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Myocardial damage is the most serious pathological consequence of cardiovascular diseases and an important reason for their high mortality. In recent years, because of the high prevalence of systemic energy metabolism disorders (e.g., obesity, diabetes mellitus, and metabolic syndrome), complications of myocardial damage caused by these disorders have attracted widespread attention. Energy metabolism disorders are independent of traditional injury-related risk factors, such as ischemia, hypoxia, trauma, and infection. An imbalance of myocardial metabolic flexibility and myocardial energy depletion are usually the initial changes of myocardial injury caused by energy metabolism disorders, and abnormal morphology and functional destruction of the mitochondria are their important features. Specifically, mitochondria are the centers of energy metabolism, and recent evidence has shown that decreased mitochondrial function, caused by an imbalance in mitochondrial quality control, may play a key role in myocardial injury caused by energy metabolism disorders. Under chronic energy stress, mitochondria undergo pathological fission, while mitophagy, mitochondrial fusion, and biogenesis are inhibited, and mitochondrial protein balance and transfer are disturbed, resulting in the accumulation of nonfunctional and damaged mitochondria. Consequently, damaged mitochondria lead to myocardial energy depletion and the accumulation of large amounts of reactive oxygen species, further aggravating the imbalance in mitochondrial quality control and forming a vicious cycle. In addition, impaired mitochondria coordinate calcium homeostasis imbalance, and epigenetic alterations participate in the pathogenesis of myocardial damage. These pathological changes induce rapid progression of myocardial damage, eventually leading to heart failure or sudden cardiac death. To intervene more specifically in the myocardial damage caused by metabolic disorders, we need to understand the specific role of mitochondria in this context in detail. Accordingly, promising therapeutic strategies have been proposed. We also summarize the existing therapeutic strategies to provide a reference for clinical treatment and developing new therapies. [Display omitted] Myocardial damage caused by energy metabolism disorders has become a serious threat to human health. Abnormal mitochondrial behaviors play a key role in myocardial damage caused by energy metabolism disorders. Mitochondrial transfer can rescue myocardial injury and has strong therapeutic potential. Disruption of redox homeostasis affects mitochondrial behaviors and exacerbates myocardial injury. Sirtuins and coupling between mitochondrial behaviors are interesting research directions. [ABSTRACT FROM AUTHOR]

To explore the genotyping characteristics of human fecal Escherichia coli (E. coli) and the relationships between antibiotic resistance genes (ARGs) and multidrug resistance (MDR) of E. coli in Miyun District, Beijing, an area with high incidence of infectious diarrheal cases but no related data. Over a period of 3 years, 94 E. coli strains were isolated from fecal samples collected from Miyun District Hospital, a surveillance hospital of the National Pathogen Identification Network. The antibiotic susceptibility of the isolates was determined by the broth microdilution method. ARGs, multilocus sequence typing (MLST), and polymorphism trees were analyzed using whole-genome sequencing data (WGS). This study revealed that 68.09% of the isolates had MDR, prevalent and distributed in different clades, with a relatively high rate and low pathogenicity. There was no difference in MDR between the diarrheal (49/70) and healthy groups (15/24). We developed a random forest (RF) prediction model of TEM.1 + baeR + mphA + mphB + QnrS1 + AAC.3-IId to identify MDR status, highlighting its potential for early resistance identification. The causes of MDR are likely mobile units transmitting the ARGs. In the future, we will continue to strengthen the monitoring of ARGs and MDR, and increase the number of strains to further verify the accuracy of the MDR markers. [ABSTRACT FROM AUTHOR]

Perfluorooctane sulfonic acid (PFOS) as an archetypal representative of per- and polyfluoroalkyl substances (PFAS) is ubiquitously distributed in the environment and extensively detected in human bodies. Although accumulating evidence is suggestive of the deleterious effects of PFOS on male reproduction, the direct toxicity of PFOS towards spermatogenic cells and the relevant mechanisms remain poorly understood. The aims of the present study were to explore the direct effects and underlying molecular mechanisms of PFOS on spermatogenesis. Through integrating animal study, transcriptome profiling, in silico toxicological approaches, and in vitro validation study, we identified the molecular initiating event and key events contributing to PFOS-induced spermatogenic impairments. The mouse experiments revealed that spermatocytes were involved in PFOS-induced spermatogenic disorders and the activation of peroxisome proliferator-activated receptor delta (PPARδ) was linked to spermatocyte loss in PFOS-administrated mice. GC-2spd(ts) cells were treated with an increased gradient of PFOS, which was relevant to environmental and occupational exposure levels of PFOS in populations. Following 72-h treatment, cells was harvested for RNA sequencing. The transcriptome profiling and benchmark dose (BMD) modeling identified endoplasmic reticulum (ER) stress as the key event for PFOS-mediated spermatocyte apoptosis and determined the point-of-departure (PoD) for perturbations of ER stress signaling. Based on the calculated PoD value, further bioinformatics analyses combined with in vitro and in vivo validations showed that PFOS caused metabolic stress by activating PPARδ in mouse spermatocytes, which was responsible for Beclin 1-involved inositol 1,4,5-trisphosphate receptor (IP3R) sensitization. The disruption of IP3R-mediated ER calcium homeostasis triggered ER calcium depletion, leading to ER stress and apoptosis in mouse spermatocytes exposed to PFOS. This study systematically investigated the direct impacts of PFOS on spermatogenesis and unveiled the relevant molecular mechanism of PFOS-induced spermatogenic disorders, providing novel insights and potential preventive/therapeutic targets for PFAS-associated male reproductive toxicity. [Display omitted] • Mouse spermatocytes are involved in PFOS-induced spermatogenic disorders. • PFOS-activated PPARδ triggers metabolic stress in mouse spermatocytes. • PFOS-induced metabolic stress causes IP3R sensitization via upregulating Beclin 1. • Disruption of IP3R-mediated Ca2+ homeostasis induces ER stress with PFOS treatment. • PFOS impair spermatogenesis via causing ER stress-related spermatocyte apoptosis. [ABSTRACT FROM AUTHOR]

Increasing evidence shows that impaired telomere function is associated with male infertility, and various environmental factors are believed to play a pivotal role in telomerase deficiency and telomere shortening. Benzo[ a ]pyrene (B[ a ]P), a ubiquitous pollutant of polycyclic aromatic hydrocarbons (PAHs), can act as a reproductive toxicant; however, the adverse effect of B[ a ]P on telomeres in male reproductive cells has never been studied, and the related mechanisms remain unclear. In this study, we explored the effects of benzo[ a ]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), the active metabolite of B[ a ]P, on telomere dysfunction in mouse spermatocyte-derived cells (GC-2) and also the potential role of telomerase in BPDE-induced spermatogenic cell damage. The results showed that BPDE induced cell viability inhibition, senescence, and apoptosis in GC-2 cells in a dose-dependent manner. Shortened telomeres, telomere-associated DNA damage, reduced telomerase activity, and TERT expression were also observed in BPDE-treated cells, accompanied with the activation of DNA damage response pathway (ATM/Chk1/p53/p21). Moreover, by establishing the TERT knockdown and re-expression cell models, we found that TERT regulated telomere length and the expression of DNA damage response-related proteins to influence senescence and apoptosis in GC-2 cells. These in vitro findings were further confirmed in vivo in the testicular cells of rats orally administrated with B[ a ]P for 7 days. B[ a ]P treatment resulted in histological lesions, apoptosis, and senescence in the testes of rats, which were accompanied by shortened telomeres, reduced levels of TERT protein, and increased expression of DNA damage response-related proteins. In conclusion, it can be concluded that TERT-mediated telomere dysfunction contributes to B[ a ]P- and BPDE-induced senescence and apoptosis through DNA damage response in male reproductive cells. [ABSTRACT FROM AUTHOR]

Rice straw pretreatment mediated by choline chloride (ChCl) or lactic acid (Lac) sequences deep eutectic solvents (DESs) was investigated in this work. Hydrogen bond acceptors (HBAs) and hydrogen bond donors (HBDs) proved to be both important for DESs pretreatment efficiency. DESs containing lots of hydroxyl or amino groups with a high intermolecular hydrogen-bond (H-bond) strength exhibited weak biomass deconstruction abilities. The presence of strong electron-withdrawing groups in DESs was benefit for xylan removal, thus furnishing higher cellulose digestibility. The relationships between the properties of DESs, xylan removal and cellulose digestibility of pretreated biomass were established. It was found that xylan removal was negatively correlated with the pKa values of HBDs, and the enzymatic cellulose digestibility of the residues was linearly and positively related to xylan removal instead of delignification. These results provide a preliminary reference for rational design of novel DESs for biomass pretreatment. [ABSTRACT FROM AUTHOR]

Nanos2 belongs to the Nanos gene-coding family and is an important RNA-binding protein that has been shown to have essential roles in male germline stem cells development and self-renewal in mouse. However, little is known about Nanos2 in inchoate buffalo spermatogonia. Here, rapid-amplification of cDNA ends (RACE) was used to obtain the full-length buffalo Nanos2 sequence and bioinformatic analysis revealed a highly conserved Nanos2 sequence between buffalo and other mammalian species. Although Nanos2 was expressed in various tissues, the highest mRNA expression levels were found in testes tissue. Moreover, Nanos2 mRNA was abundant in fetal and pre-puberal testes but markedly decreased in the testes of adults. At the protein level, immunohistochemistry in pre-puberal testes revealed a pattern of NANOS2 expression similar to that for the undifferentiated type A spermatogonia marker PGP9.5. Furthermore, NANOS2 expression was low in adult testes and restricted to elongating spermatids. Altogether, our data suggest that Nanos2 is a potential preliminary molecular marker of inchoate buffalo spermatogonia, and may play an important role in buffalo spermatogonial stem cells (SSCs) development and self-renewal, as has been observed in other model animals. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants that have adverse effects on the male reproductive function. Many studies have confirmed that PAHs preferentially accumulate in mitochondria DNA relative to nuclear DNA and disrupt mitochondrial functions. However, it is rare whether exposure to PAHs is associated with mitochondrial damage and dysfunction in sperm. To evaluate the effects of PAHs on sperm mitochondria, we measured mitochondrial membrane potential (MMP), mitochondrial DNA copy number (mtDNAcn) and mtDNA integrity in 666 individuals from the Male Reproductive Health in Chongqing College Students (MARHCS) study. PAHs exposure was estimated by measuring eight urinary PAH metabolites (1-OHNap, 2-OHNap, 1-OHPhe, 2-OHPhe, 3-OHPhe, 4-OHPhe, 2-OHFlu and 1-OHPyr). The subjects were divided into low, median and high exposure groups using the tertile levels of urinary PAH metabolites. In univariate analyses, the results showed that increased levels of 2-OHPhe, 3-OHPhe, ∑Phe metabolites and 2-OHFlu were found to be associated with decreased sperm mtDNAcn. After adjusting for potential confounders, significantly negative associations of these metabolites remained (p = 0.039, 0.012, 0.01, 0.035, respectively). Each 1 μg/g creatinine increase in 2-OHPhe, 3-OHPhe, ∑Phe metabolites and 2-OHFlu was associated with a decrease in sperm mtDNAcn of 9.427%, 11.488%, 9.635% and 11.692%, respectively. There were no significant associations between urinary PAH metabolites and sperm MMP or mtDNA integrity. The results indicated that the low exposure levels of PAHs can cause abnormities in sperm mitochondria. [ABSTRACT FROM AUTHOR]

Summary Temperature profoundly affects aging in both poikilotherms and homeotherms. A general belief is that lower temperatures extend lifespan, whereas higher temperatures shorten it. Although this “temperature law” is widely accepted, it has not been extensively tested. Here, we systematically evaluated the role of temperature in lifespan regulation in C. elegans . We found that, although exposure to low temperatures at the adult stage prolongs lifespan, low-temperature treatment at the larval stage surprisingly reduces lifespan. Interestingly, this differential effect of temperature on longevity in larvae and adults is mediated by the same thermosensitive TRP channel TRPA-1 that signals to the transcription factor DAF-16/FOXO. DAF-16/FOXO and TRPA-1 act in larva to shorten lifespan but extend lifespan in adulthood. DAF-16/FOXO differentially regulates gene expression in larva and adult in a temperature-dependent manner. Our results uncover complexity underlying temperature modulation of longevity, demonstrating that temperature differentially regulates lifespan at different stages of life. [ABSTRACT FROM AUTHOR]

To investigate the association and effects of air pollution level on male semen quality in urban and rural areas, this study examines the outdoor concentrations of particulate matter (PM10), sulfur dioxide (SO2), nitrous dioxide (NO2) and semen quality outcomes for 1346 volunteers in both urban and rural areas in Chongqing, China. We found the urban area has a higher pollution level than the rural area, contrasted with better semen quality in the rural residents, especially for sperm morphology and computer assistant semen analysis (CASA) motility parameters. A multivariate linear regression analysis demonstrates that concentrations of PM10, SO2, and NO2 significantly and negatively are associated with normal sperm morphology percentage (P < 0.001) and sperm kinetic parameters. In conclusion, exposure to higher concentrations of PM10, SO2, and NO2 in urban ambient air may account for worse semen quality in urban males. [Copyright &y& Elsevier]

Summary: Aging is characterized by a progressive decline in multiple physiological functions (i.e., functional aging). As animals age, they exhibit a gradual loss in motor activity, but the underlying mechanisms remain unclear. Here we approach this question in C. elegans by functionally characterizing its aging nervous system and muscles. We find that motor neurons exhibit a progressive functional decline, beginning in early life. Surprisingly, body-wall muscles, which were previously thought to undergo functional aging, do not manifest such a decline until mid-late life. Notably, motor neurons first develop a deficit in synaptic vesicle fusion followed by that in quantal size and vesicle docking/priming, revealing specific functional deteriorations in synaptic transmission. Pharmacological stimulation of synaptic transmission can improve motor activity in aged animals. These results uncover a critical role for the nervous system in age-dependent motor activity decline in C. elegans and provide insights into how functional aging occurs in this organism. [Copyright &y& Elsevier]

Abstract: Identification of specific etiological carcinogens is one of the most important issues in environmental-toxicology studies. In this study, cDNA microarrays were used to analyze gene expression and discern chemical-associated profiles induced by a variety of tumor promoting agents in transformed cells. Two-stage transformation model of BALB/c 3T3 cells was established with MNNG as initiator, and 12-O-tetradecanoylphorbol-13-acetate (TPA), okadaic acid (OA), or cadmium chloride (CdCl2) as tumor promoters. Nine morphologically transformed foci were isolated and the anchorage-independent growth of transformed cells was verified. The gene expression alterations in foci were evaluated using cDNA microarray with 1796 mouse genes. Unsupervised hierarchical clustering analysis revealed that the nine foci were classified into three groups in concordance with the promoters used to induce them and characteristic clusters of genes were identified. In these clusters, genes associated with oxidative stress were specially upregulated following distinct promoter exposure. Moreover, common gene expression alterations were also observed in foci, including upregulated genes associated with cell proliferation and downregulated genes associated with extracellular matrix. Our results demonstrate the presence of unique gene expression profiles in transformed cells which reflect the etiological chemicals and indicate the importance of characteristic molecular alterations as potential biomarkers of exposure to tumor promoters. [Copyright &y& Elsevier]

Abstract: One challenge in aging research concerns identifying physiological parameters or biomarkers that can reflect the physical health of an animal and predict its lifespan. In C. elegans, a model organism widely used in aging research, motor deficits develop in old worms. Here we employed machine vision to quantify worm locomotion behavior throughout lifespan. We confirm that aging worms undergo a progressive decline in motor activity, beginning in early life. Importantly, the rate of motor activity decline rather than the absolute motor activity in the early-to-mid life of individual worms in an isogenic population inversely correlates with their lifespan, and thus may serve as a lifespan predictor. Long-lived mutant strains with deficits in insulin/IGF-1 signaling or food intake display a reduction in the rate of motor activity decline, suggesting that this parameter might also be used for across-strain comparison of healthspan. Our work identifies an endogenous physiological parameter for lifespan prediction and healthspan comparison. [Copyright &y& Elsevier]

Abstract: Okadaic acid (OA) is a tumor promoter in two-stage carcinogenesis experiments. Nevertheless, the effects of OA on cell transformation, cell proliferation and apoptosis vary widely, and the molecular events underlying these effects of OA are not well understood. In the present study, we examined the promoting activity and the associated effects on cell growth and apoptosis mediated by OA in BALB/c 3T3 cells, and evaluated alterations of gene transcriptional expression by microarray analysis. The promoting activity of OA was estimated by a two-stage transformation assay, in which cells were treated first with a low dose of the initiator N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) and then with OA for 14 days. It showed that OA, at concentrations of 7.8–31.3ng/ml, enhanced the transformation of MNNG-treated cells. In the promotion phase, cells exposed to OA (7.8ng/ml) grew slowly for the first 2 days and subsequently died. As determined by Hoechst 33342 fluorescent dye and Annexin-V/PI dual-colored flow cytometry, OA induced morphologically apoptotic cells and increased the percentage of early apoptotic cells. The gene expression profile induced by OA at five time points in the promotion phase was determined by use of a specific mouse toxicological microarray containing 1796 clones, and a total of 177 differentially expressed genes were identified. By gene ontology analysis, 31 of these were determined to be functionally involved with cell growth and/or maintenance. In this group, numerous genes associated with the cell proliferation and cell cycle progression were down-regulated at early and/or middle time points. Among these was a subset of genes associated with apoptosis, in which Bnip3, Cycs, Casp3 and Bag1 genes are involved in the mitochondrial pathway of apoptosis. Ier3, Mdm2 and Bnip3 genes may be p53 targets. Furthermore, real-time PCR confirmed the expression changes of five genes selected at random from the differentially expressed genes. We conclude that OA induces cell growth inhibition and apoptosis in the two-stage, MNNG-initiated transformation of BALB/c 3T3 cells. The results of gene expression profile analysis imply that multiple molecular pathways are involved in OA-induced proliferation inhibition and apoptosis. Mitochondrial and p53-associated apoptotic pathways also may contribute to OA-induced apoptosis. [Copyright &y& Elsevier]

Exposure to outdoor fine particulate matter (PM 2.5)-bound polycyclic aromatic hydrocarbons (PAHs) is linked to reproductive dysfunction. However, it is unclear which component of PAHs is responsible for the adverse outcomes. In the Male Reproductive Health in Chongqing College Students (MARHCS) cohort study, we measured the exposure levels of 16 PAHs by collecting air PM 2.5 particles and assessed eight PAHs metabolites from four parent PAHs, including naphthalene, fluorene, phenanthrene, and pyrene in urine samples. We investigated compositional profiles and variation characteristics for 16 PAHs in PM 2.5 , and then assessed the association between PAHs exposure and semen routine parameters, sperm chromatin structure, and serum hormone levels in 1452 samples. The results showed that naphthalene (95% CI : −17.989, −8.101), chrysene (95% CI : −64.894, −47.575), benzo[a]anthracene (95% CI : −63.227, −45.936) and all the high molecular weight (HMW) PAHs in PM 2.5 were negatively associated with sperm normal morphology. Most of the low molecular weight (LMW) PAHs, such as acenaphthylene, fluorene, phenanthrene, fluoranthene, pyrene, chrysene, benzo[a]anthracene, ∑LMW PAHs and ∑16 PAHs, were correlated with increased sperm motility (all corrected P < 0.05). On the other hand, sperm normal morphology was all negatively associated with urinary metabolites of ∑OH-Nap (95% CI : −5.611, −0.536), ∑OH-Phe (95% CI : −5.741, −0.957), and ∑OH-PAHs (95% CI : −5.274, −0.361). Urinary concentrations of ∑OH-PAHs were found to be negatively associated with sperm high DNA stainability (HDS) (P = 0.023), while ∑OH-Phe were negatively associated with serum testosterone level and sperm HDS (P = 0.004). Spearman correlation analysis showed that except for the urinary OH-Nap metabolites, the rest of the urinary OH-PAHs metabolites were negatively correlated with their parent PAHs in air. The results of this study suggest that various PAHs' components may affect reproductive parameters differently. Inhalation of PAHs in air, especially HMW PAHs, may be a potential risk factor for male reproductive health. [Display omitted] • High molecular weight (HMW) PAHs exposure negatively associated with sperm normal morphology. • PAHs exposure also associated with reproductive hormone such as estradiol, LH, prolactin and testosterone. • Various PAHs component may have different effectiveness on reproductive parameters. • Assessment of urinary OH-PAHs metabolites may not predict PAHs in air. • Inhalation of HMW PAHs in air may be a potential risk factor for male reproductive health. [ABSTRACT FROM AUTHOR]

Follicular regulatory T (T FR) cells are a specialized suppressive subset that controls the germinal center (GC) response and maintains humoral self-tolerance. The mechanisms that maintain T FR lineage identity and suppressive activity remain largely unknown. Here, we show that expression of Blimp1 by FoxP3+ T FR cells is essential for T FR lineage stability, entry into the GC, and expression of regulatory activity. Deletion of Blimp1 in T FR cells reduced FoxP3 and CTLA-4 expression and increased pro-inflammatory cytokines and spontaneous production of autoantibodies, including elevated IgE. Maintenance of T FR stability reflected Blimp1-dependent repression of the IL-23R-STAT3 axis and activation of the CD25-STAT5 pathway, while silenced IL-23R-STAT3 or increased STAT5 activation rescued the Blimp1-deficient T FR phenotype. Blimp1-dependent control of CXCR5/CCR7 expression also regulated T FR homing into the GC. These findings uncover a Blimp1-dependent T FR checkpoint that enforces suppressive activity and acts as a gatekeeper of GC entry. • FoxP3-specific ablation of Blimp1 results in expansion of dysfunctional T FR cells • Inducible deletion of Blimp1 in T FR cells impairs T FR stability and function • Blimp1 controls CTLA4 expression, IL-23R-CD25 and CXCR5-CCR7 axes in T FR cells • Blimp1 controls appropriate homing and positioning of T FR cells into the GC Wang et al. identify Blimp1 as a critical transcription factor for the proper positioning and stable expression of the suppressive activity of T FR cells that control GC responses. In the absence of Blimp1, unstable T FR cells prematurely migrate into the GC and differentiate into T FH -like cells to promote dysregulated GC responses. [ABSTRACT FROM AUTHOR]

Effective obtaining fermentable sugar s and other platform chemicals from rice straw mediated by choline chloride- oxalic acid dihydrate (CO) and the corresponding micro-mechanism investigation were conducted in this work. Choosing a suitable constituents molar ratio of CO appeared to be a feasible method to achieve an appropriate pretreatment severity for a good biomass fractionation. Pretreatment by using CO with high oxalic acid dihydrate to choline chloride molar ratio could afford easily digestible cellulose-rich materials (CMRs, >80% of enzymatic digestion) and lignin-rich materials (LRMs) of high purity (>82%) due to extensive hemicellulose removal (>93%) and delignification (around 70%). Cell wall microstructure characterizations based on confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM) verified the stronger xylan and lignin removal ability of CO with higher oxalic acid dihydrate content. Moreover, the considerable removal of xylan confirmed by CLSM was beneficial to delignification and the subsequent cellulose enzymatic hydrolysis. Furthermore, ultra-structural changes of lignin distribution in cell walls based on TEM indicated the occurrence of partial delignification, preferentially in cell corner (CC) and compound middle lumen (CML) rather than in the secondary cell walls. These findings provides a new insight into the detailed mechanism of acidic DESs mediated biomass deconstruction. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Tripterygium hypoglaucum (levl.) Hutch (Celastraceae) (THH) root is a traditional Chinese medicinal herb commonly used for treating autoimmune diseases and cancer. Alkaloid is one of the most bioactive components of THH extract. To evaluate the in vitro and in vivo antitumor properties of the total alkaloids of THH (THHta). Materials and methods: THHta was extracted in pilot-scale. HCT116 cells were chose to establish human colon cancer xenograft model. The in vitro anti-tumor activity of THHta was tested by Cell malignant transformation test, Soft agar colony formation assay and MTT assay. The in vivo anti-tumor effect of THHta was confirmed by xenograft mouse model. THHta-induced apoptosis was examined by flow cytometry. The levels of apoptosis-related proteins were investigated by Western blot. Results: TPA-induced cell transformation was significantly inhibited by THHta in JB6 Cl41 cells. THHta inhibits the growth of colon cancer cells in vitro in a significant dose-dependent manner. Compared to the control set, i.p. administration of THHta to xenograft mice significantly reduced both tumor weight and volume. Apoptosis induction of THHta was mediated by activation of caspase-3, PARP and inhibiting of Bcl-2, Bcl-xL and XIAP. Conclusion: THHta was effective in inhibiting tumor growth both in vitro and in vivo at less toxic concentrations by inducing apoptosis which suggested it could be developed as a potential anticancer agent. [ABSTRACT FROM AUTHOR]

Abstract: 3-methylcholanthrene (MCA) and diethylnitrosamine (DEN) are typical genotoxic carcinogens that can induce tumors in a variety of human and rodent tissues. However, the epigenetic mechanisms underlying their tumorigenesis are unclear. In this study we used a MCA/DEN-induced multistep lung carcinogenesis rat model to study the evolution of alterations in DNA methylation. Rats were treated with a single dose of MCA and DEN in iodized oil by left intra-bronchial instillation. The animals were killed on days 15, 35, 55, 65 and 75 and samples of various pathological phases during carcinogenesis were obtained on these days. The status of global methylation was analyzed for each sample using a monoclonal antibody specific for 5-methycytosine (5-mC) and quantified by image analysis software. We found that the degree of global methylation was, in general, higher in basal cells compared to luminal cells of normal, precancerous and tumor tissues. The combined 5-mC scores of different types of tissues decreased gradually during the progression of carcinogenesis. We also used methylation-sensitive arbitrarily primed PCR (MS-AP-PCR) to screen a total of eight differentially methylated DNA fragments in both precancerous and tumor tissues isolated using laser capture microdissection (LCM), and observed that both unique hypomethylation and hypermethylation fragments coexist after exposure to genotoxic carcinogens. Remarkably, epigenetic alterations in p16 (CDKN2A), but not in p15 (CDKN2B), were observed, and these correlated with the presence of pathologic lung lesions and loss of p16 protein expression. Moreover, defective expression of p16 in methylated primary tumor cell lines recovered markedly after treated with 5-aza-2′-deoxycytidine (5-aza-dC). These results suggest that DNA methylation alterations are an early event in tumorigenesis and play an important role during MCA/DEN-induced multistep rat lung carcinogenesis. [Copyright &y& Elsevier]

Strand displacement DNA synthesis is essential for DNA replication. Gp90, the sole DNA polymerase of Pseudomonas aeruginosa phage 1, can bypass multiply DNA lesions. However, whether it can perform strand displacement synthesis is still unknown. In this work, we found that gp90 exo― could perform strand displacement synthesis, albeit its activity and processivity were lower than those of primer extension. Gp90 exo― itself could not unwind Y-shaped or fork DNA. Tail and gap at DNA fork were necessary for efficient synthesis. High GC content obviously inhibited strand displacement synthesis. Consecutive GC sequence at the entrance of fork showed more inhibition effect on DNA synthesis than that in the downstream DNA fork. The fraction of productive polymerase and DNA complex (A values) was higher for fork than gap; while their average extension rates (k p values) were similar. However, both A and k p values were lower than those for the primer/template (P/T) substrate. The binding of gp90 exo― to fork was tighter than P/T or gap in the absence of dATP. In the presence of dATP to form ternary complex, the binding affinity of gp90 exo― to P/T or gap was increased compared with that in the binary complex. Abasic site, 8-oxoG, and O 6-MeG inhibited and even blocked strand displacement synthesis. This work shows that gp90 exo― could perform strand displacement DNA synthesis at DNA fork, discovering the presence of new functions of PaP1 DNA polymerase in DNA replication and propagation of PaP1. • Gp90 exo― could perform strand displacement DNA synthesis. • Tail and gap at DNA fork were necessary for efficient synthesis. • High GC content and DNA lesions obviously inhibited strand displacement synthesis. • E. coli Pol I KF exo― and Pol T7 ― could perform this synthesis, but Dpo4 and hPol ι could nearly not. • This work discovers new functions of polymerase in DNA replication and propagation of PaP1. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Mitochondrial damage of germ cells contributed to DBP-induced male reproductive toxicity. • ROS might be involved in DBP-induced mitochondrial damage in germ cells. • The activation of Nrf2/ARE antioxidant signaling regulated by PERK can counteract DBP-induced mitochondrial damage. Abstract Dibutyl phthalate (DBP)-induced germ cell apoptosis contributes to male reproductive toxicity, however, the primary target organelle of DBP or the molecular events triggered by DBP to initiate germ cell apoptosis remain unclear. Our previous studies demonstrated DBP could stimulate the production of intracellular reactive oxygen species (ROS), which served as an upstream mediator of activation of endoplasmic reticulum (ER) stress in mouse spermatocyte-derived GC-2 cells. In the present study, the impacts of DBP-induced ROS generation on the mitochondria-related damage and the associations between ER stress and mitochondrial-related damage were investigated in GC-2 cells. We observed significant decreases of mitochondrial mass, mtDNA copy number, COX IV protein level, and ATP level in DBP-treated GC-2 cells in a dose-dependent manner. And DBP activated mitochondrial-related apoptosis, indicated by the elevation of cytoplasmic cytochrome C (Cyt C) and the activation of caspase-9/3 cascade. Pretreatment with antioxidant melatonin obviously attenuated DBP-induced mitochondrial damage and mitochondrial-dependent apoptosis in GC-2 cells, indicating the role of ROS in DBP-caused testicular toxicity. In response to oxidative stress, the Nrf2/ARE axis was activated in DBP-treated GC-2 cells to counteract ROS overproduction and subsequent mitochondrial damage. Further experiments showed DBP treatment increased the phosphorylated expression of ER stress-related protein PERK. GSK2606414, a specific inhibitor of PERK, partly attenuated the expression of Nrf2. And both DBP-induced mitochondrial damage in GC-2 cells and mitochondrial-dependent apoptosis of the germ cells in rat testes were further aggravated by PERK inhibition. Taken together, our data suggest that PERK regulates the Nrf2/ARE antioxidant pathway functioning as a self-defense mechanism against ROS-related mitochondrial damage induced by DBP in male germ cells. [ABSTRACT FROM AUTHOR]

Objective: Psychosocial factors have been associated with a decline of the quality of semen. The study was aimed at (i) estimating the association between work stress and semen quality and (ii) exploring the moderating effect of social support in semen parameters among Chinese male workers.Methods: Data were obtained from 384 adult male workers recruited from April 2014 to December 2015 in Chongqing, China. Participants completed a questionnaire assessing demographic and life-style factors. Work stress and social support was measured by the Chinese version of a 22-item Job Content Questionnaire (JCQ). They underwent a physical examination and provided a semen sample.Results: Subjects with high work stress were associated with a higher risk of being classified below WHO's thresholds for "normal," defined by sperm concentration (OR 2.14, 95% CI 1.24-3.68, p = .006) or total sperm count (OR 1.95, 95% CI 1.13-3.36, p = .02) criteria than subjects with low work stress were. However, these adverse associations were not observed among subjects with high social support (p = .80 for sperm concentration, and p = .39 for total sperm count). Interaction effects between social support and work stress on sperm concentration (p = .002) and total sperm count (p = .02) were detected.Conclusion: Work stress is associated with lower levels of semen quality. Social support attenuates the negative association between work stress and semen quality, which may have implications for reproductive health. [ABSTRACT FROM AUTHOR]

[Display omitted] Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants with well-documented hepatotoxicity. However, the mechanistic linkage between PFAS exposure and non-alcoholic fatty liver disease (NAFLD) remains largely elusive. This study aimed to explore PFAS-to-NAFLD link and the relevant molecular mechanisms. The cross-sectional analyses using National Health and Nutrition Examination Survey (NHANES) data were conducted to investigate the association between PFAS exposure and NAFLD. A combination of in silico toxicological analyses, bioinformatics approaches, animal experiments, and in vitro assays was used to explore the molecular initiating events (MIEs) and key events (KEs) in PFAS-induced hepatic lipid metabolism disorders. The cross-sectional analyses with NHANES data revealed the significant association between PFAS exposure and hepatic steatosis/NAFLD. The in silico toxicological analyses showed that PPARα activation induced by perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), prototypical representatives of PFAS, is the critical MIE associated with NAFLD-predominant liver diseases. Transcriptome-based bioinformatic annotation and analyses identified that transcriptional upregulation of hepatic acyl-CoA oxidase 1 (ACOX1) in PPARα-regulated peroxisomal β-oxidation pathway was the KE involved with PFOA/PFOS-perturbed hepatic lipid metabolic pathways in humans, mice and rats. The in vivo and in vitro assays further verified that ACOX1-mediated oxidative stress contributed to mitochondrial compromise and lipid accumulation in PFOA/PFOS-exposed mouse hepatocytes, which could be mitigated by co-treatment with ACOX1 inhibitor and mitochondria ROS scavenger. Additionally, we observed that besides PFOA and PFOS, hepatic ACOX1 exhibited good-fit response to short-term exposures of long-chain (C7-C10) perfluoroalkyl carboxylic acids (PFHpA, PFNA, PFDA) and perfluoroalkyl sulfonic acids (PFHpS, PFDS) in human hepatocyte spheroids through benchmark dose (BMD) modeling. Our study unveils a novel molecular target for PFAS-induced hepatic lipid metabolic disorders, shedding new light on prediction, assessment, and mitigation of PFAS hepatotoxicity. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this meta-analysis was to compare the efficacy and safety between patients with thoracolumbar burst fracture who underwent posterior fixation alone (non-fusion) and supplemented with fusion.Methods: A comprehensive search of related literature was performed in PubMed, Embase and the Cochrane library. Clinical outcomes (LBOS and VAS), surgical outcomes (operation time, blood loss, hospital stay and perioperative complications), and radiographic outcomes (kyphotic angle, decreased vertebral body height and segmental motion) were assessed in the meta-analysis. Data analysis was conducted with RevMan 5.3 software.Results: Five RCTs and three retrospective studies including a total of 445 cases were identified. We found that there was no significant difference in terms of LBOS, VAS, implant-related complications, kyphotic and VBH parameters. However, there was a significant difference regarding blood loss, operation time, segmental motion and donor site pain between fusion and non-fusion.Conclusion: This meta-analysis demonstrated that posterior fixation alone could achieve satisfactory clinical and radiological results in treating thoracolumbar burst fracture. Moreover, posterior fixation without fusion was superior to additional fusion with less blood loss, shorter operation time, better segmental motion and lower donor site pain. [ABSTRACT FROM AUTHOR]

It has been well demonstrated that polycyclic aromatic hydrocarbons (PAHs) can cause reproductive toxicity, and shorter telomere length in sperm may be one of the factors causing male infertility. However, whether exposure to PAHs is associated with sperm telomere length (STL) has never been evaluated. The present study aimed to assess the potential association between PAHs exposure and STL, and to explore potential biomarkers that may predict the effects of low-level exposure to PAHs on human sperm. Questionnaires and biological samples were collected from 666 volunteers participating in the Male Reproductive Health in Chongqing College Students (MARHCS) cohort study in 2014. Semen parameters were measured for 656 participants, while urinary PAH metabolites, STL and sperm apoptosis were successfully measured for 492, 444 and 628 participants, respectively. The linear regression analysis revealed that increased levels of urinary 1-hydroxypyrene (1-OHPyr) and 1-hydroxynapthalene (1-OHNap) were associated with decreased STL (− 0.385; 95% CI, − 0.749, − 0.021 for 1-OHPyr; and − 0.079; 95% CI, − 0.146, − 0.011 for 1-OHNap). The significant negative associations remained after adjusting for potential confounders. However, no significant associations were observed between urinary PAH metabolites and semen quality or sperm apoptosis. We also administrated rats with benzo[ a ]pyrene (B[ a ]P; 0, 1, 5, and 10 mg/kg) for 4 weeks and found shorter STL and decreased telomerase expression in germ cells in a dose-dependent manner. In conclusion, environmental exposure to some PAHs may be associated with decreased human STL, and the in vivo animal results also demonstrate the adverse effects of B[ a ]P on telomere of male germ cells. [ABSTRACT FROM AUTHOR]

Integrative analysis of testicular genome-wide DNA methylome and transcriptome identified key genes and pathways related to steroidogenesis and spermatogenesis processes, which may be the DNA methylation-regulated mechanism in male reproductive impairment caused by PM 2.5. [Display omitted] The effects of ambient fine particles on male reproductive health have raised widespread concern. The particular underlying mechanisms of the damage remain largely unclear and demand more research in new directions. Previous research has revealed that DNA methylation plays an important role in male reproductive development and is also vulnerable to environmental influences. However, there hasn't been enough investigation into the involvement of DNA methylation in PM 2.5 -induced male reproductive toxicity. Here, we establish a real-time PM 2.5 exposure model and revealed that PM 2.5 exposure could lead to testicular dysfunction including spermatogenesis impairment and steroid hormone dysfunction. In particular, the decrease in the testicular global level of 5-methylcytosine (5mC) indicated a possible association of DNA methylation with testicular injury induced by PM 2.5 exposure. Further genome-wide methylation analysis revealed genomic hypomethylation of testicular DNA and identified more than 1000 differentially methylated regions in both CAP and UA versus FA, indicating that PM 2.5 exposure, even low-dose, could modulate the testicular methylome. Furthermore, integrated analysis of methylome and transcriptome identified some key methylated genes and networks, which may be involved in spermatogenesis and synthesis of steroid hormone. The testicular methylation levels of key genes especially Cyp11a1 and Pax8 raised, and their consequent reduced expression may impair the testosterone and sperm production process. Our research provides fundamental knowledge as well as novel insights into the possible involvement of DNA methylation in PM 2.5 -induced male reproductive harm. [ABSTRACT FROM AUTHOR]

Epidemiological and experimental evidence for detrimental effects of cell phone use on semen quality is still equivocal. And that recruiting participants from infertility clinic not from general population may raise the possibility of a selection bias. To investigate effects of cell phone use on semen parameters in a general population,We screened and documented the cell phone use information of 794 young men from the Male Reproductive Health in Chongqing College students (MARHCS) cohort study in 2013, followed by 666 and 568 in 2014 and 2015, respectively. In the univariate regression analyses, we found that the daily duration of talking on the cell phone was significantly associated with decreased semen parameters, including sperm concentration [β coefficient = − 6.32% per unit daily duration of talking on the cell phone (h); 95% confidence interval (CI), − 11.94, − 0.34] and total sperm count (− 8.23; 95% CI, − 14.38, − 1.63) in 2013; semen volume (− 8.37; 95% CI, − 15.93, − 0.13) and total sperm count (− 16.59; 95% CI, − 29.91, − 0.73) in 2015]. Internet use via cellular networks was also associated with decreased sperm concentration and total sperm counts in 2013 and decreased semen volume in 2015. Multivariate analyses were used to adjust for the effects of potential confounders, and significant negative associations between internet use and semen parameters remained. Consistent but nonsignificant negative associations between talking on the cell phone and semen parameters persisted throughout the three study years, and the negative association was statistically significant in a mixed model that considered all three years of data on talking on the cell phone and semen quality. Our results showed that certain aspects of cell phone use may negatively affect sperm quality in men by decreasing the semen volume, sperm concentration, or sperm count, thus impairing male fertility. [ABSTRACT FROM AUTHOR]

Study of the joint action of xenobiotics is important to fully explore their toxicity and complete risk analysis. In this study, we investigated the effects of low-dose and combined exposure of bisphenol A (BPA) and diethylstilbestrol (DES) on the reproductive system in adult male rats. The results showed that the sperm motility decreased in the BPA/DES and combined groups. Sperm deformity ratios and histological lesions of the testes were significantly higher and more significant, respectively, in the combined group compared with the single treated groups. No dose-effect relationship or significant additive effect on serum hormone levels was observed after combined exposure to BPA/DES. Ultrastructural results showed lesions of the Sertoli and Leydig cells, mainly in the endoplasmic reticulum (ER), in all treated groups. ER stress molecular sensor IRE1 was phosphorylated and activated after BPA and DES treatment in this study. The protein levels of ES stress molecular marker CHOP were significantly up-regulated after exposure to BPA, DES, and BPA and DES combined. These findings indicate that ER stress is important in BPA/DES-induced damage in rat testes. Low-dose and combined exposure to BPA and DES may have toxic effects on male fertility in the adult population. [ABSTRACT FROM AUTHOR]

Recently, spermatogenic cell apoptosis was shown to play a key role in the induction of testicular atrophy by dibutyl phthalate (DBP), thus causing reproductive toxicology. However, the molecular events induced by DBP in apoptotic germ cells remain unclear. In the present study, the mouse spermatocyte-derived GC-2 cell line was exposed to different doses of DBP. We found that DBP induced marked apoptosis in GC-2 cells. The levels of the major endoplasmic reticulum (ER) stress markers GRP-78, ATF-6, and p-EIF2α were elevated when GC-2 cells were exposed to 25 μM DBP and increased in a dose-dependent manner at higher concentrations. Furthermore, at a concentration that resulted in significant apoptosis (100 μM), CHOP, which plays a convergent role in ER stress-mediated apoptosis and is regulated by various upstream ER stress signals, was activated and partially contributed to the DBP-induced apoptosis. However, inhibition of ER stress by 4-PBA, a chemical with chaperone-like activities, augmented the GC-2 cell apoptosis induced by DBP. Further experiments demonstrated that DBP-induced ER stress additionally had a protective role, mediated through the activation of autophagy. These results were confirmed in prepubertal rat testis germ cells; DBP treatment significantly induced testicular atrophy, accompanied by apoptosis, ER stress, and autophagy. Inhibition of ER stress and autophagy significantly aggravated the DBP-induced damage to the germ cells and testes. Taken together, our data suggest that DBP-induced ER stress in germ cells has a cytoprotective effect that is mediated through autophagy activation. These findings provide novel clues regarding the molecular events involved in DBP-induced germ cell apoptosis. [ABSTRACT FROM AUTHOR]

Aging involves progressive loss of cellular function and integrity, presumably caused by accumulated stochastic damage to cells. Alterations in energy metabolism contribute to aging, but how energy metabolism changes with age, how these changes affect aging, and whether they can be modified to modulate aging remain unclear. In locomotory muscle of post-fertile Caenorhabditis elegans,weidentified a progressive decrease in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), a longevity-associated metabolic enzyme, and a reciprocal increase in glycolytic pyruvate kinase (PK) that were necessary and sufficient to limit lifespan. Decline in PEPCK-C with age also led to loss of cellular functionandintegrity including muscle activity,andcellular senescence. Genetic and pharmacologic interventions of PEPCK-C, muscle activity, and AMPK signaling demonstrate that declines in PEPCK-C and muscle function with age interacted to limit reproductive life and lifespan via disrupted energy homeostasis. Quantifications of metabolic flux show that reciprocal changes in PEPCK-CandPKwith age shunted energy metabolism toward glycolysis, reducing mitochondrial bioenergetics. Last, calorie restriction countered changes in PEPCK-C andPKwith age to elicit antiaging effects via TOR inhibition. Thus, a programmed metabolic event involvingPEPCK-CandPKis a determinant of aging that can be modified to modulate aging. [ABSTRACT FROM AUTHOR]

The beneficial effects of garlic ( Allium sativum ) consumption in treating human diseases have been reported worldwide over a long period of human history. The strong antioxidant effect of garlic extract (GE) has also recently been claimed to prevent cancer, thrombus formation, cardiovascular disease and some age-related maladies. Using Caenorhabditis elegans as a model organism, aqueous GE was herein shown to increase the expression of longevity-related FOXO transcription factor daf-16 and extend lifespan by 20%. By employing microarray and proteomics analysis on C. elegans treated with aqueous GE, we have systematically mapped 229 genes and 46 proteins with differential expression profiles, which included many metabolic enzymes and yolky egg vitellogenins. To investigate the garlic components functionally involved in longevity, an integrated metabolo-proteomics approach was employed to identify metabolites and protein components associated with treatment of aqueous GE. Among potential lifespan-promoting substances, mannose-binding lectin and N -acetylcysteine were found to increase daf-16 expression. Our study points to the fact that the lifespan-promoting effect of aqueous GE may entail the DAF-16-mediated signaling pathway. The result also highlights the utility of metabolo-proteomics for unraveling the complexity and intricacy involved in the metabolism of natural products in vivo . [ABSTRACT FROM AUTHOR]

Dibutyl phthalate (DBP) is a peroxisome proliferator which can lead to germ cell loss from Sertoli cells. Collapse of vimentin filaments occurs in Sertoli cells after DBP exposure. Peroxisome proliferator activated receptor α (PPARα) is a key receptor which could be activated by DBP. The role of PPARα in this process was investigated. Results showed that, PPARα was activated in DBP-exposed Sertoli cells, GW6471 inhibited the activity of PPARα, phosphorylation level of vimentin and concentration of soluble vimentin was higher in DBP-treated Sertoli cells than GW6471+DBP-treated cells. These results suggest that PPARα directly or indirectly mediated phosphorylation of vimentin on Ser 83, and PPARα may play an important role in regulating the reorganization of vimentin filaments during exposure of Sertoli cells to DBP. [ABSTRACT FROM AUTHOR]

Abstract: This study was designed to investigate the phthalates exposure levels in general population in Chongqing City of China, and to determine the possible associations between phthalate exposure and male reproductive function parameters. We recruited 232 general men through Chongqing Family Planning Research Institute and Reproductive Center of Chongqing. In a single spot urine sample from each man, phthalate metabolites, including mono-butyl phthalate (MBP), mono-ethyl phthalate (MEP), mono-(2-ethylhexyl) phthalate (MEHP), mono-benzyl phthalate (MBzP), phthalic acid (PA), and total PA were analyzed using solid phase extraction and coupled with high-performance liquid chromatography and detection by tandem mass spectrometry. Semen parameters were dichotomized based on World Health Organization reference values. Sperm DNA damage were analyzed using the alkaline single-cell gel electrophoresis assay. Reproductive hormones were determined in serum by the radioimmunoassay kit. We observed a weak association between urinary MBP concentration and sperm concentration in Chongqing general population. MBP levels above the median were 1.97 times (95% confidence interval [CI] 0.97–4.04) more likely to have sperm concentration below the reference value. There were no other associations between phthalate metabolites and reproductive function parameters after adjusted for potential risk factors. Our study suggested that general population in Chongqing area of China exposure to the environmental level of phthalate have weak or without adverse effects on the reproduction. [Copyright &y& Elsevier]

Caloric restriction (CR) markedly extends life span and improves the health of a broad number of species. Energy metabolism fundamentally contributes to the beneficial effects of CR, but the underlying mechanisms that are responsible for this effect remain enigmatic. A multidisciplinary approach that involves quantitative proteomics, immunochemistry, metabolic quantification, and life span analysis was used to determine how CR, which occurs in the Caenorhabditis elegans eat-2 mutants, modifies energy metabolism of the worm, and whether the observed modifications contribute to the CR-mediated physiological responses.Aswitch to fatty acid metabolism as an energy source and an enhanced rate of energy metabolism by eat-2 mutant nematodes were detected. Life span analyses validated the important role of these previously unknown alterations of energy metabolism in the CR-mediated longevity of nematodes. As observed in mice, the overexpression of the gene for the nematode analog of the cytosolic form of phosphoenolpyruvate carboxykinase caused a marked extension of the life span in C. elegans, presumably by enhancing energy metabolism via an altered rate of cataplerosis of tricarboxylic acid cycle anions.We conclude that an increase, not a decrease in fuel consumption, via an accelerated oxidation of fuels in the TCA cycle is involved in life span regulation; this mechanism may be conserved across phylogeny. [ABSTRACT FROM AUTHOR]

Male reproductive damage in the general population comprises different disorders in various biomarkers, which could be respectively caused by a number of exposure factors. However, researchers considering the environmental/behavioral/psychological exposures together to evaluate their contribution to male reproductive damage are still lacking. The present study investigated the comprehensive association between 138 environmental/behavioral/psychological exposures and 32 male reproductive biomarkers in 796 young Chinese men using graph-guided fused lasso (GFLASSO) and hierarchical clustering methods. All biomarkers were found to be associated with various exposures. A combination of these exposures not only predicted the levels of single biomarkers in another test dataset, but also identified the comprehensive reproductive features by clustering the men into five subgroups with distinct damages representing disrupted spermatogenesis with abnormal sperm morphology, low sperm motility with DNA fragmentation, chromatin immaturity, aberrant endocrine, or DNA strand breakage. The findings can be used to suggest a novel way to identify the males with a high risk of reproductive damage and develop personalized preventive strategies. Unlabelled Image • Relation of 138 exposures (Es) & 32 reproductive biomarkers (Bs) screened in 796 men. • SO 2 & pyrene correlated most to Bs. Benzo(g , h , i)perylene affected largest on single B. • The screened Es can classify the 796 men into subgroups with distinct damages of Bs. [ABSTRACT FROM AUTHOR]

Glucocorticoids are commonly used in clinic, but the immunosuppression seriously hinders their usage. Herein, immunomodulatory effect of artesunate (AS) on hydrocortisone (HC)-induced immunosuppression was investigated. HC-induced immunosuppression mice (HC mice) were established by intramuscular administration with HC (20 mg/kg) once a day for 5 consecutive days. The results showed HC mice challenged with Escherichia coli on the sixth day presented a lower ability to clear bacteria, decreased TNF-α in blood, decreased spleen index and thymus index. Significantly, AS (20 mg/kg) treatment not only enhanced the ability of HC mice to clear bacteria, but also increased spleen index, the levels of pro-inflammatory cytokines from 78.7 ± 12.1 ng/ml (TNF-α) and 48.7 ± 8.6 pg/ml (IL-6) to 174.0 ± 90.5 ng/ml and 783.3 ± 90.5 pg/ml, number of white blood cells in blood, and sIgA in colon. Subsequently, HC-induced immunosuppression peritoneal macrophages model (HC cells) was established via addition of HC (0.5 μg/ml) for 0.5 h, and then LPS (100 ng/ml) was added to clarify the functional status of the cells. The results showed HC inhibited TNF-α and IL-6 mRNA expressions and their release, but AS (2.5 μg/ml) could increase TNF-α and IL-6 mRNA expressions and their release. AS inhibited GILZ mRNA up-regulated by HC and increases TLR4/NF-κB p65 expressions down-regulated by HC. Our findings revealed that AS's effect is closely related to the improvement of the TLR4/NF-κB signal transduction pathway via inhibiting the up-regulation of GILZ mRNA, demonstrating AS does possess immunomodulatory effects and is worth further investigation in the future. [ABSTRACT FROM AUTHOR]

Objective: Poor sleep quality and mental health problems are common in college students. The objective of this study is to examine whether sleep quality predicts the risk of future mental health problems, and vice versa.Methods: The sleep quality and mental health status of 686 male college students were estimated, and 582 of them were followed up a year later. Subjective sleep quality and mental health problems were measured with the Pittsburgh Sleep Quality Index (PSQI) and the Depression Anxiety Stress Scale-21 (DASS-21), respectively.Results: Either at baseline or during follow-up, the PSQI global score was positively associated with scores for depression, anxiety, and stress on the DASS-21 (p's < 0.001). Longitudinal analyses revealed that DASS-21 total score increased in line with increased of PSQI global score during the year (p < .001). More importantly, the cross-lagged analysis showed that (i) PSQI global score at baseline was positively related to depression (β = 0.261), anxiety (β = 0.321), and stress (β = 0.311) scores a year later (p's < 0.001) and (ii) depression (β = 0.259), stress (β = 0.245) and anxiety (β = 0.292) scores at baseline were related to PSQI global score a year later (p's < 0.001). Finally, we further found that among those without mental health problems at baseline, poorer baseline sleep quality predicted a higher risk of anxiety symptoms a year later (RR 3.07, 95% CI 1.36-6.97, p = .007).Conclusions: These data may suggest a bidirectionally relationship between sleep quality and mental health problems. [ABSTRACT FROM AUTHOR]

• Volunteers under worse air condition had higher levels of seminal plasma MDA. • Air pollution especially SO 2 exposure might be a risk of sperm oxidative damage. • Oxidative stress-related markers help assess air pollution-induced sperm damage. Current available evidence regarding the detrimental effects of low-level ambient air pollution on conventional semen parameters is inconclusive. In nonreproductive systems, air pollutant exposure has been demonstrated to induce oxidative stress (OS), which is a crucial mechanism that mediates sperm damage and male infertility. Thus, it may be essential to investigate the effects of air pollution on sperm quality in terms of the perspectives of OS and relative molecular damage. We assessed the associations of major air pollutant exposure to oxidative stress-mediated alterations in semen, including seminal plasma malondialdehyde (MDA), sperm mtDNA copy number, and integrity. The present study used data gathered from 516 young men participating in the Male Reproductive Health in Chongqing College student (MARCHS) cohort study during the follow-up stage in 2014 (n = 427 on the old campus, which is located in an urban area and has worse air quality, and n = 89 on the new campus, which is not urban and has better air quality). Data regarding major air pollutant exposure during 0–90, 0–9, 10–14 and 70–90 days before each semen examination (corresponding to the entire and three key periods of sperm development, respectively) were collected. The Mann-Whitney U nonparametric test was employed to compare distributions of major air pollutants and to explore differences in MDA, mtDNA copy number, and mtDNA integrity between the two campuses. A linear regression model was used as multivariable analysis to investigate associations of major air pollutant exposure with these biomarkers of oxidative damage to sperm and to adjust for potential confounders. During all four key periods of sperm development, compared with college students on the new campus, college students on the old campus were exposed to higher levels of PM10, PM2.5, NO 2 , and CO, and had higher air quality index (AQI) values, indicating that these participants suffered from worse air quality. The levels of seminal plasma MDA in college students on the old campus were higher than those for the new campus (2.0 nmol/ml; 0.7, 3.6 vs. 1.6 nmol/ml; 0.4, 3.4, p < 0.001) (medians with 5th and 95th percentiles). There were no significant differences in sperm mtDNA copy number and mtDNA integrity between the two campuses. Furthermore, daily average PM10 exposure during 0–90 days before semen ejaculation was found to be significantly and positively associated with seminal plasma MDA level (10.4; 95% CI, 4.4, 16.4) (percentage change per 10-unit increase in air pollutant concentration; same meanings for the results below); daily average SO 2 exposure for 70–90 days and NO 2 exposure for 0–9 days prior to sampling were also positively associated with MDA level (74.7; 95% CI, 32.1, 119 and 11.9; 95% CI, 4.8, 19.0, respectively). AQI for 0–90 days and 70–90 days prior to sampling positively correlated with seminal plasma MDA concentrations (11.4; 95% CI, 4.7, 18.1 and 12.2; 95% CI, 5.3, 19.1, respectively). Additionally, daily average SO 2 exposures for 10–14 and 0–9 days prior to sampling were negatively associated with sperm mtDNA copy number and mtDNA integrity, respectively (−9.0; 95% CI, −16.4, −1.6 and −38.3; 95% CI, −64.1, −11.8, respectively). However, only the correlations between SO 2 exposure and AQI value for 70–90 days prior to sampling and MDA levels remained significant after multiplicity adjustment. The results indicate that bad air quality, especially SO 2 exposure during certain periods of sperm development, might be correlated with oxidative damage to sperm. These findings can deepen the understanding of the potential impacts of air pollution on sperm quality. [ABSTRACT FROM AUTHOR]

• Differences were found between hospital workers and controls in terms of MDA. • MN frequency was correlated with duration of occupational exposure and exposure doses. • A weak positive relationship was found between MDA level and MN frequency. The aim of the present study was to assess the oxidative stress level and chromosomal damage induced by occupational exposure to low dose ionizing radiation (LDIR). Two hundred and eighteen hospital workers occupationally exposed to LDIR were included in this study, along with 118 healthy age- and gender-comparable controls. Occupational dosimetry records were collected over the last year and revealed that the accumulated annual dose for each hospital worker was below the permissible limit of the International Commission on Radiological Protection (ICRP). The individuals' oxidative and antioxidative status were determined by measuring the activities of copper zinc-superoxide dismutase (CuZn-SOD), glutathione peroxidase (GSH-Px), catalase (CAT) enzymes, and the levels of malondialdehyde (MDA) in erythrocytes. The effect of radiation on chromosomal integrity was measured by the frequency of micronuclei (MN) formation using the cytokinesis block technique. Our results showed that the activities of CuZn-SOD and CAT enzymes and MDA levels observed in the hospital workers were higher than those in the controls (p < 0.05). We did not find significant difference in GSH-Px enzyme activity between the two groups (p = 0.247). A higher frequency of MN was found in exposed groups than in the controls [3(1–5) ‰ versus 2(0.75–4) ‰; p <0.001]. The difference was significant for males (p = 0.012), but not females (p = 0.14). Multiple linear regression analysis showed differences in the oxidant activities and MN frequency between hospital workers and controls adjusted for age, gender, smoking status and drinking status. Correlation analysis indicated that the frequency of MN was positively associated with MDA levels (p < 0.05). Altogether, these results support the detrimental effects of chronic low dose radiation in humans, which involves the induction of oxidative stress and chromosomal damage. [ABSTRACT FROM AUTHOR]