Circ_0012152 Accelerates Acute Myeloid Leukemia Progression through the miR-652-3p/SOX4 Axis.

OBJECTIVE: Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by abnormal myeloid blast expansion. Recent studies have demonstrated that circular RNAs play a role in AML pathogenesis. In this study, we aimed to investigate the clinical significance of circ_0012152 in AML and elucidate its underlying molecular mechanism in the pathogenesis of this condition. METHODS: Circ_0012152 expression was detected by quantitative real-time polymerase chain reaction in samples obtained from 247 patients with AML and 40 healthy controls. A systematic analysis of clinical characteristics and prognostic factors was also conducted. Cell growth was assessed using the Cell Counting Kit-8 (CCK-8) assay, and apoptosis and cell cycle progression were evaluated by flow cytometry. Moreover, RNA pull-down was performed to identify target microRNAs, and transcriptome RNA sequencing and bioinformatics analyses were utilized to identify downstream mRNA targets. RESULTS: Circ_0012152 was significantly upregulated in samples from patients with AML and served as an independent adverse prognostic factor for overall survival (OS) (hazard ratio: 2.357; 95% confidence interval 1.258-4.415). The circ_0012152 knockdown reduced cell growth, increased apoptosis, and inhibited cell cycle progression in AML cell lines. RNA pull-down and sequencing identified miR-652-3p as a target microRNA of circ_0012152. Cell growth inhibition by circ_0012152 knockdown was significantly relieved by miR-652-3p inhibitors. We suggested that miR-652-3p targeted SOX4, as the decrease in SOX4 expression resulting from circ_0012152 knockdown was upregulated by miR-652-3p inhibitors in AML cells. CONCLUSION: Circ_0012152 is an independent poor prognostic factor for OS in AML, and it promotes AML cell growth by upregulating SOX4 through miR-652-3p.

Berberine alleviates inflammation in polycystic ovary syndrome by inhibiting hyaluronan synthase 2 expression.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous metabolic and endocrine disorder that causes anovulatory infertility and abnormal folliculogenesis in women of reproductive age. Several studies have revealed inflammation in PCOS follicles, and recent evidence suggests that Berberine (BBR) effectively reduces inflammatory responses in PCOS, however, the underlying mechanisms remain unclear. PURPOSE: To determine the underlying mechanisms by which BBR alleviates inflammation in PCOS. STUDY DESIGN: Primary human GCs from healthy women and women with PCOS, and KGN cells were used for in vitro studies. ICR mice were used for in vivo studies. METHODS: Gene expression was measured using RT-qPCR. HAS2, inflammatory cytokines, and serum hormones were assayed by ELISA. Protein expression profiles were assayed by Western blot. Chronic low-grade inflammatory mouse models were developed by intraperitoneal injection with LPS, and PCOS mouse models were established by subcutaneous intraperitoneal injection of DHEA. BBR and 4-MU were administered by gavage. Ovarian morphologic changes were evaluated using H&E staining. HAS2 expression in the ovary was assayed using Western blot and immunohistochemistry. RESULTS: Our results confirmed that HAS2 expression and hyaluronan (HA) accumulation are closely associated with inflammatory responses in PCOS. Data obtained from in vitro studies showed that HAS2 and inflammatory genes (e.g., MCP-1, IL-1ß, and IL-6) are significantly upregulated in PCOS samples and LPS-induced KGN cells compared to their control groups. In addition, these effects were reversed by blocking HAS2 expression or HA synthesis using BBR or 4-MU, respectively. Furthermore, HAS2 overexpression induces the expression of inflammatory genes in PCOS. These results were further confirmed in LPS- and DHEA-induced mouse models, where inflammatory genes were reduced by BBR or 4-MU, and ovarian morphology was restored. CONCLUSIONS: Our results define previously unknown links between HAS2 and chronic low-grade inflammation in the follicles of women with PCOS. BBR exerts its anti-inflammatory effects by down-regulating HAS2. This study provides a novel therapeutic target for alleviating ovarian inflammation in women with PCOS.

Mortality Risk and Burden From a Spectrum of Causes in Relation to Size-Fractionated Particulate Matters: Time Series Analysis.

BACKGROUND: There is limited evidence regarding the adverse impact of particulate matters (PMs) on multiple body systems from both epidemiological and mechanistic studies. The association between size-fractionated PMs and mortality risk, as well as the burden of a whole spectrum of causes of death, remains poorly characterized. OBJECTIVE: We aimed to examine the wide range of susceptible diseases affected by different sizes of PMs. We also assessed the association between PMs with an aerodynamic diameter less than 1 µm (PM1), 2.5 µm (PM2.5), and 10 µm (PM10) and deaths from 36 causes in Guangzhou, China. METHODS: Daily data were obtained on cause-specific mortality, PMs, and meteorology from 2014 to 2016. A time-stratified case-crossover approach was applied to estimate the risk and burden of cause-specific mortality attributable to PMs after adjusting for potential confounding variables, such as long-term trend and seasonality, relative humidity, temperature, air pressure, and public holidays. Stratification analyses were further conducted to explore the potential modification effects of season and demographic characteristics (eg, gender and age). We also assessed the reduction in mortality achieved by meeting the new air quality guidelines set by the World Health Organization (WHO). RESULTS: Positive and monotonic associations were generally observed between PMs and mortality. For every 10 µg/m3 increase in 4-day moving average concentrations of PM1, PM2.5, and PM10, the risk of all-cause mortality increased by 2.00% (95% CI 1.08%-2.92%), 1.54% (95% CI 0.93%-2.16%), and 1.38% (95% CI 0.95%-1.82%), respectively. Significant effects of size-fractionated PMs were observed for deaths attributed to nonaccidental causes, cardiovascular disease, respiratory disease, neoplasms, chronic rheumatic heart diseases, hypertensive diseases, cerebrovascular diseases, stroke, influenza, and pneumonia. If daily concentrations of PM1, PM2.5, and PM10 reached the WHO target levels of 10, 15, and 45 µg/m3, 7921 (95% empirical CI [eCI] 4454-11,206), 8303 (95% eCI 5063-11,248), and 8326 (95% eCI 5980-10690) deaths could be prevented, respectively. The effect estimates of PMs were relatively higher during hot months, among female individuals, and among those aged 85 years and older, although the differences between subgroups were not statistically significant. CONCLUSIONS: We observed positive and monotonical exposure-response curves between PMs and deaths from several diseases. The effect of PM1 was stronger on mortality than that of PM2.5 and PM10. A substantial number of premature deaths could be preventable by adhering to the WHO's new guidelines for PMs. Our findings highlight the importance of a size-based strategy in controlling PMs and managing their health impact.

Lipopolysaccharide accelerates tryptophan degradation in the ovary and the derivative kynurenine disturbs hormone biosynthesis and reproductive performance.

Lipopolysaccharide (LPS), also known as endotoxin, is a component of the outer membrane of gram-negative bacteria. LPS is released into the surrounding environment during bacterial death and lysis. Due to its chemical and thermal stability, LPS can be detected anywhere and easily exposed to humans and animals. Previous studies have shown that LPS causes hormonal imbalances, ovarian failure, and infertility in mammals. However, the potential mechanisms remain unclear. In this study, we investigated the effects and mechanisms of LPS on tryptophan degradation, both in vivo and in vitro. The effects of kynurenine, a tryptophan derivative, on granulosa cell function and reproductive performance were explored. Results showed that p38, NF-κB, and JNK signaling pathways were involved in LPS-induced Ido1 expressions and kynurenine accumulation. Furthermore, the kynurenine decreased estradiol production, but increased granulosa cell proliferation. In vivo, experiments showed that kynurenine decreased estradiol and FSH production and inhibited ovulation and corpus luteum formation. Additionally, pregnancy and offspring survival rates decreased considerably after kynurenine treatment. Our findings suggest that kynurenine accumulation disrupts hormone secretion, ovulation, corpus luteal formation, and reproductive performance in mammals.

TGF-ß1 suppresses de novo cholesterol biosynthesis in granulosa-lutein cells by down-regulating DHCR24 expression via the GSK-3ß/EZH2/H3K27me3 signaling pathway.

Cholesterol is a precursor to steroid hormones and can be obtained from serum LDL or de novo synthesis in steroidogenic cells. Before luteinizing hormone (LH) surge-induced ovulation, follicles remain avascular, and cholesterol required for progesterone production in granulosa cells (GCs) is derived from de novo biosynthesis. Previous studies have verified that the intrafollicular TGF-ß1 plays inhibitory roles in GCs luteinization, vascularization, and progesterone production. Nevertheless, the regulatory function of TGF-ß1 on de novo cholesterol synthesis in granulosa-lutein (GL) cells remains largely unknown. We aim to investigate this aspect in this study using in vivo cultured human GL cells. Our results suggested that TGF-ß1 significantly suppresses intracellular cholesterol levels and down-regulates the expression of the final step enzyme, DHCR24, that catalyzes de novo cholesterol synthesis. We used specific inhibitors and siRNA-mediated knockdown approaches demonstrate that TGF-ß1 suppression of DHCR24 expression in GL cells is mediated by the GSK-3ß/EZH2/H3K27me3 signaling pathway. Further ChIP assays revealed that elevated H3K27me3 levels in the promoter region of DHCR24 play a vital role in TGF-ß1-induced DHCR24 down-regulation, and RNA-sequencing results confirmed these findings. Notably, our study provides a novel insight into the molecular mechanisms by which TGF-ß1 suppresses de novo cholesterol biosynthesis in GL cells.

TGF-ß1 induces type I collagen deposition in granulosa cells via the AKT/GSK-3ß signaling pathway-mediated MMP1 down-regulation.

Type I collagen is the most abundant extracellular matrix (ECM) protein in the mammalian ovary, and comprises two COL1A1 subunits and one COL1A2 subunit. Matrix metalloproteinase 1 (MMP1) is a typical collagenase of type I collagen, that can be detected in ovarian follicles and early corpus luteum. Previous studies demonstrated that MMP1-mediated degradation of type I collagen plays a functional role in regulating corpus luteum formation, and transforming growth factor ß1 (TGF-ß1) inhibits luteinization and progesterone production in granulosa cells (GCs). Whether TGF-ß1 regulates the expression of MMP1, COL1A1, or the deposition of type I collagen during corpus luteum formation remains to be elucidated. This study aimed to investigate the molecular mechanisms through which TGF-ß1 regulates MMP1 expression and type I collagen deposition in GCs. Our results show that TGF-ß1 upregulates COL1A1 expressions and downregulates MMP1 expression. Inhibition approaches, including pharmacological inhibitors such as p38 inhibitor (SB203580), ERK1/2 inhibitor (U0126), AKT inhibitor (LY294002), and GSK-3ß inhibitor (LiCl), as well as knockdown using siRNA specific to these genes, were used. Our results suggest that TGF-ß1 decreases MMP1 production via an ALK5-mediated AKT/GSK-3ß-dependent signaling pathway, and a decrease in MMP1 levels and an increase in COL1A1 levels synergistically promote type I collagen deposition in GCs. Collectively, these findings provide novel insights into the underlying molecular mechanisms by which TGF-ß1 upregulates type I collagen deposition in GCs.

CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma: a cross-talk between FGF21 and the NRF2 pathway.

The treatment of hepatocellular carcinoma (HCC) has been dominated by multikinase inhibitors for more than a decade. However, drug resistance can severely restrict the efficacy of these drugs. Using CRISPR/CAS9 genome library screening, we evaluated Kelch-like ECH-associated protein 1 (KEAP1) as a key regulator of sorafenib's susceptibility in HCC. We also investigated whether KEAP1's knockdown can stabilize nuclear factor (erythroid-derived 2)-like 2 (NRF2) protein levels that led to sorafenib's resistance, including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC's growth in vitro and in vivo. Furthermore, we clarified that fibroblast growth factor 21 (FGF21) is an important downstream regulator of NRF2 in HCC. Intriguingly, we observed that FGF21 bound to NRF2 through the C-terminus of FGF21, thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC. These findings, therefore, propose that targeting FGF21 is a promising strategy to combat HCC sorafenib's resistance.

PM2.5 constituents and mortality from a spectrum of causes in Guangzhou, China.

As the major constituents of PM2.5, carbonaceous constituents and inorganic ions have attracted emerging attentions on their health risks, particularly on cardiorespiratory diseases. However, evidences on the risks of PM2.5 constituents on other diseases (eg. nervous disease, genitourinary disease, neoplasms and endocrine disease) remain scarce. In our study, we firstly calculated residuals of PM2.5 constituents regressed on PM2.5 to remove the confounding effect of PM2.5. Then, generalized additive model (GAM) was used to assess impacts of residuals of PM2.5 constituents on mortality from 36 diseases (10 broad categories and 26 subcategories) during 2011-2015 in Guangzhou, China. Results of constituent-residual models showed that only EC, OC and NO3- were significantly associated with all-cause mortality, with per IQR change in corresponding constituent residuals related to percentage changes of 1.69% (95% CI: 0.42, 2.97), 1.94% (95% CI: 0.37, 3.54) and 2.59% (95% CI: 1.02, 4.18) at lag 03 days. All these pollutants were significantly associated with elevated mortality risk of cardiovascular disease, but only EC was significantly associated with respiratory mortality, and NO3- with endocrine disease and neoplasm. For more specific causes, the highest effect estimates of EC and NO3-were both observed on mortality from other form of heart disease, and OC on intentional self-harm, with estimates of 11.45% (95% CI: 2.74, 20.91), 12.59% (95% CI: 1.41, 25.02) and 18.01% (95% CI: 2.14, 36.36), respectively. Our findings highlighted that stricter emission control measures are still warranted to reduce air pollution level and protect the public health.

Hsa_circ_0012152 and Hsa_circ_0001857 Accurately Discriminate Acute Lymphoblastic Leukemia From Acute Myeloid Leukemia.

Acute leukemia (AL) is a group of highly heterogeneous hematological malignancies. Circular RNAs (circRNAs) are covalently closed circRNA molecules implicated in the development of many diseases. However, the role of circRNAs in AL remains largely unknown. Therefore, this study aimed to identify new classification diagnostic biomarkers for subgroups of AL. The circRNA expression signatures discriminating acute lymphoblastic leukemia (ALL) from acute myeloid leukemia (AML) were identified by microarray, followed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) validation. Receiver operating characteristic curve analysis was used to evaluate the diagnostic efficiencies of hsa_circ_0001857 and hsa_circ_0012152, and hsa_circ_0012152 was selected for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The results showed that the circRNA expression profiles, hsa_circ_0001857, and hsa_circ_0012152 could clearly discriminate ALL from AML. The target genes of hsa_circ_0012152 might be involved in biological processes, such as myeloid cell differentiation, covalent chromatin modification, histone modification, and rat sarcoma (Ras) protein signal transduction, and participate in pathways such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3'-kinase (PI3K)-Akt signaling pathway. Hsa_circ_0012152 might be involved in the initiation and development of AML through miR-491-5p/epidermal growth factor receptor (EGFR)/MAPK1 or miR-512-3p/EGFR/MAPK1 axis. Our results showed that circRNA expression profiles and specifically expressed circRNAs were promising classification biomarkers to designate AL into ALL or AML.

Tip of the iceberg: roles of circRNAs in hematological malignancies.

Circular RNAs (circRNAs) are a new class of covalently closed RNA molecules whose 3'- and 5'-ends are linked by a back-splicing event. Emerging evidence has shown that circRNAs play a vital role in the occurrence and development of many diseases and are promising biomarkers and therapeutic targets. However, knowledge of circRNAs in hematological malignancies is limited. In this review, the biogenesis, categories, characteristics, and functions of circRNAs are summarized, especially the roles of circRNAs in hematopoiesis and hematological malignancies.

Transcriptome sequencing analysis of porcine MDM response to FSL-1 stimulation.

Mycoplasma infection can cause many diseases in pigs, resulting in great economic losses in pork production. Innate immune responses are thought to play critical roles in the pathogenesis of mycoplasma disease. However, the molecular events involved in immune responses remain to be determined. Hence, the object of this study was to use RNA-Seq to investigate the gene expression profiles of the innate immune response mediated by FSL-1 in pig monocyte-derived macrophages (MDMs). The results revealed that 1442 genes were differentially expressed in the FSL-1 group compared with the control groups, of which 777 genes were upregulated and 665 genes were downregulated. KEGG pathway analysis showed that the upregulated genes were mainly involved in innate immune-related pathways including the TNF signaling pathway, cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, Jak-STAT signaling pathway, chemokine signaling pathway, NOD-like receptor signaling pathway and NF-kappa B signaling pathway. The downregulated genes were only involved in the cGMP-PKG signaling pathway and glycerophospholipid metabolism. Our results showed that FSL-1 stimulation activated the TLR2 signaling pathway and resulted in diverse inflammatory responses. FSL-1 induced the transcription of numerous protein-coding genes involved in a complex network of innate immune-related pathways. We speculate that TNF, IL1B, IL6, NFKB1, NFKBIA, CXCL2, CXCL8, CXCL10, CCL2, CCL4 and CCL5 were the most likely hub genes that play important roles in the above pathways. This study identified the differentially expressed genes and their related signaling pathways, contributing to the comprehensive understanding of the mechanisms underlying host-pathogen interactions during mycoplasma infection and providing a reference model for further studies.

Prognostic significance of U2AF1 mutations in myelodysplastic syndromes: a meta-analysis.

INTRODUCTION: Although the effects of U2 small nuclear RNA auxiliary factor 1 gene (U2AF1) mutations on the outcomes of patients with myelodysplastic syndromes (MDS) have previously been investigated, their prognostic significance remains controversial. We performed a meta-analysis to investigate the impact of U2AF1 mutations on MDS progression. METHODS: Two reviewers independently extracted information such as hazard ratios (HRs) and 95% confidential intervals (CIs) for overall survival (OS) and leukemia-free survival (LFS) as well as the number of surviving patients each year after diagnosis from the included studies. RESULTS: Thirteen studies with a total of 3038 patients were included. The summary odds ratio (OR) for U2AF1 mutations with an OS of 5 years was 0.37, the summary HR for U2AF1 mutations in OS was 1.60, and the summary OR for an OS of 5 years in patients with U2AF1S34 and U2AF1Q157 was 3.68. There were no significant differences in leukemia-free survival or hypomethylating therapy response between patients with and without U2AF1 mutations. CONCLUSION: U2AF1 mutations were associated with poor survival in MDS patients, and patients with U2AF1Q157 had a worse OS than those with U2AF1S34. Our findings suggest that MDS patients with U2AF1 mutations could benefit more from hypomethylation therapy.

Investigation of Eph-ephrin A1 in the regulation of embryo implantation in sows.

Eph A1 and ephrin A1 (Eph-ephrin A1) is a key receptor-ligand pair of Eph-ephrin system, which plays important roles in the migration and adhesion of cells, tissue morphogenesis and vasculogenesis in mammals. In order to investigate the regulation of Eph-ephrin A1 during porcine embryo implantation, the expressions of mRNA and protein of Eph-ephrin A1 were detected in different reproductive tissues from twelve sows during embryo implantation period on pregnancy day 13, 18 and 24, respectively. Functions of Eph-ephrin A1 on the migration and adhesion of porcine endometrial epithelial cells were analysed by RNA interference (RNAi), transwell migration assays and MTT assays. Results showed that mRNA levels of Eph-ephrin A1 were highly expressed in endometrial attachment site when compared to other reproductive tissues (p < 0.05) and were peaked on pregnancy day 18 during embryo implantation (p < 0.05). Protein levels of Eph-ephrin A1 were highly expressed in endometrial attachment site and were peaked on pregnancy day 18 (p < 0.05). Eph-ephrin A1 proteins were located in endometrial luminal epithelium, stroma of attachment site and inter-attachment site during embryo implantation, and the protein levels were higher during implantation compared to pre-implantation or post-implantation. Furthermore, silencing ephrin A1 gene significantly reduced the migration and adhesion capacity of porcine endometrial epithelial cells. These findings suggest that the Eph-ephrin A1 protein likely targets endometrial attachment site to enhance the migration and adhesion of porcine endometrial epithelial cells around pregnancy day 18 during pregnancy in sows.

[Source Profiles and Chemical Reactivity of Volatile Organic Compounds from Surface Coating of Aluminum Products in Foshan, China].

Volatile organic compounds (VOCs) samples were collected and analyzed for the surface coating processes of aluminum products in Foshan. The concentration levels of VOCs from solvent-based coating (63.90-149.67 mg·m-3) are much higher than that from water-based, electrophoretic, and powder coating (2.99-21.93 mg·m-3). With respect to the VOC composition, aromatics are the main VOC group of solvent-based coating emission, ranging from 52.32%-71.55%. Typical species include toluene, ethylbenzene, xylene, and ethyl acetate. The VOCs emitted from water-based coating are mainly oxygenated VOCs, such as ethyl acetate (48.59%) and tetrahydrofuran (8.43%), while the percentage of aromatics (11.32%) is lower than that of solvent-based coating. Isopropanol is the most abundant species of electrophoretic coating emissions, accounting for up to 81.19% of the VOCs. The major VOC compounds of powder coating processes are acetone (30.25%), propane (15.48%), ethylene (12.15%), ethane (9.35%), and n-butane (5.16%). The calculation of the ozone formation potential (OFP) shows that the solvent-based coating has the highest OFP (3.89 g·g-1), followed by powder coating (2.53 g·g-1), while water-based and electrophoretic coating have lower OFPs (1.31 and 0.85 g·g-1, respectively). The most important contributor to OFP of solvent-based coating are aromatics, especially C7-C10 aromatics. The major contributors of water-based coating are ethyl acetate, m/p-xylenes, and toluene, with contributions of 23.24%, 21.76%, and 17.07%, respectively. The key reactive components of powder coating are ethylene, propene, and 1-butene; the sum of alkenes accounts for 71.11% of the OFP. With respect to the contribution of VOCs emitted from electrophoretic coating to the OFP, the percentage of isopropanol (65.08%) is significantly larger than that of other species (<6%).