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Vascular pharmacology

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https://www.readbyqxmd.com/read/28938025/the-kaposi-s-sarcoma-associated-herpesvirus-kshv-non-structural-membrane-protein-k15-is-required-for-viral-lytic-replication-and-may-represent-a-therapeutic-target
#1
Bizunesh Abere, Tamrat M Mamo, Silke Hartmann, Naira Samarina, Elias Hage, Jessica Rückert, Sven-Kevin Hotop, Guntram Büsche, Thomas F Schulz
Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of the highly vascularized tumor Kaposi's sarcoma (KS), which is characterized by proliferating spindle cells of endothelial origin, extensive neo-angiogenesis and inflammatory infiltrates. The KSHV K15 protein contributes to the angiogenic and invasive properties of KSHV-infected endothelial cells. Here, we asked whether K15 could also play a role in KSHV lytic replication. Deletion of the K15 gene from the viral genome or its depletion by siRNA lead to reduced virus reactivation, as evidenced by the decreased expression levels of KSHV lytic proteins RTA, K-bZIP, ORF 45 and K8...
September 22, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28936196/anti-inflammatory-targets-for-the-treatment-of-reperfusion-injury-in-stroke
#2
REVIEW
Atsushi Mizuma, Midori A Yenari
While the mainstay of acute stroke treatment includes revascularization via recombinant tissue plasminogen activator or mechanical thrombectomy, only a minority of stroke patients are eligible for treatment, as delayed treatment can lead to worsened outcome. This worsened outcome at the experimental level has been attributed to an entity known as reperfusion injury (R/I). R/I is occurred when revascularization is delayed after critical brain and vascular injury has occurred, so that when oxygenated blood is restored, ischemic damage is increased, rather than decreased...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28935700/mitochondrial-based-therapeutics-for-the-treatment-of-spinal-cord-injury-mitochondrial-biogenesis-as-a-potential-pharmacological-target
#3
Natalie E Scholpa, Rick G Schnellmann
Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, directly reducing the ability of mitochondria to maintain homeostasis, leading to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity and oxidative stress, further exacerbating injury. Restoration of mitochondria dysfunction during the acute phases of secondary injury post-SCI represents a potentially effective therapeutic strategy...
September 21, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28932632/local-endothelial-complement-activation-reverses-endothelial-quiescence-enabling-t-cell-homing-and-tumor-control-during-t-cell-immunotherapy
#4
Andrea Facciabene, Francesco De Sanctis, Stefano Pierini, Edimara S Reis, Klara Balint, John Facciponte, Jens Rueter, Masahiro Kagabu, Paola Magotti, Evripidis Lanitis, Robert A DeAngelis, Ronald J Buckanovich, Wenchao C Song, John D Lambris, George Coukos
Cancer immunotherapy relies upon the ability of T cells to infiltrate tumors. The endothelium constitutes a barrier between the tumor and effector T cells, and the ability to manipulate local vascular permeability could be translated into effective immunotherapy. Here, we show that in the context of adoptive T cell therapy, antitumor T cells, delivered at high enough doses, can overcome the endothelial barrier and infiltrate tumors, a process that requires local production of C3, complement activation on tumor endothelium and release of C5a...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28932625/vascular-aging-implications-for-cardiovascular-disease-and-therapy
#5
Yohannes T Ghebre, Eduard Yakubov, Wing Tak Wong, Prasanna Krishnamurthy, Nazish Sayed, Andrew G Sikora, Mark D Bonnen
The incidence and prevalence of cardiovascular disease is highest among the elderly, in part, due to deleterious effects of advancing age on the heart and blood vessels. Aging, a known cardiovascular risk factor, is progressively associated with structural and functional changes to the vasculature including hemodynamic disturbance due to increased oxidative stress, premature cellular senescence and impairments in synthesis and/or secretion of endothelium-derived vasoactive molecules. These molecular and physiological changes lead to vessel wall stiffening and thickening, as well as other vascular complications that culminate to loss of vascular tone regulation and endothelial function...
December 2016: Translational Medicine: Current Research
https://www.readbyqxmd.com/read/28931753/ask1-dependent-endothelial-cell-activation-is-critical-in-ovarian-cancer-growth-and-metastasis
#6
Mingzhu Yin, Huanjiao Jenny Zhou, Jiqin Zhang, Caixia Lin, Hongmei Li, Xia Li, Yonghao Li, Haifeng Zhang, David G Breckenridge, Weidong Ji, Wang Min
We have recently reported that tumor-associated macrophages (TAMs) promote early transcoelomic metastasis of ovarian cancer by facilitating TAM-ovarian cancer cell spheroid formation. ASK1 is known to be important for macrophage activation and inflammation-mediated tumorigenesis. In the present study, we show that ASK1 deficiency attenuates TAM-spheroid formation and ovarian cancer progression in an orthotopic ovarian cancer model. Interestingly, ASK1 in stroma, but not in TAMs, is critical for peritoneal tumor growth of ovarian cancer...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28923474/beyond-the-inhaled-nitric-oxide-in-persistent-pulmonary-hypertension-of-the-newborn
#7
REVIEW
Mei-Yin Lai, Shih-Ming Chu, Satyan Lakshminrusimha, Hung-Chih Lin
Persistent pulmonary hypertension (PPHN) is a consequence of failed pulmonary vascular transition at birth and leads to pulmonary hypertension with shunting of deoxygenated blood across the ductus arteriosus (DA) and foramen ovale (FO) resulting in severe hypoxemia, and it may eventually lead to life-threatening circulatory failure. PPHN is a serious event affecting both term and preterm infants in the neonatal intensive care unit. It is often associated with diseases such as congenital diaphragmatic hernia, meconium aspiration, sepsis, congenital pneumonia, birth asphyxia and respiratory distress syndrome...
August 10, 2017: Pediatrics and Neonatology
https://www.readbyqxmd.com/read/28921447/structure-pharmacology-and-roles-in-physiology-of-the-p2y12-receptor
#8
Ivar von Kügelgen
P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. The platelet ADP-receptor which has been denominated P2Y12 receptor is an important target in pharmacotherapy. The receptor couples to Gαi2 mediating an inhibition of cyclic AMP accumulation and additional downstream events including the activation of phosphatidylinositol-3-kinase and Rap1b proteins. The nucleoside analogue ticagrelor and active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel block P2Y12 receptors and, thereby, inhibit ADP-induced platelet aggregation...
September 12, 2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28914193/chalcone-derivatives-anti-inflammatory-potential-and-molecular-targets-perspectives
#9
Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Vivek Asati
Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold has gained considerable scientific interest in medicinal chemistry owing to its simple chemistry, ease in synthesizing a variety of derivatives and exhibiting a broad range of promising pharmacological activities by modulating several molecular targets. A number of natural and (semi-) synthetic chalcone derivatives have demonstrated admirable anti-inflammatory activity due to their inhibitory potential against various therapeutic targets like cyclooxygenase (COX), lipooxygenase (LOX), interleukins (IL), prostaglandins (PGs), nitric oxide synthase (NOS), leukotriene D4 (LTD4), nuclear factor-κB (NF-κB), intracellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and TLR4/MD-2, etc...
September 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28910789/end-stage-renal-disease-inflammation-and-cardiovascular-outcomes
#10
Lu Dai, Edyta Golembiewska, Bengt Lindholm, Peter Stenvinkel
Despite marked improvements in renal replacement therapy during the last 30 years, the age-adjusted mortality rate in end-stage renal disease (ESRD) patients is still unacceptably high and comparable to that of many malignancies. Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in ESRD patients. However, traditional risk factors can only partially explain the high premature cardiovascular burden in this population. Nontraditional risk factors, including persistent low-grade inflammation, are critical in the pathogenesis of atherosclerosis, vascular calcification, and other causes of CVD and may also contribute to protein-energy wasting and other complications in chronic kidney disease (CKD) patients...
2017: Contributions to Nephrology
https://www.readbyqxmd.com/read/28910587/trichosanthin-attenuates-vascular-injury-induced-neointimal-hyperplasia-following-balloon-catheter-injury-in-rats
#11
Min Qiu, Zheng Yang, Xiao-Hua Guo, Yu-Ting Song, Ming An, Guo-Jun Zhao, Miao Song, Xiao-Min Zhao, Yun-Shan Zhao, Quan-Li Liu
Trichosanthin (TCS), isolated from the root tuber of Trichosantheskirilowii, a well-known traditional Chinese medicinal plant, belonging to the Cucurbitaceae family, was found to exhibit numerous biological and pharmacological activities including anti-inflammatory. However, the effects of TCS on arterial injury induced neointimal hyperplasia and inflammatory cell infiltration remains poorly understood. The aim of study was to examine the effectiveness of TCS on arterial injury-mediated inflammatory processes and underlying mechanisms...
September 14, 2017: Journal of Toxicology and Environmental Health. Part A
https://www.readbyqxmd.com/read/28910144/ask1-inhibition-halts-disease-progression-in-preclinical-models-of-pulmonary-arterial-hypertension
#12
Grant R Budas, Mario Boehm, Baktybek Kojonazarov, Gayathri Viswanathan, Xia Tian, Swathi Veeroju, Tatyana Novoyatleva, Friedrich Grimminger, Ford Hinojosa-Kirschenbaum, Hossein A Ghofrani, Norbert Weissmann, Werner Seeger, John T Liles, Ralph T Schermuly
RATIONALE Progression of pulmonary arterial hypertension (PAH) is associated with pathologic remodeling of the pulmonary vasculature and the right ventricle (RV). Oxidative stress drives the remodeling process through activation of mitogenactivated protein kinases (MAPKs) which stimulate apoptosis, inflammation and fibrosis. OBJECTIVES We investigated whether pharmacological inhibition of the redoxsensitive apical MAPK Apoptosis Signal-Regulating Kinase 1 (ASK1) can halt the progression of pulmonary vascular and RV remodeling...
September 14, 2017: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/28904002/assessing-microvascular-function-in-humans-from-a-chronic-disease-perspective
#13
Alfons J H M Houben, Remy J H Martens, Coen D A Stehouwer
Microvascular dysfunction (MVD) is considered a crucial pathway in the development and progression of cardiometabolic and renal disease and is associated with increased cardiovascular mortality. MVD often coexists with or even precedes macrovascular disease, possibly due to shared mechanisms of vascular damage, such as inflammatory processes and oxidative stress. One of the first events in MVD is endothelial dysfunction. With the use of different physiologic or pharmacologic stimuli, endothelium-dependent (micro)vascular reactivity can be studied...
September 13, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28903775/nonclinical-and-clinical-pharmacology-evidence-for-cardiovascular-safety-of-saxagliptin
#14
REVIEW
Pia S Pollack, Kristina D Chadwick, David M Smith, Martin Billger, Boaz Hirshberg, Nayyar Iqbal, David W Boulton
BACKGROUND: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin...
September 13, 2017: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/28893450/emergency-medicine-evaluation-and-management-of-the-end-stage-renal-disease-patient
#15
REVIEW
Brit Long, Alex Koyfman, Courtney M Lee
BACKGROUND: End stage renal disease (ESRD) is increasing in the U.S., and these patients demonstrate greater all-cause mortality, cardiovascular events, and hospitalization rates when compared to those with normal renal function. These patients may experience significant complications associated with loss of renal function and dialysis. OBJECTIVE: This review evaluates complications of ESRD including cardiopulmonary, neurologic, infectious disease, vascular, and access site complications, as well as medication use in this population...
September 5, 2017: American Journal of Emergency Medicine
https://www.readbyqxmd.com/read/28887194/hypoxia-inducible-factor-1%C3%AE-is-involved-in-isoflurane-induced-blood-brain-barrier-disruption-in-aged-rats-model-of-pocd
#16
Yiyun Cao, Zhengqian Li, Hongping Li, Cheng Ni, Lunxu Li, Ning Yang, Chengmei Shi, Yanfeng Zhong, Dehua Cui, Xiangyang Guo
Prolonged exposure to inhaled anesthetics may lead to postoperative cognitive dysfunction (POCD). Nevertheless, the underlying mechanisms are not known. Hypoxia-inducible factor-1α (HIF-1α) and its target gene vascular endothelial growth factor (VEGF) were shown to be activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF-1α in isoflurane-induced blood-brain barrier (BBB) disruption and resultant cognitive impairment. After a 4-h exposure to 1.5% isoflurane in 20-month-old rats, increases in vascular permeability, and disrupted BBB ultrastructure were accompanied by the degradation of tight junction proteins occludin and collagen type IV in brain blood vessels...
September 5, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28886276/systems-approach-to-the-pharmacological-actions-of-hdac-inhibitors-reveals-ep300-activities-and-convergent-mechanisms-of-regulation-in-diabetes
#17
Haloom Rafehi, Antony Kaspi, Mark Ziemann, Jun Okabe, Tom C Karagiannis, Assam El-Osta
Given the skyrocketing costs to develop new drugs, repositioning of approved drugs, such as histone deacetylase (HDAC) inhibitors, may be a promising strategy to develop novel therapies. However, a gap exists in the understanding and advancement of these agents to meaningful translation for which new indications may emerge. To address this, we performed systems-level analyses of 33 independent HDAC inhibitor microarray studies. Based on network analysis, we identified enrichment for pathways implicated in metabolic syndrome and diabetes (insulin receptor signaling, lipid metabolism, immunity and trafficking)...
September 8, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28883845/the-impact-of-hyperglycemia-and-hyperlipidemia-on-plasma-p-selectin-and-platelet-markers-after-ischemic-stroke
#18
Malgorzata Pawelczyk, Beata Kaczorowska, Zbigniew Baj
INTRODUCTION: Platelet activation plays a key role in the pathogenesis of ischemic cerebrovascular diseases. Thus, it is very important to identify novel pharmacological targets for platelet inhibition to improve ischemic stroke treatment. The aim of the study was to assess the relationship between metabolic disorders and platelet activity markers in patients with acute ischemic stroke. MATERIAL AND METHODS: Ninety-four patients with acute ischemic stroke were divided into four groups with: normolipidemia and normoglycemia (NL/NG), n = 25; normolipidemia and hyperglycemia (NL/HG), n = 21; hyperlipidemia and normoglycemia (HL/NG), n = 27; hyperlipidemia and hyperglycemia (NL/NG), n = 21...
August 2017: Archives of Medical Science: AMS
https://www.readbyqxmd.com/read/28882868/genetic-ablation-of-microrna-33-attenuates-inflammation-and-abdominal-aortic-aneurysm-formation-via-several-anti-inflammatory-pathways
#19
Tetsushi Nakao, Takahiro Horie, Osamu Baba, Masataka Nishiga, Tomohiro Nishino, Masayasu Izuhara, Yasuhide Kuwabara, Hitoo Nishi, Shunsuke Usami, Fumiko Nakazeki, Yuya Ide, Satoshi Koyama, Masahiro Kimura, Naoya Sowa, Satoko Ohno, Hiroki Aoki, Koji Hasagawa, Kazuhisa Sakamoto, Kenji Minatoya, Takeshi Kimura, Koh Ono
OBJECTIVE: Abdominal aortic aneurysm (AAA) is an increasingly prevalent and ultimately fatal disease with no effective pharmacological treatment. Because matrix degradation induced by vascular inflammation is the major pathophysiology of AAA, attenuation of this inflammation may improve its outcome. Previous studies suggested that microRNA-33 inhibition and genetic ablation of microRNA-33 increased serum high-density lipoprotein cholesterol and attenuated atherosclerosis. APPROACH AND RESULTS: MicroRNA-33a-5p expression in central zone of human AAA was higher than marginal zone...
September 7, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28880966/the-prolyl-4-hydroxylase-inhibitor-gsk360a-decreases-post-stroke-brain-injury-and-sensory-motor-and-cognitive-behavioral-deficits
#20
Jin Zhou, Jie Li, Daniel M Rosenbaum, Jian Zhuang, Carrie Poon, Pu Qin, Katrina Rivera, John Lepore, Robert N Willette, Erding Hu, Frank C Barone
There is interest in pharmacologic preconditioning for end-organ protection by targeting the HIF system. This can be accomplished by inhibition of prolyl 4-hydroxylase (PHD). GSK360A is an orally active PHD inhibitor that has been previously shown to protect the failing heart. We hypothesized that PHD inhibition can also protect the brain from injuries and resulting behavioral deficits that can occur as a result of surgery. Thus, our goal was to investigate the effect of pre-stroke surgery brain protection using a verified GSK360A PHD inhibition paradigm on post-stroke surgery outcomes...
2017: PloS One
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