Prostaglandins (PG), produced by the uterine endometrium, are key regulators of several reproductive events, including estrous cyclicity, implantation, pregnancy maintenance and parturition. Phospholipase A2 (PLA2) catalyzes the release of arachidonic acid from membrane phospholipids, the rate-limiting step in PG biosynthesis. The bovine endometrial (BEND) cell line has served as a model system for investigating regulation of signaling mechanisms involved in uterine PG production but information concerning the specific PLA2 enzymes involved and their role in regulation of this process is limited. The objectives of this investigation were to evaluate the expression and activities of calcium-dependent group IVA (PLA2G4A) and calcium-independent group VI (PLA2G6) enzymes in the regulation of BEND cell PG production.

HDM2 is a p53-specific E3 ubiquitin ligase. Its overexpression leads to excessive inactivation of tumor protein p53, diminishing its tumor suppressor function. HDM2 also affects the cell cycle, apoptosis and tumorigenesis through interacting with other molecules, including several ribosomal proteins. To identify novel HDM2 regulators, we performed a yeast two-hybrid screening using HDM2 as bait. Among the candidates, ribosomal protein L26 (RPL26) was characterized as a novel HDM2-interactor. The interaction between HDM2 and RPL26 was further validated by in vivo and in vitro assays. RPL26 modulates the HDM2-p53 interaction by forming a ternary complex among RPL26, HDM2 and p53, which stabilize p53 through inhibiting the ubiquitin ligase activity of HDM2. The ribosomal stress caused by a low dose of Act D enhances RPL26-HDM2 interaction and activates p53. Overexpression of RPL26 results in activating of p53, inhibits cell proliferation and induces a p53-dependent cell cycle arrest. These results provide a novel regulatory mechanism of RPL26 to activate p53 by inhibiting HDM2.

This study aimed to investigate the differential expression of plasma proteins in patients suffering from high-altitude pulmonary edema (HAPE) at different phases. A complete proteomic analysis was performed using two-dimensional gel electrophoresis followed by mass spectrometry in three patients with HAPE at the acute stage and recovery phase. Comparisons between the expression patterns of the patients with HAPE at the two different phases led to the identification of eight protein spots with a >1.5-fold difference in expression between the acute and recovery phases. These differentially expressed proteins were apolipoproteins, serum amyloid P component, complement components and others. Apolipoprotein A-I (Apo A-I), serum amyloid P component and fibrinogen were overexpressed in the patients with HAPE in the acute stage compared with their expression levels in the recovery phase. However, Apo A-IV and antithrombin-III were overexpressed in the patients with HAPE in the recovery phase compared with their expression levels in the acute stage. The results indicate that the differential plasma proteome in patients with HAPE may be associated with the occurrence of HAPE, and the expression changes of Apo A-I and A-IV may offer further understanding of HAPE to aid its prognosis, diagnosis and treatment.

Accumulating evidence reveals that hormone leptin, mainly produced by adipocyte, plays a unique role in promotion of liver fibrosis. Hepatic stellate cell (HSC) activation is a key step in liver fibrosis and peroxisome-proliferator activated receptor γ (PPARγ) exerts a crucial role in inhibition of HSC activation. Our previous researches demonstrated that leptin reduced PPARγ1 (a major subtype of PPARγ in HSCs) expression through GATA binding protein 2 (GATA2) binding to a site around -2323 in PPARγ1 promoter. The present researches aimed to examine the effect of GATA3 on leptin-induced inhibition of PPARγ1 and elucidate the relationship between GATA3 and GATA2. Gene expressions were analysed by real-time PCR, western blot, luciferase assay and immunostaining. C57BL/6J ob/ob mouse model of thioacetamide-induced liver injury was used in vivo. Results demonstrate that leptin significantly induces GATA3 expression in HSCs by multiple signalling pathways including NADPH oxidase pathway. There exist crosstalks between NADPH oxidase pathway and the other pathways. GATA3 can bind to GATA2-binding site in PPARγ1 promoter and interacts with GATA2, contributing to leptin inhibition of PPARγ1 expression in HSCs. These data demonstrated novel molecular events for leptin inhibition of PPARγ1 expression in HSCs and thus might have potential implications for clarifying the detailed mechanisms underlying liver fibrosis in diseases in which circulating leptin levels are elevated such as non-alcoholic steatohepatitis in obese patients.

The acute myeloid leukemia 1 (AML1)-eight-twenty-one (ETO) fusion protein generated by the t(8;21)(q22;q22) translocation is considered to display a crucial role in leukemogenesis in AML. By focusing on the anti-leukemia effects of eyes absent 4 (EYA4) gene on AML cells, we investigated the biologic and molecular mechanism associated with AML1-ETO expressed in t(8;21) AML.

Metastatic renal cell carcinoma (mRCC) is nearly incurable and accounts for most of the mortality associated with RCC. Von Hippel Lindau (VHL) is a tumour suppressor that is lost in the majority of clear cell RCC (ccRCC) cases. Its role in regulating hypoxia-inducible factors-1α (HIF-1α) and -2α (HIF-2α) is well-studied. Recent work has demonstrated that VHL knock down induces an epithelial-mesenchymal transition (EMT) phenotype. In this study we showed that a CRISPR/Cas9-mediated knock out of VHL in the RENCA model leads to morphologic and molecular changes indicative of EMT, which in turn drives increased metastasis to the lungs. RENCA cells deficient in HIF-1α failed to undergo EMT changes upon VHL knockout. RNA-seq revealed several HIF-1α-regulated genes that are upregulated in our VHL knockout cells and whose overexpression signifies an aggressive form of ccRCC in the cancer genome atlas (TCGA) database. Independent validation in a new clinical dataset confirms the upregulation of these genes in ccRCC samples compared to adjacent normal tissue. Our findings indicate that loss of VHL could be driving tumour cell dissemination through stabilization of HIF-1α in RCC. A better understanding of the mechanisms involved in this phenomenon can guide the search for more effective treatments to combat mRCC.

The molecular mechanisms responsible for specifying the dorsal-ventral pattern of neuronal identities in dorsal root ganglia (DRG) are unclear. Here we demonstrate that Sonic hedgehog (Shh) contributes to patterning early DRG cells. In vitro, Shh increases both proliferation and programmed cell death (PCD). Increasing Shh in vivo enhances PCD in dorsal DRG, while inducing greater proliferation ventrally. In such animals, markers characteristic of ventral sensory neurons are expanded to more dorsal positions. Conversely, reducing Shh function results in decreased proliferation of progenitors in the ventral region and decreased expression of the ventral marker trkC. Later arising trkA(+) afferents make significant pathfinding errors in animals with reduced Shh function, suggesting that accurate navigation of later arising growth cones requires either Shh itself or early arising, Shh-dependent afferents. These results indicate that Shh can regulate both cell number and the distribution of cell types in DRG, thereby playing an important role in the specification, patterning and pathfinding of sensory neurons.

Histone lysine methyltransferases (HMTs), a category of enzymes, play essential roles in regulating transcription, cellular differentiation, and chromatin construction. The genomic landscape and clinical significance of HMTs in renal cell carcinoma (RCC) remain uncovered.

Cancer stem cells (CSCs) play an important role in osteosarcoma (OS) metastasis and recurrence, and both Wnt/β-catenin and Notch signaling are essential for the development of the biological traits of CSCs. However, the mechanism that underlies the simultaneous hyperactivation of both Wnt/β-catenin and Notch signaling in OS remains unclear. Here, we report that expression of miR-135b correlates with the overall and recurrence-free survival of OS patients, and that miR-135b has an activating effect on both Wnt/β-catenin and Notch signaling. The overexpression of miR-135b simultaneously targets multiple negative regulators of the Wnt/β-catenin and Notch signaling pathways, including glycogen synthase kinase-3 beta (GSK3β), casein kinase 1a (CK1α), and ten-eleven translocation 3 (TET3). Therefore, upregulated miR-135b promotes CSC traits, lung metastasis, and tumor recurrence in OS. Notably, antagonizing miR-135b potently inhibits OS lung metastasis, cancer cell stemness, CSC-induced tumor formation, and recurrence in xenograft animal models. These findings suggest that miR-135b mediates the constitutive activation of Wnt/β-catenin and Notch signaling, and that the inhibition of miR-135b is a novel strategy to inhibit tumor metastasis and prevent CSC-induced recurrence in OS.

The brown plant hopper (BPH), Nilaparvata lugens, is one of the major pest of rice (Oryza sativa). Plant defenses against insect herbivores have been extensively studied, but our understanding of insect responses to host plants' resistance mechanisms is still limited. The purpose of this study is to characterize transcripts of BPH and reveal the responses of BPH insects to resistant rice at transcription level by using the advanced molecular techniques, the next-generation sequencing (NGS) and the single-molecule, real-time (SMRT) sequencing.

The physiological role of Rho-specific guanine nucleotide dissociation inhibitor (RhoGDI) in vascular remodeling remains unknown. We investigated the function of RhoGDI in angiotensin II (Ang II)-induced vascular remodeling in cultured human aortic vascular smooth muscle cells (HA-VSMCs) and in an Ang II-infusion vascular remodeling mouse model.

Metabolism serves mammalian feeding and active behavior, and is controlled by circadian clock. The molecular mechanism by which clock factors regulate metabolic homeostasis under oxidative stress is unclear. Here, we have characterized that the daily oxygen consumption rhythm was deregulated in Per1 deficient mice. Per1 deficiency impaired daily mitochondrial dynamics and deregulated cellular GPx-related ROS fluctuations in the peripheral organs. We identified that PER1 enhanced GPx activity through PER1/GPX1 interaction in cytoplasm, consequently improving the oxidative phosphorylation efficiency of mitochondria. Per1 expression was specifically elevated in the fasting peripheral organs for protecting mitochondrial from oxidation stress. These observations reveal that Per1-driven mitochondrial dynamics is a critical effector mechanism for the regulation of mitochondrial function in response to oxidation stress.

Renal cell carcinoma (RCC) is a deadly malignancy due to its tendency to metastasize and resistance to chemotherapy. Stem-like tumor cells often confer these aggressive behaviors. We discovered an endoglin (CD105)-expressing subpopulation in human RCC xenografts and patient samples with a greater capability to form spheres in vitro and tumors in mice at low dilutions than parental cells. Knockdown of CD105 by short hairpin RNA and CRISPR/cas9 reduced stemness markers and sphere-formation ability while accelerating senescence in vitro. Importantly, downregulation of CD105 significantly decreased the tumorigenicity and gemcitabine resistance. This loss of stem-like properties can be rescued by CDA, MYC, or NANOG, and CDA might act as a demethylase maintaining MYC and NANOG. In this study, we showed that Endoglin (CD105) expression not only demarcates a cancer stem cell subpopulation but also confers self-renewal ability and contributes to chemoresistance in RCC.

Acute lung injury (ALI) is a pulmonary disorder, which can result in fibrosis of the lung tissues. Recently, mesenchymal stem cell (MSC) has become a novel therapeutic method for ALI. However, the potential mechanism by which MSC regulates the progression of ALI remains blurry. The present study focused on investigating the mechanism underneath MSC-reversed lung injury and fibrosis. At first, we determined that coculture with MSC led to the inactivation of NF-κB signaling and therefore suppressed hedgehog pathway in LPS-treated MLE-12 cells. Besides, we confirmed that MSC-exosomes were responsible for the inhibition of EMT process in LPS-treated MLE-12 cells through transmitting miRNAs. Mechanism investigation revealed that MSC-exosome transmitted miR-182-5p and miR-23a-3p into LPS-treated MLE-12 cells to, respectively, target Ikbkb and Usp5. Of note, Usp5 interacted with IKKβ to hamper IKKβ ubiquitination. Moreover, co-inhibition of miR-182-5p and miR-23a-3p offset the suppression of MSC on EMT process in LPS-treated MLE-12 cells as well as in LPS-injured lungs of mice. Besides, the retarding effect of MSC on p65 nuclear translocation was also counteracted after co-inhibiting miR-182-5p and miR-23a-3p, both in vitro and in vivo. In summary, MSC-exosome transmitted miR-23a-3p and miR-182-5p reversed the progression of LPS-induced lung injury and fibrosis through inhibiting NF-κB and hedgehog pathways via silencing Ikbkb and destabilizing IKKβ.

The World Health Organization states that China had 0.9 million cases of tuberculosis in 2017, accounting for 9% of cases globally. Despite a decrease in the incidence and mortality of tuberculosis in China over time, development in choosing the appropriate prevention and control of TB is required.

The kidney function of patients with chronic kidney disease (CKD) is impaired irreversibly. Organ transplantation is the only treatment to restore kidney function in CKD patients. The assessment of new potential therapeutic procedures relies heavily on experimental animal models, but it is limited by its human predictive capacity. In addition, the frequently used two-dimensional in vitro human renal cell models cannot replicate all the features of the in vivo situation. In this study, we developed a three-dimensional (3D) in vitro human renal organoid model from whole kidney cells as a promising drug screening tool. At present, the renal tissue generated from human pluripotent stem cells (hPSCs) exhibits intrinsic tumorigenicity properties. Here we first developed a 3D renal organoid culture system that originated from adult differentiated cells without gene modification. Renal organoids composed of multiple cell types were created under optimal experimental conditions and evaluated for morphology, viability and erythropoietin production. As a novel screening tool for renal toxicity, 3D organoids were exposed to three widely used drugs: aspirin, penicillin G and cisplatin. The study results showed this 3D renal organoid model can be used as a drug screening tool, a new in vitro 3D human kidney model, and provide hope for potential regenerative therapies for CKD.

Kidney-yin deficiency syndrome (KYDS) is a typical syndrome encountered in traditional Chinese medicine (TCM) and is characterized by impaired lipid and glucose homeostasis. The hypothalamus acts as an important regulatory organ by controlling lipid and glucose metabolism in the body. Therefore, proteins in the hypothalamus could play important roles in KYDS development; however, the mechanisms responsible for KYDS remain unclear. Herein, iTRAQ-based proteomics was performed to analyze the protein expression in the hypothalamus of KYDS rats induced by levothyroxine (L-T4). Results revealed a total of 44 downregulated and 18 upregulated proteins in KYDS group relative to the control group. Gene Ontology (GO) analysis revealed that the differently expressed proteins (DEPs) were related to single-organism metabolism process under the biological process (BP), extracellular region part and organelle under the cellular component (CC), and oxidoreductase activity under the molecular function (MF). Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis showed that fatty acid degradation and pyruvate metabolism participated in the metabolism regulation in KYDS rats. RT-PCR validation of five distinctly expressed proteins related to the two pathways was consistent with the results of proteomics analysis. Taken together, the inhibition of fatty acid degradation and pyruvate metabolism in hypothalamus could potentially cause the dysfunction of the lipid and glucose metabolism in KYDS rats. This current study identified some novel potential biomarkers of KYDS and provided the basis for further research of KYDS.

Background: The programmed death 1 (PD1)/programmed death ligand 1 (PDL1) targeted therapies have gained positive outcomes in several tumors, but the evidence of the expression and prognosis value of PD1/PDL1 in high risk prostate cancer was rare. Methods: Immunohistochemical analysis of PDL1/PD1 expression by a validated antibody was performed in a retrospectively collected high risk prostate cancer cohort who received adjuvant hormonal therapy (AHT) after radical prostatectomy (RP). The association between PDL1/PD1 expression and prognosis was determined. Results: In total, 127 patients were enrolled. 49.6% patients were considered PDL1-high expression while the PD1-positive expression proportion was 24.4%. High PDL1 and negative PD1 expression were significantly associated with lower prostate specific antigen (PSA) density (p=0.010 and p=0.033, respectively). Compared with the PDL1-low expression patients, the PDL1-high expression patients had significantly shorter time to PSA nadir (TTN) (P=0.001) and biochemical recurrence (BCR) (P=0.004). In Kaplan-Meier analysis, the PDL1-high expression group (p<0.0001) and the PDL1-high/PD1-negative expression group (p<0.0001) showed markedly lower BCR-free survival in localized disease. Univariate cause-specific Cox proportional hazard regression model concluded total PSA (p=0.047), PDL1-high-expression (p<0.001), PDL1-high/PD1-negative expression (p<0.001) were significant risk factors of shorter progression time to BCR in localized disease. PDL1-high-expression was the independent predictor of time to BCR in multiple Cox regression of all patients (Hazard ratio [HR]: 3.901; 95% Confidence interval [CI]: 1.287-11.824; p=0.016). Conclusions: PDL1 expression is not only highly prevalent in high-risk prostate cancer, but is also an independent biomarker in the prognosis of high-risk prostate cancer received AHT after RP. PDL1/PD1 targeted therapy might be a potentially adjuvant treatment option for high-risk prostate cancer after RP.

Aberrant alternative splicing events play critical roles in carcinogenesis and progression of many cancers, while sparse studies regarding to alternative splicing are available for clear cell renal cell carcinoma (ccRCC). We identified that alternative splicing of coiled-coil domain containing 50 (CCDC50) was dysregulated in ccRCC, whereas the clinical significance of this splicing event and its splicing regulation mechanisms were still elusive.

Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2-0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31-0.96; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18-1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.