Zinc mediates the SREBP-SCD axis to regulate lipid metabolism in Caenorhabditis elegans.

Maintenance of lipid homeostasis is crucial for cells in response to lipid requirements or surplus. The SREBP transcription factors play essential roles in regulating lipid metabolism and are associated with many metabolic diseases. However, SREBP regulation of lipid metabolism is still not completely understood. Here, we showed that reduction of SBP-1, the only homolog of SREBPs in Caenorhabditis elegans, surprisingly led to a high level of zinc. On the contrary, zinc reduction by mutation of sur-7, encoding a member of the cation diffusion facilitator (CDF) family, restored the fat accumulation and fatty acid profile of the sbp-1(ep79) mutant. Zinc reduction resulted in iron overload, which thereby directly activated the conversion activity of stearoyl-CoA desaturase (SCD), a main target of SREBP, to promote lipid biosynthesis and accumulation. However, zinc reduction reversely repressed SBP-1 nuclear translocation and further downregulated the transcription expression of SCD for compensation. Collectively, we revealed zinc-mediated regulation of the SREBP-SCD axis in lipid metabolism, distinct from the negative regulation of SREBP-1 or SREBP-2 by phosphatidylcholine or cholesterol, respectively, thereby providing novel insights into the regulation of lipid homeostasis.

Targeting PSG1 to enhance chemotherapeutic efficacy: new application for anti-coagulant the dicumarol.

Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-ß (TGF-ß)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM.

Experimental evidence for cancer resistance in a bat species.

Mammals exhibit different rates of cancer, with long-lived species generally showing greater resistance. Although bats have been suggested to be resistant to cancer due to their longevity, this has yet to be systematically examined. Here, we investigate cancer resistance across seven bat species by activating oncogenic genes in their primary cells. Both in vitro and in vivo experiments suggest that Myotis pilosus (MPI) is particularly resistant to cancer. The transcriptomic and functional analyses reveal that the downregulation of three genes (HIF1A, COPS5, and RPS3) largely contributes to cancer resistance in MPI. Further, we identify the loss of a potential enhancer containing the HIF1A binding site upstream of COPS5 in MPI, resulting in the downregulation of COPS5. These findings not only provide direct experimental evidence for cancer resistance in a bat species but also offer insights into the natural mechanisms of cancer resistance in mammals.

Integrative Functional Transcriptomic Analyses Implicate Shared Molecular Circuits in Sensorineural Hearing Loss.

Sensorineural hearing loss (SNHL) is referred to as the most common type of hearing loss and typically occurs when the inner ear or the auditory nerve is damaged. Aging, noise exposure, and ototoxic drugs represent three main causes of SNHL, leading to substantial similarities in pathophysiological characteristics of cochlear degeneration. Although the common molecular mechanisms are widely assumed to underlie these similarities, its validity lacks systematic examination. To address this question, we generated three SNHL mouse models from aging, noise exposure, and cisplatin ototoxicity, respectively. Through constructing gene co-expression networks for the cochlear transcriptome data across different hearing-damaged stages, the three models are found to significantly correlate with each other in multiple gene co-expression modules that implicate distinct biological functions, including apoptosis, immune, inflammation, and ion transport. Bioinformatics analyses reveal several potential hub regulators, such as IL1B and CCL2, both of which are verified to contribute to apoptosis accompanied by the increase of (ROS) in in vitro model system. Our findings disentangle the shared molecular circuits across different types of SNHL, providing potential targets for the broad effective therapeutic agents in SNHL.

[Evaluation of immune status of kidney transplant recipients by combined HLA-G5 and sCD30].

OBJECTIVE: to study the relationship between the expression of serum human leucocyte antigen-G5 (HLA-G5)/soluble CD30 (sCD30) and the function of renal graft in kidney transplant recipients and investigate the immune status of recipients with combined HLA-G5 and sCD30. METHODS: from January 2002 to November 2008, a total of 66 kidney transplant recipients in our centre were selected as subjects and divided into three groups: stable function of renal graft (n = 38), acute rejection (n = 15) and chronic rejection (n = 13). The expressions of serum HLA-G5 and sCD30 were detected. There were two different immune conditions with acute/chronic allograft rejection and normal renal graft in kidney transplant recipients as evaluated by combined HLA-G5 and sCD30. The sensitivity, specificity and critical value of the method were analyzed by the curve of receiver operating characteristic. RESULTS: the levels of HLA-G5 and sCD30 were significantly correlated with serum creatinine (r = -0.493, 0.691, both P < 0.01). Within the first year post-transplantation, the sensitivity was 78.6% and the specificity 85.7% when HLA-G5 critical value 82 microg/L and sCD30 critical value 12.2 microg/L. After one year post-transplantation: the sensitivity was 92.3% and the specificity 84.6% when HLA-G5 critical value 141 microg/L and sCD30 critical value 10.3 microg/L. CONCLUSION: the immune state of recipients are evaluated by combine HLA-G5 and sCD30 which may be a simple and valid method.

Multiple-biomarkers provide powerful prediction of early acute renal allograft rejection by combination of serum fractalkine, IFN-γ and IP-10.

Biomarkers are urgently required for predicting rejection so that anti-rejection treatment can be taken early to protect the allograft from irreversible damage. We hypothesized that the combination of circulating fractalkine, IFN-γ and IP-10 might serve as effective biomarkers for predicting early acute renal allograft rejection. We conducted a retrospective study of 87 subjects, who were classified into acute rejection group (ARG; n = 38) and non-rejection group (NRG; n = 49). Serum fractalkine, IFN-γ and IP-10 levels were measured by Luminex. The levels of fractalkine on day 0 and 7th day, IP-10 on 4th and 7th day, and IFN-γ on 7th day in ARG was significantly higher than that in NRG. Kaplan-Meier survival analysis highlighted the higher-levels groups of fractalkine on day 0, 4th and 7th day, IFN-γ on day 0, 1st, 4th, and 7th day and IP-10 on the 4th and 7th day in rejection-free survival probability were significantly lower than low-levels groups. ROC analyses highlight the superiority of fractalkine on day 0, IP-10 on day 0, 4th and 7th day, and IFN-γ on day 0, 1st and 7th day in prediction of acute rejection. We found the combination of fractalkine on day 0, IP-10 on 7th day and IFN-γ on 7th day had the highest AUC (0.866) for predicting rejection with a sensitivity of 86.8% and a specificity of 89.8%. Our findings demonstrated a more powerful prediction of early acute renal allograft rejection during the first month after transplantation by combination of multiple-biomarkers of fractalkine, IFN-γ and IP-10, and the results might help stratify the immunologic risk of acute allograft rejection in recipients.

Genome-wide profiles of methylation, microRNAs, and gene expression in chemoresistant breast cancer.

Cancer chemoresistance is regulated by complex genetic and epigenetic networks. In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX). We found that: ① both of the chemoresistant cell lines had similar, massive changes in gene expression, methylation, and miRNA expression versus chemosensitive controls. ② Pairwise integration of the data highlighted sets of genes that were regulated by either methylation or miRNAs, and sets of miRNAs whose expression was controlled by DNA methylation in chemoresistant cells. ③ By combining the three sets of high-throughput data, we obtained a list of genes whose expression was regulated by both methylation and miRNAs in chemoresistant cells; ④ Expression of these genes was then validated in clinical breast cancer samples to generate a 17-gene signature that showed good predictive and prognostic power in triple-negative breast cancer patients receiving anthracycline-taxane-based neoadjuvant chemotherapy. In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance.