Novel Social Stimulation Ameliorates Memory Deficit in Alzheimer's Disease Model through Activating α-Secretase.

As the most common form of dementia in the world, Alzheimer's disease (AD) is a progressive neurological disorder marked by cognitive and behavioral impairment. According to previous researches, abundant social connections shield against dementia. However, it is still unclear how exactly social interactions benefit cognitive abilities in people with AD and how this process is used to increase their general cognitive performance. In this study, we found that single novel social (SNS) stimulation promoted c-Fos expression and increased the protein levels of mature ADAM10/17 and sAPPα in the ventral hippocampus (vHPC) of wild-type (WT) mice, which are hippocampal dorsal CA2 (dCA2) neuron activity and vHPC NMDAR dependent. Additionally, we discovered that SNS caused similar changes in an AD model, FAD4T mice, and these alterations could be reversed by α-secretase inhibitor. Furthermore, we also found that multiple novel social (MNS) stimulation improved synaptic plasticity and memory impairments in both male and female FAD4T mice, accompanied by α-secretase activation and Aß reduction. These findings provide insight into the process underpinning how social interaction helps AD patients who are experiencing cognitive decline, and we also imply that novel social interaction and activation of the α-secretase may be preventative and therapeutic in the early stages of AD.

Sex-specific associations of adolescent motherhood with cognitive function, behavioral problems, and autistic-like traits in offspring and the mediating roles of family conflict and altered brain structure.

BACKGROUND: Previous studies have linked adolescent motherhood to adverse neurodevelopmental outcomes in offspring, yet the sex-specific effect and underlying mechanisms remain unclear. METHODS: This study included 6952 children aged 9-11 from the Adolescent Brain Cognitive Development study. The exposed group consisted of children of mothers < 20 years at the time of birth, while the unexposed group was composed of children of mothers aged 20-35 at birth. We employed a generalized linear mixed model to investigate the associations of adolescent motherhood with cognitive, behavioral, and autistic-like traits in offspring. We applied an inverse-probability-weighted marginal structural model to examine the potential mediating factors including adverse perinatal outcomes, family conflict, and brain structure alterations. RESULTS: Our results revealed that children of adolescent mothers had significantly lower cognitive scores (ß, - 2.11, 95% CI, - 2.90 to - 1.31), increased externalizing problems in male offspring (mean ratio, 1.28, 95% CI, 1.08 to 1.52), and elevated internalizing problems (mean ratio, 1.14, 95% CI, 0.99 to 1.33) and autistic-like traits (mean ratio, 1.22, 95% CI, 1.01 to 1.47) in female. A stressful family environment mediated ~ 70% of the association with internalizing problems in females, ~ 30% with autistic-like traits in females, and ~ 20% with externalizing problems in males. Despite observable brain morphometric changes related to adolescent motherhood, these did not act as mediating factors in our analysis, after adjusting for family environment. No elevated rate of adverse perinatal outcomes was observed in the offspring of adolescent mothers in this study. CONCLUSIONS: Our results reveal distinct sex-specific neurodevelopmental outcomes impacts of being born to adolescent mothers, with a substantial mediating effect of family environment on behavioral outcomes. These findings highlight the importance of developing sex-tailored interventions and support the hypothesis that family environment significantly impacts the neurodevelopmental consequences of adolescent motherhood.

Singleton effect decreases under time pressure: An fNIRS study.

Time pressure affects multiple cognitive processes but how it affects attention capture remains unclear. Two experiments were carried out in the present study to assess whether time pressure prevents attention from capturing by salient distractors and explore the underlying neural mechanisms using functional near-infrared spectroscopy. The results of behavioral tests showed that the singleton effect decreased (Experiment 2) or even disappeared (Experiment 1) when the subject was under time pressure. Neuroimaging data showed that under time pressure, a salient distractor elicited greater activation in the left middle frontal gyrus/inferior frontal gyrus and bilateral superior parietal lobule, brain areas that are thought to be involved in cognitive inhibition and control of spatial attentional shifts. These findings suggest that the reduction or disappearance of the singleton effect under time pressure results from enhanced inhibition of and/or accelerated disengagement from salient distractors.

Identification of the potential TLR7 antagonists by virtual screening and experimental validation.

Toll-like receptor 7 (TLR7) is highly expressed in dendritic cells (DCs) and B cells, and its aberrant activation can promote disease progression in systemic lupus erythematosus (SLE). We utilized structure-based virtual screening and experimental validation to screen natural products from TargetMol for potential TLR7 antagonists. Our results of molecular docking and molecular dynamics simulation showed that Mogroside V (MV) strongly interacted with TLR7, with stable open-TLR7-MV and close-TLR7-MV complexes. Furthermore, in vitro experiments demonstrated that MV significantly inhibited B cell differentiation in a concentration-dependent manner. In addition to TLR7, we also revealed a strong interaction of MV with all TLRs, including TLR4. The above results suggested that MV might be a potential TLR7 antagonist deserving of further study.

Manganese-induced apoptosis through the ROS-activated JNK/FOXO3a signaling pathway in CTX cells, a model of rat astrocytes.

Manganese (Mn) is an essential trace element that maintains many normal physiological functions. However, multi-system disorders would occur once overexposure to Mn, especially neurotoxicity. Despite evidence demonstrating the critical role of ROS-activated JNK/FOXO3a signaling pathway in neuronal survival, the specific mechanisms by which it contributes to Mn-induced neurotoxicity are still unclear. The objectives of this study was to examine the modulation of the JNK/FOXO3a signaling pathway, which is activated by ROS, in Mn-induced apoptosis, using a rat brain astrocyte cell line (CTX cells). This study found that a dose-dependent decrease in cell viability of CTX cells was observed with 150, 200, 250, 300 µmol/L Mn. The results of apoptosis-related protein assay showed that Mn decreased the expression of anti-apoptotic protein Bcl-2 and enhanced the expression of apoptosis-related proteins like Bax and Cleaved-Caspase3. In addition, treatment with Mn resulted in elevated ROS levels and increased phosphorylation levels of JNK. Conversely, phosphorylation of nuclear transcription factors FOXO3a, which regulates expression of transcription factors including Bim and PUMA, was decreased. Depletion of ROS by N-acetyl-L-cysteine (NAC) and inhibition of the JNK pathway by SP600125 prevented Mn-induced JNK/FOXO3a pathway activation and, more importantly, the level of apoptosis was also significantly reduced. Confirmation of Mn-induced apoptosis in CTX cells through ROS generation and activation of the JNK/FOXO3a signaling pathway was the outcome of this study. These findings offer fresh insights into the neurotoxic mechanisms of Mn and therapeutic targets following Mn exposure.

Sex-specific associations between cord blood lead and neurodevelopment in early life: The mother-child cohort (Shanghai, China).

The extent to which neurodevelopment is affected by prenatal lead exposure has not been conclusive. In addition, studies on the effects of sex on these relationships are inconsistent. The aim of this study was to investigate the impact of cord blood lead on neurodevelopment in children within sex subgroups. A total of 275 mother-child pairs from the Shanghai mother-child cohort were included. Umbilical cord blood lead was measured using graphite furnace atomic absorption spectrophotometry. The Bayley Scales for Infant Development-III (BSID-III) was used to measure the neurodevelopment of infants at the age of 18 ± 1.5 months. The median and interquartile range of cord blood lead levels in the total participants, male, and female children were 44.0 (24.5) µg/L, 44.0 (24.3) µg/L, and 46.0 (24.0) µg/L, respectively. According to multiple linear regression, cord blood lead concentrations showed a negative association with fine motor scores in all models associated with female children (ß = -1.5; 95%confidence interval: -2.6, -0.4). However, prenatal lead levels were not associated with any of the BSID-III scores in male children. In addition, cord serum DHA was found positively related to fine motor scores in male children. Our findings suggest that prenatal lead exposure could lead to decreased motor function, although this phenomenon was only observed in female children. And DHA may be a protective factor against lead exposure in boys. Thus, further studies are needed to investigate the associations between prenatal lead exposure and neurobehavioral development, as well as the mechanism of sex differences.

Effects of food-borne cholesterol supplementation on lead-induced neurodevelopmental impairments of rats based on BDNF signaling pathway and cholesterol metabolism.

Despite the ubiquity and prevalence of lead (Pb) in the environment and industry, the mechanism of lead-induced neurotoxicity in the brain remains unclear, let alone its prevention and treatment. In this study, we hypothesized that exogenous cholesterol supplementation acts as an effective remedy for lead-induced neurodevelopmental impairments caused by lead. Forty 21-day-old male rats were randomly divided into four groups and administered 0.1 % lead water and/or 2 % cholesterol-containing feed for 30 d. Ultimately, rats in the lead group lost weight, accompanied by spatial learning and memory impairments as verified by the Morris water maze test, in which the escape latency of rats was prolonged, and the number of crossings in the target platform and the residence time in the target quadrant were significantly diminished compared to the control group. Hematoxylin-Eosin (H&E) staining and Nissl staining illustrated that typical pathological morphology occurred in the brain tissue of the lead group, where the tissue structure was loose, the number of hippocampal neurons and granulosa cells decreased significantly and were arranged loosely, along with enlarged intercellular space, light matrix staining, and decline in Nissl bodies. In addition, inflammatory response and oxidative stress were significantly induced by lead. Immunofluorescence experiments showed apparent activation of astrocytes and microglia, followed by the enhancement of TNF-α and IL-ß levels. Moreover, the MDA content in the lead group was elevated dramatically, whereas the activities of SOD and GSH were significantly inhibited. As for the mechanism, western blot and qRT-PCR experiments were performed, where lead could significantly inhibit the BDNF-TrkB signaling pathway, lowering the protein expression of BDNF and TrkB. Cholesterol metabolism was also affected by lead exposure, in which cholesterol metabolism-related protein expression and gene transcription, including SREBP2, HMGCR, and LDLR, were downregulated. However, cholesterol supplementation efficiently detoxified the negative effects of lead-induced neurotoxicity, reversing the inflammatory response, oxidative stress, inactivation of the BDNF signaling pathway, and imbalance of cholesterol metabolism, thus improving the learning and memory ability of rats. In brief, our study demonstrated that cholesterol supplementation could ameliorate the deficiency of learning and memory induced by lead, which is closely associated with the initiation of the BDNF/TrkB signaling pathway and regulation of cholesterol metabolism.

Subclinical hypothyroidism in pregnancy rats impaired offspring's spatial learning and memory and the cerebellar development.

Subclinical hypothyroidism (SCH) is a very common preclinical condition during pregnancy. The adverse effect of maternal clinical hypothyroidism (CH) on the nervous system development of offspring is beyond doubt, but it is still controversial in SCH. The aim of this study was to investigate whether spatial learning and memory ability of offspring is inhibited in SCH rat model and its possible mechanism. 45 Wistar female rats were randomly divided into SCH, CH and control (CON) groups, which were induced by semi-thyroid electrocauterization, total thyroidectomy and sham operation, respectively. Rat pups were sacrificed at embryonic day 14 (E14), E18, postnatal day 1 (P1), P3, and P10, and pups' cerebellar tissues were collected. The proliferation, differentiation and migration of cerebellar cells were observed, and RNA level of the thyroid hormone receptor α (TRα) and TRß in the cerebellum was detected by real-time PCR, respectively. Morris Water Maze (MWM) test was performed to detect the spatial learning and memory ability of pups at P40. Our data indicated that maternal SCH will significantly extend the offspring's escape latency time, and pups perform worse in the spatial probe test compared with the CON group. Except for E14, the proliferation of pups' cerebellar granule cells (GCs), and the migration of pups' Purkinje cells (PCs) in the SCH group was significantly inhibited compared with that in the CON group at other time points (P < 0.05 or P < 0.01), and the differentiation of cerebellar astrocytes (As) in SCH group was higher than that in CON group at P3 and P10. Except for E14, the expression of TRα mRNA in SCH group was significantly lower than that in CON group (P < 0.05 or P < 0.01). And the difference of the differentiation of As and the spatial learning and memory between SCH and CH groups was not statistically significant. Our findings suggested that SCH during pregnancy nuisances the offspring's spatial learning and memory. It may be related to the decrease of the expression of TRα in cerebellum, which may further inhibit the proliferation of GCs and the migration of PCs, and increase the differentiation of As.

Effects of prenatal exposure to persistent organic pollutants on neonatal Outcomes:A mother-child cohort (Shanghai, China).

Persistent organic pollutants (POPs), known as common environmental pollutants, which have adverse effects on neurobehavioral development, are widely applied in industry and agriculture. However, evidence about neurodevelopmental toxicity of POPs in humans is limited. This study aimed to explore the relationship between prenatal exposure to POPs and birth outcome of the newborn including birth length, weight, and head circumference. In this study, 1522 mother-child pairs were included in this study and cord blood samples were collected, which were detected to determine exposure level of 37 POPs in total. After delivery, the neonatal anthropometric indices detection (birth length, weight, and head circumference) was performed. According to the multivariate linear regression, the newborn with high detection rates (≥75 percentile) of hexachlorobenzene (HCB), beta-hexachlorocyclohexane (ß-HCH), p,p'-dichlorodiphenyl dichloroethylene (p,p'-DDE) in the umbilical cord blood were demonstrated negative relationship with birth head circumference after adjusting for confounding factors, but not related with birth length and weight. After confirming that there was a nonlinear relationship between HCB and birth head circumference based on sex stratification through the generalized additive model (GAM), further two-piecewise linear regression model was conducted to explore the saturation threshold effect between HCB and birth head circumference, which showed cord serum HCB concentration greater than 0.5 µg/L was negatively associated with birth head circumference in girls. Our study provided evidence for the adverse influence of HCB, ß-HCH and p,p'-DDE exposure during pregnancy on the birth head circumference of offspring. Although HCB induced reduction of birth head circumference was found in girls, the mechanism of gender difference remained unclear. Further studies are needed to explore the effect of POPs on the growth and development of offspring based on in vivo or in vitro experimental models.

Amelioration of cholesterol sulfate for lead-induced CTX cell apoptosis based on BDNF signaling pathway mediated cholesterol metabolism.

Lead (Pb), as a deleterious heavy metal, ubiquitously exists in environment and industry, which engenders multi-organ disfunction, especially the brain of infants who are vulnerable to attack from lead-induced neurotoxicity. Although cholesterol sulfate (CS) is crucial constituent of cell membranes and precursor of neurosteroids, which maintains the function and survival of neurons, the role of CS in lead-induced neurological damage still remains incomplete. In this work, Rat Brain Astrocytes cell line (CTX cells) was applied into exploration that protective effects of CS on CTX cell apoptosis induced by lead via the regulation of BDNF/TrkB signaling pathway mediated cholesterol metabolism. We found that CTX cells exposed to lead manifested apparent cytotoxicity, where the viability of CTX cells was significantly suppressed, accompanied with the elevation of apoptosis, in response to a trend towards increases in reactive oxygen species (ROS) production and pro-apoptotic protein Cleaved-caspase3, synchronized with the decline in anti-apoptotic protein Bcl-2. Moreover, accumulation of lead in CTX cells showed a dose-dependent increase, and meanwhile, decrements in cholesterol content occurred along with increase in lead exposure, in which expressions of cholesterol metabolism related proteins and transcriptions of its genes (SREBP2, LDLR, and HMGCR) were diminished. Furthermore, BDNF signaling pathway was obviously blocked after lead exposure, down-regulating expressions of proteins BDNF and TrkB. However, pretreatment with CS detoxified the negative impacts of lead-invoked CTX cell damage, acting as an effective remedy for apoptosis, imbalance of cholesterol metabolism and inhibition of BDNF signaling pathway. In addition, the relationship between BDNF signaling pathway and cholesterol metabolism was further verified, in which cholesterol metabolism related proteins and genes were promoted significantly after the activation of BDNF/TrkB signaling pathway using 7,8-Dihydroxyflavone (7,8-DHF), thereby detoxifying lead-induced CTX cell injury. However, the pretreatment of TrkB inhibitor ANA-12 offset the promotion of 7,8-DHF and ultimately inhibit cholesterol metabolism. Overall, our study demonstrated that CS could initiate the BDNF/TrkB signaling pathway, regulating the cholesterol metabolism against CTX cell apoptosis invoked by lead.

Metagenomics analysis unraveled the influence of sulfate radical-mediated compost nitrogen transformation process.

The mechanism of nitrogen transformation of sulfate radical (SO- 4⋅) in the process of composting is unclear. The objectives of this study were to investigate the influence of SO- 4⋅ on nitrogen biotransformation during composting and to compare the differences in physicochemical parameters and metagenomics analysis between CK (fresh dairy manure and bagasse pith) and PS (the composting raw materials added with potassium persulfate). The results indicated that SO-4⋅ guides electron transfer in the conversion of NH+4-N to NO- 3-N and breaches the extracellular polysaccharide (EPS) structure to promote nitrogen removal. Aminomonooxygenase (AMO) and nitrate reductase (NR) levels displayed an interactive relationship between microorganisms and substrates. Metagenomics analysis revealed distinct microbial community compositions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between nitrification and denitrification. Correlation analysis indicated that Methanobrevibacter, Bacillus and Pseudomonas were closely related to these processes. This work demonstrates the effect of SO- 4⋅ on nitrogen cycling and retention, and possible mechanisms of nitrification and denitrification during composting.

Biochar-based solid acid accelerated carbon conversion by increasing the abundance of thermophilic bacteria in the cow manure composting process.

This study investigated the effects of biochar-based solid acids (SAs) on carbon conversion, alpha diversity and bacterial community succession during cow manure composting with the goal of providing a new strategy for rapid carbon conversion during composting. The addition of SA prolonged the thermophilic phase and accelerated the degradation of lignocellulose; in particular, the degradation time of cellulose was shortened by 50% and the humus content was increased by 22.56% compared with the control group (CK). In addition, high-throughput sequencing results showed that SA improved the alpha diversity and the relative abundance of thermophilic bacteria, mainly Actinobacteria, increased by 12.955% compared with CK. A redundancy analysis (RDA) showed that Actinobacteria was positively correlated with the transformation of carbon.

The enantioselective study of the toxicity effects of chiral acetochlor in HepG2 cells.

Acetochlor is one of the most widely used chiral herbicides in the world, and it is usually produced and used as racemic form (Rac). The potential effects of acetochlor in human body are mainly induced by its residue in agriculture food. The direct target exposed is the liver in human body. However, the potential toxic and mechanism threat to human liver cells caused by chiral acetochlor has been rarely reported. The purpose of this study is to explore the potential mechanism of the toxicity caused by chiral acetochlor in HepG2 cells. The results revealed that acetochlor and its enantiomers could inhibit cell activity and cause DNA damage in HepG2 cells. The toxicity of Rac was higher than that of the two enantiomers, mainly derived from S configuration. The mechanism is through inducing decreased membrane potential (△Ψ), up-regulated Bax/BcL-2 expression, caused a cascade reaction, activated casepase-3 and casepase-9 and cleaved PARP, which maybe lead to cell death through apoptotic-signaling pathway in the end. These results illuminate that the genotoxic and cytotoxic risks of chiral acetochlor are major coming from S configuration. It provides a theoretical basis for the production of single pesticide to reduce the effects of human health.

Association between prenatal exposure to persistent organic pollutants and neurodevelopment in early life: A mother-child cohort (Shanghai, China).

As common environmental pollutants, persistent organic pollutants (POPs) that are widely applied in industry and agriculture have adverse effects on neurodevelopment. However, evidence on the neurotoxicity of POPs in neural development of offspring is limited. This study explored the relationship between prenatal exposure to POPs and neurodevelopment of 18-month-old toddlers in a mother-child cohort in Shanghai, China. In this study, we determined exposure levels of 37 POPs in cord blood serum collected at the time of delivery. The detection rate of pollutants HCB, ß-HCH, and p,p'-DDE was higher than 60%, so these will be discussed in the following analysis. From birth to approximately 18 months, we followed up infants to longitudinally explore whether POPs influenced their language, motor, and cognitive development according to a Bayley-Ⅲ assessment . Based on multivariable regression analyses, the ß-HCH concentration in cord serum was negatively related to motor development scores in children at 18 months by adjusting for the covariates, but there was no change in language and cognition. Further piecewise linear regression analysis showed that a cord serum ß-HCH concentration greater than 0.2 µg/L had a significantly negative correlation with the motor development scores. p,p'-DDE was positively associated with language development at 18 months before and after adjusting for covariates. But prenatal HCB levels were not associated with any of the Bayley-Ⅲ subscales at 18 months. We concluded that prenatal exposure to ß-HCH might have adverse effects on infants' motor development. The minimum harmful concentration of ß-HCH was estimated at 0.2 µg/L in cord serum. The unexpected positive association between p,p'-DDT and language development could be due to live birth bias.

Hydrogen peroxide plus ascorbic acid enhanced organic matter deconstructions and composting performances via changing microbial communities.

This work aims to investigate the influence of hydrogen peroxide (H2O2) and ascorbic acid (ASCA) on the physicochemical characteristics, organic matter (OM) deconstructions, humification degree and succession of bacterial communities for co-composting of bagasse pith and dairy manure. The results indicated that H2O2 and ASCA accelerated the degradation of lignocellulose, improved the transformation of dissolved organic matter (DOM), and enhanced the content of humic substance (HS) and the degree of its aromatization. The bacterial communities were significantly changed in the presence of additives, in which the relative abundances of Firmicutes and Actinobacteria significantly increased. Redundancy analysis (RDA) indicated that the degradation of OM and lignocellulose more influenced the bacterial community compositions. Conclusively, adding H2O2 and ASCA accelerated lignocellulose degradation efficiency, and improved the composting process, which provided an optimized method to dispose of lignocellulose wastes and livestock manure.

Lead acetate induces apoptosis in Leydig cells by activating PPARγ/caspase-3/PARP pathway.

This study was designed to investigate the cytotoxicity of lead acetate (Pb(AC)2, a representative air pollutant) by focusing on PPARγ/caspase-3/PARP apoptotic signaling pathway and to explore the inhibitory effect of PPARγ antagonist on apoptosis of TM3 Leydig cells. MTT assay was utilized to examine cell viability. Cell apoptosis was analyzed using a flow cytometry by staining with Annexin V-PE/7AAD staining and a fluorescence microscope by staining with Hoechst 33,258. The levels of apoptosis-related proteins were examined using western blot. From the results, Pb reduced significantly TM3 cell proliferation in concentration- and time-dependent manner. It increased significantly apoptosis; increased the PPARγ, Bax, procaspase-3, cleaved caspase-3, proPARP, cleaved PARP levels; and decreased Bcl-2 level in Pb-treated TM3 cells as compared to control cells. Furthermore, pretreatment with PPARγ antagonist significantly attenuated the apoptosis and cleavage of caspase-3 and PARP induced by Pb. Our results suggested that Pb induced cytotoxicity on TM3 Leydig cells, at least in part, by increasing PPARγ expression, stimulating cleavage of caspase-3 and PARP, and then induced cell apoptosis.

Selenium ameliorates cadmium-induced mouse leydig TM3 cell apoptosis via inhibiting the ROS/JNK /c-jun signaling pathway.

Despite the well-known acknowledgement of both the toxicity of cadmium (Cd) and the ameliorative effect of selenium (Se), the mechanism of the protective effect of selenium on cadmium-induced Mouse Leydig (TM3) cell apoptosis remains unknown. In this study, we hypothesized that the reactive oxygen species (ROS)-mediated c-jun N-terminal kinase (JNK) signaling pathway is involved in anti-apoptosis of selenium against cadmium in TM3 cells. We found that exposure to cadmium caused evident cytotoxicity, in which cell viability was inhibited, followed by inducement of apoptosis. Moreover, the level of ROS generation was elevated, leading to the phosphorylation of JNK. In addition, following cadmium exposure, the nuclear transcription factor c-jun was significantly activated, which led to increased expression of downstream gene c-jun, resulting in downstream activation of the apoptosis-related protein Caspase3 and upregulation of Cleaved-PARP, as well as inhibition of the anti-apoptosis protein Bcl-2. However, pretreatment with selenium remarkably suppressed cadmium-induced TM3 cell apoptosis. Furthermore, the level of ROS declined, and the JNK signaling pathway was blocked. Following this, the gene expression of c-jun decreased while Bcl-2 increased, which was consistent with the effects on proteins, that Caspase3 activity and Cleaved-PARP were inhibited while Bcl-2 level was restored. In order to explain the relationship between molecules of the signaling pathway, N-acetyl-L-cysteine (NAC), the ROS inhibitor, and JNK1/2 siRNA were administered, which further indicated the mediatory role of the ROS/JNK/c-jun signaling pathway in regulating anti-apoptosis of selenium against cadmium-induced TM3 cell apoptosis.

Cadmium-induced apoptosis through reactive oxygen species-mediated mitochondrial oxidative stress and the JNK signaling pathway in TM3 cells, a model of mouse Leydig cells.

Cadmium (Cd) is a heavy metal that widely exists in the environment and industry, and which causes serious damages to reproductive system. Recent studies have reported that cadmium induces apoptosis of various germ cells in testes, resulting in male infertility. However, the exact mechanism of cadmium-induced apoptosis remains unclear. In this study, we hypothesized that reactive oxygen species (ROS)-mediated c-jun N-terminal kinase (JNK) signaling pathway was involved in cadmium-induced apoptosis in TM3 cells, a model of mouse Leydig cells. TM3 cells were exposed for various times to a range of cadmium concentrations. We found that cadmium reduced TM3 cell viability and increased apoptosis in a time- and dose- dependent manner. Moreover, the levels of ROS generation and the phosphorylation of JNK were elevated by cadmium treatment. In addition, the nuclear transcription factor c-jun was significantly activated, which led to increased expression of downstream c-jun targets and Bcl-2 was decreased, accompanied with downstream activation of apoptosis-related proteins such as Cleaved-Caspase3 and Cleaved-PARP. However, pretreatment with the ROS inhibitor N-acetyl-L-cysteine (NAC) and JNK inhibitor JNK-IN-8, ROS, JNK and cadmium-induced TM3 cell apoptosis were remarkably suppressed. Based on above-mentioned results, this study provides a mechanistic understanding of cadmium induced TM3 cell apoptosis through the ROS/JNK signaling pathways.

High expression of KIFC1 is a poor prognostic biomarker and correlates with TP53 mutation in lung cancer.

The Kinesin Family Member C1 (KIFC1) is highly expressed in a variety of tumors. Since it is linked with tumorigenesis and progression, KIFC1 has emerged as a promising candidate for targeted chemotherapies. Thus, this study aims to find out the association between KIFC1 and lung cancer. The original data were assessed from The Cancer Genome Atlas and Gene Expression Omnibus databases. Compared to normal lung tissues, both mRNA and protein levels of KIFC1 were significantly increased in lung cancer tissues. The upregulation of KIFC1 was significantly correlated with sex, pathological stage, and TMN stage. Survival analysis revealed that increased KIFC1 expression was associated with poor overall survival, first-progression survival and post-progression survival in lung cancer. Based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, we observed that KIFC1 upregulation was linked to enrichment of the cell cycle and TP53 signaling pathway. Additionally, the overexpression of KIFC1 was positively correlated with TP53 mutations in lung cancer. Based on real-world cohort results, western blotting and RT-qPCR showed high-KIFC1 expression in lung cancer, which may be related to the malignancy of lung cancer. Finally, experiments in vitro showed that KIFC1 inhibitor could significantly inhibit the proliferation and invasion of lung cancer cells. In conclusion, KIFC1 is a poor prognostic biomarker, and patients with high-KIFC1 levels may benefit from targeted therapy.

North-south regional differential decomposition and spatiotemporal dynamic evolution of China's industrial green total factor productivity.

"Green development" has become the way for countries around the world to strengthen industries, and it is an important part of China's high-quality economic development. The key for China to strike a balance between economic growth and environmental management is to optimize green total factor productivity (GTFP). This paper measures the GTFP of industry in 30 provinces of China from 2003 to 2019, based on the perspective of energy and carbon emission constraints. It empirically examines the spatial disequilibrium and dynamic evolution of industrial GTFP in China using Dagum Gini coefficients, Kernel density estimation, and Markov chain analysis. The study finds that, (1) although China's industrial GTFP is not high, it shows an increasing trend. The industrial GTFP in the southern region is higher than that in the northern region. (2) Technical efficiency is the shortcoming of China's industrial GTFP improvement. Technological progress is the main driving force of China's industrial GTFP improvement. (3) The relative and absolute differences in China'' industrial GTFP, technical efficiency, and technological progress have all shown a widening trend. Regional differences between the southern and northern regions are the main source of relative differences in industrial GTFP, technical efficiency, and technological progress. (4) China's industrial GTFP shows a clear "club convergence" phenomenon and the "Matthew effect." However, after the introduction of the spatial factor, the "club convergence" phenomenon and the "Matthew effect" have weakened. The driving effect of industrial GTFP on neighboring provinces is stronger in the south than in the north. This paper enriches the analysis of industrial GTFP and provides an important basis for the coordinated regional development of Chinese industry.