis showed that MAPK pathway was changed in aged Leydig cells, and immunoblotting displayed that p38 MAPK was activated in aged Leydig cells. The intensity of SA-ß-Gal staining on Leydig cells and the number of p21-postive Leydig cells in aged mice were more than those of young mice. Similar to aged mice, the testosterone-related indexes decreased, and the age-related indexes increased in the testicular Leydig cells of high fat diet (HFD) mice. Aged p38LCKO mice had higher levels of testosterone and steroidogenic enzymes than those of age-matched wild-type (WT) littermates, with reduced the intensity of SA-ß-Gal staining and the expression of p21 protein. Conclusion: Our study suggested that obesity was an important risk factor for Leydig cell aging. p38 MAPK was involved in Leydig cell aging induced by age and obesity. The inhibition of p38 MAPK could delay Leydig cell aging and alleviate decline in testosterone.

The time-dependent adverse effects of a high-fat diet on sperm parameters.

BACKGROUND: Studies indicate a relationship between a high-fat diet (HFD) and sperm quality. However, the time-dependent adverse effects of a HFD on sperm parameters and the underlying mechanisms remain unclear. OBJECTIVES: The present study was designed to determine the effects of a HFD on sperm quality at various time points in order to assess whether a HFD causes cumulative damage to sperm. MATERIAL AND METHODS: Male C57BL/6 mice were fed a normal diet (the ND group) or a HFD (the HFD group) for 16, 30 or 42 weeks (n = 6 for each group). Body weight, lipid profile, sperm parameters, testicular morphology, and testicular oxidative stress levels were evaluated alongside the proliferation, DNA damage and rate of germ cell apoptosis. RESULTS: Sperm quality was reduced in HFD-fed animals in a time-dependent manner, which was demonstrated by a decline in sperm density, motility and progressive motility. Further analysis showed a progressive deterioration of the testicular histoarchitecture of HFD-fed mice, which was accompanied by a decrease in DEAD-box helicase 4 (DDX4) expression and superoxide dismutase (SOD) levels, increased malondialdehyde (MDA) levels and gamma-H2A histone family member X (γ-H2AX) expression, and increased apoptosis of germ cells. CONCLUSIONS: These findings demonstrate that a HFD exerted adverse effects on sperm quality, and the deteriorating effect was progressive with long-term feeding. The inhibited proliferation and apoptosis of germ cells, and the increased oxidative stress levels and DNA damage may be the underlying mechanisms.

Investigating causal associations among gut microbiota, metabolites and autoimmune hypothyroidism: a univariable and multivariable Mendelian randomization study.

Background: Accumulating evidence suggests that the gut microbiota and its metabolites may be involved in autoimmune hypothyroidism. However, the causal association between gut microbiota, metabolites and autoimmune hypothyroidism remains to be determined. Methods: Instrumental variables were screened from the GWAS datasets of 211 gut microbiota taxonomic groups, gut microbiota-derived metabolites, and autoimmune hypothyroidism. Univariable Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) were used to analyse the potential causal relationship between autoimmune hypothyroidism, these metabolites, or these microbiota. During the MR analysis, we alternated multiple MR methods with different model assumptions to assess the consistency and robustness of the findings: inverse variance weighted (IVW), weighted median, MR pleiotropy residual sum and outlier (MRPRESSO) and MR-Egger methods. Reverse MR analysis was performed to assess the possibility of reverse causality. Finally, enrichment analyses were used to investigate potential biofunctions. Results: The IVW results of univariable MR showed that the phyla Actinobacteria, genus DefluviitaleaceaeUCG011, genus Eggerthella, family Defluviitaleaceae, genus Subdoligranulum, genus RuminococcaceaeUCG011, and genus Intestinimonas were associated with autoimmune hypothyroidism. After FDR adjustment, the absence of a causal relationship between gut microbiota and autoimmune hypothyroidism (PFDR > 0.05) suggested a possible marginal association. The results on gut metabolites showed that N-(3-furoyl)glycine, pipecolate, phenylalanine, allantoin, indololactate and alanine were associated with autoimmune hypothyroidism. After FDR correction, only indololactate was associated with hypothyroidism (OR=1.592; 95% CI, 1.228-2.065; PFDR= 0.036). Family Defluviitaleaceae and genus DefluviitaleaceaeUCG011 were suggestively significant in the MVMR. The results of reverse MR analysis showed no reverse causality between autoimmune hypothyroidism and the identified gut microbiota. Enrichment analysis revealed that several key regulatory pathways were significantly enriched. Conclusion: This study supported that there were beneficial or detrimental causal effects of gut microbiota and its metabolites on autoimmune hypothyroidism risk, which provides more theoretical support for mechanistic research on the "thyroid-gut" axis.

Power Equipment Fault Diagnosis Method Based on Energy Spectrogram and Deep Learning.

With the development of industrial manufacturing intelligence, the role of rotating machinery in industrial production and life is more and more important. Aiming at the problems of the complex and changeable working environment of rolling bearings and limited computing ability, fault feature information cannot be effectively extracted, and the current deep learning model is difficult to be compatible with lightweight and high efficiency. Therefore, this paper proposes a fault detection method for power equipment based on an energy spectrum diagram and deep learning. Firstly, a novel two-dimensional time-frequency feature representation method and energy spectrum feature map based on wavelet packet transform is proposed, and an energy spectrum feature map dataset is made for subsequent diagnosis. This method can realize multi-resolution analysis, fully extract the feature information contained in the fault signal, and accelerate the convergence of the subsequent diagnosis model. Secondly, a lightweight residual dense convolutional neural network model (LR-DenseNet) is proposed. This model combines the advantages of residual learning and a dense connection, and can not only extract deep features more easily, but can also effectively use shallow features. Then, based on the lightweight residual dense convolutional neural network model, an LR-DenseSENet model is proposed. By introducing the transfer learning strategy and adding the channel domain, an attention mechanism is added to the channel feature fusion layer, with the accuracy of detection up to 99.4%, and the amount of parameter calculation greatly reduced to one-fifth of that of VGG. Finally, through an experimental analysis, it is verified that the fault detection model designed in this paper based on the combination of an energy spectrum feature map and LR-DenseSENet achieves a satisfactory detection effect.

Atlas of metabolism reveals palmitic acid results in mitochondrial dysfunction and cell apoptosis by inhibiting fatty acid ß-oxidation in Sertoli cells.

In recent years, the impact of lipotoxicity on male fertility has received extensive attention, especially on Sertoli cells (SCs). In SCs, energy metabolism is important as disorders of energy metabolism result in infertility eventually. However, the underlying mechanism of lipotoxicity on energy metabolism in SCs remains unknown. Advances in high-throughput metabolomics and lipidomics measurement platforms provide powerful tools to gain insights into complex biological systems. Here, we aimed to explore the potential molecular mechanisms of palmitic acid (PA) regulating energy metabolism in SCs based on metabolomics and lipidomics. The results showed that glucose metabolism-related metabolites were not significantly changed, which suggested that PA treatment had little effect on glucose metabolism and may not influence the normal energy supply from SCs to germ cells. However, fatty acid ß-oxidation was inhibited according to accumulation of medium- and long-chain acylcarnitines in cells. In addition, the pool of amino acids and the levels of most individual amino acids involved in the tricarboxylic acid (TCA) cycle were not changed after PA treatment in SCs. Moreover, PA treatment of SCs significantly altered the lipidome, including significant decreases in cardiolipin and glycolipids as well as remarkable increases in ceramide and lysophospholipids, which indicated that mitochondrial function was affected and apoptosis was triggered. The increased apoptosis rate of SCs was verified by elevated protein expression levels of Cleaved Caspase-3 and Bax as well as decreased Bcl-2 protein expression level. Together, these findings indicated that PA may result in mitochondrial dysfunction and increased apoptosis by inhibiting fatty acid ß-oxidation of SCs.

Association of longitudinal changes in serum lipids with the natural history of subclinical hypothyroidism: A retrospective cohort study using data from the REACTION study.

Background: Subclinical hypothyroidism (SCH) often leads to alterations in lipid profile, which may negatively impact humans health. Whether lipids in turn affect the natural history of SCH is unknown. We aimed to assess the association between longitudinal changes in serum lipid levels and the natural history of SCH. Methods: This retrospective cohort study using data from the REACTION study included 581 patients with SCH who were enrolled between July 1, 2011, and December 19, 2014, with a median follow-up of three [IQR, 2·86-3·21] years. Patients with missing data or conditions that can affect thyroid function were excluded. Changes in serum lipid levels were calculated from serum lipid measurements 3 years apart and classified in two ways: 1) the first, second, and third tertiles of the difference between baseline and follow-up and 2) the percent change from baseline, namely, serum lipid decrease ≥ 25%, minor change, and serum lipid increase ≥ 25%. The natural history of SCH includes regression to euthyroidism, SCH persistence, or progression to overt hypothyroidism (OH). Odds ratios (ORs) were estimated by multivariable logistic regression. Validation was performed on data from a health management cohort study conducted from January 1, 2012, to December 31, 2016, with a median follow-up of two [IQR, 1·92-2·08] years. After using the same inclusion and exclusion criteria as the REACTION cohort study, 412 patients with SCH were eligible for the validation analysis. Findings: There were 132 (22·7%) men and 449 (77·3%) women in the study, with a median age of 56 [IQR,49-62] years. During follow-up, 270 (46·5%), 266 (45·8%), and 27 (4·6%) patients had regression to euthyroidism, persistent SCH, and progression to OH, respectively. Both grouping manners showed a significant association between changes in lipid levels and the natural history of SCH. A total cholesterol (TC)-level increase was independently associated with a greater risk of progression to OH (OR for ≥ 25% TC increase vs. minor change: 5·40; 95% CI 1·46-21·65), whereas TC-level declines increased the likelihood of regressing to euthyroidism (OR for ≥ 25% TC decrease vs. minor change: 3·45; 95% CI 1·09-12·43). Similarly, the likelihood of regression according to changes in triglyceride (TG) levels exhibited a consistent trend with that according to TC-level changes. A similar pattern of association was observed in the validation cohort. Interpretation: Changes in serum lipid levels in SCH are associated with future progression or regression risk, suggesting that the changes in serum lipid levels may affect the natural history of SCH. Clinicians should pay attention to the long-term control of serum lipids levels in populations with SCH, which may benefit thyroid function. Funding: This work was supported by grants from the National Key Research and Development Program of China (2017YFC1309800), the National Natural Science Foundation (81430020, 82070818), and the "Outstanding University Driven by Talents" Program and Academic Promotion Program of Shandong First Medical University (2019LJ007).

Effect of iodoacetic acid on the reproductive system of male mice.

Iodoacetic acid (IAA) is one of the most common water disinfection byproducts (DBPs). Humans and animals are widely and continuously exposed to it. Many species of water DBPs are harmful to the reproductive system of organisms. Nevertheless, the potential effects of IAA exposure on testosterone and spermatogenesis in vivo remain ambiguous. Spermatogenous cells are the site of spermatogenesis, Leydig cells are the site of testosterone synthesis, and Sertoli cells build the blood-testis barrier (BTB), providing a stable environment for the aforementioned important physiological functions in testicular tissue. Therefore, we observed the effects of IAA on spermatogenic cells, Leydig cells, and Sertoli cells in the testis. In this study, we found that oral administration of IAA (35 mg/kg body weight per day for 28 days) in male mice increased serum LH levels and reduced sperm motility, affecting average path velocity and straight line velocity of sperm. In addition, IAA promoted the expression of γH2AX, a marker for DNA double-strand breaks. Moreover, IAA downregulated the protein expression of the scavenger receptor class B type 1 (SRB1), and decreased lipid droplet transport into Leydig cells, which reduced the storage of testosterone synthesis raw materials and might cause a drop in testosterone production. Furthermore, IAA did not affect the function of BTB. Thus, our results indicated that IAA exposure affected spermatogenesis and testosterone synthesis by inducing DNA damage and reducing lipid droplet transport.

Role of p38 MAPK Signalling in Testis Development and Male Fertility.

The testis is an important male reproductive organ, which ensures reproductive function via the secretion of testosterone and the generation of spermatozoa. Testis development begins in the embryonic period, continues after birth, and generally reaches functional maturation at puberty. The stress-activated kinase, p38 mitogen-activated protein kinase (MAPK), regulates multiple cell processes including proliferation, differentiation, apoptosis, and cellular stress responses. p38 MAPK signalling plays a crucial role in testis development by regulating spermatogenesis, the fate determination of pre-Sertoli, and primordial germ cells during embryogenesis, the proliferation of testicular cells in the postnatal period, and the functions of mature Sertoli and Leydig cells. In addition, p38 MAPK signalling is involved in decreased male fertility when exposed to various harmful stimuli. This review will describe in detail the biological functions of p38 MAPK signalling in testis development and male reproduction, together with its pathological role in male infertility.

Clinical Effect of Digital Subtraction Angiography Combined with Neurointerventional Thrombolysis for Acute Ischemic Cerebrovascular Disease and Its Influence on Vascular Endothelial Function and Oxidative Stress.

Objective: Ischemic cerebrovascular disease is a commonly seen vascular disorder in clinical practice. Given the difficulty of drug therapy to achieve ideal curative effects, interventional therapy has gradually become the preferred treatment for the disease. This research primarily discusses the short-term efficacy of digital subtraction angiography- (DSA-) guided neurointerventional thrombolysis for acute ischemic cerebrovascular disease (AICVD) and its influence on vascular endothelial function (VEF) and oxidative stress (OS). Methods: All the clinical data of 162 patients diagnosed with AICVD and treated between June 2019 and December 2021 were collected and analyzed retrospectively. They were assigned to two cohorts according to the difference in interventional methods: a conventional group (CG) given recombinant tissue plasminogen activator (rt-PA) therapy and an observation group (OG) intervened by DSA-guided neurointerventional thrombolysis. The two groups were compared with respect to short-term treatment efficacy, the National Institutes of Health Stroke Scale (NIHSS) score, cerebral hemodynamics, and VEF and OS indexes. Results: The short-term efficacy was better in OG (93.98%) than in CG (82.28%). After treatment, the NIHSS score decreased in both cohorts with obvious differences within the group at different time points, and the posttreatment NIHSS score was lower in OG as compared to CG. OG had higher Q m and V m while lower W v, Z cv, and R v than CG. Higher endothelial-dependent flow-mediated dilatation (FMD) was observed in OG, as well as lower ankle-brachial index (ABI) and pulse wave velocity (PWV). And the posttreatment MDA was lower while SOD, GSH-Px, and TAC were higher in OG compared with those on CG. All the above differences were of statistical significance (P < 0.05). Conclusions: DSA-guided neurointerventional thrombolysis is highly effective in the treatment of AICVD, which can not only effectively improve patients' neurological function and cerebral hemodynamics but also mitigate VEF injury and help to alleviate patients' OS.