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Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Circular RNAs (circRNAs), a novel class of non-coding RNA, have been reported to be involved in the etiology of various malignancies. However, the underlying cellular mechanisms of circRNAs implicated in the pathogenesis of HCC remain unknown. In this study, we identified a functional RNA, hsa_circ_0000384 (circMRPS35), from public tumor databases using a set of computational analyses, and we further identified that circMRPS35 was highly expressed in 35 pairs of HCC from patients. Moreover, knockdown of the expression of circMRPS35 in Huh-7 and HCC-LM3 cells suppressed their proliferation, migration, invasion, clone formation, and cell cycle in vitro, and it suppressed tumor growth in vivo as well. Mechanically, circMRPS35 sponged microRNA-148a-3p (miR-148a), regulating the expression of Syntaxin 3 (STX3), which modulated the ubiquitination and degradation of phosphatase and tensin homolog (PTEN). Unexpectedly, we detected a peptide encoded by circMRPS35 (circMRPS35-168aa), which was significantly induced by chemotherapeutic drugs and promoted cisplatin resistance in HCC. These results demonstrated that circMRPS35 might be a novel mediator in HCC progress, and they raise the potential of a new biomarker for HCC diagnosis and prognosis, as well as a novel therapeutic target for HCC patients.

In obesity, macrophages drive a low-grade systemic inflammation (LSI) and insulin resistance (IR). The ribosome biosynthesis protein NOC4 (NOC4) mediates 40 S ribosomal subunits synthesis in yeast. Hereby, we reported an unexpected location and function of NOC4L, which was preferentially expressed in human and mouse macrophages. NOC4L was decreased in both obese human and mice. The macrophage-specific deletion of Noc4l in mice displayed IR and LSI. Conversely, Noc4l overexpression by lentivirus treatment and transgenic mouse model improved glucose metabolism in mice. Importantly, we found that Noc4l can interact with TLR4 to inhibit its endocytosis and block the TRIF pathway, thereafter ameliorated LSI and IR in mice., Macrophage inflammation promotes insulin resistance during diet-induced obesity. Here the authors show that macrophage NOC4L is decreased in humans and mice with obesity, that macrophage NOC4L deficiency aggravated high-fat diet induced inflammation and insulin resistance, and that NOC4L interacts with toll-like receptor 4, to inhibit endocytosis, and thus blocks TLF4/TRIF inflammatory signaling.

Hepatocellular carcinoma (HCC), a common malignant tumor, is one of the main causes of cancer-related deaths worldwide. Circular RNAs (circRNAs), a novel class of non-coding RNA, have been reported to be involved in the etiology of various malignancy. However, the functions of circRNAs in HCC remain unclear. In this study, through mining the RNA sequencing databases from GEO datasets and subsequent experimental verification, we identified that hsa_circ_0000384 (circMRPS35) was highly expressed in HCC. Knockdown of circMRPS35 suppressed the proliferation, migration, invasion, clone formation and cell cycle of HCC cell lines both in vitro and in a xenograft mouse model. Mechanically, circMRPS35 sponged microRNA-148a-3p (miR-148a), which in turn regulated STX3-PTEN axis. Surprisingly, we detected a peptide encoded by circMRPS35 (circMRPS35-168aa), which was significantly induced by chemotherapeutic drugs and promoted cisplatin resistance in HCC cells. These results demonstrated that circMRPS35 might be a novel factor in HCC progress, and has a great potential as a new diagnosis and therapeutic target for treatment of HCC.

Zika virus (ZIKV) was first isolated in 1947 from a rhesus monkey in the Zika forest of Uganda. ZIKV has since been silently circulating in a number of equatorial countries for over 50 years. The largest outbreak in humans occurred in Brazil in 2015-2016. Unlike its flavivirus relatives, sexual and post-transfusion transmissions of ZIKV have been reported. In addition, fetal infection can result in microcephaly and congenital Zikv syndrome has been reported in neonates. Moreover, ZIKV RNA can persist for at least 6 months in semen and 11 weeks in vaginal secretions after the infection, suggesting potential tropism for the male and female genital tracts. Accordingly, it is important to determine whether genital ZIKV infection could have deleterious effects on the male and female reproductive systems.

Polycystic ovary syndrome (PCOS) is a common endocrine abnormality in women characterized by a menstrual disturbance with chronic anovulation and hyperandrogenism, polycystic ovaries, and insulin resistance. MicroRNAs (miRNAs) are important fine-tune regulators involved in various physiological and pathological processes, but their actions are not fully understood. In this study, we observed the increased expression of miR-27a-3p in the ovaries of mice with PCOS and explored its functions in primary mouse granulosa cells (mGCs) and the mouse granulosa-like tumor cell line, KK-1, using several approaches. QPCR results showed that miR-27a-3p expression was significantly higher in mGCs at the preantral follicle (PrF) stage. Using flow cytometry and hormone analysis, we found that overexpression of miR-27a-3p promoted apoptosis and inhibited estradiol (E2) production in KK-1 cells. Moreover using a luciferase assay and Western blotting analysis, we verified that the gene of cyclic AMP response element (CRE)-binding protein 1 (Creb1) was a potential target of miR-27a-3p, which in effect hindered the expression of its downstream factor cytochrome P450 family 19 subfamily A polypeptide 1 (Cyp19a1). With the decrease of aromatase activity, testosterone (T) is reduced to dihydrotestosterone (DHT) and this exerts its effect of upregulation of the miR-27a-3p expression. The imbalance of androgen and E2 levels affected by miR-27a-3p and its function of promoting GC apoptosis could be involved in the pathophysiology of PCOS. Our results indicate that miR-27a-3p in PCOS GCs may play an important role in ovarian follicular development and provide new insights into GC dysfunction in PCOS.

Serum amyloid A (SAA), one of the major highly conserved acute-phase proteins in most mammals, is predominantly produced by hepatocytes and also by a variety of cells in extrahepatic tissues. It is well-known that the expression of SAA is sharply increased in bacterial infections. However, the exact physiological function of SAA during bacterial infection remains unclear. Herein, we showed that SAA expression significantly increased in abscesses of Staphylococcus aureus cutaneous infected mice, which exert direct antibacterial effects by binding to the bacterial cell surface and disrupting the cell membrane in acidic conditions. Mechanically, SAA disrupts anionic liposomes by spontaneously forming small vesicles or micelles under acidic conditions. Especially, the N-terminal region of SAA is necessary for membrane disruption and bactericidal activity. Furthermore, we found that mice deficient in SAA1/2 were more susceptible to infection by S. aureus. In addition, the expression of SAA in infected skin was regulated by interleukin-6. Taken together, these findings support a key role of the SAA in host defense and may provide a novel therapeutic strategy for cutaneous bacterial infection.

Recent advances in the multi-omics characterization necessitate pathway-level abstraction and knowledge integration across different data types. In this study, we apply independent component analysis (ICA) to human breast cancer proteogenomics data to retrieve mechanistic information. We show that as an unsupervised feature extraction method, ICA was able to construct signatures with known biological relevance on both transcriptome and proteome levels. Moreover, proteome and transcriptome signatures can be associated by their respective correlation with patient clinical features, providing an integrated description of phenotype-related biological processes. Our results demonstrate that the application of ICA to proteogenomics data could lead to pathway-level knowledge discovery. Potential extension of this approach to other data and cancer types may contribute to pan-cancer integration of multi-omics information.

Zika virus (ZIKV) persists in the semen of male patients, a first for flavivirus infection. Here, we demonstrate that ZIKV can induce inflammation in the testis and epididymidis, but not in the prostate or seminal vesicle, and can lead to damaged testes after 60 days post-infection in mice. ZIKV induces innate immune responses in Leydig, Sertoli, and epididymal epithelial cells, resulting in the production of pro-inflammatory cytokines/chemokines. However, ZIKV does not induce a rapid and abundant cytokine production in peritubular cell and spermatogonia, suggesting that these cells are vulnerable for ZIKV infection and could be the potential repositories for ZIKV. Our study demonstrates a correlation between ZIKV and testis infection/damage and suggests that ZIKV infection, under certain circumstances, can eventually lead to male infertility.