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Unlike humans and other mammals, zebrafish demonstrate a remarkable capacity to regenerate their injured hearts throughout life. Mitochondrial fatty acid ß-oxidation (FAO) contributes to major energy demands of the adult hearts under physiological conditions; however, its functions in regulating cardiac regeneration and the underlying mechanisms are not completely understood. Different strategies targeting FAO have yield mixed outcomes. Here, we demonstrated that pharmacological inhibition of mitochondrial FAO with mildronate (MD) caused lipid accumulation in zebrafish larvae and suppressed ventricle regeneration. MD treatment impeded cardiogenic factor reactivation and cardiomyocyte (CM) proliferation, and impaired ventricle regeneration could be rescued by exogenous l-carnitine supplementation. Moreover, compared with the ablated hearts of wild-type fish, ventricle regeneration, cardiogenic factor reactivation and CM proliferation were significantly blocked in the ablated hearts of carnitine palmitoyltransferase-1b (cpt1b) knockout zebrafish. Further experiments suggested that NF-κB signaling and increased inflammation may be involved in the impediment of ventricle regeneration caused by systemic mitochondrial FAO inhibition. Overall, our study demonstrates the essential roles of mitochondrial FAO in zebrafish ventricle regeneration and reaffirms the sophisticated and multifaceted roles of FAO in heart regeneration with regard to different injury models and means of FAO inhibition.
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Ácidos Graxos , Ventrículos do Coração , Oxirredução , Regeneração , Peixe-Zebra , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Proliferação de Células/efeitos dos fármacos , Ácidos Graxos/metabolismo , Ventrículos do Coração/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Metilidrazinas/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B/metabolismo , Oxirredução/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Thyroid hormones(THs) are essential for the proper functioning of the ovaries, and multiple studies have shown that thyroid abnormalities, especially during adolescence and reproductive age, can lead to lifelong ovarian dysfunction. Autoimmune thyroid disease (AITD), one of the most common organ specific autoimmune diseases, is mainly mediated by cellular autoimmune reactions, and has strong inflammatory infiltration and immune active cells, including chemokines and cytokines, which are important components of ovarian aging. This suggests that autoimmune and inflammatory molecular processes may play a role in the emergence of ovarian dysfunction. The purpose of this review is to summarize recent in vivo and in vitro evidence of a complex relationship between AITD and ovarian dysfunction. AITD is closely related to the decline of ovarian function from the perspective of antibody, cytokine, oxidative stress, and genetic factors. Finally, some of the currently known treatments for AITD and hypo ovarian disease are summarized.
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Doenças Autoimunes , Humanos , Feminino , Doenças Autoimunes/imunologia , Doenças Ovarianas/imunologia , Doenças da Glândula Tireoide/imunologia , Doenças da Glândula Tireoide/complicações , Doenças da Glândula Tireoide/fisiopatologia , Ovário/fisiopatologia , Ovário/imunologia , AnimaisRESUMO
An antitumour chemo-photodynamic therapy nanoplatform was constructed based on phospholipid-coated NaYF4: Yb/Er upconversion nanoparticles (UCNPs). In this work, the amphiphilic block copolymer DSPE-PEG2000 was combined with the surface ligand oleic acid of the UCNPs through hydrophobic interaction to form liposomes with a dense hydrophobic layer in which the photosensitizer hypocrellin B (HB) was assembled. The coated HB formed J-aggregates, which caused a large redshift in the absorption spectrum and improved the quantum efficiency of energy transfer. Furthermore, MnO2 nanosheets grew in-situ on the liposomes through OMn coordination. Therefore, a multifunctional tumour microenvironment (TME)-responsive theranostic nanoplatform integrating photodynamic therapy (PDT) and chemodynamic therapy (CDT) was successfully developed. The results showed that this NIR-mediated chemo-photodynamic therapy nanoplatform was highly efficient for oncotherapy.
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Compostos de Manganês , Nanopartículas , Óxidos , Perileno , Fotoquimioterapia , Fármacos Fotossensibilizantes , Quinonas , Fotoquimioterapia/métodos , Perileno/análogos & derivados , Perileno/farmacologia , Perileno/química , Perileno/administração & dosagem , Humanos , Quinonas/química , Quinonas/farmacologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Óxidos/química , Óxidos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/administração & dosagem , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Animais , Fenol/química , Fenol/farmacologia , Lipossomos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Camundongos , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacosRESUMO
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.
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Diabetes Mellitus Tipo 2 , Masculino , Feminino , Humanos , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Obesidade Abdominal/complicações , Obesidade Abdominal/epidemiologia , Estudos Longitudinais , Depressão/complicações , Obesidade/complicações , Fatores de RiscoRESUMO
Wheat grain production is a vital component of the food supply produced by smallholder farms but faces significant threats from climate change. This study evaluated eight environmental impacts of wheat production using life cycle assessment based on survey data from 274 households, then built random forest models with 21 input features to contrast the environmental responses of different farming practices across three shared socioeconomic pathways (SSPs), spanning from 2024 to 2100. The results indicate significant environmental repercussions. Compared to the baseline period of 2018-2020, a similar upward trend in environmental impacts is observed, showing an average annual growth rate of 5.88 % (ranging from 0.45 to 18.56 %) under the sustainable pathway (SSP119) scenario; 5.90 % (ranging from 1.00 to 18.15 %) for the intermediate development pathway (SSP245); and 6.22 % (ranging from 1.16 to 17.74 %) under the rapid economic development pathway (SSP585). Variation in rainfall is identified as the primary driving factor of the increased environmental impacts, whereas its relationship with rising temperatures is not significant. The results suggest adopting farming practices as a vital strategy for smallholder farms to mitigate climate change impacts. Emphasizing appropriate fertilizer application and straw recycling can significantly reduce the environmental footprint of wheat production. Standardized fertilization could reduce the environmental impact index by 11.10 to 47.83 %, while straw recycling might decrease respiratory inorganics and photochemical oxidant formation potential by over 40 %. Combined, these approaches could lower the impact index by 12.31 to 63.38 %. The findings highlight the importance of adopting enhanced farming practices within smallholder farming systems in the context of climate change. SPOTLIGHTS.
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Agricultura , Triticum , Animais , Agricultura/métodos , Meio Ambiente , Aprendizado de Máquina , Estágios do Ciclo de VidaRESUMO
Zebrafish have a remarkable ability to regenerate injured hearts. Altered hemodynamic forces after larval ventricle ablation activate the endocardial Klf2a-Notch signaling cascade to direct zebrafish cardiac regeneration. However, how the heart perceives blood flow changes and initiates signaling pathways promoting regeneration is not fully understood. The present study demonstrated that the mechanosensitive channel Trpv4 sensed the altered hemodynamic forces in injured hearts and its expression was regulated by blood flow. In addition to mediating the endocardial Klf2a-Notch signal cascade around the atrioventricular canal (AVC), we discovered that Trpv4 regulated nitric oxide (NO) signaling in the bulbus arteriosus (BA). Further experiments indicated that Notch signaling primarily acted at the early stage of regeneration, and the major role of NO signaling was at the late stage and through TGF-ß pathway. Overall, our findings revealed that mechanosensitive channels perceived the changes in hemodynamics after ventricle injury, and provide novel insights into the temporal and spatial coordination of multiple signaling pathways regulating heart regeneration.
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Óxido Nítrico , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Óxido Nítrico/metabolismo , Coração , Endocárdio/metabolismo , Hemodinâmica , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Based on upconversion nanoparticles (UCNPs) as energy donor and herring sperm DNA (hsDNA) as molecular recognition element, an unlabelled upconversion luminescence (UCL) affinity biosensor was constructed for the detection of anthraquinone (AQ) anticancer drugs in biological fluids. AQ anticancer drugs can insert into the double helix structure of hsDNA on the surface of UCNPs, thereby shortening the distance from UCNPs. Therefore, the luminescence resonance energy transfer (LRET) phenomenon is effectively triggered between UCNPs and AQ anticancer drugs. Hence, AQ anticancer drugs can be quantitatively detected according to the UCL quenching rate. The biosensor showed good sensitivity and stability for the detection of daunorubicin (DNR) and doxorubicin (ADM). For the detection of DNR, the linear range is 1-100 µg·mL-1 with a limit of detection (LOD) of 0.60 µg·mL-1, and for ADM, the linear range is 0.5-100 µg·mL-1 with a LOD of 0.38 µg·mL-1. The proposed biosensor provides a convenient method for monitoring AQ anticancer drugs in clinical biological fluids in the future.
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Antineoplásicos , Técnicas Biossensoriais , Masculino , Humanos , Sêmen , DNA , Técnicas Biossensoriais/métodos , AntraquinonasRESUMO
In this work, an upconversion luminescence (UCL) nanosensor for fast detection of ferric ion (Fe3+) and phosphate ion (Pi) is developed based on the inner-filter effect (IFE) between NaYF4:Yb/Er upconversion nanoparticles (UCNPs) and Fe3+-hypocrellin B (HB) complex. Fe3+-HB complex has strong absorption band (450-650 nm), which overlaps with the green emission peak of UCNPs at 545 nm. By adding Fe3+ and Pi, the UCNPs-HB system produces the red-shift change of absorption spectrum, which leads to the "on-off-on" process of IFE. So, with the specific recognition ability of HB for Fe3+ and the competitive complexation of Pi for Fe3+, the proposed nanosensor utilizes the UCL change to achieve the detection of the targets. For the detections of Fe3+, the linear range is 10-600 µM with a limit of detection (LOD) of 2.62 µM, and for Pi, the linear range is 5-100 µM with a LOD of 1.25 µM. The results for selectivity, precision, and recovery test are also satisfactory. Furthermore, the real sample detection shows that the proposed nanaosensor has a great potential in environmental and biological systems. An upconversion luminescence (UCL) nanosensor based on the inner-filter effect (IFE) between upconversion nanoparticles (UCNPs) and Fe3+-hypocrellin B (HB) complex for the detection of Fe3+ and phosphate ion has been proposed, which is promising to be a convenient and sensitive assay for monitoring Fe3+ and phosphate ion in different environments and biological systems.
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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.
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Fígado Gorduroso , Resistência à Insulina , Adulto , Humanos , Masculino , Estudos Longitudinais , Estudos Transversais , Fatores de Risco , Fígado Gorduroso/etiologia , Índice de Massa Corporal , TestosteronaRESUMO
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.
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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.
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Dieta Hiperlipídica , Infertilidade Masculina , Feminino , Masculino , Animais , Camundongos , Humanos , Dieta Hiperlipídica/efeitos adversos , Fertilidade , Infertilidade Masculina/etiologia , Glucose , Peso Corporal , Lipídeos , Hormônio FoliculoestimulanteRESUMO
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.
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Hipercolesterolemia , Doenças Testiculares , Humanos , Masculino , Ratos , Animais , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Análise do Sêmen , Ratos Sprague-Dawley , Sêmen , Testículo/fisiologia , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/patologia , Testosterona , Doenças Testiculares/etiologia , Dieta , ColesterolRESUMO
OBJECTIVE: Systemic immune-inflammation index (SII), a novel inflammatory indicator based on platelets, neutrophils and lymphocytes, has been shown to be associated with prognostic value in several solid tumors. However, its prognostic value in nonalcoholic fatty liver disease (NAFLD) has not been reported yet. Therefore, the present study aimed to investigate the prognostic value of SII in individuals with NAFLD. METHODS: Data was collected from the 2005 to 2014 National Health and Nutrition Examination Survey (NHANES, https://www.cdc.gov/nchs/nhanes/index.htm), and vital status was derived from the National Death Index (NDI) up to 31 December 2015. NAFLD was diagnosed based on Hepatic Steatosis Index (HSI). Multivariate Cox regression and Kaplan-Meier survival curves were performed to measure the hazard ratios (HRs) and 95% confidence interval (CI). Our study investigated the relationship between SII and all-cause mortality by using two-part linear regression models with penalized splines, as well as Cox models with penalized splines. RESULTS: A total of 10,787 NAFLD participants (44.14% men) aged ≥20 years old were enrolled. There were 776 deaths from all causes after a mean follow-up period of 5.6 years. According to the full adjusted Cox regression analysis, the low log2-SII group (quartile 1) and the highest log2-SII group (quartile 4) were significantly associated with increased mortality from all causes (aHR =1.86; 95% CI: 1.47-2.37; p < 0.0001). After controlling for confounders, an increase in log2-SII was associated with an increased all-cause mortality risk of 41% for every unit raised (aHR = 1.41; 95% CI: 1.26-1.57; p < 0.0001). After adjusting for multiple potential confounders, the association between log2-SII and all-cause mortality was nonlinear, and the threshold value was 8.8. There was no association between an increase of one unit in log2-SII and all-cause mortality below the threshold (aHR = 0.90, 95% CI: 0.71-1.15, p = 0.419). However, a higher log2-SII was associated with a higher risk of death from any cause when it exceeded the threshold (aHR = 1. 73, 95% CI: 1.49-2.02, p < 0.001).Based on a study of US NAFLD patients, it was found that the baseline log2-SII is associated with all-cause mortality. Elevated SII is associated with poor survival among NAFLD patients.KEY MESSAGESUsing a large nationally representative survey of individuals among US adults, the study demonstrated that log2-SII was J-shaped and associated with all-cause death among individuals with NAFLD.Spline analyses demonstrated that the association between log2-SII and all-cause mortality was non-linear after adjusting for multiple potential confounders, and the threshold value was 8.8.Higher log2-SII associated with poor survival in NAFLD.
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Neoplasias , Hepatopatia Gordurosa não Alcoólica , Adulto , Masculino , Humanos , Adulto Jovem , Feminino , Hepatopatia Gordurosa não Alcoólica/complicações , Inquéritos Nutricionais , Inflamação/complicações , PrognósticoRESUMO
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.
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Dieta Hiperlipídica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Masculino , Camundongos , Animais , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Sêmen , Espermatozoides , Testículo , Estresse OxidativoRESUMO
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.
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Células Intersticiais do Testículo , Testosterona , Humanos , Camundongos , Masculino , Animais , Idoso , Testículo/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Envelhecimento/fisiologia , Senescência Celular , Inflamação/metabolismoRESUMO
Based on the mechanism of luminescence resonance energy transfer (LRET) and using a special single strand DNA as the recognition element, a portable paper-based sensor for the accurate detection of total heavy rare-earth ions (mainly Gd3+, Tb3+ and Dy3+) concentration was proposed. The RNA cleaving-DNAzyme should recognize rare-earth ions to cleave RNA on DNA duplexes linking UCNPs and AuNPs, causing UCNPs and AuNPs to approach each other, inducing LRET, which attenuated the green upconversion luminescence (UCL) triggered by the 980 nm laser. UCL was captured by a charge-coupled device (CCD) image sensor and processed with the red-green-blue (RGB) image to quantitatively analyze heavy rare-earth ions in the samples. In the range of 5-50 µmol·L-1, the sensor has good sensitivity, with the limit of detection of 1.26 µmol L-1.
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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.
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Ácido Palmítico , Células de Sertoli , Aminoácidos/metabolismo , Apoptose , Cardiolipinas/metabolismo , Cardiolipinas/farmacologia , Caspase 3/metabolismo , Caspase 3/farmacologia , Ceramidas/metabolismo , Glucose/metabolismo , Glicolipídeos/metabolismo , Humanos , Lisofosfolipídeos/metabolismo , Lisofosfolipídeos/farmacologia , Masculino , Mitocôndrias/metabolismo , Ácido Palmítico/farmacologia , Ácidos Tricarboxílicos/metabolismo , Ácidos Tricarboxílicos/farmacologia , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/farmacologiaRESUMO
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.
RESUMO
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.
Assuntos
Testículo , Proteínas Quinases p38 Ativadas por Mitógeno , Fertilidade , Humanos , Masculino , Maturidade Sexual , Transdução de Sinais , Testículo/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Mutations in ERCC2/XPD helicase, an important component of the TFIIH complex, cause distinct human genetic disorders which exhibit various pathological features. However, the molecular mechanisms underlying many symptoms remain elusive. Here, we have shown that Ercc2/Xpd deficiency in zebrafish resulted in hypoplastic digestive organs with normal bud initiation but later failed to grow. The proliferation of intestinal endothelial cells was impaired in ercc2/xpd mutants, and mitochondrial abnormalities, autophagy, and inflammation were highly induced. Further studies revealed that these abnormalities were associated with the perturbation of rRNA synthesis and nucleolar stress in a p53-independent manner. As TFIIH has only been implicated in RNA polymerase I-dependent transcription in vitro, our results provide the first evidence for the connection between Ercc2/Xpd and rRNA synthesis in an animal model that recapitulates certain key characteristics of ERCC2/XPD-related human genetic disorders, and will greatly advance our understanding of the molecular pathogenesis of these diseases.