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Endometriosis (EMs) is a life-long endocrine disorder and a common cause for female infertility and pelvic pain. The key characteristics of eutopic endometrium of EMs patients are high proliferative and migratory potentials. Cuproptosis is a recently identified copper- and-mitochondrial-dependent regulated cell death. Regretfully, its role in EMs remains unclear. In this study, Kyoto Encyclopedia of Genes and Genomes analyses of differentially expressed genes (DEGs) indicated strong activation of the PI3K-Akt-mTOR pathway and biological process analysis reported positive regulation of kinase activity. Next, we screened 11 cuproptosis-related DEGs and found all of them were downregulated in the EMs group, which indicated the suppression of cuproptosis in EMs. One key cuproptosis-related gene, PDHA1, was selected via support vector machine, random forest algorithm and lasso regularization to build a risk-scoring model, which was tested in both internal and external validations. In conclusion, the downregulation and kinase activity of PDHA1 may function with the PI3K-Akt-mTOR pathway in some way, which could suppress the cuproptosis level and account for the cancer-like pathology in EMs., (© 2022. The Author(s).)

The present study aimed to elucidate the mechanism of myocardial damage induced by simulated transport stress. Sprague-Dawley rats were subjected to 35 °C and 60 rpm (0.1×g rcf) on a constant temperature shaker. The blood samples were prepared for detection of epinephrine (E), norepinephrine (NE), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and serum cardiac troponin T (cTNT); myocardium samples were prepared for morphological examination and signaling protein quantitative. The result showed that plasma norepinephrine (NE) and epinephrine (E) concentrations increased in all stressed groups (P < 0.01). Levels of serum cardiac troponin T (cTNT) were elevated in both the S2d (P < 0.05) and S3d groups (P < 0.01). The concentration of plasma BNP was increased significantly in S3d group (P < 0.05); the difference in ANP was not remarkable. Morphological observation demonstrated obvious microstructure and ultrastructure damage after simulated transport stress. There was also a significant increase in the number of TUNEL-positive cardiomyocytes in stressed hearts. Western blot analysis found that the mitogen-activated protein kinase (MAPK) pathways were activated by strengthening phosphorylation of ASK-1, JNK, P38 and ERK in rat myocardial tissue after simulated transport stress (P < 0.05, P < 0.01). In addition, the ratio of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins was increased in stressed rats (P < 0.01), and the amount of cleaved-caspase3 increased in all stressed rats (P < 0.01). The expression of cleaved-caspase9 protein was also elevated in S2d and S3d groups (P < 0.01). Consequently simulated transport stress induced obvious myocardial damage, which may be attributed to the activation of caspase 9-mediated mitochondrial apoptotic pathway and MAPK pathways.

In this study, we suggested the level of miR-1297 was downreguled in the human hepatocellular carcinoma compared to the normal cells. We demonstrate ectopic expression of miR-1297 could significantly suppress hepatocellular carcinoma cells proliferation and enhance the cell apoptosis. In vitro reporter assay suggested EZH2 is a direct target gene of miR-1297. Furthermore, knockdown of EZH2 have the same effect with miR-1297 overeexpression in hepatocellular carcinoma cells. These findings provide evidence that miR-1297 plays a key role in inhibition of the hepatocellular carcinoma cells proliferation, and enhancing cell apoptosis through targeting EZH2, and strongly suggest that ex ogenous miR-1297 may have therapeutic value in treating hepatocellular carcinoma.

Background: Endometriosis is a benign chronic gynecological disease that affects women of reproductive age, characterized by the presence of functional endometrial tissues outside the uterine cavity. GnRH agonists exhibit anti-proliferative and apoptosis-enhancing activities and have long been used for the treatment of endometriosis. There is a critical need to identify the signaling modules involving GnRH agonist therapy for the treatment of endometriosis. In this study, we compared the proteomic profiles of endometriosis in patients before and after GnRH agonist therapy to identify proteins that might provide further information concerning the mechanisms underlying the functions of GnRH agonists., Methods: A total of 55 protein spots with different abundances were observed using Difference Gel Electrophoresis (DIGE), and 26 of these proteins were assigned clear identities through Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Tandem Mass Spectroscopy (MALDI-TOF/TOF MS)., Results: We validated four of these proteins through Western blotting and immunohistochemistry using human endometrial tissue. We also characterized the effect of Leuprolide acetate (LA) on the apoptosis of eutopic endometrial epithelial cells. LA treatment significantly promoted the apoptosis of eutopic endometrial epithelial cells and inhibited the expression of the anti-apoptotic factor GRP78. GRP78 knockdown enhanced LA-induced cell apoptosis, whereas, the overexpression of GRP78 in eutopic endometrial epithelial cells suppresses LA-induced apoptosis., Conclusion: These results suggest that GnRH agonists induce endometrial epithelial cell apoptosis via GRP78 down-regulation. This study might provide an important molecular framework for further evaluation of GnRH agonist therapy.

The present study investigated the effects of simulated transport stress on morphology and gene expression in the small intestine of laboratory rats. Sprague Dawley rats were subjected to 35°C and 0.1×g on a constant temperature shaker for physiological, biochemical, morphological and microarray analysis before and after treatment. The treatment induced obvious stress responses with significant decreases in body weight (P<0.01), increases in rectal temperature, serum corticosterone (CORT), serum glucose (GLU), creatine kinase (CK) and lactate dehydrogenase (LDH) levels (P<0.01), as well as expression of Hsp27/70/90 mRNA (P<0.05; P<0.01). The rat jejunum was severely damaged and apoptotic after mimicking transport stress, which may mainly be related to cell death, oxidation reduction and hormone imbalance determined by microarray analysis. The bioinformatics analysis from the present study would provide insight into the potential mechanisms underlying transport stress-induced injury in the rat small intestine., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: As the world warms up, heat stress is becoming a major cause of economic loss in the livestock industry. Long-time exposure of animals to hyperthermia causes extensive cell apoptosis, which is harmful to them. AKT and AKT-related serine-threonine kinases are known to be involved in signaling cascades that regulate cell survival, but the mechanism remains elusive. In the present study, we demonstrate that phosphoinositide 3-kinase (PI3K) /AKT signal pathway provides protection against apoptosis induced by heat stress to ascertain the key point for treatment., Results: Under heat stress, rats showed increased shedding of intestinal epithelial cells. These rats also had elevated levels of serum cortisol and improved expression of heat shock proteins (Hsp27, Hsp70 and Hsp90) in response to heat stress. Apoptosis analysis by TUNEL assay revealed a higher number of villi epithelial cells that were undergoing apoptosis in heat-treated rats than in the normal control. This is supported by gene expression analysis, which showed an increased ratio of Bax/Bcl-2 (p < 0.05), an important indicator of apoptosis. During heat-induced apoptosis, more AKTs were activated, showing increased phosphorylation. An increase of BAD phosphorylation, which is an inhibitory modification, ensued. In rat IEC-6 cell line, a significant higher level of AKT phosphorylation was observed at 2 h after heat exposure. This coincided with a marked reduction of apoptosis., Conclusion: Together, these results suggest that heat stress caused damages to rat jejunum and induced apoptosis to a greater degree. HSPs and pro-survival factors were involved in response to heat stress. Among them, AKT played a key role in inhibiting heat-induced apoptosis.

PTEN is a lipid phosphatase, and PTEN mutations are associated with gliomas, macrocephaly, and mental deficiencies. We have used PTEN +/- mice to assess PTEN's role in subventricular zone (SVZ) precursor cells. For cultured SVZ neurosphere cells, haploinsufficiency for PTEN increases phosphorylation of Akt and forkhead transcription factor and slightly enhances proliferation. Based on a filter penetration assay, PTEN +/- cells are substantially more migratory and invasive than +/+ cells. The +/- cells also are more resistant to H(2)O(2)-induced apoptosis. Analysis of PTEN +/- and +/+ mice by BrdU labeling reveals no difference in the rate of cell proliferation in the SVZ. Exit of BrdU-labeled cells from the SVZ and radial migration to the outer layers of the olfactory bulb are more rapid for +/- cells. These observations indicate that PTEN regulates SVZ precursor cell function and is particularly important for migration and apoptosis in response to oxidative stress., ((c) 2002 Elsevier Science (USA).)

Extreme heat stress-induced gastrointestinal injury and dysfunction may occur during summer. We investigated possible mechanisms of heat stress-induced damage in the small intestine using male Sprague-Dawley rats subjected to 2 h of heat stress (40°C, 60% relative humidity) daily for 10 consecutive days. Rats were killed at specific times immediately following heat treatment to determine: morphological changes by optical and electron microscopy; intestinal permeability using fluorescein isothiocyanate-dextran; production of reactive oxygen species (ROS), malondialdehyde (MDA), and activities of superoxide-dismutase and glutathione-peroxidase by specific assays; phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) by immunocytochemistry and western-blot analysis. The rat intestinal epithelial cell line (IEC-6) and specific MAPK inhibitors were used for in vitro investigation of effects of activation of MAPKs by heat stress. Heat stress caused marked morphological damage to the small intestine and significantly increased intestinal permeability. Heat stress increased ROS and MDA production, and significantly reduced anti-oxidase activity. MAPK activity in small intestine was increased by heat stress. In vitro, heat stress caused damage and apoptosis in IEC-6 cells; inhibition of ERK1/2 activation (by U0126) exacerbated these effects, which were attenuated by inhibition of JNK (by SP600125) and p38 (by SB203580) activation. Hence, heat stress caused severe small intestine injury, increased oxidative stress, and activated MAPK signaling pathways. The in vitro studies indicated that ERK1/2 activation is anti-apoptotic, and JNK and p38 activation are pro-apoptotic in heat stressed intestinal epithelial cells. [ABSTRACT FROM AUTHOR]

Objective: Protease-activated receptor 2 plays an important role in the pathogenesis of endometriosis. We studied the effect of ENMD-1068, a protease-activated receptor 2 antagonist, on the development of endometriosis in a noninvasive fluorescent mouse model. Study Design: A red fluorescent protein–expressing xenograft model of human endometriosis was created in nude mice. After endometriosis induction, the mice were injected intraperitoneally with either 25 mg/kg or 50 mg/kg ENMD-1068 or with 200 μL of the vehicle control daily for 5 days. The endometriotic lesions that developed in the mice were then counted, measured, and collected. The lesions were assessed for the production of interleukin 6 and monocyte chemotactic protein-1 by enzyme-linked immunosorbent assays and evaluated for the activation of nuclear factor-κB and the expression of vascular endothelial growth factor by immunohistochemical analyses. Cell proliferation and apoptosis were assessed by immunohistochemistry for Ki-67 and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, respectively. Results: ENMD-1068 dose-dependently inhibited the development of endometriotic lesions (P < .05) without apparent toxicity to various organs of the treated mice. Consistently, ENMD-1068 dose-dependently inhibited the expression of interleukin 6 and nuclear factor-κB (P < .05) and cell proliferation (P < .05) in the lesions, as well as increased the percentage of apoptotic cells (P < .05). ENMD-1068 reduced the levels of monocyte chemotactic protein-1 and vascular endothelial growth factor in the lesions (P < .05), but not in a dose-dependent manner. Conclusion: Our study suggests that ENMD-1068 is effective in suppressing the growth of endometriosis, which might be attributed to the drug's antiangiogenic and antiinflammatory activities. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to investigate the in vitro effect of anti-MUC1 monoclonal antibody (MAb) C595 alone and in combination with docetaxel, on the growth and survival of different epithelial ovarian cancer (EOC) cell lines. MUC1 expression was assessed on EOC cell lines (OVCAR-3, IGROV-1, A2780, CAOV-3, TOV-21G, TOV-112D, SKOV-3 and OV-90) using immunofluorescence labeling and flow cytometry. The effect of MAb C595 alone or in combination with docetaxel on the cell lines was studied by proliferation, colony and TUNEL assays. Our results indicate that all primary and metastatic EOC cell lines tested were positive to MAb C595 (MUC1); MAb C595 inhibited EOC cell proliferation in a MUC1- and dose-dependent manner; low-dose MAb C595 (1/2 of IC50) combined with docetaxel greatly improved efficiency of cell killing in EOC cells and induced apoptosis; the additive effect of MAb C595 was further confirmed in colony forming assays; and cell death following single or combined treatments was associated with the release of cytochrome c and increased caspase-3 activity. These results suggest that MAb C595 used either alone, or combined with docetaxel, is an attractive strategy for targeting human EOC. [ABSTRACT FROM AUTHOR]