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Endogenous hydrogen sulfide-mediated MAPK inhibition preserves endothelial function through txnip signaling

FREE RADICAL BIOLOGY AND MEDICINE 2017年 110卷 291-299页

作者： Tian, Danyang Dong, Jinghui Jin, Sheng Teng, Xu Wu, Yuming Hebei Med Univ Dept Physiol 361 Zhong Shan East Rd Shijiazhuang 050017 Hebei Peoples R China Hebei Collaborat Innovat Ctr Cardio Cerebrovasc D Shijiazhuang 050017 Hebei Peoples R China

Mounting evidence demonstrated deficient cystathionine-gamma- lyase (CSE)/H2S implicated the development of cardiovascular disease. The present study aimed to evaluating the favorable action of CSE derived H2S on endothelial function in CSE-/- mice. CSE-/- mice exhibited attenuated endothelium- dependent relaxations, coupled with reduction of endothelial nitric oxide synthase (eNOS) phosphorylation at site of Ser1177, increase of thioredoxin interacting protein (txnip) level and MAPK phosphorylation, which were corrected by sodium hydrosulfide chronic treatment for 8 weeks. Impaired relaxations to ACh and upregulated txnip of CSE-/- mice aorta were partially corrected by p38 inhibitor, extracellular regulated protein kinase (ERK) inhibitor and c- Jun N-terminal kinase (JNK) inhibitor and totally corrected by combined treatment. Pharmacological inhibition of CSE with DL-propargylglycine (PPG) in vivo and ex vivo induced endothelial dysfunction. PPG stimulated the phosphorylation of p38, JNK and ERK in human umbilical vein endothelial cells (HUVECs). MAPK inhibition by combined treatment of p38, JNK and ERK inhibitors normalized the endothelial changes of eNOS phosphorylation and txnip protein level in CSE-/- mice aorta and PPG-treated HUVECs. NaHS offered similar effect with MAKP inhibitors. txnip siRNA prevented against endothelial function by PPG and txnip overexpression mimics the detrimental effect of PPG treatment on endothelial function, whereas MAPK inhibitor or NaHS has no beneficial effect. In a word, Endogenous CSE/H2S benefits against endothelial dysfunction through suppressing MAPK/txnip cascade. CSE deficiency and consequently lowered endogenous H2S level should be considered as risk factors and biomarkers for endothelial dysfunction.

关键词： Endothelial function Hydrogen sulfide MAPK txnip

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Berberine, an isoquinoline alkaloid suppresses txnip mediated NLRP3 inflammasome activation in MSU crystal stimulated RAW 264.7 macrophages through the upregulation of Nrf2 transcription factor and alleviates MSU crystal induced inflammation in rats

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INTERNATIONAL IMMUNOPHARMACOLOGY 2017年 44卷 26-37页

作者： Dinesh, Palani Rasool, MahaboobKhan VIT Univ Sch Bio Sci & Technol Immunopathol Lab SMV 240 Vellore 632014 Tamil Nadu India

The current study was designed to investigate the therapeutic potential of berberine on monosodium urate (MSU) crystal stimulated RAW 264.7 macrophages and in MSU crystal induced rats. Our results indicate that berberine (25, 50 and 75 mu M) suppressed the levels of pro-inflammatory cytokines (interleukin-ibeta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha)) and intracellular reactive oxygen species in MSU crystal stimulated RAW 264.7 macrophages. The mRNA expression levels of IL-1 beta caspase 1, nucleotide-binding oligomerization domain -like receptor pyrin domain containing 3 (NLRP3), thioredoxin interacting protein (txnip) and kelchlike ECH-associated protein 1 (Keapi) were found downregulated with the upregulation of nuclear factor erythroid-2-related factor 2 (Nrf2) transcription factor and its associated anti-oxidant enzymes: Heme oxygenase I (HO-1), superoxide dismutase (SOD1), glutathione peroxidase (GPx), NADPH quinone oxidoreductase-1 (NQO1) and catalase (CAT) in MSU crystal stimulated RAW 264.7 macrophages upon berberine treatment. Subsequently, western blot analysis revealed that berberine decreased the protein expression of IL-1 beta and caspase 1 and increased Nrf2 expression in RAW 264.7 macrophages. Immunofluorescence analysis also explored increased expression of Nrf2 in MSU crystal stimulated RAW 264.7 macrophages by berberine treatment. In addition, the paw edema, pain score, pro-inflammatory cytokines (IL-1 beta and TNF alpha) and articular elastase activity were found significantly reduced in berberine (50 mg/kg ***) administered MSU crystal-induced rats. Conclusively, our current findings suggest that berberine may represent as a potential candidate for the treatment of gouty arthritis by suppressing inflammatory mediators and activating Nrf2 anti-oxidant pathway. (C) 2016 Elsevier B.V. All rights reserved.

关键词： Berberine Gouty arthritis Inflammatory proteins Nrf2 transcription factor txnip

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1,25(OH)₂D₃ disrupts glucose metabolism in prostate cancer cells leading to a truncation of the TCA cycle and inhibition of txnip expression

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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017年第10期1864卷 1618-1630页

作者： Abu el Maaty, Mohamed A. Alborzinia, Hamed Khan, Shehryar J. Buettner, Michael Woelfl, Stefan Heidelberg Univ Inst Pharm & Mol Biotechnol Neuenheimer Feld 364 D-69120 Heidelberg Germany UCL Sch Pharm 29-39 Brunswick Sq London WC1N 1AX England Heidelberg Univ Ctr Organismal Studies Metabol Core Technol Platform Neuenheimer Feld 360 D-69120 Heidelberg Germany

Prostate cell metabolism exhibits distinct profiles pre- and post-malignancy. The malignant metabolic shift converts prostate cells from "citrate-producing" to "citrate-oxidizing" cells, thereby enhancing glucose metabolism, a phenotype that contrasts classical tumoral Warburg metabolism. An on-line biosensor chip system (BIONAS 2500) was used to monitor metabolic changes (glycolysis and respiration) in response to the putative anti-cancer nutraceutical 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], in different prostate cancer (PCa) cell lines (LNCaP, VCaP, DU145 and PC3). LNCaP cells exhibited profound metabolic responsiveness to the treatment and thus extensive analysis of metabolism-modulating effects of 1,25(OH)(2)D-3 were performed, including mRNA expression analysis of key metabolic genes (e.g. GLUT1 and PDHK1), analysis of TCA cycle metabolites, glucose uptake/consumption measurements, ATP production, and mitochondrial biogenesis/activity. Altogether, data demonstrate a vivid disruption of glucose metabolism by 1,25(OH)(2)D-3, illustrated by a decreased glucose uptake and an accumulation of citrate/isocitrate due to TCA cycle truncation. Depletion of glycolytic intermediates led to a consistent decrease in txnip expression in response to 1,25(OH)(2)D-3, an effect that coincided with the activation of AMPK signaling and a reduction in c-MYC expression. Reduction in txnip levels in response to 1,25(OH)(2)D-3 was rescued by an AMPK signaling inhibitor and mimicked by a MYC inhibitor highlighting the possible involvement of both pathways in mediating 1,25(OH)(2)D-3's metabolic effects in PCa cells. Furthermore, pharmacological and genetic modulation of the androgen receptor showed similar and disparate effects on metabolic parameters compared to 1,25(OH)(2)D-3 treatment, highlighting the AR-independent nature of 1,25(OH)(2)D-3's metabolism -modulating effects.

关键词： 1,25-Dihydroxyvitamin D-3 Prostate cancer Metabolism txnip AMPK Androgen receptor

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Vascular endothelial cells senescence is associated with NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation via reactive oxygen species (ROS)/thioredoxin-interacting protein (txnip) pathway

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INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 2017年 84卷 22-34页

作者： Yin, Yanlin Zhou, Zhihui Liu, Weiwei Chang, Qun Sun, Guanqun Dai, Yalei Shanghai East Hosp Dept Cardiol Shanghai Peoples R China Tongji Univ Sch Med Dept Immunol Shanghai Peoples R China

Endothelial dysfunction caused by endothelial cells senescence and chronic inflammation is tightly linked to the development of cardiovascular diseases. NLRP3 (NOD-like receptor family pyrin domain-containing3) inflammasome plays a central role in inflammatory response that is associated with diverse inflammatory diseases. This study explores the effects and possible mechanisms of NLRP3 inflammasome in endothelial cells senescence. Results show an increment of pro-inflammatory cytokine interleukin (IL)-1 beta secretion and caspase-1 activation during the senescence of endothelial cells induced by bleomycin. Moreover, secreted IL-1 beta promoted endothelial cells senescence through up-regulation of p53/p21 protein expression. NLRP3 inflammasome was found to mediate IL-1 beta secretion through the production of ROS (reactive oxygen species) during the senescence of endothelial cells. Furthermore, the association of txnip (thioredoxin-interacting protein) with NLRP3 induced by ROS promoted NLRP3 inflammasome activation in senescent endothelial cells. In addition, the expressions of NLRP3 inflammasome related genes, ASC (apoptosis associated speck-like protein containing a CARD), txnip, cleaved caspase-1 and IL-1 beta, were also increased in vitro and in vivo studies. These findings indicate that endothelial senescence could be mediated through ROS and NLRP3 inflammasome signaling pathways, suggesting a potential target for the prevention of endothelial senescence-related cardiovascular diseases. (C) 2017 Elsevier Ltd. All rights reserved.

关键词： Senescence IL-1 beta NLRP3 inflammasome ROS txnip

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Phosphorylation of txnip by AKT Mediates Acute Influx of Glucose in Response to Insulin

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CELL REPORTS 2017年第10期19卷 2005-2013页

作者： Waldhart, Althea N. Dykstra, Holly Peck, Anderson S. Boguslawski, Elissa A. Madaj, Zachary B. Wen, Jennifer Veldkamp, Kelsey Hollowell, Matthew Zheng, Bin Cantley, Lewis C. McGraw, Timothy E. Wu, Ning Van Andel Res Inst Grand Rapids MI 49503 USA Cornell Univ Weill Med Coll Dept Biochem New York NY 10065 USA Calvin Coll Grand Rapids MI 49546 USA Massachusetts Gen Hosp Cutaneous Biol Res Ctr Boston MA 02129 USA Cornell Univ Weill Med Coll Sandra & Edward Meyer Canc Ctr New York NY 10065 USA

Growth factors, such as insulin, can induce both acute and long-term glucose uptake into cells. Apart from the rapid, insulin-induced fusion of glucose transporter (GLUT) 4 storage vesicles with the cell surface that occurs in muscle and adipose tissues, the mechanismbehind acute induction has been unclear in other systems. Thioredoxin interacting protein (txnip) has been shown to be a negative regulator of cellular glucose uptake. txnip is transcriptionally induced by glucose and reduces glucose influx by promoting GLUT1 endocytosis. Here, we report that txnip is a direct substrate of protein kinase B (AKT) and is responsible for mediating AKT-dependent acute glucose influx after growth factor stimulation. Furthermore, txnip functions as an adaptor for the basal endocytosis of GLUT4 in vivo, its absence allows excess glucose uptake in muscle and adipose tissues, causing hypoglycemia during fasting. Altogether, txnip serves as a key node of signal regulation and response for modulating glucose influx through GLUT1 and GLUT4.

关键词： GLUT4 txnip insulin AKT glucose

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txnip-NLRP3炎性小体通路在Ang Ⅱ诱导的胰岛β细胞凋亡中的作用

TXNIP-NLRP3炎性小体通路在Ang Ⅱ诱导的胰岛β细胞凋亡中的作用

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作者：冯艳金山西医科大学

学位级别：硕士

研究背景:随着居民生活水平的提高,糖尿病在我国的发病率逐年提升,已然成为当前社会最主要的健康杀手。糖尿病是遗传因素和环境因素共同影响而引起的疾病,造成其病情恶化的最主要原因为胰岛β细胞的损伤和数目的减少。近年来发现,肾素-... 详细信息

研究背景:随着居民生活水平的提高,糖尿病在我国的发病率逐年提升,已然成为当前社会最主要的健康杀手。糖尿病是遗传因素和环境因素共同影响而引起的疾病,造成其病情恶化的最主要原因为胰岛β细胞的损伤和数目的减少。近年来发现,肾素-血管紧张素系统（Renin-angiotensin system,RAS）在局部胰腺组织中存在表达,更重要的是在糖尿病时RAS激活,致使其主要的效应物质,血管紧张素Ⅱ（Angiotensin Ⅱ,Ang Ⅱ）水平升高,而后者的过表达会引起胰岛功能紊乱和胰岛β细胞凋亡增加,但其具体机制尚不明确。越来越多的研究证实,慢性炎症反应是导致糖尿病发生发展的重要因素。NLRP3炎性小体是一种多蛋白复合物,在各种病原刺激下发生活化,随后继续激活Pro Caspase-1,使其裂解为Caspase-1 p10活性片段,后者通过促进成熟的IL-1β的分泌而诱发细胞炎症损伤。关于NLRP3炎性小体的活化机制众说纷纭,但氧化应激引发ROS生成增多,进而促进txnip过表达或与NLRP3结合增多是其最主要的激活途径。因此,本研究旨在探讨Ang Ⅱ发挥胰岛β细胞损伤作用是否通过txnip-NLRP3炎性小体通路而实现。目的:1.使用Ang Ⅱ刺激正常大鼠胰岛组织,观察其对胰岛β细胞分泌胰岛素水平的影响;*** Ⅱ孵育正常大鼠胰岛及INS-1胰岛β细胞,观察其对胰岛细胞凋亡及NLRP3炎性小体表达的影响;3.探究Ang Ⅱ影响NLRP3炎性小体表达的具体机制。方法:1.动物实验:构建糖尿病大鼠模型,分离胰岛并检测Ang Ⅱ水平;2.离体实验:（1）分离正常大鼠胰岛组织,使用Ang Ⅱ刺激,ELISA法检测胰岛素分泌量;（2）Western Blot检测Ang Ⅱ对胰岛凋亡及NLRP3炎性小体表达的影响;（3）CCK-8检测不同浓度(0、1×10-8、1×10-7、1×10-6、1×10-55 mol/L)及不同作用时间（0、6、12、24、48 h）的Ang Ⅱ对INS-1胰岛β细胞存活率的影响;（4）流式细胞术及Western Blot检测Cleaved Caspase-3/Caspase-3,探究Ang Ⅱ对INS-1胰岛β细胞凋亡的影响;（5）Western Blot检测Ang Ⅱ作用下INS-1胰岛β细胞NLRP3炎性小体、txnip、ChREBP、AT1R的表达情况;（6）RT-PCR检测Ang Ⅱ对INS-1胰岛β细胞txnip、ChREBP的mRNA水平的表达影响;（7）IF/ICC法观察Ang Ⅱ处理对INS-1胰岛β细胞txnip、ChREBP及AT1R的表达影响。结果:1.糖尿病鼠胰岛组织中Ang Ⅱ含量升高分离糖尿病鼠胰岛,ELISA实验检测胰岛中Ang Ⅱ含量的结果显示,T1DM组Ang Ⅱ水平显著上调（P<0.01,n=7）;T2DM组的Ang Ⅱ含量也明显升高（P<0.01,n=7）。（见图1）*** Ⅱ对原代胰岛的功能及蛋白表达的影响2.1 Ang Ⅱ可以降低胰岛β细胞的胰岛素分泌水平检测胰岛功能显示,Ang Ⅱ组葡萄糖刺激的胰岛素分泌指数降低（P<0.05,n=6）,说明Ang Ⅱ造成胰岛功能受损。（见图2A-C）2.2 Ang Ⅱ可以诱导胰岛细胞凋亡Western Blot结果表明,与对照组相比,Ang Ⅱ组Cleaved Caspase-3/Caspase-3比值升高（P<0.01,n=6）,提示Ang Ⅱ诱导胰岛细胞凋亡增加。（见图2D）2.3 Ang Ⅱ可以激活胰岛细胞NLRP3炎性小体与对照组相比,Ang Ⅱ组的NLRP3、ASC、Caspase-1的活性片段p10的蛋白表达均升高（P<0.01,n=6;P<0.01,n=6;P<0.05,n=6）,培养液中IL-1β的分泌增多（P<0.01,n=6）,说明Ang Ⅱ可引起NLRP3炎性小体的激活。（见图2E、F）*** Ⅱ诱导INS-1胰岛β细胞存活率下降CCK-8结果显示,随着Ang Ⅱ作用浓度的升高,INS-1胰岛β细胞存活率逐渐下降,在1×10-6mol/L时作用显著（P<0.01,n=6）;给予INS-1胰岛β细胞孵育Ang Ⅱ不同时间,发现随着Ang Ⅱ作用时间的延长,细胞存活率逐渐降低,Ang Ⅱ作用24 h时细胞活力显著下降（P<0.01,n=6）。（见图3）*** Ⅱ促进INS-1胰岛β细胞凋亡流式细胞术结果显示,Ang Ⅱ组细胞凋亡率相比对照组升高（P<0.05,n=6）。Western Blot方法检测Caspase-3及Cleaved Caspase-3,Ang Ⅱ组CleavedCaspase-3/Caspase-3比值升高（P<0.05,n=6）。（见图4）*** Ⅱ通过NLRP3炎性小体诱导INS

关键词： Ang Ⅱ NLRP3炎性小体 txnip AT1R

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txnip通过介导自噬紊乱促进胰岛β细胞功能障碍的机制研究

TXNIP通过介导自噬紊乱促进胰岛β细胞功能障碍的机制研究

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作者：邓文珍重庆医科大学

学位级别：硕士

第一部分txnip通过影响自噬介导高脂高糖导致的胰岛功能障碍目的:探讨txnip与胰岛细胞分泌功能障碍及胰岛自噬功能紊乱的关系方法:选择1月龄C57BL/6J雄性小鼠、txnip基因敲除雄性小鼠(txnip-/-)各12只,每种小鼠分成SD组（普通饮食）、HF... 详细信息

第一部分txnip通过影响自噬介导高脂高糖导致的胰岛功能障碍目的:探讨txnip与胰岛细胞分泌功能障碍及胰岛自噬功能紊乱的关系方法:选择1月龄C57BL/6J雄性小鼠、txnip基因敲除雄性小鼠(txnip-/-)各12只,每种小鼠分成SD组（普通饮食）、HFD组（高脂高糖饮食）喂养16周。行葡萄糖耐受性实验（GTT）和胰岛素耐量实验（ITT）检测。分离胰岛细胞,冻存胰腺组织检测txnip、P62、LC3B蛋白表达水平。结果:高脂高糖饲养后,C57BL/6J小鼠胰腺组织中txnip表达升高（p<0.01）。与对应普食组相比,高脂高糖各组小鼠空腹血糖升高,GTT、ITT血糖曲线下面积增大（p<0.01）。txnip-/-小鼠与同种喂养方式的C57BL/6J小鼠相比,其空腹血糖较低,GTT、ITT血糖曲线下面积较小（p<0.05）。与普食组相比,高脂高糖各组小鼠胰腺中自噬相关蛋白P62、LC3B、LC3Ⅱ/Ⅰ比值上升（P<0.01）,而它们在txnip-/-小鼠HFD组的表达较C57BL/6J小鼠HFD组减少（p<0.05）。结论:高脂高糖饲养促进胰腺组织txnip表达增加、胰岛素分泌水平下降、胰岛素抵抗增加,同时导致胰岛细胞自噬底物蛋白累积;txnip缺失能够有效抵抗高脂高糖诱导的胰岛自噬功能紊乱及胰岛细胞功能障碍。第二部分txnip介导胰岛细胞自噬和功能障碍的机制研究目的:探讨txnip对胰岛细胞自噬的影响及其相关机制方法:常规培养MIN6小鼠胰岛细胞,用慢病毒感染构建稳定阴性对照病毒（LV-GFP）、txnip过表达（LV-txnip）、txnip抑制（LV-txnip-si RNA）三组细胞,荧光显微镜及Western Blot法检测感染效率。使用游离脂肪酸（FFA）、自噬激动剂雷帕霉素、抑制剂巴佛洛霉素A1分别处理上述各组细胞。使用电镜观察自噬小体;用Western blot法检测txnip、P62、LC3B、Atg3、Atg5、Atg12、Atg16蛋白表达水平及mTOR通路激活水平。结果:与LV-GFP组相比,LV-txnip组txnip、P62、Atg12、Atg16蛋白表达明显增加（P<0.01）,Atg3、Atg5及LC3Ⅱ/Ⅰ、m TOR磷酸化水平升高（p<0.05）;LV-txnip-si RNA组txnip、P62、Atg3、Atg5表达明显降低（p<0.01）,Atg16表达减少（p<0.05）,LC3Ⅱ/Ⅰ比值增加（p<0.01）,而m TOR磷酸化水平、Atg12无明显差异。MIN6细胞用雷帕霉素处理后,P62表达下降（P<0.01）,LC3Ⅱ/Ⅰ比值增加（p<0.01）;LV-txnip组较LV-GFP组相比,P62升高（p<0.01）,LC3Ⅱ/Ⅰ比值增加（p<0.05）。FFA处理各组细胞后,P62、LC3B及LC3Ⅱ/Ⅰ比值均增加（p<0.05）;与LV-GFP组相比,LV-txnip组的P62、LC3B表达增加（p<0.05）,自噬小体增多,LC3Ⅱ/Ⅰ比值无明显变化;LV-txnip-si RNA组与LV-GFP组相比,自噬小体减少,P62表达下降、LC3Ⅱ/Ⅰ比值增大（p<0.05）。自噬抑制剂巴佛洛霉素A1作用后,LV-txnip组P62、LC3Ⅱ/Ⅰ较LV-GFP组表达上调（p<0.05）。结论:txnip过表达能够促进MIN6细胞自噬体形成相关蛋白表达上调、自噬底物蛋白及自噬小体累积;沉默txnip后,自噬小体及自噬相关蛋白表达均减少。说明txnip上调能导致胰岛细胞自噬转换流通功能障碍。这可能与txnip激活mTOR信号通路,或抑制溶酶体降解途径相关。

关键词： txnip 胰岛细胞功能障碍细胞自噬 txnip 自噬相关蛋白自噬小体

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Black raspberry anthocyanins protect BV2 microglia from LPS-induced inflammation through down-regulating NOX2/TXNI/NLRP3 signaling

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JOURNAL OF BERRY RESEARCH 2021年第2期11卷 333-347页

作者： Mu, Teng Guan, Yang Chen, Tianqiao Wang, Shuning Li, Mei Chang, Alan K. Yang, Zhe Bi, Xiuli Liaoning Univ Coll Life Sci 66 Chongshan Rd Shenyang 110036 Peoples R China Wenzhou Univ Coll Life & Environm Sci Wenzhou Peoples R China

BACKGROUND: Increasing evidence has established neuroinflammation as the hallmark of neurodegenerative disorders such as Alzheimer's disease (AD). However, despite the underlying immunological mechanisms are far from being understood, the involvement of excessive activation of microglia is attracting more and more attention. OBJECTIVE: In the present study, we investigated the protective effect of black raspberry (BRB) anthocyanins on LPS-induced neuroinflammation in BV2 microglia. METHODS: LPS-induced mouse BV2 microglia were treated with black raspberry anthocyanins and the levels of NO, ROS, IL-1 beta and IL-18 produced by the cells were measured to determine the extent of oxidative stress and inflammatory response. RESULTS: The results showed that BRB anthocyanins reduced the production of ROS in LPS-induced BV2 microglia by down-regulating the level of NOX2 and its downstream factors, including thioredoxin-interacting protein (txnip) and NOD-like receptor protein 3 (NLRP3) inflammasome. Furthermore, BRB anthocyanins inhibited the secretion of Interleukin-18 (IL-18) and Interleukin-1 beta (IL-1 beta), eventually attenuating the LPS-induced inflammatory response of BV2 microglia. CONCLUSIONS: BRB anthocyanins might play an important neuroprotective role in inflammation-related neurodegenerative disease, potentially, by down-regulating the NOX2/txnip/NLRP3 signaling axis in brain microglia.

关键词： BRB anthocyanins LPS-induced BV2 microglia NOX2 txnip NLRP3

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Disease-modifying pharmacological treatments of type 1 diabetes: Molecular mechanisms, target checkpoints, and possible combinatorial treatments

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PHARMACOLOGICAL REVIEWS 2025年第2期77卷 100044页

作者： Kosheleva, Liudmila Koshelev, Daniil Lagunas-Rangel, Francisco Alejandro Levit, Shmuel Rabinovitch, Alexander Schioth, Helgi B. Uppsala Univ Dept Surg Sci Funct Pharmacol & Neurosci Uppsala Sweden Latvian Inst Organ Synth Lab Pharmaceut Pharmacol Riga Latvia Assuta Med Ctr Diabet & Metab Inst Tel Aviv Israel

After a century of extensive scientific investigations, there is still no curative or disease-modifying treatment available that can provide long-lasting remission for patients diagnosed with type 1 diabetes (T1D). Although T1D has historically been regarded as a classic autoimmune disorder targeting and destroying pancreatic islet 3-cells, significant research has recently demonstrated that 3-cells themselves also play a substantial role in the disease's progression, which could explain some of the unfavorable clinical outcomes. We offer a thorough review of scientific and clinical insights pertaining to molecular mechanisms behind pathogenesis and the different therapeutic interventions in T1D covering over 20 possible pharmaceutical intervention treatments. The interventions are categorized as immune therapies, treatments targeting islet endocrine dysfunctions, medications with dual modes of action in immune and islet endocrine cells, and combination treatments with a broader spectrum of activity. We suggest that these collective findings can provide a valuable platform to discover new combinatorial synergies in search of the curative disease-modifying intervention for T1D. Significance Statement: This research delves into the underlying causes of T1D and identifies critical mechanisms governing 3-cell function in both healthy and diseased states. Thus, we identify specific pathways that could be manipulated by existing or new pharmacological interventions. These interventions fall into several categories: (1) immunomodifying therapies individually targeting immune cell processes, (2) interventions targeting 3-cells, (3) compounds that act simultaneously on both immune cell and 3-cell pathways, and (4) combinations of compounds simultaneously targeting immune and 3-cell pathways. (c) 2025 The Authors. Published by Elsevier Inc. on behalf of American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the CC BY license (htt

关键词： AbATE antibody for tolerance in recently diagnosed type 1 diabetes ABL1 abelson murine leukemia viral oncogene homolog 1 AC adenylate cyclase ADCC antibody-dependent cell-mediated cytotoxicity ADR α 2A-adrenergic receptor AICD ATG activation-induced cell death AMPK AMP-activated protein kinase AP action potentials APC antigen-presenting cells ATG anti-thymocyte globulins AUC area under the curve cAMP cyclic adenosine monophosphate CAR coxsackie and adenovirus receptor CCKB cholecystokinin CDC complement-dependent cytotoxicity ChREBP carbohydrate response-element binding protein CNS central nervous system CRAC Ca2+ release-activated Ca2+ channel CTLA4Ig cytotoxic T-lymphocyte associated protein Ig CXCL10 interferon gamma-inducible protein 10 kDa DPP4 dipeptidyl peptidase-4 DPP-4i DPP4 inhibitor DRD D2-like dopamine receptor DXM dextromethorphan EBV Epstein-Barr virus ER endoplasmic reticulum FOXO1 forkhead box O1 GABA γ -aminobutyric acid GAD65 Alum Alum-formulated human recombinant GAD65 GAD65 glutamic acid decarboxylase 65 GCSF granulocyte colony-stimulating factor GIP insulinotropic polypeptide GLP-1 glucagon-like peptide-1 GPCR G protein-coupled receptor GSIS glucose-induced insulin secretion GSK3 β glycogen synthase kinase 3 β H+ hydrogen HLA human leukocyte antigen ICOS inducible T-cell co-stimulator IFN- γ interferon gamma IGF-1 insulin-growth factor 1 IGFBP3 IGF-binding protein 3 IgG2 immunoglobulin G2 IL-1R IL-1 receptors ILP insulin like peptide IR insulin receptor IRAK-1 interleukin-1 receptor-associated serine/threonine kinase 1 IRF-1 interferon gamma regulatory factor-1 JAK Janus kinase K+ potassium KATP ATP-sensitive potassium channel KV voltage-gated potassium channels mAb monoclonal antibody mDPP-4 membrane-bound dipeptidyl peptidase-4 NFAT nuclear factor of activated T-cells NKA Na+/K+ ATPase NMDAR glutamate N-Methyl-D-Aspartate receptors NOD non-obese diabetic PC1/3 prohormone convertase 1/3 PCD programmed cell death PD-1 programmed death protein PDX1 pancreatic duodenal homeobox-1 protein PHA ph

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Identification of immune suppressor candidates utilizing comparative transcriptional profiling in histiocytic sarcoma

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CANCER IMMUNOLOGY IMMUNOTHERAPY 2025年第2期74卷 1-8页

作者： Lenz, Jennifer A. Peng, Brandon Assenmacher, Charles-Antoine King, Austin Zhang, Paul J. Maki, Robert G. Blanco, M. Andres Radaelli, Enrico Atherton, Matthew J. Univ Penn Sch Vet Med Dept Clin Sci & Adv Med Philadelphia PA 19104 USA Univ Penn Sch Vet Med Dept Biomed Sci Philadelphia PA 19104 USA Univ Penn Sch Vet Med Dept Pathobiol Philadelphia PA USA Univ Penn Perelman Sch Med Dept Pathol & Lab Med Philadelphia PA USA Mem Sloan Kettering Canc Ctr New York NY USA

Histiocytic sarcoma (HS) is a rare yet lethal malignancy with no established standard of care therapies. A lack of pre-clinical models limits our understanding of HS pathogenesis and identification of therapeutic targets. Canine HS shares multiple clinical and genetic similarities with human HS, supporting its use as a unique translational model. Prior studies have investigated the immunogenicity of HS. Although increased tumor infiltrating lymphocyte (TIL) density is associated with favorable outcomes in canine HS, virtually all canine patients eventually succumb to progressive disease consistent with ultimate failure of anti-tumor immunity. To investigate potential regulators of the immune tumor microenvironment (TME), we undertook a comparative transcriptional approach of three long-lived cases of canine pulmonary HS with heavy T cell infiltrate and three short-lived cases of splenic HS that lacked significant T cell inflammation and compared these data to corresponding grossly normal tissues from dogs undergoing necropsy. This comparison identified PDCD1, encoding the immune checkpoint PD-1, and SPP1, encoding the secreted pro-tumorigenic protein osteopontin, as positive differentially expressed genes (DEGs) in canine HS. txnip, encoding the tumor suppressor txnip, was the most significant negative DEG. Comparative transcriptomic studies revealed conservation of enriched (including SPP1) and depleted (including txnip) DEGs between canine and human HS patients. Immunohistochemistry demonstrated osteopontin in the TMEs of canine and human HS. Collectively, we uncover PD-1, osteopontin, and txnip as putative actionable targets in HS and further establish canine HS as a preclinical platform to screen novel immunotherapeutic approaches for this deadly disease.

关键词： Histiocytic sarcoma Osteopontin PD-1 txnip

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