Objective
This study tested whether IL-17A is involved in the pathogenesis of mouse myocardial ischemia-reperfusion (I/R) injury and investigated the mechanisms.
Background
Inflammatory processes play a major role in myocardial I/R injury. We recently identified interleukin (IL)-17A as an important cytokine in inflammatory cardiovascular diseases such as atherosclerosis and viral myocarditis. However, its role in myocardial I/R injury remains unknown.
Methods
The involvement of IL-17A was assessed in functional assays in mouse myocardial I/R injury by neutralization/repletion or genetically deficiency of IL-17A, and its mechanism on cardiomyocyte apoptosis and neutrophil infiltration were further studied in vivo and in vitro.
Results
IL-17A was elevated following murine left coronary artery ligation and reperfusion. Intracellular cytokine staining revealed that γδT lymphocytes, but not CD4+ helper T cells, were a major source of IL-17A. Anti-IL-17A mAb treatment or IL-17A knockout markedly ameliorated I/R injury, as demonstrated by reduced infarct size, reduced cardiac troponin T levels and improved cardiac function. This improvement was associated with a reduction in cardiomyocyte apoptosis and neutrophil infiltration. On the contrary, repletion of exogenous IL-17A induced the opposite effect. In vitro study showed that IL-17A mediated cardiomyocyte apoptosis through regulating the Bax/Bcl-2 ratio, induced CXC chemokine-mediated neutrophil migration and promoted neutrophil-endothelial cell adherence through induction of endothelial cell E-selectin and inter-cellular adhesion molecule (ICAM)-1 expression.
Conclusions
IL-17A mainly produced by γδT cells plays a pathogenic role in myocardial I/R injury by inducing cardiomyocyte apoptosis and neutrophil infiltration.
9 l e t t e r sFlatfish have the most extreme asymmetric body morphology of vertebrates. During metamorphosis, one eye migrates to the contralateral side of the skull, and this migration is accompanied by extensive craniofacial transformations and simultaneous development of lopsided body pigmentation 1-5 . The evolution of this developmental and physiological innovation remains enigmatic. Comparative genomics of two flatfish and transcriptomic analyses during metamorphosis point to a role for thyroid hormone and retinoic acid signaling, as well as phototransduction pathways. We demonstrate that retinoic acid is critical in establishing asymmetric pigmentation and, via cross-talk with thyroid hormones, in modulating eye migration. The unexpected expression of the visual opsins from the phototransduction pathway in the skin translates illumination differences and generates retinoic acid gradients that underlie the generation of asymmetry. Identifying the genetic underpinning of this unique developmental process answers long-standing questions about the evolutionary origin of asymmetry, but it also provides insight into the mechanisms that control body shape in vertebrates.
The development and progression of human cancer are believed to be due to the alterations of multiple genes or/ and their protein products. For identifying the proteins associated with esophageal cancer, we analysed the protein profiles of 24 pairs of esophageal squamous cell carcinomas/matched adjacent normal epithelia. Microdissection of routinely unstained frozen sections was performed to purify cancerous and epithelial cells. The protein expression profiles were obtained by twodimensional electrophoresis. Selected proteins dysregulated in tumors were identified by MALDI-TOF-MS. Three isoforms of annexin I were detected in normal esophageal mucosa and down-regulated in esophageal squamous cell carcinomas. RT -PCR analysis showed annexin I mRNA levels were significantly reduced in 17 out of 24 carcinomas. Immunohistochemistry demonstrated that annexin I appeared strong positive in all normal epithelia layers except basal cells. In cancer tissues, decreased expression of annexin I was observed in 12 out of 16 well differentiated tumors, 16 out of 17 moderately differentiated tumors, and 3 out of 3 poorly differentiated tumors as compared with the corresponding normal esophageal epithelia. There was a significant correlation between annexin I expression and the status of tumor differentiation. Well differentiated tumors presented stronger immunohistochemical reaction than moderately and poorly differentiated tumors. These data suggested that there existed three different isoforms of annexin I in normal esophageal epithelia, which may be the results of post-translational modification. Downexpression of three annexin I isoforms was a frequent event in esophageal carcinogenesis.
P ulmonary arterial hypertension (PAH) is a disease of progressive vascular remodeling characterized by dysregulated growth of pulmonary vascular cells and inflammation. [1][2][3][4] In the search for new medicines, the focus is moving toward therapies targeting these mechanisms, drawing on approved oncology interventions, such as tyrosine kinase inhibitors (eg, imatinib) 5,6 and metabolic modulators (eg, dichloroacetate), 7,8 and antiinflammatory treatments. 9 The evaluation of these antiremodeling and anti-inflammatory strategies in PAH patients poses a considerable challenge that may hamper their development.
Background-Pulmonary arterial hypertension (PAH) is a disease of progressive vascular remodeling, characterizedby dysregulated growth of pulmonary vascular cells and inflammation. A prevailing view is that abnormal cellular metabolism, notably aerobic glycolysis that increases glucose demand, underlies the pathogenesis of PAH. Increased lung glucose uptake has been reported in animal models. Few data exist from patients with PAH. Methods and Results-Dynamic positron emission tomography imaging with fluorine-18-labeled 2-fluoro-2-deoxyglucose (
Clinical Perspective on p 1224Noninvasive molecular imaging with the use of positron emission tomography (PET) offers enormous potential for monitoring cellular and biochemical events in otherwise inaccessible tissue and has been used in oncology to assess antiproliferative therapeutics. Specifically, fluorine-18-labeled 2-fluoro-2-deoxyglucose ( 18 FDG), a glucose analogue, is widely used for the detection and staging of a variety of malignant lesions and can provide a quantitative assessment of response to treatment.10-13 18 FDG PET exploits the "Warburg effect," 14,15 the observation that many cancers use aerobic cytoplasmic glycolysis as opposed to mitochondrial glucose oxidation as a major energy source, a process that requires increased cellular glucose uptake.Aerobic glycolysis is also a characteristic of nonmalignant proliferating cells and is observed in human pulmonary endothelial cells isolated and cultured from idiopathic PAH (IPAH) patient lungs, 16 as well as in pulmonary arterial smooth muscle cells from rodent PAH models.17 Lung parenchymal glucose uptake, measured by 18 FDG PET, has been reported to be increased in IPAH patients compared with healthy controls. 16,18 Recently, Marsboom et al 19 showed an increased lung 18 FDG PET signal in animal PAH models that is reduced by treatment with imatinib and dichloroacetate. These data provide the foundation for further investigation of the utility of 18 FDG PET as a tool in the assessment of patients with PAH. We set out to explore 3 questions: (1) the utility of dynamic 18 FDG PET acquisition in discriminating between PAH patients and healthy controls; (2) the feasibility of 18 FDG PET in tracking the pathology of pulmonary hypertension in in vivo PAH models and their response to treatment; and (3) the impact of treatments on cellular 18 FDG uptake with the use of IPAH-derived cells in vitro. Our da...
Background-Cardiovascular magnetic resonance has provided important information on the diagnosis and risk stratification of hypertrophic cardiomyopathy (HCM) in adults; however, comparable data are absent for HCM in children.
• DTI can be used to assess renal function impairment in patients with chronic glomerulonephritis. • ADC and FA values were correlated with tubulointerstitial fibrosis and glomerulosclerosis. • Identification of renal impairment is helpful for timely treatment. • DTI can be used for non-invasive assessment of renal pathology.
The results suggest that ER stress is involved in human and Ang II induced AAA formation in ApoE mice. TUDCA attenuates Ang II induced AAA formation in ApoE mice by inhibiting ER stress mediated apoptosis.
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