Exposure to Airborne PM2.5 Water-Soluble Inorganic Ions Induces a Wide Array of Reproductive Toxicity.

Water-soluble inorganic ions (WSIIs, primarily NH4+, SO42-, and NO3-) are major components in ambient PM2.5, but their reproductive toxicity remains largely unknown. An animal study was conducted where parental mice were exposed to PM2.5 WSIIs or clean air during preconception and the gestational period. After delivery, all maternal and offspring mice lived in a clean air environment. We assessed reproductive organs, gestation outcome, birth weight, and growth trajectory of the offspring mice. In parallel, we collected birth weight and placenta transcriptome data from 150 mother-infant pairs from the Rhode Island Child Health Study. We found that PM2.5 WSIIs induced a broad range of adverse reproductive outcomes in mice. PM2.5 NH4+, SO42-, and NO3- exposure reduced ovary weight by 24.22% (p = 0.005), 14.45% (p = 0.048), and 16.64% (p = 0.022) relative to the clean air controls. PM2.5 SO42- exposure reduced the weight of testicle by 5.24% (p = 0.025); further, mice in the PM2.5 SO42- exposure group had 1.81 (p = 0.027) fewer offspring than the control group. PM2.5 NH4+, SO42-, and NO3- exposure all led to lower birth than controls. In mice, 557 placenta genes were perturbed by exposure. Integrative analysis of mouse and human data suggested hypoxia response in placenta as an etiological mechanism underlying PM2.5 WSII exposure's reproductive toxicity.

LINC00869 Promotes Hepatocellular Carcinoma Metastasis via Protrusion Formation.

Coordination of filament assembly and membrane remodeling is required for the directional migration of cancer cells. The Wiskott-Aldrich syndrome protein (WASP) recruits the actin-related protein (ARP) 2/3 complex to assemble branched actin networks. The goal of our study was to assess the potential regulatory role exerted by the novel long noncoding RNA (lncRNA) LINC00869 on hepatocellular carcinoma (HCC) cells. We used HCC cells to overexpress or knockdown LINC00869, analyzed patient data from publicly available databases and Cancer Hospital Affiliated with Zhengzhou University, and used a xenograft mouse model of HCC to study the molecular mechanism associated with LINC00869 expression. We found that high levels of LINC00869 expression were associated with poor prognosis in patients with HCC. Next, we detected an interaction between LINC00869 and both WASP and ARP2 in HCC cells, and observed a modulatory effect of LINC00869 on the phosphorylation of WASP at Y291 and the activity of cell division control protein 42 (CDC42). These modulatory roles were required for WASP/CDC42 activity on F-actin polymerization to enhance membrane protrusion formation and maintain persistent cell polarization. This, in turn, promoted the migration and invasion abilities of HCC cells. Finally, we confirmed the role of LINC00869in vivo, using the tumor xenograft mouse model; and identified a positive correlation between LINC00869 expression levels and the phosphorylation levels of WASP in HCC samples. Overall, our findings suggest a unique mechanism by which LINC00869 orchestrates membrane protrusion during migration and invasion of HCC cells. IMPLICATIONS: LncRNA LINC00869 regulates the activity of CDC42-WASP pathway and positively affects protrusion formation in HCC cells, which expands the current understanding of lncRNA functions as well as gives a better understanding of carcinogenesis.

Profiling Microbiota from Multiple Sites in the Respiratory Tract to Identify a Biomarker for PM2.5 Nitrate Exposure-Induced Pulmonary Damages.

The microbiota present in the respiratory tract (RT) responds to environmental stimuli and engages in a continuous interaction with the host immune system to maintain homeostasis. A total of 40 C57BL/6 mice were divided into four groups and exposed to varying concentrations of PM2.5 nitrate aerosol and clean air. After 10 weeks of exposure, assessments were conducted on the lung and airway microbiome, lung functions, and pulmonary inflammation. Additionally, we analyzed data from both mouse and human respiratory tract (RT) microbiomes to identify possible biomarkers for PM2.5 exposure-induced pulmonary damages. On average, 1.5 and 13.5% inter-individual microbiome variations in the lung and airway were explained by exposure, respectively. In the airway, among the 60 bacterial OTUs (operational taxonomic units) > 0.05% proportion, 40 OTUs were significantly affected by PM2.5 exposure (FDR ≤ 10%). Further, the airway microbiome was associated with peak expiratory flow (PEF) (p = 0.003), pulmonary neutrophil counts (p = 0.01), and alveolar 8-OHdG oxidative lesions (p = 0.0078). The Clostridiales order bacteria showed the strongest signals. For example, the o_Clostridiales;f_;g_ OTU was elevated by PM2.5 nitrate exposure (p = 4.98 × 10-5) and negatively correlated with PEF (r = -0.585 and p = 2.4 × 10-4). It was also associated with the higher pulmonary neutrophil count (p = 8.47 × 10-5) and oxidative lesion (p = 7.17 × 10-3). In human data, we confirmed the association of airway Clostridiales order bacteria with PM2.5 exposure and lung function. For the first time, this study characterizes the impact of PM2.5 exposure on the microbiome of multiple sites in the respiratory tract (RT) and its relevance to airflow obstructive diseases. By analyzing data from both humans and mice, we have identified bacteria belonging to the Clostridiales order as a promising biomarker for PM2.5 exposure-induced decline in pulmonary function and inflammation.

Adipose-derived stem cells promote the repair of chemotherapy-induced premature ovarian failure by inhibiting granulosa cells apoptosis and senescence.

BACKGROUND: Chemotherapeutic drugs, particularly alkylating cytotoxics such as cyclophosphamide (CTX), play an important role to induce premature ovarian failure (POF). Hormone replacement therapy (HRT) is a widely used treatment to improve hormone secretion. However, the long-term HRT increases the risk of breast cancer and cardiovascular disease are attracting concerns. Therefore, there is an urgent need to develop a safe and effective treatment for POF. METHOD: Adipose-derived stem cells (ADSCs) were isolated and identified from human adipose tissue. For POF modeling, CTX were intraperitoneal injected into CTX-acute group, CTX-chronic group, CTX-acute + ADSCs group and CTX-chronic + ADSCs group rats; For transplantation, ADSCs were transplanted into POF rats through tail-vein. The control group rats were injected with PBS. The effects of POF modeling and transplantation were determined by estrous cycle analysis, histopathological analysis, immunohistochemical staining and apoptosis-related marker. To evaluate the effects of ADSC on granulosa cells in vitro, CTX-induced senescent KGN cells were co-cultured with ADSCs, and senescent-related marker expression was investigated by immunofluorescent staining. RESULTS: In vivo studies revealed that ADSCs transplantation reduced the apoptosis of ovarian granulosa cells and secretion of follicle-stimulating hormone. The number of total follicles, primordial follicles, primary follicles, and mature follicles and secretion of anti-Müllerian hormone and estradiol (E2) were also increased by ADSCs. The estrous cycle was also improved by ADSC transplantation. Histopathological analysis showed that CTX-damaged ovarian microenvironment was improved by ADSCs. Furthermore, TUNEL staining indicated that apoptosis of granulosa cells was decreased by ADSCs. In vitro assay also demonstrated that ADSC markedly attenuated CTX-induced senescence and apoptosis of granulosa cell. Mechanistically, both in vivo and in vitro experiments proved that ADSC transplantation suppressed activation of the PI3K/Akt/mTOR axis. CONCLUSION: Our experiment demonstrated that a single injection of high-dose CTX was a less damaging chemotherapeutic strategy than continuous injection of low-dose CTX, and tail-vein injection of ADSCs was a potential approach to promote the restoration of CTX-induced POF.

Effects of a Dulaglutide plus Calorie-Restricted Diet versus a Calorie-Restricted Diet on Visceral Fat and Metabolic Profiles in Women with Polycystic Ovary Syndrome: A Randomized Controlled Trial.

The effects of dulaglutide and a calorie-restricted diet (CRD) on visceral adipose tissue (VAT) and metabolic profiles in polycystic ovary syndrome (PCOS) have not been extensively investigated. In this study, we investigated whether dulaglutide combined with CRD could further reduce VAT and promote clinical benefits as compared with a CRD regimen alone in overweight or obese PCOS-affected women. Between May 2021 and May 2022, this single-center, randomized, controlled, open-label clinical trial was conducted. Overall, 243 participants with PCOS were screened, of which 68 overweight or obese individuals were randomly randomized to undergo dulaglutide combined with CRD treatment (n = 35) or CRD treatment alone (n = 33). The duration of intervention was set as the time taken to achieve a 7% weight loss goal from baseline body weight, which was restricted to 6 months. The primary endpoint was the difference in the change in VAT area reduction between the groups. The secondary endpoints contained changes in menstrual frequency, metabolic profiles, hormonal parameters, liver fat, and body composition. As compared with the CRD group, the dulaglutide + CRD group had a considerably shorter median time to achieve 7% weight loss. There was no significant between-group difference in area change of VAT reduction (-0.97 cm2, 95% confidence interval from -14.36 to 12.42, p = 0.884). As compared with CRD alone, dulaglutide + CRD had significant advantages in reducing glycated hemoglobin A1c and postprandial plasma glucose levels. The results of the analyses showed different changes in menstruation frequency, additional metabolic profiles, hormonal markers, liver fat, and body composition between the two groups did not differ significantly. Nausea, vomiting, constipation, and loss of appetite were the main adverse events of dulaglutide. These results emphasize the value of dietary intervention as the first line of treatment for PCOS-affected women, while glucagon-like peptide 1 receptor agonist therapy provides an efficient and typically well tolerated adjuvant therapy to aid in reaching weight targets based on dietary therapy in the population of overweight/obese PCOS-affected women.

LINC02870 facilitates SNAIL translation to promote hepatocellular carcinoma progression.

Exploring the roles of long noncoding RNAs (lncRNAs) in tumorigenesis and metastasis could contribute to the recognition of novel diagnostic and therapeutic targets. LINC02870 is a novel lncRNA, whose role in tumors has not been reported. Herein, we focused on the function and mechanism of LINC02870 in human hepatocellular carcinoma (HCC). We first carried out a pan-cancer study of LINC02870 expression and its relationship to prognosis, and LINC02870 was determined to be a possible oncogene in HCC. Upregulated expressions of LINC02870 were also found in our HCC samples compared to the para-tumor samples. Moreover, overexpression of LINC02870 promoted the growth, migration, and invasion of HCC cells. Subsequently, binding proteins of LINC02870 were identified by a number of in silico analyses, including correlation analysis, signaling network analysis, and survival analysis. Intriguingly, the most promising binding protein of LINC02870 was predicted and confirmed to be eukaryotic translation initiation factor 4 gamma 1 (EIF4G1), an important component of the eukaryotic translation initiation factor 4F complex that initiates cap-dependent translation. Further investigation showed that LINC02870 increased the translation of SNAIL to induce malignant phenotypes in HCC cells. Additionally, HCC patients with higher expression levels of LINC02870 and EIF4G1 had shorter survival times than those with lower expression levels. Thus, our findings suggested that LINC02870 induced SNAIL translation and correlated with poor prognosis and tumor progression in HCC.

Within- and cross-tissue gene regulations were disrupted by PM2.5 nitrate exposure and associated with respiratory functions.

BACKGROUND: Pathogenesis of complex diseases often involves multiple organs/tissue-types. To date, the PM2.5 exposure's toxic effects and induced disease risks were not studied at multi-tissue level. METHODS: C57BL/6 mice (n = 40) were exposed to PM2.5 NO3- and clean air, respectively, and afterwards assessed respiratory functions and transcriptome in relevant tissues: blood and lung. We constructed within- and cross-tissue gene regulation networks and identified network modules associated with exposure and respiratory functions. RESULTS: PM2.5 NO3- exposure elevated naïve B cells proportion in blood (p = 0.0028). Among the 6000 highest expressed genes in blood, 18.8 % (1133 genes) were altered by exposure at p ≤ 0.05 level, among which 763 genes were also associated with respiratory function (enrichment folds = 7.63, p = 2.7E-189). The exposure disrupted blood genes were primarily in the immunoregulation pathways. Both within- and cross-tissue gene network modules were perturbed by exposure and associated with respiratory function. An immunodeficiency related cross-tissue module of 555 genes was affected by exposure (p = 0.0023) and strongly correlated with FEV0.05/FVC (r = 0.61 and p = 3E-5). CONCLUSIONS: This study aims to fill in a major knowledge gap and investigated the effect of PM2.5 exposure simultaneously in multiple tissues. We provided novel evidence that PM2.5 NO3- exposure profoundly perturbed within- and cross-tissue gene regulations, and highlighted their roles in the etiology of respiratory decline.

Efficacy of canagliflozin versus metformin in women with polycystic ovary syndrome: A randomized, open-label, noninferiority trial.

OBJECTIVES: To determine the safety and efficacy of canagliflozin in comparison to metformin in polycystic ovary syndrome (PCOS) patients with insulin resistance (IR). METHODS: A single-centre, prospective, randomized open-label (ratio 1:1) noninferiority trial was conducted at the Department of Endocrinology, Shanghai Tenth People's Hospital, between July 2019 and April 2021. Women aged 18 to 45 years with PCOS and IR were enrolled and randomly assigned to either 100 mg (n = 33) canagliflozin daily or 1500 to 2000 mg metformin daily (n = 35) for 12 weeks. The primary outcome was changes in homeostatic model assessment (HOMA)-IR after 12 weeks of treatment. The secondary outcomes included changes in anthropometric measurements, menstrual frequency, sex hormone levels, metabolic variables and body fat distribution. RESULTS: For lowering of HOMA-IR after 12 weeks of treatment, canagliflozin was found to be noninferior to metformin (least-squares mean difference -0.81% [95% confidence interval -2.13 to 0.51]). Both canagliflozin and metformin significantly improved menstrual pattern, reduced body weight and total fat mass, and decreased triglyceride levels. Compared with metformin, canagliflozin had significant advantages in reducing uric acid and dehydroepiandrosterone sulphate levels. Pruritus vulvae (9.09%) and gastrointestinal reaction (55.55%) were the main adverse events in the metformin group and canagliflozin group, respectively. CONCLUSION: This study demonstrates that canagliflozin was not inferior to metformin in PCOS patients with IR, which suggests that sodium-glucose cotransporter-2 inhibitors should be considered as effective drugs in the treatment of PCOS patients with IR.

Identification of the Ferroptosis-Associated Gene Signature to Predict the Prognostic Status of Endometrial Carcinoma Patients.

Endometrial carcinoma (EC) is one of the most common gynecological carcinomas. As previously described, ferroptosis was reported to exhibit a significant association with the development of malignant neoplasms. Nevertheless, there are few studies towards the association between the implication of ferroptosis-related genes (FRGs) and the prognostic status of patients with EC. Our study demonstrated that ferroptosis-related genes were evidently differently expressed in EC. Further analysis showed that SLC7A11, SAT1, CDKN1A, and TP5MC3 expression was linked to the low stage, grade of pTNM, and longer survival time. Bioinformatics analysis demonstrated that these ferroptosis-related regulators played a crucial role in EC by modulating multiple biological processes, such as cell cycle, citrate cycle (TCA cycle), metabolism-related pathways, ERK activation, p53 signaling pathway, cellular senescence, TAp63 pathway, and Notch signaling pathway. Of note, our results showed that ATP5MC3, CDKN1A, and SLC7A11 expression was dramatically positively related with the tumor mutational burden (TMB) score in EC. However, we did not observe a significant correlation between SAT1 and the TMB score in EC. These findings for the first time demonstrated that ferroptosis was displayed crucially in EC progression. We speculated that our findings offered novel targets and strategies for personalized treatment.

The high platelet counts as predictor for early foetal demise.

Objectives: Early fetal demise (absence of cardiac activity in a visible fetus) is a very common event, but there are no reliable biomarkers to predict it. The purpose of the study was to assess the association of platelet parameters with early fetal demise.Methods: In this case-control study, we included women with normal deliveries or those ultrasound diagnosed as early fetal demise. For those who were identified with early fetal demise, the platelet parameters were analyzed before the ultrasound diagnosis, which is based on the absence of either an embryo within a gestational sac or cardiac activity in a visible embryo in the 5-10 weeks of gestation. The association between the risk of early fetal demise with the women's mean platelet volume (MPV) and platelet counts was calculated by logistic regression. Duplicate measurements of platelet aggregation were performed with VerifyNow. Results: In total, 99 women identified with early fetal demise and 170 women who had an uncomplicated pregnancy with normal delivery from January 2017 and August 2020 were included in the study. We found that platelet counts in the early fetal demise group were significantly higher than healthy pregnancies. In addition, platelet reactivity is higher in the normal delivery group than those in early fetal demise group (p < .05). High levels of platelet counts resulted in an adjusted odds ratio (OR) of 2.075 (95% confidence interval [95% CI], 1.215-3.544; p = .008) for early fetal demise. Conclusions: Increased platelet counts in the first trimester may be a predictor for the risk of early fetal demise.

ADSC Exosomes Mediate lncRNA-MIAT Alleviation of Endometrial Fibrosis by Regulating miR-150-5p.

BACKGROUND: Secondary infertility remains a major complication of endometrial fibrosis in women. The use of exosomes from adipose-derived mesenchymal stem cells (ADSCs) has shown promising results for the treatment of endometrial fibrosis. However, the mechanisms of action of ADSC-exosome (ADSC-Exo) therapy remain unclear. MATERIALS AND METHODS: An endometrial fibrosis model was established in mice treated with alcohol and endometrial epithelial cells (ESCs) treated with TGF-ß1. ADSCs were isolated from Sprague Dawley (SD) rats, and exosomes were isolated from ADSCs using ExoQuick reagent. Exosomes were identified by transmission electron microscopy (TEM), NanoSight, and Western blot analysis. The expression level of lncRNA-MIAT was detected by qPCR analysis. Western blot analysis was carried out to determine the protein levels of fibrosis markers (TGFßR1, α-SMA, and CK19). A dual-luciferase reporter gene assay was used to verify the relationship between target genes. The endometrial tissues of the endometrial fibrosis model were stained with HE and Masson's trichrome. RESULTS: ADSCs and ADSC-Exos were successfully isolated, and the expression level of lncRNA-MIAT was significantly down-regulated in endometrial tissue and the TGF-ß1-induced ESC injury model, whereas ADSC-Exos increased the expression of lncRNA-MIAT in the TGF-ß1-induced ESC model. Functionally, ADSC-Exo treatment repressed endometrial fibrosis in vivo and in vitro by decreasing the expression of hepatic fibrosis markers (α-SMA and TGFßR1) and increasing the expression of CK19. Moreover, miR-150-5p expression was repressed by lncRNA-MIAT in the TGF-ß1-induced ESC injury model. The miR-150-5p mimic promoted TGF-ß1-induced ESC fibrosis. CONCLUSION: ADSC-Exos mediate lncRNA-MIAT alleviation of endometrial fibrosis by regulating miR-150-5p, which suggests that lncRNA-MIAT from ADSC-Exos may be a viable treatment for endometrial fibrosis.

Correlation Between Serum Uric Acid and Body Fat Distribution in Patients With Polycystic Ovary Syndrome.

Objective: This study aims to investigate the correlation between serum uric acid levels and body fat distribution in patients with polycystic ovary syndrome (PCOS). Methods: Between May 2017 and March 2021, a total of 199 patients with PCOS were recruited from the Department of Endocrinology and Metabolism at the Shanghai Tenth People's Hospital. Anthropometric characteristics, metabolic parameters, and reproductive hormones were measured. Hyperuricemia was defined as serum uric acid (SUA) greater than 420 µmol/l. Dual-energy X-ray absorptiometry (DEXA) was used to measure body fat distribution. Results: The prevalence of hyperuricemia in patients with PCOS was 28.64%. PCOS patients with hyperuricemia are more obese and have a higher waist-to-hip ratio (WHR) and worse lipid metabolism than those without hyperuricemia. According to SUA quartiles, patients in the highest quartile had higher total testosterone (TT), body fat accumulation, and lower sex hormone-binding globulin (SHBG) than patients in the lowest quartile. SUA was correlated with percentage of total body fat, arm fat mass, leg fat mass, trunk fat mass, android/gynoid (A/G) ratio, and visceral adipose tissue (VAT) mass. After controlling possible confounders, logistic regression analysis found that only excessive VAT mass could significantly increase the risk of hyperuricemia in patients with PCOS. Conclusion: In patients with PCOS, a high level of VAT mass, but not other fat compartments, will exacerbate the risk of hyperuricemia. Attention should be paid to the role of excessive VAT in the occurrence and development of PCOS with hyperuricemia.

Tetracaine combined with propofol for painless oocyte retrieval: from a single center study.

BACKGROUND: In vitro fertilization-embryo transfer is a main assisted reproductive technique that can improve the success rate of conception. At present, the ultrasound-guided oocyte retrieval is often employed in clinics, but this process will cause pain and fear in outpatients. This study explored the safety and satisfaction of patients who received egg retrieval under vaginal topical tetracaine anesthesia combined with intravenous propofol anesthesia. METHODS: Patients who underwent elective egg retrieval in the Reproductive Center of Shanghai Tenth People's Hospital were recruited from January 2017 to August 2018 [tetracaine + propofol group (n=53); propofol group (n=48)]. RESULTS: Results showed that tetracaine combined with propofol anesthesia could effectively reduce the dose of propofol during surgery, ensure the quality of follicles, effectively reduce the postoperative pain and improve the operational satisfaction without affecting the prognosis. CONCLUSIONS: Our findings provide evidence for further clinical applications of this technique.

Prenatal exposure to ambient air multi-pollutants significantly impairs intrauterine fetal development trajectory.

BACKGROUND: Impaired in utero fetal growth trajectory may have long term health consequences of the newborns and increase risk of adulthood metabolic diseases. Prenatal exposure to air pollution has been linked to fetal development restriction; however, the impact of exposure to ambient air pollutants on the entire course of intrauterine fetal development has not been comprehensively investigated. METHODS: During 2015-2018, two cohorts of mother-infant dyads (N = 678 and 227) were recruited in Shanghai China, from which three categories of data were systematically collected: (1) daily exposure to six air pollutants during pregnancy, (2) fetal biometry in the 2nd (gestational week 24, [GW24]) and 3rd trimester (GW36), and (3) neonatal outcomes at birth. We investigated the impact of prenatal exposure to air pollutant mixture on the trajectory of fetal development during the course of gestation, adjusting for a broad set of potential confounds. RESULTS: Prenatal exposure to PM2.5, PM10, SO2 and O3 significantly reduced fetal biometry at GW24, where SO2 had the most potent effect. For every 10 µg/m3 increment increase of daily SO2 exposure during the 1st trimester shortened femur length by 2.20 mm (p = 6.7E-21) translating to 5.3% reduction from the average of the study cohort. Prenatal air pollution exposure also decreased fetal biometry at GW36 with attenuated effect size. Comparing to the lowest exposed quartile, fetus in the highest exposed quartile had 6.3% (p = 3.5E-5) and 2.1% (p = 2.4E-3) lower estimated intrauterine weight in GW24 and GW36, respectively; however, no difference in birth weight was observed, indicating a rapid catch-up growth in the 3rd trimester. CONCLUSIONS: To our knowledge, for the first time, we demonstrated the impact of prenatal exposure to ambient air pollutants on the course of intrauterine fetal development. The altered growth trajectory and rapid catch-up growth in associated with high prenatal exposure may lead to long-term predisposition for adulthood metabolic disorders.

p57Kip2 is a master regulator of human adipose derived stem cell quiescence and senescence.

Although human adipose derived stem cells (hADSCs) hold great promises for regenerative medicine, their key biological properties remain poorly understood. In particular, proliferation defects resulted from deep quiescence (dormancy) and senescence represent a major hurdle in hADSC production and clinical application. We have developed a model system for mechanistic dissection of hADSC quiescence and senescence. p57Kip2, a major CDK inhibitor, was highly expressed in quiescent and senescent hADSCs but its level quickly declined upon stem cell activation. p57Kip2 overexpression induced quiescence in spite of proliferative signals and its knockdown promoted cell cycle reentry even with induction of quiescence presumably through modulating the CDK2-CyclinE1 complex. Given its key role in quiescence and senescence, p57Kip2 may be exploited for innovative strategies to amplify hADSCs of high quality for clinics.

Adipose-derived stem cells transplantation improves endometrial injury repair.

Endometrial injury is an important cause of intrauterine adhesion (IUA), amenorrhea and infertility in women, with limited effective therapies. Recently, stem cells have been used in animal experiments to repair and improve injured endometrium. To date, our understanding of adipose-derived stem cells (ADSCs) in endometrial injury repair and their further therapeutic mechanisms is incomplete. Here, we examined the benefit of ADSCs in restoration of injured endometrium by applying a rat endometrial injury model. The results revealed by immunofluorescence showed that green fluorescent protein (GFP)-labelled ADSCs can differentiate into endometrial epithelial cells in vivo. At 30 days after ADSCs transplantation, injured endometrium was significantly improved, with increased microvessel density, endometrial thickness and glands when compared with the model group. Furthermore, the fertility of rats with injured endometrium in ADSCs group was improved and had a higher conception rate (60% vs 20%, P = 0.014) compared with the control phosphate-buffered saline (PBS) group. However, there was no difference in the control group compared with the sham group. In addition, expression levels of the oestrogen receptor Eα/ß (ERα, ERß) and progesterone receptor (PR) detected by western blot and enzyme-linked immunosorbent assay (ELISA) were higher in the ADSCs group than in the PBS group. Taken together, these results suggested that ADSC transplantation could improve endometrial injury as a novel therapy for IUA.

Integration of metabolomics and expression of enolase-phosphatase 1 links to hepatocellular carcinoma progression.

Reprogramming of cellular metabolism is one of the hallmarks for cancer, in which tumor cells rewire their metabolic fluxes to generate sufficient energy and biosynthetic intermediates. Therefore, elucidating the correlation between cellular metabolism and hepatocellular carcinoma (HCC) progression may provide insights into novel approaches to cancer therapy. Methods: We assembled an integrated pathway-level metabolic profiling by mining metabolomic, transcriptomic and proteomic data of three HCC cell lines with increasing metastatic potentials. Immunohistochemical staining was performed in a tissue microarray from 185 HCC clinical specimens. Kaplan-Meier survival and Cox regression analyses were applied to test the association between gene expression and survival outcome. In vitro assays were conducted to investigate the functional role of enolase-phosphatase 1 (ENOPH1) in HCC malignant behaviors. Reversed genetics analysis was performed to determine the function of ENOPH1 in HCC metastasis. An intrahepatic mouse model further confirmed the role of ENOPH1 in metastasis. Results: We have determined that HCC cell metastasis is associated with alterations in metabolite levels and expressions of metabolic enzymes in the cysteine/methionine metabolism pathway, and show that one of metabolic enzymes, enolase-phosphatase 1 (ENOPH1), is persistently upregulated with an increase in metastatic potential. The upregulation of ENOPH1 expression was observed as an independent prognostic factor for HCC patients. ENOPH1 overexpression promoted cell migration and invasion, whereas ENOPH1 downregulation inhibited cell migration and invasion. Furthermore, an enhanced phosphorylation of AKT with ENOPH1 upregulation was observed. ENOPH1-mediated malignant capacity in HCC cells can be rescued by an AKT inhibitor. Conclusion: Taken together, our findings illustrate that ENOPH1 promotes HCC progression and could serve as a novel biomarker and therapeutic target for HCC.

Ubiquitination and Long Non-coding RNAs Regulate Actin Cytoskeleton Regulators in Cancer Progression.

Actin filaments are a major component of the cytoskeleton in eukaryotic cells and play an important role in cancer metastasis. Dynamics and reorganization of actin filaments are regulated by numerous regulators, including Rho GTPases, PAKs (p21-activated kinases), ROCKs (Rho-associated coiled-coil containing kinases), LIMKs (LIM domain kinases), and SSH1 (slingshot family protein phosphate 1). Ubiquitination, as a ubiquitous post-transcriptional modification, deceases protein levels of actin cytoskeleton regulatory factors and thereby modulates the actin cytoskeleton. There is increasing evidence showing cytoskeleton regulation by long noncoding RNAs (lncRNAs) in cancer metastasis. However, which E3 ligases are activated for the ubiquitination of actin-cytoskeleton regulators involved in tumor metastasis remains to be fully elucidated. Moreover, it is not clear how lncRNAs influence the expression of actin cytoskeleton regulators. Here, we summarize physiological and pathological mechanisms of lncRNAs and ubiquitination control mediators of actin cytoskeleton regulators which that are involved in tumorigenesis and tumor progression. Finally, we briefly discuss crosstalk between ubiquitination and lncRNA control mediators of actin-cytoskeleton regulators in cancer.

microRNA-196a promotes osteogenic differentiation and inhibit adipogenic differentiation of adipose stem cells via regulating ß-catenin pathway.

microRNAs play important roles in proliferation and differentiation of stem cells, but mechanisms by which microRNAs regulate osteogenic or adipogenic differentiation of adipose stem cells (ASCs) are still poorly understood. In the present study, results showed up-regulation of microRNA-196a was able to promote the osteogenic differentiation of ACSs, but down-regulation of microRNA-196a induced adipogenic differentiation. Further investigation indicated microRNA-196a could regulate Wnt signaling pathway to affect osteogenic or adipogenic differentiation of ASCs, addition of Wnt agonist 1 was able to reverse the down-regulated osteogenic differentiation of ASCs caused by microRNA-196a deficiency and inhibition of Wnt signaling pathway with XAV939 promoted the adipogenic differentiation of ASCs. Taken together, microRNA-196a may regulate Wnt signaling pathway to promote the osteogenic differentiation and inhibit the adipogenic differentiation of ASCs.