Translational research : the journal of laboratory and clinical medicine
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An increasing body of evidence shows a role for macrophages and monocytes (as their precursors) in hypertension, but with conflicting results with regard to whether they are protective or harmful. Therefore, we systematically reviewed the effect of macrophage interventions on blood pressure in animal models, to explore which factors determine the blood pressure increasing vs. decreasing effect. A search in PubMED and EMBASE yielded 9620 records, 26 of which were included. ⋯ Prespecified subgroup analysis did reveal a potential role for the route in which the macrophage-depleting agent is being administrated (intraperitoneal vs intravenous subgroup difference of P = 0.07 (k = 22), or P < 0.001 in studies achieving considerable (ie, >50%) depletion (k = 18)). Along with findings from specific macrophage protein deletion studies-showing that deletion of one single macrophage protein (like TonEBP, endothelin-B, EP4, NOX-2 and the angiotensin II type 1 receptor) can alter blood pressure responses to hypertensive stimuli-the indication that each route has its specific depletion pattern regarding targeted tissues and macrophage phenotypes suggests a determinative role for these features. These hypothesis-generating results encourage more detailed depletion characterization of each technique by direct experimental comparisons, providing a chance to obtain more knowledge on which macrophages are beneficial versus detrimental in hypertension development.
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Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-age women. Reduced progesterone levels are associated with luteal phase deficiency in women with PCOS. The levels of C-X-C motif chemokine ligand-14 (CXCL14) were previously reported to be decreased in human-luteinized granulosa (hGL) cells derived from PCOS patients. ⋯ P38 and Jun N-terminal kinase (JNK) pathways were also activated by CXCL14 and inhibition of p38 and JNK attenuated the increase of phosphorylation of CREB, STAR expression and progesterone production caused by CXCL14. Our findings revealed the novel role of CXCL14 in upregulation of STAR expression and progesterone synthesis through CREB phosphorylation via activation of p38 and JNK pathways in hGL cells. This is likely contributing to the dysfunction in steroidogenesis in granulosa cells from PCOS patients.
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A fraction of the transcriptome is translated into proteins. The rest is classified as non-protein coding RNA (Ribonucleic Acid) but has gained increased attention as functional and regulatory group of transcripts. The gene regulatory role of non-coding RNAs (ncRNAs) has now been widely accepted in diverse biological processes in both physiology and disease. ⋯ The presence of RISC components including microRNAs in the nucleus supports this notion. They may integrate with chromatin modifiers, microprocessing machinery and mRNA stabilizing transcripts to play a multifunctional role in the nucleus. Although a limited number of studies appreciate this novel activity of microRNAs relevant to the cardiovascular system, they provide proof-of-concept that requires consideration while targeting miRNAs with therapeutic potential.
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Functional studies of long noncoding RNAs (lncRNAs) are often performed in the context of only a single cancer type. However, the tissue-specific expression patterns of lncRNAs raise the question of whether lncRNA associations identified in one cancer type are relevant to other cancer types. Here, we examine the relationships between the expression levels of 50 cancer-related lncRNAs and survival data from 24 types of cancer in The Cancer Genome Atlas (TCGA) with the goal of identifying prognosis related lncRNAs. ⋯ In addition, in low-grade glioma (LGG), prognostic-related lncRNAs are identified after conditioning on known clinical biomarker and common therapy, revealing that 2 lncRNAs, FOXP4-AS1, and NEAT1, are associated with temozolomide response-a standard-of-care in LGG. Pathway analysis suggests NF-kB/STAT3 signaling pathway enrichment in LGG patients with high NEAT1 expression and DNA repair/myc gene set enrichment in LGG patients with high expression of FOXP4-AS1. Our work demonstrates the context dependency of lncRNAs across cancer types and highlights a number of lncRNAs as potential novel cancer prognosis markers.
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Loss of hepatocellular carcinoma-related protein 1 (HCRP1) (alias VPS37A) plays a role in endocytosis of receptor tyrosine kinases as a member of the ESCRT complex and has been linked to poor patient outcome in various types of epithelial cancer. To this date, the molecular and biological mechanisms explaining how its absence would contribute to tumor progression remain unknown. Using genomic editing with CRISPR-Cas9, we generated ovarian and breast cancer cell lines with loss-of-function mutations of HCRP1. ⋯ In our study, we show that endogenous deletion of HCRP1 leads to elevated phosphorylation of the transcription factor Signal transducer and activator of transcription 3 (STAT3) and induces upregulation of PD-L1, an important regulator of immune checkpoint inhibition. HCRP1 loss further leads to a mesenchymal phenotype switch in cancer cells, leading to increased proliferation and migration. Concludingly, our data emphasize the role of the tumor microenvironment in tumors with low or absent HCRP1 expression and suggest HCRP1 loss as a potential marker for metastatic potential and immunogenicity of epidermal growth factor receptor-driven cancer.