المؤلفون: Cai, Yongfeng, Zhou, Yaqi, Yang, Qiuhua, Xu, Jiean, Da, Qingen, Ma, Qian, Zhao, Dingwei, Lu, Tammy, Kim, Ha Won, Fulton, David, Jiang, Xuejun, Weintraub, Neal L., Dong, Kunzhe, Xu, Suowen, Hong, Mei, Liu, Zhiping, Huo, Yuqing

المساهمون: Shenzhen Science and Technology Innovation Program, National Institutes of Health, National Natural Science Foundation of China, Science, Technology and Innovation Commission of Shenzhen Municipality, Shenzhen Basic Research Program, American Heart Association Inc, Foundation for the National Institutes of Health

المصدر: Pharmacological Research ; volume 203, page 107156 ; ISSN 1043-6618

مصطلحات موضوعية: Pharmacology

الإتاحة: https://doi.org/10.1016/j.phrs.2024.107156Test
https://api.elsevier.com/content/article/PII:S1043661824001002?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1043661824001002?httpAccept=text/plainTest

المؤلفون: Zaidi, Syed A. H., Xu, Zhimin, Lemtalsi, Tahira, Sandow, Porsche, Athota, Sruthi, Liu, Fang, Haigh, Stephen, Huo, Yuqing, Narayanan, S. Priya, Fulton, David J. R., Rojas, Modesto A., Fouda, Abdelrahman Y., Caldwell, Robert W., Caldwell, Ruth B.

المساهمون: U.S. Department of Health & Human Services | NIH | National Eye Institute

المصدر: Cell Death & Disease ; volume 14, issue 10 ; ISSN 2041-4889

مصطلحات موضوعية: Cancer Research, Cell Biology, Cellular and Molecular Neuroscience, Immunology

الوصف: We previously found that global deletion of the mitochondrial enzyme arginase 2 (A2) limits optic nerve crush (ONC)-induced neuronal death. Herein, we examined the cell-specific role of A2 in this pathology by studies using wild type (WT), neuronal-specific calbindin 2 A2 KO (Calb2 cre/+ A2 f/f ), myeloid-specific A2 KO (LysM cre/+ A2 f/f ), endothelial-specific A2 KO (Cdh5 cre/+ A2 f/f ), and floxed controls. We also examined the impact of A2 overexpression on mitochondrial function in retinal neuronal R28 cells. Immunolabeling showed increased A2 expression in ganglion cell layer (GCL) neurons of WT mice within 6 h-post injury and inner retinal neurons after 7 days. Calb2 A2 KO mice showed improved neuronal survival, decreased TUNEL-positive neurons, and improved retinal function compared to floxed littermates. Neuronal loss was unchanged by A2 deletion in myeloid or endothelial cells. We also found increased expression of neurotrophins (BDNF, FGF2) and improved survival signaling (pAKT, pERK1/2) in Calb2 A2 KO retinas within 24-hour post-ONC along with suppression of inflammatory mediators (IL1β, TNFα, IL6, and iNOS) and apoptotic markers (cleavage of caspase3 and PARP). ONC increased GFAP and Iba1 immunostaining in floxed controls, and Calb2 A2 KO dampened this effect. Overexpression of A2 in R28 cells increased Drp1 expression, and decreased mitochondrial respiration, whereas ABH-induced inhibition of A2 decreased Drp1 expression and improved mitochondrial respiration. Finally, A2 overexpression or excitotoxic treatment with glutamate significantly impaired mitochondrial function in R28 cells as shown by significant reductions in basal respiration, maximal respiration, and ATP production. Further, glutamate treatment of A2 overexpressing cells did not induce further deterioration in their mitochondrial function, indicating that A2 overexpression or glutamate insult induce comparable alterations in mitochondrial function. Our data indicate that neuronal A2 expression is neurotoxic after injury, and ...

الإتاحة: https://doi.org/10.1038/s41419-023-06180-6Test
https://www.nature.com/articles/s41419-023-06180-6.pdfTest
https://www.nature.com/articles/s41419-023-06180-6Test

المؤلفون: Paladines, Nathalie, Dawson, Shantiece, Ryan, Weston, Serrano-Lopez, Rogelio, Messer, Regina, Huo, Yuqing, Cutler, Christopher W., Ramos-Junior, Erivan S., Morandini, Ana Carolina

المساهمون: Augusta University

المصدر: Frontiers in Immunology ; volume 14 ; ISSN 1664-3224

مصطلحات موضوعية: Immunology, Immunology and Allergy

الوصف: Introduction Fibroblasts are the dominant stromal cells in the gingival lamina propria with a well-established relevance in regulation of inflammation, and in innate immunity. This is exemplified by their hypersecretion of CXCL8, enhancing leukocyte infiltration in chronic and sustained inflammatory conditions. We have previously shown adenosine to be a key metabolic nucleoside that regulates stromal inflammation, but the underlying mechanisms linking adenosine to the metabolic status of fibroblasts and to the resultant inflammatory response are unclear. This study examined, by seahorse real-time cell metabolic analysis, the bioenergetics of the stromal fibroblast response to extracellular adenosine and IL-1β, focusing on CXCL8 secretion by primary human gingival fibroblasts (HGF). Methods Markers of the glycolytic pathway and mitochondrial biogenesis were tracked through immunoblot. Further, the influence of adenosine on mitochondrial accumulation was measured by uptake of MitoTracker Red fluorescent probe and assessment of the role of FCCP (a mitochondrial uncoupler) in CXCL8 secretion and mitochondrial accumulation. Results Our results show that the anti-inflammatory response of HGF to extracellular adenosine, typified by reduced CXCL8 secretion, is mediated by mitochondrial oxidative phosphorylation, reflected in higher oxygen consumption rate (OCR). In the presence of IL-1β, adenosine-treated cells induced higher ATP production, basal respiration and proton leak compared to IL-1β without adenosine. Surprisingly, adenosine had no additional effect on the IL-1β-induced higher glycolysis rate demonstrated by the extracellular acidification rate (ECAR). In addition, the higher OCR in adenosine-stimulated cells was not due to the mitochondrial fuel dependency or capacity, but due to an increase in mitochondrial biogenesis and accumulation in the cells with concomitant decrease in mitophagy-required p-PINK1 marker. We detected the accumulation of functional mitochondria with increased activation of the ...

الإتاحة: https://doi.org/10.3389/fimmu.2023.1148216Test

المؤلفون: Wang, Peng, Gao, Rifeng, Wu, Tingting, Zhang, Jinyan, Sun, Xiaolei, Fan, Fan, Wang, Cong, Qian, Sanli, Li, Bingyu, Zou, Yunzeng, Huo, Yuqing, Fassett, John, Chen, Yingjie, Ge, Junbo, Sun, Aijun

المصدر: Redox Biology ; volume 67, page 102884 ; ISSN 2213-2317

مصطلحات موضوعية: Organic Chemistry, Biochemistry, Clinical Biochemistry

الإتاحة: https://doi.org/10.1016/j.redox.2023.102884Test
https://api.elsevier.com/content/article/PII:S2213231723002859?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2213231723002859?httpAccept=text/plainTest

المؤلفون: Li, Honggui, Zheng, Juan, Xu, Qian, Yang, Yongjian, Zhou, Jing, Guo, Xinlei, Cai, Yongfeng, Cai, James J., Xie, Linglin, Awika, Joseph, Han, Xianlin, Li, Qingsheng, Kennedy, Lindsey, Francis, Heather, Glaser, Shannon, Huo, Yuqing, Alpini, Gianfranco, Wu, Chaodong

المصدر: Gastroenterology ; volume 164, issue 1, page 134-146 ; ISSN 0016-5085

مصطلحات موضوعية: Gastroenterology, Hepatology

الإتاحة: https://doi.org/10.1053/j.gastro.2022.09.027Test
https://api.elsevier.com/content/article/PII:S001650852201085X?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S001650852201085X?httpAccept=text/plainTest

المؤلفون: Hu, Xiaoru, Ma, Zhengwei, Li, Siyao, Wen, Lu, Huo, Yuqing, Wu, Guangyu, Manicassamy, Santhakumar, Dong, Zheng

المصدر: Laboratory Investigation ; volume 103, issue 3, page 100009 ; ISSN 0023-6837

مصطلحات موضوعية: Cell Biology, Molecular Biology, Pathology and Forensic Medicine

الإتاحة: https://doi.org/10.1016/j.labinv.2022.100009Test
https://api.elsevier.com/content/article/PII:S0023683722000095?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0023683722000095?httpAccept=text/plainTest

المؤلفون: Wen, Lu, Wei, Qingqing, Livingston, Man J., Dong, Guie, Li, Siyao, Hu, Xiaoru, Li, Ying, Huo, Yuqing, Dong, Zheng

المصدر: Translational Research ; volume 253, page 31-40 ; ISSN 1931-5244

مصطلحات موضوعية: Biochemistry (medical), Public Health, Environmental and Occupational Health, General Medicine, Physiology (medical)

الإتاحة: https://doi.org/10.1016/j.trsl.2022.10.001Test
https://api.elsevier.com/content/article/PII:S1931524422002201?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1931524422002201?httpAccept=text/plainTest

المؤلفون: Xu, Yiming, Wang, Yong, Yan, Siyuan, Yang, Qiuhua, Zhou, Yaqi, Zeng, Xianqiu, Liu, Zhiping, An, Xiaofei, Toque, Haroldo A, Dong, Zheng, Jiang, Xuejun, Fulton, David J, Weintraub, Neal L, Li, Qinkai, Bagi, Zsolt, Hong, Mei, Boison, Detlev, Wu, Chaodong, Huo, Yuqing

المصدر: Nature communications. 8(1)

مصطلحات موضوعية: Blood Vessels, Cerebral Cortex, Endothelial Cells, Animals, Mice, Reperfusion Injury, Inflammation, Adenosylhomocysteinase, Adenosine Kinase, Adenosine, Gene Expression Regulation, Epigenesis, Genetic, Atherosclerosis, Gene Knockdown Techniques, Mice, Knockout, ApoE, Cardiovascular, 2.1 Biological and endogenous factors, Inflammatory and Immune System, Epigenesis, Genetic, Knockout, ApoE

الوصف: The molecular mechanisms underlying vascular inflammation and associated inflammatory vascular diseases are not well defined. Here we show that endothelial intracellular adenosine and its key regulator adenosine kinase (ADK) play important roles in vascular inflammation. Pro-inflammatory stimuli lead to endothelial inflammation by increasing endothelial ADK expression, reducing the level of intracellular adenosine in endothelial cells, and activating the transmethylation pathway through increasing the association of ADK with S-adenosylhomocysteine (SAH) hydrolase (SAHH). Increasing intracellular adenosine by genetic ADK knockdown or exogenous adenosine reduces activation of the transmethylation pathway and attenuates the endothelial inflammatory response. In addition, loss of endothelial ADK in mice leads to reduced atherosclerosis and affords protection against ischemia/reperfusion injury of the cerebral cortex. Taken together, these results demonstrate that intracellular adenosine, which is controlled by the key molecular regulator ADK, influences endothelial inflammation and vascular inflammatory diseases.The molecular mechanisms underlying vascular inflammation are unclear. Here the authors show that pro-inflammatory stimuli lead to endothelial inflammation by increasing adenosine kinase expression, and that its knockdown in endothelial cells inhibits atherosclerosis and cerebral ischemic injury in mice.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9gj0d3hkTest

المؤلفون: Xu, Yiming, Wang, Yong, Yan, Siyuan, Zhou, Yaqi, Yang, Qiuhua, Pan, Yue, Zeng, Xianqiu, An, Xiaofei, Liu, Zhiping, Wang, Lina, Xu, Jiean, Cao, Yapeng, Fulton, David J, Weintraub, Neal L, Bagi, Zsolt, Hoda, Nasrul, Wang, Xiaoling, Li, Qinkai, Hong, Mei, Jiang, Xuejun, Boison, Detlev, Weber, Christian, Wu, Chaodong, Huo, Yuqing

المصدر: EMBO Molecular Medicine. 9(9)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Genetics, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Adenosine, Adenosine Kinase, Animals, Aorta, DNA Methylation, Epigenesis, Genetic, Human Umbilical Vein Endothelial Cells, Humans, Mice, Neovascularization, Physiologic, Promoter Regions, Genetic, Vascular Endothelial Growth Factor Receptor-2, adenosine, adenosine kinase, angiogenesis, DNA methylation, endothelial cells, Medical and Health Sciences, Biochemistry and cell biology

الوصف: The nucleoside adenosine is a potent regulator of vascular homeostasis, but it remains unclear how expression or function of the adenosine-metabolizing enzyme adenosine kinase (ADK) and the intracellular adenosine levels influence angiogenesis. We show here that hypoxia lowered the expression of ADK and increased the levels of intracellular adenosine in human endothelial cells. Knockdown (KD) of ADK elevated intracellular adenosine, promoted proliferation, migration, and angiogenic sprouting in human endothelial cells. Additionally, mice deficient in endothelial ADK displayed increased angiogenesis as evidenced by the rapid development of the retinal and hindbrain vasculature, increased healing of skin wounds, and prompt recovery of arterial blood flow in the ischemic hindlimb. Mechanistically, hypomethylation of the promoters of a series of pro-angiogenic genes, especially for VEGFR2 in ADK KD cells, was demonstrated by the Infinium methylation assay. Methylation-specific PCR, bisulfite sequencing, and methylated DNA immunoprecipitation further confirmed hypomethylation in the promoter region of VEGFR2 in ADK-deficient endothelial cells. Accordingly, loss or inactivation of ADK increased VEGFR2 expression and signaling in endothelial cells. Based on these findings, we propose that ADK downregulation-induced elevation of intracellular adenosine levels in endothelial cells in the setting of hypoxia is one of the crucial intrinsic mechanisms that promote angiogenesis.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6gs051b7Test

المؤلفون: Bordan, Zsuzsanna, Batori, Robert, Haigh, Stephen, Li, Xueyi, Meadows, Mary Louise, Brown, Zach L., West, Madison A., Dong, Kunzhe, Han, Weihong, Su, Yunchao, Ma, Qian, Huo, Yuqing, Zhou, Jiliang, Abdelbary, Mahmoud, Sullivan, Jennifer, Weintraub, Neal. L., Stepp, David W., Chen, Feng, Barman, Scott A., Fulton, David J.R.

المصدر: Circulation ; ISSN 0009-7322 1524-4539

الوصف: BACKGROUND: Pulmonary arterial hypertension (PAH) is high blood pressure in the lungs that originates from structural changes in small resistance arteries. A defining feature of PAH is the inappropriate remodeling of pulmonary arteries (PA) leading to right ventricle failure and death. Although treatment of PAH has improved, the long-term prognosis for patients remains poor, and more effective targets are needed. METHODS: Gene expression was analyzed by microarray, RNA sequencing, quantitative polymerase chain reaction, Western blotting, and immunostaining of lung and isolated PA in multiple mouse and rat models of pulmonary hypertension (PH) and human PAH. PH was assessed by digital ultrasound, hemodynamic measurements, and morphometry. RESULTS: Microarray analysis of the transcriptome of hypertensive rat PA identified a novel candidate, PBK (PDZ-binding kinase), that was upregulated in multiple models and species including humans. PBK is a serine/threonine kinase with important roles in cell proliferation that is minimally expressed in normal tissues but significantly increased in highly proliferative tissues. PBK was robustly upregulated in the medial layer of PA, where it overlaps with markers of smooth muscle cells. Gain-of-function approaches show that active forms of PBK increase PA smooth muscle cell proliferation, whereas silencing PBK, dominant negative PBK, and pharmacological inhibitors of PBK all reduce proliferation. Pharmacological inhibitors of PBK were effective in PH reversal strategies in both mouse and rat models, providing translational significance. In a complementary genetic approach, PBK was knocked out in rats using CRISPR/Cas9 editing, and loss of PBK prevented the development of PH. We found that PBK bound to PRC1 (protein regulator of cytokinesis 1) in PA smooth muscle cells and that multiple genes involved in cytokinesis were upregulated in experimental models of PH and human PAH. Active PBK increased PRC1 phosphorylation and supported cytokinesis in PA smooth muscle cells, whereas ...

الإتاحة: https://doi.org/10.1161/circulationaha.123.067095Test