Di(2-ethylhexyl) phthalate induces apoptosis through mitochondrial pathway in GC-2spd cells

Di(2-ethylhexyl) phthalate (DEHP), a plasticizer of synthetic polymers, is a well-known endocrine disrupting chemical (EDC) and reproductive toxicant. Addressing the unclear mechanism of DEHP-induced reproductive dysfunction, this study used GC-2spd cells to investigate the molecular mechanism involved in the DEHP-induced toxicity in the male reproductive system. The results indicated that the apoptotic cell death was significantly induced by DEHP exposure over 100 μM. Furthermore, DEHP treatment could induce oxidative stress in GC-2spd cells involving in the decrease of superoxide dismutase (SOD) activity (200 μM) and glutathione peroxidase (GSH-Px) activity (50 and 100 μM). In addition, DEHP induction also caused the elevated ratios of Bax/Bcl-2, release of cytochrome c and decomposition of procaspase-3 and procaspase-9 in GC-2spd cells. Taken together, our work provided the evidence that DEHP exposure might induce apoptosis of GC-2spd cells via mitochondria pathway mediated by oxidative stress. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016

Targeting the BRD4/FOXO3a/CDK6 Axis Sensitizes AKT Inhibition in Luminal Breast Cancer

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer

Impaired long-term potentiation and long-term memory deficits in xCT-deficient sut mice

xCT is the functional subunit of the cystine/glutamate antiporter system xc−, which exchanges intracellular glutamate with extracellular cystine. xCT has been reported to play roles in the maintenance of intracellular redox and ambient extracellular glutamate, which may affect neuronal function. To assess a potential role of xCT in the mouse hippocampus, we performed fear conditioning and passive avoidance for long-term memories and examined hippocampal synaptic plasticity in wild-type mice and xCT-null mutants, sut mice. Long-term memory was impaired in sut mice. Normal basal synaptic transmission and short-term presynaptic plasticity at hippocampal Schaffer collateral–CA1 synapses were observed in sut mice. However, LTP (long-term potentiation) was significantly reduced in sut mice compared with their wild-type counterparts. Supplementation of extracellular glutamate did not reverse the reduction in LTP. Taken together, our results suggest that xCT plays a role in the modulation of hippocampal long-term plasticity

Genome Sequencing and Comparative Transcriptomics of the Model Entomopathogenic Fungi Metarhizium anisopliae and M. acridum

Metarhizium spp. are being used as environmentally friendly alternatives to chemical insecticides, as model systems for studying insect-fungus interactions, and as a resource of genes for biotechnology. We present a comparative analysis of the genome sequences of the broad-spectrum insect pathogen Metarhizium anisopliae and the acridid-specific M. acridum. Whole-genome analyses indicate that the genome structures of these two species are highly syntenic and suggest that the genus Metarhizium evolved from plant endophytes or pathogens. Both M. anisopliae and M. acridum have a strikingly larger proportion of genes encoding secreted proteins than other fungi, while ∼30% of these have no functionally characterized homologs, suggesting hitherto unsuspected interactions between fungal pathogens and insects. The analysis of transposase genes provided evidence of repeat-induced point mutations occurring in M. acridum but not in M. anisopliae. With the help of pathogen-host interaction gene database, ∼16% of Metarhizium genes were identified that are similar to experimentally verified genes involved in pathogenicity in other fungi, particularly plant pathogens. However, relative to M. acridum, M. anisopliae has evolved with many expanded gene families of proteases, chitinases, cytochrome P450s, polyketide synthases, and nonribosomal peptide synthetases for cuticle-degradation, detoxification, and toxin biosynthesis that may facilitate its ability to adapt to heterogenous environments. Transcriptional analysis of both fungi during early infection processes provided further insights into the genes and pathways involved in infectivity and specificity. Of particular note, M. acridum transcribed distinct G-protein coupled receptors on cuticles from locusts (the natural hosts) and cockroaches, whereas M. anisopliae transcribed the same receptor on both hosts. This study will facilitate the identification of virulence genes and the development of improved biocontrol strains with customized properties

Influence of sodium thiosulfate on coronary artery calcification of patients on dialysis: a meta-analysis

AbstractCoronary artery calcification (CAC) is common in dialysis patients and is associated with a higher risk of future cardiovascular events. Sodium thiosulfate (STS) is effective for calciphylaxis in dialysis patients; however, the influence of STS on CAC in dialysis patients remains unclear. This systematic review and meta-analysis were conducted to evaluate the effects of STS on CAC in patients undergoing dialysis. PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases were searched from inception to 22 March 2023 for controlled studies comparing the influence of STS versus usual care without STS on CAC scores in dialysis patients. A random effects model incorporating the potential influence of heterogeneity was used to pool the results. Nine studies, including two non-randomized studies and seven randomized controlled trials, were included in the meta-analysis. Among these, 365 patients on dialysis were included in the study. Compared with usual care without STS, intravenous STS for 3–6 months was associated with significantly reduced CAC scores (mean difference [MD] = −180.17, 95% confidence interval [CI]: −276.64 to −83.70, p  0.05). In conclusion, intravenous STS may be effective in attenuating CAC in dialysis patients

MOS1 Osmosensor of Metarhizium anisopliae Is Required for Adaptation to Insect Host Hemolymph▿

Entomopathogenic fungi such as Metarhizium anisopliae infect insects by direct penetration of the cuticle, after which the fungus adapts to the high osmotic pressure of the hemolymph and multiplies. Here we characterize the M. anisopliae Mos1 gene and demonstrate that it encodes the osmosensor required for this process. MOS1 contains transmembrane regions and a C-terminal Src homology 3 domain similar to those of yeast osmotic adaptor proteins, and homologs of MOS1 are widely distributed in the fungal kingdom. Reverse transcription-PCR demonstrated that Mos1 is up-regulated in insect hemolymph as well as artificial media with high osmotic pressure. Transformants containing an antisense vector directed to the Mos1 mRNA depleted transcript levels by 80%. This produced selective alterations in regulation of genes involved in hyphal body formation, cell membrane stiffness, and generation of intracellular turgor pressure, suggesting that these processes are mediated by MOS1. Consistent with a role in stress responses, transcript depletion of Mos1 increased sensitivity to osmotic and oxidative stresses and to compounds that interfere with cell wall biosynthesis. It also disrupted developmental processes, including formation of appressoria and hyphal bodies. Insect bioassays confirmed that Mos1 knockdown significantly reduces virulence. Overall, our data show that M. anisopliae MOS1 mediates cellular responses to high osmotic pressure and subsequent adaptations to colonize host hemolymph

Influence of sodium thiosulfate on coronary artery calcification of patients on dialysis: a meta-analysis

Coronary artery calcification (CAC) is common in dialysis patients and is associated with a higher risk of future cardiovascular events. Sodium thiosulfate (STS) is effective for calciphylaxis in dialysis patients; however, the influence of STS on CAC in dialysis patients remains unclear. This systematic review and meta-analysis were conducted to evaluate the effects of STS on CAC in patients undergoing dialysis. PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases were searched from inception to 22 March 2023 for controlled studies comparing the influence of STS versus usual care without STS on CAC scores in dialysis patients. A random effects model incorporating the potential influence of heterogeneity was used to pool the results. Nine studies, including two non-randomized studies and seven randomized controlled trials, were included in the meta-analysis. Among these, 365 patients on dialysis were included in the study. Compared with usual care without STS, intravenous STS for 3–6 months was associated with significantly reduced CAC scores (mean difference [MD] = −180.17, 95% confidence interval [CI]: −276.64 to −83.70, p 2 = 0%). Sensitivity analysis limited to studies of patients on hemodialysis showed similar results (MD: −167.33, 95% CI: −266.57 to −68.09, p = 0.001; I2 = 0%). Subgroup analyses according to study design, sample size, mean age, sex, dialysis vintage of the patients, and treatment duration of STS also showed consistent results (p for subgroup differences all > 0.05). In conclusion, intravenous STS may be effective in attenuating CAC in dialysis patients.</p

HMGB 1 acetylation mediates trichloroethylene-induced immune kidney injury by facilitating endothelial cell-podocyte communication

More and more clinical evidence shows that occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) patients often present immune kidney damage. However, the exact mechanisms of cell-to-cell transmission in TCE-induced immune kidney damage remain poorly understood. The present study aimed to explore the role of high mobility group box-1 (HMGB 1) in glomerular endothelial cell-podocyte transmission. 17 OMDT patients and 34 controls were enrolled in this study. We observed that OMDT patients had renal function injury, endothelial cell activation and podocyte injury, and these indicators were associated with serum HMGB 1. To gain mechanistic insight, a TCE-sensitized BALB/c mouse model was established under the interventions of sirtuin 1 (SIRT 1) activator SRT 1720 (0.1 ml, 5 mg/kg) and receptor for advanced glycation end products (RAGE) inhibitor FPS-ZM 1 (0.1 ml, 1.5 mg/kg). We identified HMGB 1 acetylation and its endothelial cytoplasmic translocation following TCE sensitization, but SRT 1720 abolished the process. RAGE was located on podocytes and co-precipitated with extracellular acetylated HMGB 1, promoting podocyte injury, while SRT 1720 and FPS-ZM 1 both alleviated podocyte injury. The results demonstrate that interventions to upstream and downstream pathways of HMGB 1 may weaken glomerular endothelial cell-podocyte transmission, thereby alleviating TCE-induced immune renal injury