Search

Tumor necrosis factor superfamily-15 ( TNFSF15; VEGI; TL1A) is a negative modulator of angiogenesis for blood vessel homeostasis and is produced by endothelial cells in a mature vasculature. It is known to be downregulated by vascular endothelial growth factor ( VEGF), a major regulator of neovascularization but the mechanism of this interaction is unclear. Here we report that VEGF is able to stimulate the production of two micro RNAs, miR-20a and miR-31, which directly target the 3′- UTR of TNFSF15. Additionally, we show that two VEGF-stimulated cell growth signals, Erk and Akt, are responsible for promoting the expression of miR-20a and miR-31. Treatment of human umbilical vein endothelial cells ( HUVECs) with Akt inhibitor LY294002 results in diminished miR-20a and miR-31 production, while Erk inhibitor U0126 prevented VEGF-stimulated expression of miR-20a but not that of miR-31. Furthermore, inactivation of either Erk or Akt signals restores TNFSF15 gene expression. In an angiogenesis assay, elevated miR-20a or miR-31 levels in HUVECs leads to enhancement of capillary-like tubule formation in vitro, whereas lowered miR-20a and miR-31 levels results in an inhibition. These findings are consistent with the view that miR-20a and miR-31 mediate VEGF-induced downregulation of TNFSF15. Targeting these micro RNA molecules may therefore provide an effective approach to inhibit angiogenesis. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2S) is an important endogenous signaling molecule with a variety of biological functions. Development of fluorescent probes for highly selective and sensitive detection of H2S is necessary. We show here that dual-reactable fluorescent H2S probes could react with higher selectivity than single-reactable probes. One of the dual-reactable probes gives more than 4000-fold turn-on response when reacting with H2S, the largest response among fluorescent H2S probes reported thus far. In addition, the probe could be used for high-throughput enzymatic assays and for the detection of Cys-induced H2S in cells and in zebrafish. These dual-reactable probes hold potential for highly selective and sensitive detection of H2S in biological systems. [ABSTRACT FROM AUTHOR]

Introduction: Basal cell carcinoma (BCC) is the most common skin cancer, lacking reliable biomarkers or therapeutic targets for effective treatment. Genome-wide association studies (GWAS) can aid in identifying drug targets, repurposing existing drugs, predicting clinical trial side effects, and reclassifying patients in clinical utility. Hence, the present study investigates the association between plasma proteins and skin cancer to identify effective biomarkers and therapeutic targets for BCC., Methods: Proteome-wide mendelian randomization was performed using inverse-variance-weight and Wald Ratio methods, leveraging 1 Mb cis protein quantitative trait loci (cis-pQTLs) in the UK Biobank Pharma Proteomics Project (UKB-PPP) and the deCODE Health Study, to determine the causal relationship between plasma proteins and skin cancer and its subtypes in the FinnGen R10 study and the SAIGE database of Lee lab. Significant association with skin cancer and its subtypes was defined as a false discovery rate (FDR) < 0.05. pQTL to GWAS colocalization analysis was executed using a Bayesian model to evaluate five exclusive hypotheses. Strong colocalization evidence was defined as a posterior probability for shared causal variants (PP.H4) of ≥0.85. Mendelian randomization-Phenome-wide association studies (MR-PheWAS) were used to evaluate potential biomarkers and therapeutic targets for skin cancer and its subtypes within a phenome-wide human disease category., Results: PTGES2, RNASET2, SF3B4, STX8, ENO2, and HS3ST3B1 (besides RNASET2, five other plasma proteins were previously unknown in expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL)) were significantly associated with BCC after FDR correction in the UKB-PPP and deCODE studies. Reverse MR showed no association between BCC and these proteins. PTGES2 and RNASET2 exhibited strong evidence of colocalization with BCC based on a posterior probability PP.H4 >0.92. Furthermore, MR-PheWAS analysis showed that BCC was the most significant phenotype associated with PTGES2 and RNASET2 among 2,408 phenotypes in the FinnGen R10 study. Therefore, PTGES2 and RNASET2 are highlighted as effective biomarkers and therapeutic targets for BCC within the phenome-wide human disease category., Conclusion: The study identifies PTGES2 and RNASET2 plasma proteins as novel, reliable biomarkers and therapeutic targets for BCC, suggesting more effective clinical application strategies for patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Han, Zhu, Sun, Ding, Wang and Zhang.)

Near-infrared (NIR) fluorescence-based sensors capable of selective detection of H 2 S in vivo would be useful tools to understand the mechanisms of diseases. A new NIR fluorescence probe 1 was developed for the detection of endogenous H 2 S in colorectal cancer cells in mice. 1 displayed an 87-fold fluorescence enhancement at 796 nm (with excitation at 730 nm) when reacted with H 2 S in a buffer (pH 7.4). 1 was water-soluble, cell-membrane-permeable, had low cytotoxicity and high selectivity and sensitivity for H 2 S. The properties of 1 enable its use in monitoring endogenous H 2 S in living cells, tissues, and mice. The bioimaging results indicated that (1) d-Cys could induce endogenous H 2 S production in living cells and stimulate angiogenesis; (2) tail intravenous injection of 1 into mice generated strong fluorescence in the liver while intraperitoneal injection of d-Cys could further enhance fluorescence in the liver in vivo ; (3) importantly, endogenous H 2 S in colorectal cancer cells (HCT116, HT29) in vitro and in murine tumor models could be quickly and selectively detected by intratumoral injection of 1 . These results indicated that our new probe could serve as an efficient tool for the detection of cellular H 2 S in living animals and even for cancer diagnosis.

Vascular endothelial cell growth factor (VEGF) plays a pivotal role in promoting neovascularization. VEGF gene expression in vascular endothelial cells in normal tissues is maintained at low levels but becomes highly up-regulated in a variety of disease settings including cancers. Tumor necrosis factor superfamily 15 (TNFSF15; VEGI; TL1A) is an anti-angiogenic cytokine prominently produced by endothelial cells in a normal vasculature. We report here that VEGF production in mouse endothelial cell line bEnd.3 can be inhibited by TNFSF15 via microRNA-29b (miR-29b) that targets the 3'-UTR of VEGF transcript. Blocking TNFSF15 activity by using either siRNA against the TNFSF15 receptor known as death domain-containing receptor-3 (DR3; TNFRSF25), or a neutralizing antibody 4-3H against TNFSF15, led to inhibition of miR-29b expression and reinvigoration of VEGF production. In addition, we found that TNFSF15 activated the JNK signaling pathway as well as the transcription factor GATA3, resulting in enhanced miR-29b production. Treatment of the cells either with SP600125, an inhibitor of JNK, or with JNK siRNA, led to eradication of TNFSF15-induced GATA3 expression. Moreover, GATA3 siRNA suppressed TNFSF15-induced miR-29b expression. These findings suggest that VEGF gene expression can be suppressed by TNFSF15-stimulated activation of the JNK-GATA3 signaling pathway which gives rise to up-regulation of miR-29b.

Hydrogen sulfide (H2 S) is an important endogenous signaling molecule with multiple biological functions. New selective fluorescent turn-on probes based on fast thiolyling of NBD (7-nitro-1,2,3-benzoxadiazole) amine were explored for sensing H2 S in aqueous buffer and in living cells. The syntheses of both probes are simple and quite straightforward. The probes are highly sensitive and selective toward H2 S over other biologically relevant species. The fluorescein-NBD-based probe showed 65-fold green fluorescent increase upon H2 S activation. The rhodamine-NBD-based probe reacted rapidly with H2 S (t1/2 ≈1 min) to give a 4.5-fold increase in red fluorescence. Moreover, both probes were successfully used for monitoring H2 S in living cells and in mice. Based on such probe-based tools, we could observe H2 O2 -induced H2 S biogenesis in a concentration-dependent and time-dependent fashion in living cells., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)