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Endoplasmic reticulum (ER) stress mediates Cd-caused germ cell apoptosis in testis. The effects of 4-phenylbutyric acid (PBA), a classical chaperone, were investigated on Cd-induced apoptosis in mouse GC-1 spermatogonia cells. The cells were pretreated with PBA before Cd exposure. TUNEL and flow cytometry assays were applied to determine apoptosis. Some key biomarkers of ER stress were analyzed using RT-PCR and western blot. as expected, the apoptotic cells exposed to Cd apparently increased. The mRNA and protein expression levels of GRP78 and ATF6α, were elevated in the Cd groups. Additional experiments displayed that Cd notably increased IRE1α and JNK phosphorylation, and upregulated XBP-1 mRNA and protein expression. Moreover, p-eIF2α and CHOP expressions were clearly elevated in the Cd groups. Interestingly, PBA almost completely inhibited ER stress and protected spermatogonia against apoptosis induced by Cd. PBA alleviated Cd-induced ER stress and spermatogonia apoptosis, and may have the therapeutic role in Cd-induced male reproductive toxicity. • CdCl 2 induced spermatogonia apoptosis in vitro. • CdCl 2 triggered spermatogonia ER stress. • 4-PBA alleviated CdCl 2 -induced spermatogonia apoptosis. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a common pollutant with reproductive toxicity. Our previous study revealed that Cd triggered spermatogonia ferroptosis. However, the underlying mechanisms remain unclear. Nuclear receptor coactivator 4 (NCOA4) mediates ferritinophagy and specific degradation of ferritin through lysosomes, resulting in the release of ferrous ions. Excessive autophagy can lead to ferroptosis. This study investigated the role of autophagy in Cd-triggered ferroptosis using GC-1 spermatogonial (spg) cells which exposed to CdCl 2 (5 μM, 10 μM, or 20 μM) for 24 without/with CQ. The cells which transfected with Ncoa4-siRNA were used to explore the role of NCOA4-mediated ferritinophagy in Cd-triggered ferroptosis. The results revealed that Cd caused mitochondrial swelling, rupture of cristae, and vacuolar-like changes. The Cd-treated cells exhibited more autophagosomes. Simultaneously, Cd increased intracellular iron, reactive oxygen species, and malondialdehyde concentrations while decreasing glutathione content and Superoxide Dismutase-2 activity. Moreover, Cd upregulated mRNA levels of ferritinophagy-associated genes (Ncoa4, Lc3b and Fth1), as well as enhanced protein expression of NCOA4, LC3B, and FTH1. While Cd decreased the mRNA and protein expression of p62/SQSTM1. These results showed that Cd caused ferritinophagy and ferroptosis. The use of chloroquine to inhibit autophagy ameliorated Cd-induced iron overload and ferroptosis. Moreover, Ncoa4 knockdown in spermatogonia significantly reduced intracellular iron concentration and alleviated Cd-triggered ferroptosis. In conclusion, our findings demonstrate that Cd activates the ferritinophagy pathway mediated by NCOA4, resulting in iron accumulation through ferritin degradation. This causes oxidative stress, ultimately initiating ferroptosis in spermatogonia. Our results may provide new perspectives and potential strategies for preventing and treating Cd-induced reproductive toxicity. [Display omitted] • Cd causes iron overload and triggers ferroptosis in spermatogonia. • Cd induces ferritinophagy in spermatogonia. • CQ antagonizes against Cd-caused iron overload in spermatogonia. • NCOA4-mediated ferritinophagy participates in Cd-triggered ferroptosis. [ABSTRACT FROM AUTHOR]

Background: The Cancer Genome Atlas (TCGA) is an important data resource for cancer biologists and oncologists. However, a lack of bioinformatics expertise often hinders experimental cancer biologists and oncologists from exploring the TCGA resource. Although a number of tools have been developed for facilitating cancer researchers to utilize the TCGA data, these existing tools cannot fully satisfy the large community of experimental cancer biologists and oncologists without bioinformatics expertise. Methods: We developed a new web-based tool The Cancer Omics Atlas (TCOA, http://tcoa.cpu.edu.cn) for fast and straightforward querying of TCGA “omics” data. Results: TCOA provides the querying of gene expression, somatic mutations, microRNA (miRNA) expression, protein expression data based on a single molecule or cancer type. TCOA also provides the querying of expression correlation between gene pairs, miRNA pairs, gene and miRNA, and gene and protein. Moreover, TCOA provides the querying of the associations between gene, miRNA, or protein expression and survival prognosis in cancers. In addition, TCOA displays transcriptional profiles across various human cancer types based on the pan-cancer analysis. Finally, TCOA provides the querying of molecular profiles for 2877 immune-related genes in human cancers. These immune-related genes include those that are established or promising targets for cancer immunotherapy such as CTLA4, PD1, PD-L1, PD-L2, IDO1, LAG3, and TIGIT. Conclusions: TCOA is a useful tool that supplies a number of unique and new functions complementary to the existing tools to facilitate exploration of the TCGA resource. [ABSTRACT FROM AUTHOR]

• The antidepressant-like effects of formononetin was confirmed for the first time. • Formononetin has been verified to reduce neuronal damage and promote neurogenesis. • The protein levels of BDNF and GR in the hippocampus were increased by formononetin. Previous studies reported the neuroprotective effects of formononetin (FMN), however, whether it has antidepressant-like effects have not been reported. To evaluate the antidepressant-like effects of FMN, a mice model of depression was established by chronic corticosterone (CORT) injection. The serum corticosterone levels and hippocampal protein expression were detected by ELISA and Western blot. Nissl staining was used to observe the damage of hippocampal neurons and immunofluorescence was used to observe the neurogenesis in the hippocampus. Our results showed that FMN significantly increased the sucrose preference and shorten the immobility time in the forced swimming test in CORT-treated mice. Moreover, FMN reduced the serum corticosterone levels, upregulated the protein expression levels of the glucocorticoid receptor (GR), and brain-derived neurotrophic factor (BDNF) in the hippocampus, protected against the CORT-induced neuronal impairment, and promoted the neurogenesis in the hippocampus. Taken together, the present study was the first to demonstrate the antidepressant-like effects of FMN in the CORT-induced mice model of depression, which may contribute to the discovery of a new candidate for treating depression. [ABSTRACT FROM AUTHOR]

Posterior capsule opacification (PCO) is a common complication of cataract surgery, resulting from a combination of proliferation, migration, epithelial-mesenchymal transition (EMT) of residual capsular epithelial cells and fibrosis of myofibroblasts. HSP90 is known to regulate the proteostasis of cells under pathophysiological conditions. The role of HSP90 in PCO formation, however, is not clear. To do this, the lens epithelial cell lines and an ex vivo cultured rat capsular bag model were used to study the role of HSP90 in PCO formation. The expression of protein and mRNA was measured by immunoblotting and quantitative RT-PCR, and cell apoptosis was measured by TUNEL(TdT-mediated dUTP nick-end labeling). The cell proliferation was measured by cell viability assays. The results showed that 17-AAG (Tanespimycin), an inhibitor of HSP90, suppresses the proliferation of immortalized lens epithelial cell lines HLE-B3, SRA01/04, and mLEC, with IC 50 values of 0.27, 0.27, and 0.49 μM, respectively. In an ex vivo cultured rat capsular model, the capsular residual epithelial cells resisted the stress of the capsulorhexis surgery and took 3–6 days to completely overlay the capsular posterior wall. During this process, heat shock factor 1 and its downstream targets HSP90, HSP25, αB-crystallin, and HSP40 were upregulated. Treatment with 17-AAG inhibited the viability of capsular residual epithelial cells and induced the cells apoptosis, characterized by increases in ROS levels, apoptotic DNA injury, and the activation of caspases 9 and 3. HSP90 participated in regulating both EGF receptor (EGFR) and TGF receptor (TGFR) signaling pathways. HSP90 was found to interact with the EGFR, such that inhibition of HSP90 by 17-AAG destabilized the EGFR protein and suppressed p-ERK1/2 and p-AKT levels. 17-AAG also inhibited the TGF-β-induced phosphorylation of SMAD2/3 and ERK1/2 and the decrease in E-cadherin and ZO-1 expression. Accordingly, these data suggest that the induction of HSP90 protects capsular residual epithelial cells against capsulorhexis-induced stress and participates in regulating the processes of proliferation, EMT and migration of rat capsular residual epithelial cells, at least partly, through the EGFR and TGFR signaling pathways. Treatment with 17-AAG suppresses PCO formation and is therefore a potential therapeutic candidate for PCO prevention. • HSP90 is induced in ex vivo cultured rat capsular residual cells. • 17-AAG exhibits the cytotoxicity to rat capsular residual cells but not to corneal cells. • HSP90 interacts with EGFR signaling pathway regulating capsular residual cell proliferation. • 17-AAG is a novel potential therapeutic drug for PCO. [ABSTRACT FROM AUTHOR]