Polycystic ovary syndrome (PCOS) a long-known endocrinopathy and one of the most common endocrine-reproductivemetabolic disorders in women, which can lead to infertility. Although the precise etiology remains unclear, PCOS is considered as a complex genetic trait, with a high degree of heterogeneity. Besides, hormones and immune cells, including both innate and adaptive immune cells, are reportedly a cross talk in PCOS. Chronic low-grade inflammation increases autoimmune disease risk. This proinflammatory condition may, in turn, affect vital physiological processes that ultimately cause infertility, such as ovulation failure and embryo implantation. Here, we review the accumulating evidence linking PCOS with inflammatory status providing an overview of the underlying hormone-mediated dysregulation of immune cells. We mainly focus on the correlational evidence of associations between immune status in women and the increased prevalence of PCOS, along with the specific changes in immune responses. Further recognition and exploration of these interactions may help elucidate PCOS pathophysiology and highlight targets for its treatment and prevention.

In recent years, a large number of studies have been carried out in the field of immune metabolism, highlighting the role of metabolic energy reprogramming in altering the function of immune cells. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a large array of pathological conditions, such as cancer, inflammation, and infection, and show remarkable ability to suppress T-cell responses. These cells can also change their metabolic pathways in response to various pathogen-derived or inflammatory signals. In this review, we focus on the roles of glucose, fatty acid (FA), and amino acid (AA) metabolism in the differentiation and function of MDSCs in the tumour microenvironment, highlighting their potential as targets to inhibit tumour growth and enhance tumour immune surveillance by the host. We further highlight the remaining gaps in knowledge concerning the mechanisms determining the plasticity of MDSCs in different environments and their specific responses in the tumour environment. Therefore, this review should motivate further research in the field of metabolomics to identify the metabolic pathways driving the enhancement of MDSCs in order to effectively target their ability to promote tumour development and progression.

MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs, which play a critical role in regulating varieties of the biological and pathologic processes. miR-181a has been reported to participate in tumorigenic progression. However, the roles of miR-181a in cervical cancer (CC) are still unknown. The aim of this research was to explore the effects and molecular mechanism of miR-181a in CC cells. In this paper, the levels of miR-181a in CC cell lines were determined by real-time PCR. We found that the levels of miR-181a were evidently enhanced in CC cell lines compared with normal cervical epithelium cells. Then, the miR-181a inhibitor was transiently transfected into HeLa and CaSKi cells using Lipofectamine 2000 reagent. Subsequently, the Cell Counting Kit-8 (CCK-8) and BrdU-ELISA results showed that down-regulation of miR-181a inhibited the cell viability and proliferation. Our data also demonstrated that miR-181a inhibitor arrested cell cycle progression of HeLa and CaSKi cells by up-regulation of p21 and p27 expressions. In addition, inhibition of miR-181a promoted apoptosis of HeLa and CaSKi cells due to increasing Bax expression and decreasing Bcl-2 expression. Ultimately, the effect of miR-181a inhibitor on the PTEN/Akt/FOXO1 signaling pathway was investigated by Western blot. From our results, down-regulation of miR-181a increased the expression of PTEN and decreased phosphorylation of Akt and FOXO1. Altogether, miR-181a might be an oncogene in CC cells. The potential mechanism was that inhibition of miR-181a might suppress proliferation and invasion and promote apoptosis of HeLa and CaSKi cells by modulating the PTEN/Akt/FOXO1 signaling pathway.

Background B7-H3, an immune-checkpoint molecule and a transmembrane protein, is overexpressed in non-small cell lung cancer (NSCLC), making it an attractive therapeutic target. Here, we aimed to systematically evaluate the value of B7-H3 as a target in NSCLC via T cells expressing B7-H3-specific chimeric antigen receptors (CARs) and bispecific killer cell engager (BiKE)-redirected natural killer (NK) cells. Methods We generated B7-H3 CAR and B7-H3/CD16 BiKE derived from an anti-B7-H3 antibody omburtamab that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. Antitumor efficacy and induced-immune response of CAR and BiKE were evaluated in vitro and in vivo. The effects of B7-H3 on aerobic glycolysis in NSCLC cells were further investigated. Results B7-H3 CAR-T cells effectively inhibited NSCLC tumorigenesis in vitro and in vivo. B7-H3 redirection promoted highly specific T-cell infiltration into tumors. Additionally, NK cell activity could be specially triggered by B7-H3/CD16 BiKE through direct CD16 signaling, resulting in significant increase in NK cell activation and target cell death. BiKE improved antitumor efficacy mediated by NK cells in vitro and in vivo, regardless of the cell surface target antigen density on tumor tissues. Furthermore, we found that anti-B7-H3 blockade might alter tumor glucose metabolism via the reactive oxygen species-mediated pathway. Conclusions Together, our results suggest that B7-H3 may serve as a target for NSCLC therapy and support the further development of two therapeutic agents in the preclinical and clinical studies.

Immune cells play important roles in systemic lupus erythematosus (SLE). We previously found that myeloid-derived suppressor cell (MDSC)-derived arginase-1 (Arg-1) promoted Th17 cell differentiation in SLE. In this study, we performed RNA-chip to identify the microRNA regulation network between MDSCs and Th17 cells. miR-542-5p in humans, as the homologous gene of miR-322-5p in mice was significantly upregulated in the Th17+MDSC group compared to Th17 cells cultured alone and downregulated in the Th17+MDSC+Arg-1 inhibitor group compared to the Th17+MDSC group. We further evaluated the miR-322-5p and Th17/Treg balance in mice and found that the proportions of both Th17 cells and Tregs were elevated and that miR-322-5p overexpression activated the transforming growth factor-β pathway. Moreover, although miR-322-5p expression was higher in SLE mice, it decreased after treatment with an Arg-1 inhibitor. The proportion of Th17 cells and Th17/Treg ratio correlated with miR-322-5p levels. In conclusion, MDSC-derived Arg-1 and mmu-miR-322-5p not only promote Th17 cell and Treg differentiation, but also shift the Th17/Treg ratio in SLE. The Arg-1/miR-322-5p axis may serve as a novel treatment target for SLE.

BackgroundEtomidate is a rapid hypnotic intravenous anesthetic agent. The major side effect of etomidate is the reduced plasma concentration of corticosteroids, leading to the abnormal reaction of adrenals. Cortisol and testosterone biosynthesis has similar biosynthetic pathway, and shares several common steroidogenic enzymes, such as P450 side chain cleavage enzyme (CYP11A1) and 3β-hydroxysteroid dehydrogenase 1 (HSD3B1). The effect of etomidate on Leydig cell steroidogenesis during the cell maturation process is not well established.MethodologyImmature Leydig cells isolated from 35 day-old rats were cultured with 30 μM etomidate for 3 hours in combination with LH, 8Br-cAMP, 25R-OH-cholesterol, pregnenolone, progesterone, androstenedione, testosterone and dihydrotestosterone, respectively. The concentrations of 5α-androstanediol and testosterone in the media were measured by radioimmunoassay. Leydig cells were cultured with various concentrations of etomidate (0.3–30 μM) for 3 hours, and total RNAs were extracted. Q-PCR was used to measure the mRNA levels of following genes: Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Srd5a1, and Akr1c14. The testis mitochondria and microsomes from 35-day-old rat testes were prepared and used to detect the direct action of etomidate on CYP11A1 and HSD3B1 activity.Results and ConclusionsIn intact Leydig cells, 30 μM etomidate significantly inhibited androgen synthesis. Further studies showed that etomidate also inhibited the LH- stimulated androgen production. On purified testicular mitochondria and ER fractions, etomidate competitively inhibited both CYP11A1 and HSD3B1 activities, with the half maximal inhibitory concentration (IC50) values of 12.62 and 2.75 μM, respectively. In addition, etomidate inhibited steroidogenesis-related gene expression. At about 0.3 μM, etomidate significantly inhibited the expression of Akr1C14. At the higher concentration (30 μM), it also reduced the expression levels of Cyp11a1, Hsd17b3 and Srd5a1. In conclusion, etomidate directly inhibits the activities of CYP11A1 and HSD3B1, and the expression levels of Cyp11a1 and Hsd17b3, leading to the lower production of androgen by Leydig cells.

Purpose: Gastric cancer is one of the most common cancers with high mortality. Emerging evidences show that ribosomal s6 kinase4 (RSK4) may be an anti-oncogene in several types of cancers, while its function in GC is still unclear. In the present study, we investigated the role of RSK4 in GC progression using MGC-803 and HGC-27 cell lines in vitro and in vivo. Methods: The expression of RSK4 in gastric cancer cells was evaluated using RT-qPCR and Western blot analysis. We transfected cells with RSK4 siRNA to reduce the expression of RSK4 and then evaluated the effect of RSK4 on cellular function. MTT and cell cycle assays were used to study its effect on cell growth. Flow cytometry was used to evaluate cell apoptosis. Wound healing and Transwell assays were performed to investigate metastasis. Stable cell lines with or without RSK4 knockdown were constructed with lentivirus and tumor-bearing mice were used to investigate the effect of RSK4 on cancer progression. Results: The results revealed that reduction of RSK4 expression inhibited cell apoptosis and promoted cell proliferation, migration, and invasion. Additionally, RSK4 knockdown promoted tumorigenesis in vivo. Conclusion: Our study demonstrated that RSK4 serves as a tumor suppressor in GC.

Network pharmacology is considered to be the next-generation drug development model that uses bioinformatics to predict and identify multiple drug targets and interactions in diseases. Here, network pharmacology was used to investigate the mechanism by which Curculigoside A (CA) acts in rheumatoid arthritis (RA) and osteoporosis. Methods: First, TCMSP and SwissADME were applied to predict the druggability of CA. Then, potential targets were identified from overlapping data in SwissTarget and TargetNet, and targets were analyzed using Genemania and DAVID6.8 to obtain information about the GO and KEGG pathways. Ultimately, the drug-target-pathway network was identified after using Cytoscape 3.0 for visualization. Besides, qPCR was used to validate the predicted five major genes targets (EGFR, MAP2K1, MMP2, FGFR1, and MCL1). Results: The results of TCMSP and SwissADME demonstrated that CA exhibits good druggability; 26 potential protein targets were classified by SwissTarget and TargetNet. The results of Genemania and DAVID6.8 indicated that CA probably caused antiosteoporosis and anti-RA effects by regulating some biological pathways, especially nitrogen metabolism, estrogen signaling pathway, Rap1 signaling pathway, and PI3K/Akt signaling pathway. Besides, the result of Cytoscape 3.0 showed that the 26 targets participate in osteoporosis and RA-related pathways, metabolism, and other physiological processes. In vitro induced inflammation cell model experiments, the qPCR results showed that CA pretreatment significantly decreased the expression of EGFR, MAP2K1, MMP2, FGFR1, and MCL1 genes. Conclusion: These results suggested that network pharmacology may provide possible mechanism of how CA exerts therapeutic effects in osteoporosis and RA.