Differentially expressed transcripts and associated protein pathways in basilar artery smooth muscle cells of the high-salt intake–induced hypertensive rat
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The pathology of cerebrovascular disorders, such as hypertension, is associated with genetic changes and dysfunction of basilar artery smooth muscle cells (BASMCs). Long-term high-salt diets have been associated with the development of hypertension. However, the molecular mechanisms underlying salt-sensitive hypertension-induced BASMC modifications have not been well defined, especially at the level of variations in gene transcription. Here, we utilized high-throughput sequencing and subsequent signaling pathway analyses to find a two–fold change or greater upregulated expression of 203 transcripts and downregulated expression of 165 transcripts in BASMCs derived from rats fed a high-salt diet compared with those from control rats. These differentially expressed transcripts were enriched in pathways involved in cellular, morphological, and structural plasticity, autophagy, and endocrine regulation. These transcripts changes in the BASMCs derived from high-salt intake–induced hypertensive rats may provide critical information about multiple cellular processes and biological functions that occur during the development of cerebrovascular disorders and provide potential new targets to help control or block the development of hypertension.Hypoxia
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WP1130, a partially selective deubiquitinases (DUB) inhibitor, inhibits the deubiquitinating activities of USP5, USP9X, USP14, USP37, and UCHL1. In this study, we investigate whether WP1130 exerts sensitizing effect on TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. Combinations of WP1130 and TRAIL significantly induced apoptosis in renal carcinoma, lung carcinoma and hepatocellular carcinoma cells, but not in normal cells (human mesangial cells (MC) and normal mouse kidney cells (TCMK-1)). The downregulation of c-FLIP protein expression was involved in combined treatment-induced apoptosis. WP1130-induced c-FLIP downregulation was regulated by microRNA (miR)-708 upregulation via inhibition of USP9X. Interestingly, knockdown of USP9X markedly induced c-FLIP downregulation, upregulation of miR-708 expression and sensitivity to TRAIL. Furthermore, ectopic expression of USP9X prevented c-FLIP downregulation and apoptosis upon combined treatment. In sum, WP1130 sensitized TRAIL-induced apoptosis through miR-708-mediated downregulation of c-FLIP by inhibition of USP9X.
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Most of advanced hypopharyngeal squamous cell carcinoma (HSCC) are resistant to chemotherapy, and there is still lack of effective treatment for HSCC now. The present study aimed to investigate whether downregulation of RNA-binding motif protein 17 (RBM17) could enhance cisplatin sensitivity and inhibit cell invasion in HSCC and the underlying mechanism. We observed that RBM17 was upregulated in tumor tissues and associated with poor progression. Treatment of FaDu cells with cisplatin increased RBM17 expression in mRNA levels. Downregulation of RBM17 enhanced cisplatin-mediated inhibition of FaDu cells. In addition, downregulation of RBM17 effectively suppressed tumor cell migration and invasion through the reversion of epithelial-mesenchymal transition. Moreover, downregulation of RBM17 could significantly slow tumor growth in FaDu xenograft tumor model. Liquid chromatography-mass spectrometry/mass spectrometry detection and independent PRM analysis showed that 21 differentially expressed proteins were associated with the downregulation of RBM17. Taken together, our study implied that downregulation of RBM17 could serve as a novel approach to enhance cisplatin sensitivity in HSCC.
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Two Ca 2+ ‐activated Cl − currents ( I Cl(Ca) ) are present in vascular smooth muscle (VSMC). One is cGMP dependent, the other is characterized as a classical I Cl(Ca) . Here we downregulate bestrophin‐3 (best3) and TMEM16A, to assess their importance for the two I Cl(Ca) and for the role of I Cl(Ca) in vascular function. Best3 and TMEM16A were downregulated in rat small mesenteric arteries using siRNA. Knockdown was confirmed at mRNA and protein levels 3 days after transfection. Best3 downregulation suppressed the cGMP‐dependent I Cl(Ca) while TMEM16A downregulation suppresed both I Cl(Ca) s. Both best3 and TMEM16A downregulation suppressed oscillations in vascular tone i.e. vasomotion. Best3 downregulation was without effect on sensitivity and maximal force production to norepinephrine while TMEM16A downregulation significantly reduced both. Also the force production to 125 mM KCl was reduced by TMEM16A downregulation. We conclude that TMEM16A is essential for both I Cl(Ca) s while best3 may be modifying the TMEM16A current characteristics in a subset of channels. The cGMP‐dependent I Cl(Ca) is critical for vasomotion and normal expression of TMEM16 is essential for VSMC conctractility.
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Maritoclax, an active constituent isolated from marine bacteria, has been known to induce Mcl-1 downregulation through proteasomal degradation. In this study, we investigated the sensitizing effect of maritoclax on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. We found that combined treatment with maritoclax and TRAIL markedly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung cancer (A549) and hepatocellular carcinoma (SK-Hep1) cells. The upregulation of death receptor 5 (DR5) and downregulation of cellular FLICE-inhibitory protein (cFLIP) were involved in maritoclax plus TRAIL-induced apoptosis. Maritoclax-induced DR5 upregulation was regulated by induction of C/EBP homologous protein (CHOP) expression. Interestingly, maritoclax induced cFLIP downregulation through the increased expression of miR-708. Ectopic expression of cFLIP prevented combined maritoclax and TRAIL-induced apoptosis. Taken together, maritoclax sensitized TRAIL-induced apoptosis through CHOP-mediated DR5 upregulation and miR-708-mediated cFLIP downregulation.
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Maternal viral infection is known to increase the risk for schizophrenia and autism in their offspring (Brown et al, 2004). C57BL/6 mice were infected with human influenza virus on day E18 of pregnancy and brains were collected at PN days 0, 14, or 56, from virally-exposed (N=3) or sham-infected control's (N=3) offspring. Microarray analysis of virally-exposed mouse brains showed significant (p<0.05) upregulation of 15 genes and downregulation of 3 genes in cerebellum, upregulation of 42 genes and downregulation of 9 genes in hippocampus, and upregulation of 4 genes and downregulation of 5 genes in prefrontal cortex vs. controls in day 0 mice. At day 14, there was a significant upregulation of 2 genes and downregulation of 0 genes in cerebellum, upregulation of 1 gene and downregulation of 1 gene in hippocampus, and upregulation of 3 genes and downregulation of 3 genes in prefrontal cortex vs. controls. At day 56, there was a significant upregulation of 13 genes and downregulation of 2 genes in cerebellum, upregulation of 4 genes and downregulation of 3 genes in hippocampus, and upregulation of 4 genes and downregulation of 1 gene in prefrontal cortex vs. controls. Implications of changes in brain genes for development of abnormal brain structure and function will be discussed. The generous support by the National Institute for Child Health and Human Development (1-R01-HD046589-01A2) to S.H.F. is greatly appreciated.
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Cancer cells differ from normal cells in both gain of functions (i.e., upregulation) and loss of functions (i.e., downregulation). While it is common to suppress gain of function for chemotherapy, it remains challenging to target downregulation in cancer cells. Here we show the combination of enzyme-instructed assembly and disassembly to target downregulation in cancer cells by designing peptidic precursors as the substrates of both carboxylesterases (CESs) and alkaline phosphatases (ALPs). The precursors turn into self-assembling molecules to form nanofibrils upon dephosphorylation by ALP, but CES-catalyzed cleavage of the ester bond on the molecules results in disassembly of the nanofibrils. The precursors selectively inhibit the cancer cells that downregulate CES (e.g., OVSAHO) but are innocuous to a hepatocyte that overexpresses CES (HepG2), while the two cell lines exhibit comparable ALP activities. This work illustrates a potential approach for the development of chemotherapy via targeting downregulation (or loss of functions) in cancer cells.
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