[Advances in Targeted Therapy for Malignant Pleural Mesothelioma].

Malignant pleural mesothelioma (MPM) is a rare cancer with high malignancy and aggressiveness on the pleural, caused by the following risk factors including asbestos inhalation, genetic factors, and genetic mutation. The present chemotherapy, antiangiogenic therapy, and immunotherapy methods are ineffective and the survival time of patients is very short. There is an urgent need to find potential therapeutic targets for MPM. At present, it has been found the following types of targets: gene mutation targets such as BRCA associated protein 1 (BAP1) and cyclin-dependent kinase 2A (CDKN2A); epigenetic targets such as lysine (K)-specific demethylase 4A (KDM4A) and lysine-specific demethylase 1 (LSD1), and signal protein targets such as glucose-regulated protein 78 (GRP78) and signal transducer and activator of transcription 3 (STAT3). So far, available clinical trials include phase II clinical trials of histone methyltransferase inhibitor Tazemetostat, poly (ADP-ribose) polymerase (PARP) inhibitor Rucaparib and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib, as well as phase I clinical trials of mesothelin-targeting chimeric antigen receptor T-cell immunotherapy (CAR-T) cell injection in the thoracic cavity and TEA domain family member (TEAD) inhibitor VT3989 and IK-930, and the results of these trials have showed certain clinical efficacy.
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Polystyrene microplastics disturb maternal glucose homeostasis and induce adverse pregnancy outcomes.

Pregnant women are a special group that is sensitive to adverse external stimuli, causing metabolic abnormalities and adverse pregnancy outcomes. Microplastics (MPs), an environmental pollutant widely used in various fields, can induce a variety of toxic responses in mammals. Recent studies verified an association between MPs and metabolic disorders. Our research built a gestational mouse model in which polystyrene microplastics (PS-MPs) of 1 µm size were consumed at concentrations of 0.1, 1, and 10 mg/L during pregnancy. Results indicated that PS-MPs induced placental malfunction and fetal growth retardation. Significant glucose disorders, decreased liver function, hepatic inflammation, and oxidative stress were also observed after PS-MPs exposure. The hepatic SIRT1/IRS1/PI3K pathway was inhibited in the 10 mg/L PS-MPs exposure group. Our study found that PS-MPs activated inflammatory response and oxidative stress by increasing hepatic lipopolysaccharide (LPS) that inhibited the hepatic SIRT1/IRS1/PI3K pathway, ultimately leading to insulin resistance, glucose metabolism disorders, and adverse pregnancy outcomes. This study provides a basis for preventing environment-related gestational diabetes and concomitant adverse pregnancy outcomes.

Maternal F-53B exposure during pregnancy and lactation induced glucolipid metabolism disorders and adverse pregnancy outcomes by disturbing gut microbiota in mice.

In the metal plating industry, F-53B has been widely used for almost half a century as a replacement for perfluorooctane sulfonate. However, F-53B can reach the food chain and affect human health. Pregnant women have distinct physiological characteristics and may thus be more sensitive to the toxicity of F-53B. In the present study, F-53B was added to the drinking water of pregnant mice during gestation and lactation at doses of 0 mg/L (Ctrl), 0.57 mg/L (L-F), and 5.7 mg/L (H-F). The aim was to explore the potential effects of F-53B on glucolipid metabolism and pregnancy outcomes in dams. Results showed that F-53B induced disordered glucolipid metabolism, adverse pregnancy outcomes, hepatic inflammation, oxidative stress and substantially altered related biochemical parameters in maternal mice. Moreover, F-53B induced remarkable gut barrier damage and gut microbiota perturbation. Correlation analysis revealed that gut microbiota is associated with glucolipid metabolism disorders and hepatic inflammation. The fecal microbiota transplant experiment demonstrated that altered gut microbiota induced by F-53B caused metabolic disorders, adverse pregnancy outcomes, and gut barrier damage. These results suggested that maternal mice exposed to F-53B during gestation and lactation had an increased risk of developing metabolic disorders and adverse pregnancy outcomes and highlighted the crucial role of the gut microbiota in this process, offering novel insights into the risk of F-53B to health.

Protective effect of Luffa cylindrica fermentation liquid on cyclophosphamide-induced premature ovarian failure in female mice by attenuating oxidative stress, inflammation and apoptosis.

Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. The purpose of this study was to investigate the protective effects of Luffa cylindrica fermentation liquid (LF) on cyclophosphamide (CTX) -induced POF in mice and to preliminarily investigate the underlying mechanisms. Thirty-two Balb/c mice were divided into four groups randomly. One group served as the control, while the other three received CTX injections to establish POF models. A 14-day gavage of either 5 or 10 µL/g LF was administered to two LF pretreatment groups. To analyze the effects of LF, the ovarian index, follicle number, the levels of serum sex hormones, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), inflammatory factors, and apoptosis of the ovarian cells were measured. The effects of LF pretreatment on the expression of TLR4/NF-κB and apoptosis pathways were also evaluated. We found that LF pretreatment increased the ovarian index and the number of primordial and antral follicles while decreasing those of atretic follicles. LF pretreatment also increased the serum levels of estradiol (E2) and anti-Müllerian hormone (AMH), while decreasing those of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Furthermore, LF pretreatment increased the levels of SOD and GSH in the ovaries, while decreasing those of MDA, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). LF administration reduced the amount of TUNEL+ ovarian cells and the levels of TLR4 and NF-κB P65 protein expression. In conclusion, LF has antioxidant, anti-inflammatory as well as anti-apoptotic effects against CTX-induced POF, and the inhibition of TLR4/NF-κB and apoptosis pathways may be involved in its mechanisms.

Predictive Model of CK7 Expression in Patients With Clear Cell Renal Cell Carcinoma by Combined Multimodal Ultrasound Diagnostic Techniques: A Retrospective Study.

OBJECTIVE: The aim of the work described here was to develop and validate a predictive model for cytokeratin 7 (CK7) expression in clear cell renal cell carcinoma (ccRCC) patients by combining multimodal ultrasound diagnostic techniques. METHODS: This retrospective study enrolled 157 surgically confirmed ccRCC patients. All patients underwent pre-operative multimodal ultrasound diagnostic examinations, including B-mode ultrasound (US), color Doppler flow imaging (CDFI) and contrast-enhanced ultrasound (CEUS). The patients were randomly divided into a training group (103 cases) and a testing group (54 cases). Univariate and multivariate logistic regression analyses were performed in the training group to identify independent indicators associated with CK7 positivity. These indicators were included in the predictive model. Receiver operating characteristic (ROC) curves and calibration curves were used to evaluate the model's discriminative ability and accuracy. Decision curve analysis (DCA) and nomogram visualization were used to assess the clinical utility of the predictive model. RESULTS: Univariate logistic regression analysis revealed that US and CDFI observations were not correlated with CK7 expression and could not predict it. Multivariate logistic regression analysis identified age (odds ratio [OR] = 0.953, 95% confidence interval [CI]: 0.909-0.999), wash-in pattern (OR = 0.180, 95% CI: 0.063-0.513) and enhancement homogeneity (OR = 11.610, 95% CI: 1.394-96.675) as independent factors related to CK7 positivity in ccRCC. Incorporating these variables into the predictive model resulted in areas under the receiver operating characteristic curve of 0.812 (95% CI: 0.711-0.913) for the training group and 0.792 (95% CI: 0.667-0.924) for the testing group. The calibration curve and DCA revealed that the model had good accuracy and clinical utility of the model. CONCLUSION: The combination of multimodal ultrasound diagnostic techniques in constructing a predictive model for CK7 expression in ccRCC patients has significant predictive value.

Associations between contrast-enhanced ultrasound features and WHO/ISUP grade of clear cell renal cell carcinoma: a retrospective study.

BACKGROUND: Clear cell renal cell carcinoma (CCRCC) comprises 70%-80% of RCCs. The World Health Organization/International Society of Urology Pathology (WHO/ISUP) classification is the most important prognostic factor for CCRCC. By evaluating the variations of tumor microvascular density, contrast-enhanced ultrasound (CEUS) can noninvasively predict the WHO/ISUP grade of CCRCC, and provide the appropriate treatment plan before clinical operation. METHODS: In this study, we used CEUS features to analyze 116 CCRCC cases and assess the value of correlation between each indicator and CCRCC WHO/ISUP grading. RESULTS: When compared to high-grade (WHO/ISUP grade III/IV) tumors, low-grade (WHO/ISUP grade I/II) tumors had reduced relative peak intensity (ΔPI) (P = 0.021), relative area under the curve (ΔAUC) (P = 0.019). However, the frequency of incomplete pseudocapsule (P = 0.021) was significantly higher in high-grade tumors. A cut-off value of mean diameter > 5.5 cm, ΔPI > 304 × 10-3, ΔAUC > 350 × 10-3 allowed identification of high-grade tumors with an area under the curve (AUC) of 74.6%, 71.7%, 70.7%, respectively (95% confidence interval). CONCLUSIONS: The features of CEUS are effective for differentiating high-grade tumors from low-grade tumors, thus CEUS can be considered an acceptable method for the preoperative assessment of tumor grade.

Rapamycin nanoparticles increase the therapeutic window of engineered interleukin-2 and drive expansion of antigen-specific regulatory T cells for protection against autoimmune disease.

Interleukin-2 (IL-2) therapies targeting the high affinity IL-2 receptor expressed on regulatory T cells (Tregs) have shown promising therapeutic benefit in autoimmune diseases through nonselective expansion of pre-existing Treg populations, but are potentially limited by the inability to induce antigen-specific Tregs, as well as by dose-limiting activation of effector immune cells in settings of inflammation. We recently developed biodegradable nanoparticles encapsulating rapamycin, called ImmTOR, which induce selective immune tolerance to co-administered antigens but do not increase total Treg numbers. Here we demonstrate that the combination of ImmTOR and an engineered Treg-selective IL-2 variant (termed IL-2 mutein) increases the number and durability of total Tregs, as well as inducing a profound synergistic increase in antigen-specific Tregs when combined with a target antigen. We demonstrate that the combination of ImmTOR and an IL-2 mutein leads to durable inhibition of antibody responses to co-administered AAV gene therapy capsid, even at sub-optimal doses of ImmTOR, and provides protection in autoimmune models of type 1 diabetes and primary biliary cholangitis. Importantly, ImmTOR also increases the therapeutic window of engineered IL-2 molecules by mitigating effector immune cell expansion and preventing exacerbation of disease in a model of graft-versus-host-disease. At the same time, IL-2 mutein shows potential for dose-sparing of ImmTOR. Overall, these results establish that the combination of ImmTOR and an IL-2 mutein show synergistic benefit on both safety and efficacy to provide durable antigen-specific immune tolerance to mitigate drug immunogenicity and to treat autoimmune diseases.

Effectiveness of telehealth interventions on depression symptoms after stroke: A systematic review and meta-analysis.

BACKGROUND: Depression symptoms are common after stroke, and affect survivors' recovery of neurological function, ability to return to society, and quality of life. Telehealth has been shown to improve depression symptoms and quality of life among patients post-stroke. However, evidence from clinical trials has not previously been systematically synthesized. OBJECTIVE: This study aimed to systematically evaluate the effectiveness of telehealth interventions in reducing depression symptoms among patients post-stroke. METHODS: Following the PRISMA guidelines, we conducted a meta-analysis of randomized control trials of telehealth interventions for post-stroke depression symptoms. The quality of included studies was assessed using the Cochrane risk of bias tool. RevMan 5.4 software was used for the meta-analysis. Data were synthesized by fixed (I2 ≤ 50 %) or random (I2 > 50 %) effects models based on a heterogeneity test. RESULTS: In total, ten studies with 1717 participants were included, eight of which were eligible for the meta-analysis. There were no significant differences in efficacy between the telehealth and control groups for depression symptoms (standardized mean difference [SMD] = -0.16, 95 % confidence interval [CI] -0.67 to 0.36; P = .54), quality of life (SMD = 0.00, 95%CI -0.18 to 0.18; P = .99), limb function (SMD = 0.46, 95%CI -0.26 to 1.18; P = .21), and daily living ability (SMD = 0.38, 95%CI -1.39 to 2.15; P = .67). The telemedicine group had significantly lower anxiety scores than the control group (SMD = -1.05, 95%CI -1.22 to -0.89; P < .001). LIMITATIONS: The number of randomized controlled trials (RCTs) included in the review was relatively small. CONCLUSIONS: This study suggests that telehealth interventions have comparable effects to usual nursing care in improving depression symptoms after a stroke. However, large-scale, high-quality RCTs are needed to further explore the potential of telehealth interventions in improving mental health among patients post-stroke.

Advances of exosomal miRNAs in the diagnosis and treatment of ovarian cancer.

Ovarian cancer is a tumor with the highest fatalities among female malignant tumors. This disease has no typical symptoms in its early stage, and most of the patients are in an advanced stage when being treated. The treatment effect is poor and it is easy to develop chemotherapy resistance. Therefore, it is particularly urgent to clarify the pathogenesis of ovarian cancer, explore its early diagnosis of biomarkers, and discover new treatment methods. As a carrier of intercellular information and genetic material transfer, exosomes are widely distributed in body fluids (e.g. blood and urine), which are regarded as latent tumor markers and take effects on tumor occurrence and invasion. Several articles have recently signified that exosomal miRNAs are widely implicated in the formation of the ovarian cancer tumor microenvironment, disease initiation and progression, and the generation of chemotherapy resistance. This article reviews the research on exosomal miRNAs in ovarian cancer.

Germacrane Sesquiterpene Dilactones from Mikania micrantha and Their Antibacterial and Cytotoxic Activity.

Four new germacrane sesquiterpene dilactones, 2ß-hydroxyl-11ß,13-dihydrodeoxymikanolide (1), 3ß-hydroxyl-11ß,13-dihydrodeoxymikanolide (2), 1α,3ß-dihydroxy-4,9-germacradiene-12,8:15,6-diolide (3), and (11ß,13-dihydrodeoxymikanolide-13-yl)-adenine (4), together with five known ones (5-9) were isolated from the aerial parts of Mikania micrantha. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compound 4 is featured with an adenine moiety in the molecule, which is the first nitrogen-containing sesquiterpenoid so far isolated from this plant species. These compounds were evaluated for their in vitro antibacterial activity against four Gram-(+) bacteria of Staphyloccocus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), Bacillus cereus (BC) and Curtobacterium. flaccumfaciens (CF), and three Gram-(-) bacteria of Escherichia coli (EC), Salmonella. typhimurium (SA), and Pseudomonas Solanacearum (PS). Compounds 4 and 7-9 were found to show strong in vitro antibacterial activity toward all the tested bacteria with the MIC values ranging from 1.56 to 12.5 µg/mL. Notably, compounds 4 and 9 showed significant antibacterial activity against the drug-resistant bacterium of MRSA with MIC value 6.25 µg/mL, which was close to reference compound vancomycin (MIC 3.125 µg/mL). Compounds 4 and 7-9 were further revealed to show in vitro cytotoxic activity toward human tumor A549, HepG2, MCF-7, and HeLa cell lines, with IC50 values ranging from 8.97 to 27.39 µM. No antibacterial and cytotoxic activity were displayed for the other compounds. The present research provided new data to support that M. micrantha is rich in structurally diverse bioactive compounds worthy of further development for pharmaceutical applications and for crop protection in agricultural fields.

Polystyrene Microplastics Induced Ovarian Toxicity in Juvenile Rats Associated with Oxidative Stress and Activation of the PERK-eIF2α-ATF4-CHOP Signaling Pathway.

Numerous reports confirm that microplastics exposure could induce reproductive toxicity in mammals. However, the effects of microplastics exposure during juveniles on ovarian apoptosis through oxidative and endoplasmic reticulum (ER) stresses remains unclear, which is the focus of our study. In the present study, female rats (4 weeks old) were exposed to polystyrene microplastics (PS-MPs, 1 µm) at different dosages (0, 0.5, and 2.0 mg/kg) for 28 days. Findings revealed that 2.0 mg/kg of PS-MPs distinctly increased the atretic follicle ratio in the ovary and dramatically reduced the serum levels of estrogen and progesterone. Additionally, the oxidative stress indicators declined, including the activity of superoxide dismutase and catalase, whereas the malondialdehyde content in the ovary was considerably enhanced in the 2.0 mg/kg PS-MPs group. Furthermore, the expressions of genes related to ER stress (PERK, eIF2α, ATF4, and CHOP) and apoptosis were remarkably elevated in the 2.0 mg/kg PS-MPs group compared with those in the control group. We found that PS-MPs induced oxidative stress and activated the PERK-eIF2α-ATF4-CHOP signaling pathway in juvenile rats. Moreover, with the oxidative stress inhibitor N-acetyl-cysteine and eIF2α dephosphorylation blocker Salubrinal treatment, ovarian damage induced by PS-MPs was repaired and associated enzyme activities were improved. Overall, our results indicated that PS-MPs exposure induced ovarian injury associated with oxidative stress and activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in juvenile rats, providing new prospects for assessing the health risks of children exposed to microplastics.

Zinc Oxide Particles Can Cause Ovarian Toxicity by Oxidative Stress in Female Mice Model.

Introduction: Zinc oxide nanoparticles (ZnO NPs) participate in all aspects of our lives, but with their wide application, more and more disadvantages are exposed. The goal of this study was to investigate the toxicity of ZnO NPs in female mice ovaries and explore its potential mechanism. Methods: In this study, adult female mice were orally exposed to 0, 100, 200, and 400 mg/kg ZnO NPs for 7 days. We explored the underlying mechanisms via the intraperitoneal injection of N-acetyl-cysteine (NAC), an inhibitor of oxidative stress, and salubrinal (Sal), an inhibitor of endoplasmic reticulum (ER) stress. Results: The results indicated that serum estradiol and progesterone levels declined greatly with increasing ZnO NPs dosage. Hematoxylin and eosin (HE) staining revealed increased atretic follicles and exfoliated follicular granulosa cells. Moreover, at the transcriptional level, antioxidant-related genes such as Keap1 and Nrf2, and ER stress-related genes PERK, eIF2α, and ATF4 were markedly upregulated. In addition, the expression of Caspase12, Caspase9, and Caspase3, which are genes related to apoptosis, was also upregulated in all ZnO NPs treatment groups. Serum malondialdehyde (MDA) content was remarkably up-regulated, whereas superoxide dismutase (SOD) activity was down-regulated. The 400 mg/kg ZnO NPs treatment group suffered the most substantial harm. However, ovarian damage was repaired when NAC and Sal were added to this group. Conclusion: ZnO NPs had toxic effects on the ovary of female mice, which were due to oxidative stress, ER stress, and the eventual activation of apoptosis.

Co-exposure to polystyrene microplastics and lead aggravated ovarian toxicity in female mice via the PERK/eIF2α signaling pathway.

Generally, individual microplastics (MPs) or lead (Pb) exposure could initiate ovarian toxicity. However, their combined effects on the ovary and its mechanism in mammals remained unclear. Female C57BL/6 mice were used in this study to investigate the combined ovarian toxicity of polystyrene MPs (PS-MPs, 0.1 mg/d/mouse) and Pb (1 g/L) for 28 days. Results showed that co-exposure to PS-MPs and Pb increased the accumulation of Pb in ovaries, the histopathological damage in ovaries and uterus, the serum malondialdehyde levels and decreased serum superoxide dismutase and sex hormone levels significantly when compared with single PS-MPs and Pb exposure. These observations indicated that co-exposure exerted more severe toxicity to mouse ovaries and uterus. Furthermore, co-exposure to PS-MPs and Pb caused endoplasmic reticulum (ER) stress by activating the PERK/eIF2α signaling pathway in the ovary, which resulted in apoptosis. However, the oxidative and ovarian damage were alleviated, and the mRNA levels of genes related to the PERK/eIF2α signaling pathway were down-regulated to levels of the control mice in the PS-MPs and Pb co-exposed mice administered with ER stress inhibitor (Salubrinal, Sal) or the antioxidant (N-acetyl-cysteine, NAC). In conclusion, our findings suggested that the combination of PS-MPs and Pb aggravated ovarian toxicity in mice by inducing oxidative stress and activating the PERK/eIF2α signaling pathway, thereby providing a basis for future studies into the combined toxic mechanism of PS-MPs and Pb in mammals.

Targeting RPL23 restores chemosensitivity of cisplatin-resistant ovarian carcinoma by inhibiting EMT.

Chemoresistance is the inevitable outcome of chemotherapy for epithelial ovarian carcinoma (EOC), and its mechanism is still not fully understood. This study explored the role of ribosomal protein L23 (RPL23) in cisplatin resistance of EOC. WGCNA based on TCGA and GEO was used to screen and analyze target genes related to EOC chemotherapy sensitivity. Clinical samples of cisplatin resistance were collected to detect the expression of target genes. Cisplatin resistance was induced in EOC cell lines A2780 and SKOV3. The cell abilities of invasion, migration and adhesion were observed. Western blotting was used to detect protein expressions. Bioinformatics analysis showed that RPL23 may be related to EOC chemotherapy sensitivity, and was highly expressed in clinical samples and cell lines of cisplatin-resistant. After A2780 and SKOV3 were resistant to cisplatin, the inhibitory abilities of therapeutic dose of cisplatin on their invasion, migration and adhesion were significantly attenuated, and N-cadherin and vimentin were significantly up-regulated while E-cadherin was significantly down-regulated. However, above phenomena were significantly reversed after RPL23 knockdown. Taken together, the overexpressed RPL23 may lead to platinum resistance by inducing epithelial-mesenchymal transition (EMT) in EOC. Targeting knockdown RPL23 would restore the sensitivity of EOC cells to cisplatin by inhibiting EMT, suggesting that RPL23 is a potential therapeutic target for EOC after platinum resistance.

Abnormal spindle-like microcephaly-associated protein promotes proliferation by regulating cell cycle in epithelial ovarian cancer.

Background: Epithelial ovarian cancer (EOC) ranks first for female gynecological tumor-related deaths. Due to the limited efficacy of traditional chemotherapy strategies, potential therapeutic targets are urgently needed. Previous studies have reported a relationship between abnormal spindle-like microcephaly-associated protein (ASPM) and ovarian cancer based on immunohistochemistry (IHC) and bioinformatics analysis. However, the potential role of ASPM in the proliferation of ovarian cancer cells and its molecular mechanism remain to be elucidated. Therefore, we aimed to further investigate the potential role of ASPM and its underlying mechanism in EOC using integrated online databases, clinical samples, and cell models. Methods: We used online databases (Gene Expression Profiling Interactive Analysis, Cbioportal and Kaplan-Meier Plotter) to analyze differential ASPM expression in ovarian carcinoma and explore its prognostic value in ovarian cancer (OvCa) patients. Immunohistochemistry staining based on a clinical tissue microarray (TMA) comprised 75 cases of EOC tissue and 5 cases of adjacent normal ovary tissue was used to detect the ASPM expression and analyze the relationship between ASPM expression and EOC characteristics. Various cell function experiments related to tumorigenesis were performed including the CCK8 assay, 5-ethynyl-2'-deoxyuridine (EdU), colony formation assay and Transwell assay in EOC cell models (A2780 and OVCAR3) with knocked down ASPM by small interfering RNA (siRNA) to observe its role. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was conducted to determine the signaling pathways in which ASPM was involved in the pathogenesis of ovarian cancer. Analysis of cell cycle distribution using flow cytometry was further performed to verify the pathways. Results: The expression profile based on data from The Cancer Genome Atlas (TCGA) database confirmed ASPM expression in EOC was higher compared with normal tissue, and further analysis suggested that higher expression was correlated with worse patient prognosis. Immunohistochemical analysis further indicated that ASPM was highly expressed in OvCa tissues and associated with a higher pathological stage, grade, and positive lymphatic metastasis. Cell models with knocked down ASPM by small interfering RNA (siRNA) significantly inhibited proliferation and migration. KEGG pathway enrichment and cell cycle analysis showed that ASPM silencing could inhibit ovarian cancer cell proliferation via synthesis (S) phase arrest. Conclusions: Our study confirmed that ASPM promoted proliferation and caused S phase arrest in EOC cells. ASPM may become a potential molecular marker for early screening and a valuable therapeutic target in EOC. Keywords: Abnormal spindle-like microcephaly-associated protein (ASPM); epithelial ovarian cancer (EOC); prognosis; proliferation.

Polystyrene microplastics induced nephrotoxicity associated with oxidative stress, inflammation, and endoplasmic reticulum stress in juvenile rats.

Introduction: Unintended intake of microplastic particles has been demonstrated to exert adverse health effects, however, studies on relevant nephrotoxicity in juvenile mammals are lacking. Methods: Therefore, we investigated the potential nephrotoxicity of oral-exposed polystyrene microplastics (PSMPs) (1,000 nm, 2.0 mg/kg/d) for 28 days in juvenile rats. Levels of oxidative stress, inflammation, and endoplasmic reticulum (ER) stress in kidneys were analyzed. Results and discussion: Results revealed that PSMPs noticeably decreased the growth rate of bodyweight, and organ index of the kidney, cardiac, and ovary. The intestinal injury caused by PSMPs exposure was also observed, which was distinctly alleviated with N-acetyl-cysteine (NAC) and Salubrinal (Sal) treatment compared with the single PSMPs group. PSMPs caused histological lesions of the kidney via disrupting the serum blood urea nitrogen (BUN), creatinine (CRE), and pro-inflammatory mediators IL-1ß, IL-6, and TNF-α. Furthermore, PSMPs exposure induced ER stress and inflammation presumably potentially mediated by oxidative stress in kidneys of rats. Eventually, PSMPs also promoted renal cells apoptosis, manifested as an obvious increase in the number of positive cells for the dUTP nick end labeling of Terminal deoxynucleotidyl transferase, which also can be confirmed by the elevated expression of genes associated with apoptosis Bcl-2, Bax, Caspase-12, Caspase-9, Caspase-3, and IHC score of Caspase-12 in the PSMPs group. Supplementation of NAC and Sal not only ameliorated the PSMPs-induced oxidative stress and ER stress but also the inflammation and apoptosis in the kidney. Collectively, this study suggested that PSMPs caused nephrotoxicity in juvenile rats potentially through oxidative damage and ER stress, which call for greater efforts to be taken on regulating the PSMPs ingestion in children.

TiO2 NPs induce the reproductive toxicity in mice with gestational diabetes mellitus through the effects on the endoplasmic reticulum stress signaling pathway.

The effect of one of the most widely studied nanomaterials at present, TiO2 nanoparticles (NPs), on pregnancy-related diseases is not clear. In this study, the adverse effects of TiO2 NPs on mice with gestational diabetes mellitus (GDM) and their possible mechanism were investigated. GDM mice were orally administered 0, 10, 50 and 250 mg/kg TiO2 NPs for 14 days. GDM reduced the weight of pregnant mice, destroyed the placental structure and caused abnormal fetal development. After exposure to increasing doses of TiO2 NPs, blood glucose levels increased significantly and body weight further decreased in GDM mice. The accumulation of the Ti content was detected in the placenta and fetus, which may further damage the placental structure in GDM mice, thereby exacerbating abnormal fetal development. In addition, the MDA and SOD activities were obviously increased, and the expression of genes associated with endoplasmic reticulum stress (ERS) (PERK, eIF2α, AFT4, IRE1α, and XBP1s) and apoptosis (CHOP, JNK, Bax/Bcl-2, Caspase-12, Caspase-9, and Caspase-3) were also obviously increased in the placenta, which reflected the possible activation of apoptosis. It could be speculated that the reproductive toxicity of TiO2 NPs in GDM mice triggered oxidative stress that subsequently activated ERS pathways to induce cell apoptosis.

Cysteine-Rich Intestinal Protein 1 Served as an Epithelial Ovarian Cancer Marker via Promoting Wnt/ß-Catenin-Mediated EMT and Tumour Metastasis.

OBJECTIVE: To explore the expression, functions, and the possible mechanisms of cysteine-rich intestinal protein 1 (CRIP1) in epithelial ovarian cancer. METHODS: Using open microarray datasets from The Cancer Genome Atlas (TCGA), we identified the tumorigenic genes in ovarian cancer. Then, we detected CRIP1 expression in 26 pairs of epithelial ovarian cancer tissue samples by immunohistochemistry (IHC) and performed a correlation analysis between CRIP1 and the clinicopathological features. In addition, epithelial ovarian cancer cell lines A2780 and OVCAR3 were used to examine CRIP1 expression by western blot and qRT-PCR. Various cell function experiments related to tumorigenesis were performed including the CCK8 assay, EdU, Annexin V-FITC/PI apoptosis assay, wound healing, and Transwell assay. In addition, the expression of epithelial-mesenchymal transition (EMT) markers was detected by western blot to illustrate the relationship between CRIP1 and EMT. Furthermore, KEGG pathway enrichment analysis and western blot were conducted to reveal the signaling pathways in which CRIP1 is involved in ovarian cancer pathogenesis. RESULTS: CRIP1 was identified as an oncogene from the TCGA database. The IHC score demonstrated that the CRIP1 protein was expressed at a higher level in tumours than in tumour-adjacent tissues and was associated with a higher pathological stage, grade, and positive lymphatic metastasis. In cell models, CRIP1 was overexpressed in serous epithelial ovarian cancer. Cell function experiments showed that the knockdown of CRIP1 did not significantly affect cell proliferation or apoptosis but could exert an inhibitory effect on cell migration and invasion, and also induce changes in EMT markers. Furthermore, KEGG pathway enrichment analysis and western blot showed that CRIP1 could induce ovarian cancer cell metastasis through activation of the Wnt/ß-catenin pathway. CONCLUSION: This study is the first to demonstrate that CRIP1 acts as an oncogene and may promote tumour metastasis by regulating the EMT-related Wnt/ß-catenin signaling pathway, suggesting that CRIP1 may be an important biomarker for ovarian cancer metastasis and progression.

MiR-200b is upregulated in plasma-derived exosomes and functions as an oncogene by promoting macrophage M2 polarization in ovarian cancer.

BACKGROUND: Ovarian cancer is the seventh most common cancer in women and the second most reason of gynecologic cancer-related death. Growing evidence showed that exosomal miRNA plays a crucial role in the progression of ovarian cancer. METHODS: Exosomes were identified using nanoparticle tracking analysis, transmission electron microscopy and marker proteins detection. The levels of mRNA and proteins were ensured by qRT-PCR and western blot, respectively. Immunofluorescence, flow cytometry and ELISA assay were carried out to analyze macrophages polarization. CCK-8 and Transwell assay were used to measure the cell viability and invasion of ovarian cancer cells. The interaction of miR-200b and Kruppel like factor 6 (KLF6) was ensured by using luciferase reporter assay. RESULTS: Here, we obtained plasma-derived exosomes successfully, and proved that miR-200b was increased in the exosomes of ovarian cancer patients. Subsequently, our data showed that increasing of miR-200b could promote macrophage M2 polarization, but inhibit M1 polarization. miR-200b-overexpressed macrophages-conditioned medium notably enhanced the cell viability and invasion of ovarian cancer cells. Moreover, increasing of miR-200b inhibited KLF6 expression, while decreasing of miR-200b promoted KLF6 expression. Overexpression of KLF6 recused miR-200b-induced macrophage polarization toward M2, and the inhibitory effect of miR-200b on M1 polarization. CONCLUSIONS: Overall, our results demonstrated that miR-200b was highly expressed in the plasma-derived exosome of ovarian cancer patients, and promoted the proliferation and invasion of ovarian cancer cells through inducing macrophage M2 polarization by suppressing KLF6 expression. Our results suggested that miR-200b might be a novel target for ovarian cancer treatment.

Overexpression of MYBL2 predicts poor prognosis and promotes oncogenesis in endometrial carcinoma.

Endometrial cancer (EC) is the most common gynecologic malignancy and still remains clinically challenging. We aimed to explore the potential biomarkers of EC and provide a theoretical basis for early screening and targeted therapy. The available transcriptome data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to identify differentially expressed genes. Immunohistochemistry was performed to detect gene expression. We analyzed the associations of MYBL2 with clinicopathological features and survival time and the biological effect of MYBL2 on the proliferation of EC cells. The effect of MYBL2 silencing on the transcriptome of EC cell model was analyzed by RNA-Seq. MYBL2 was significantly upregulated with obvious copy number alteration (CNA) in EC. Copy number amplification significantly increased MYBL2 mRNA expression, which led to a poor prognosis and severe pathological types of EC. Additionally, MYBL2 silencing significantly inhibited proliferation and induced apoptosis and G1-phase cell cycle arrest in EC cell lines. Our results indicate that MYBL2 is closely related to the cell cycle and apoptosis pathways in EC. The findings in this study provide evidence that MYBL2 can serve as a new candidate prognostic marker and a target for future therapeutic intervention in EC.