作者: Xiao, Xueqi ; Liu, Shengduo ; Zou, Jian ; Liu, Yutong ; Zhang, Qian ; Shen, Qin ; Lian, Lili ; Chen, Shasha ; Liang, Tingbo ; Chen, Chen ; Le, Zhenmin ; Zhang, Dan ; Wang, Ailian ; Zheng, Qinxiang ; Xu, Pinglong

Characterized by progressive degeneration of retinal ganglion cells (RGCs) and vision loss, glaucoma is the primary cause of irreversible blindness, incurable and affecting over 78 million patients. However, pathogenic mechanisms leading to glaucoma-induced RGC loss are incompletely understood. Unexpectedly, we found that cGAS–STING (2′3′-cyclic GMP-AMP–stimulator of interferon genes) signaling, which surveils displaced double-stranded DNA (dsDNA) in the cytosol and initiates innate immune responses, was robustly activated during glaucoma in retinal microglia in distinct murine models. Global or microglial deletion of STING markedly relieved glaucoma symptoms and protected RGC degeneration and vision loss, while mice bearing genetic cGAS–STING supersensitivity aggravated retinal neuroinflammation and RGC loss. Mechanistically, dsDNA from tissue injury activated microglial cGAS–STING signaling, causing deleterious macroglia reactivity in retinas by cytokine-mediated microglia–macroglia interactions, progressively driving apoptotic death of RGCs. Remarkably, preclinical investigations of targeting cGAS–STING signaling by intraocular injection of TBK1i or anti-IFNAR1 antibody prevented glaucoma-induced losses of RGCs and vision. Therefore, we unravel an essential role of cGAS–STING signaling underlying glaucoma pathogenesis and suggest promising therapeutic strategies for treating this devastating disease.

2013-07-01·International Journal of Molecular Medicine3区 · 医学

Inhibition of arginine ADP-ribosyltransferase 1 reduces the expression of poly(ADP-ribose) polymerase-1 in colon carcinoma

3区 · 医学

Article

作者: Wei Xiong ; Yi Tang ; Jian-Xia Xu ; Ming Li ; Ya-Lan Wang ; Lian Yang ; Ming Xiao

Poly(ADP-ribose) polymerase-1 (PARP-1) which mediates poly-ADP-ribosylation, has been extensively investigated in carcinoma compared to arginine ADP-ribosyltransferase 1 (ART1), which mediates mono‑ADP‑ribosylation. Previous studies have demonstrated that these enzymes promote proliferation and tumor development in colon carcinoma. However, whether there is any association between PARP-1 and ATR1 in colon carcinoma, remains unelucidated. In this study, using immunohistochemical analysis, we detected a higher expression of PARP-1 and ART1 in 63 samples from patients with colon carcinoma compared to 10 samples of normal colonic mucosa; our results revealed a positive correlation between the expression of PARP-1 and ART1 in the 63 human colon carcinoma tissue samples. To determine the correlation between PARP-1 and ART1, inhibitors of PARP-1 and ART1 and lentivirus vector‑mediated ART1 short‑hairpin RNA (shRNA) were used to culture CT26 murine colon adenocarcinoma cells separately. Using double‑label immunofluorescence assay, we detected the expression of PARP-1 in the CT26 cells, which was decreased following treatment with 5‑aminoisoquinolinone (5-AIQ, a PARP-1 inhibitor) or meta‑iodobenzylguanidine (MIBG, an ART1 inhibitor). However, the expression of ART1 only decreased when the CT26 cells were treated with MIBG. Furthermore, our results demonstrated that silencing ART1 inhibited PARP‑1 expression by decreasing the expression of nuclear factor-κB (NF-κB), inhibiting ras homolog A (RhoA). Hence, our data demonstrate the positive correlation between ART1 and PARP-1; the inhibition of ART1 activity downregulates PARP-1 expression by decreasing the activity of NF-κB in CT26 colon carcinoma cells.

2005-09-30·Journal of Medical Ultrasonics4区 · 医学

Contribution of the renin-angiotensin system to the intrarenal resistive index in chronic unilateral partial ureteral obstruction in dogs

4区 · 医学

Article

作者: Tsuji, Yuji ; Yokoyama, Hiroshi

PURPOSEWe investigated the role of the renin-angiotensin system on intrarenal hemodynamics in chronic unilateral partial ureteral obstruction (UPUO) using Doppler ultrasound (US).METHODSIn 11 dogs with chronic UPUO, we determined the renal resistive index (RI) before and 1 h after the intravenous infusion of an angiotensin-converting enzyme (ACE) inhibitor (captopril), an angiotensin II receptor type 1 (ART1) antagonist (L-158,809), and the combination of these two drugs. Change in resistive index (ΔRI) was calculated as RI after the administration of each tested material minus baseline RI.RESULTSAt the baseline measurement, significant differences in RI were seen between obstructed and nonobstructed kidneys. ACE inhibitor, ART1 antagonist, or the combination of these drugs did not result in any significant changes in RI in either obstructed or nonobstructed kidneys. However, in obstructed kidneys, ΔRI in the combination of ACE inhibitor and ART1 antagonist were significantly greater than those in ACE inhibitor or ART1 antagonist alone, whereas there were no significant differences in those values in nonobstructed kidneys.CONCLUSIONThese observations suggest that the renin-angiotensin system in dogs with chronic UPUO may not contribute significantly to the differences in intrarenal RI between obstructed and nonobstructed kidneys. However, the angiotensin-producing pathways and angiotensin II receptor subtypes other than ACE and ART1 may have some different effects between obstructed and nonobstructed kidneys.

100 项与抗ART1单抗(Weill Cornell Medicine) 相关的药物交易

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