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Smoking-mediated reprogramming of the phenotype and function of airway basal cells (BCs) disrupts airway homeostasis and is an early event in chronic obstructive pulmonary disease (COPD)-associated airway remodeling. Here, we examined the expression and regulation of the transmembrane glycoprotein TROP2 (trophoblast antigen 2), a putative stem cell marker in airway BCs, in lung tissue samples from healthy smokers and healthy nonsmokers and in models in culture to identify therapeutic targets. TROP2 expression was upregulated in the airway epithelia of smokers and positively correlated with the smoking index. In vitro, cigarette smoke extract (CSE) induced TROP2 expression in airway BCs in a time- and dose-dependent manner. The p38 MAPK and NF-κB pathways were also activated by CSE, and their specific antagonists inhibited CSE-induced TROP2 expression. A therapeutic component derived from traditional Chinese medicine, ginsenoside Rb3, inhibited CSE-induced TROP2 expression as well as activation of the p38 MAPK and NF-κB pathways in BCs in monolayer culture. Furthermore, ginsenoside Rb3 prevented the increase in TROP2 expression and antagonized CSE-induced BC hyperplasia and expression of inflammatory factors and epithelial-mesenchymal transition changes in an air-liquid culture model. Thus, CSE-induced TROP2 is a possible biomarker for early changes in the epithelium of smokers, and ginsenoside Rb3 may serve as a therapeutic molecule, preventing the disruption of epithelial homeostasis in COPD.

ObjectiveDiabetic cardiomyopathy (DCM) is characterized by cardiac remodeling, dysfunction, and insulin resistance; however, the underlying mechanism has not been fully elucidated. Programmed cell death 4 (PDCD4) is a novel inflammation and apoptosis gene, but its role in type 2 DCM remains elusive. We aimed to determine if PDCD4 intervention improves DCM by affecting left ventricular remodeling, function, and insulin resistance.Research design and methodsWe designed a PDCD4-/- rat, established a type 2 diabetes animal model, and constructed a PDCD4 overexpressed adenovirus and PDCD4 small interfer RNA (siRNA) vectors to alter PDCD4 expression in H9c2 cardiomyocytes. Thereafter, glucose levels, lipid metabolism, echocardiography, and extent of myocardial fibrosis, inflammation, and apoptosis were compared in vivo and in vitro.ResultsPDCD4 deficiency improved insulin resistance, cardiac remodeling, and dysfunction in type 2 DCM rats and improved myocardial hypertrophy, fibrosis, inflammation, and apoptosis. Proliferation and transformation of cardiac fibroblasts was reduced via PDCD4 downregulation in vitro under high-glucose stimulation. Furthermore, PDCD4 regulated the myocardial phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) pathway in vivo and in vitro. PDCD4 intervention affected cardiac remodeling, dysfunction, and insulin resistance by influencing fibrosis, inflammation, and apoptosis via the PI3K-AKT pathway in vivo.ConclusionsPDCD4 knockdown protected against left ventricular remodeling, dysfunction, and insulin resistance in type 2 DCM rats. The underlying mechanisms may involve reducing cardiomyocyte apoptosis, inflammation, fibrosis, and normalized PI3K-AKT phosphorylation. To the best of our knowledge, our study is the first to report the effects and underlying mechanisms of PDCD4 in type 2 DCM. These results provide a potential new treatment avenue for improving the prognosis of patients with type 2 DCM.

Programmed cell death 4 (PDCD4) has been recognized as a novel tumor suppressor gene, which inhibits the activation and translation of activator protein (AP)-1. Dysregulated expression of PDCD4 is also involved in various human tumors and is linked to tumor progression and development. However, the function and clinical implication of PDCD4 in giant cell tumors of the bone (GCTBs) has not been previously investigated. In the present study, PDCD4 expression was determined in 83 samples of GCTBs at mRNA and protein levels by quantitative reverse transcription-polymerase chain reaction, western blotting and immunohistochemistry. The results demonstrated that PDCD4 mRNA expression was reduced in 63% of GCTB samples (17/27) and protein expression was decreased in 65% of samples (54/83), compared with adjacent non-tumor tissues. Furthermore, decreased expression of PDCD4 was significantly associated with certain clinicopathological characteristics, including the Campanacci grade and recurrence. A strong negative correlation was determined between PDCD4 expression and the Ki-67 positive rate in GCTBs (r=−0.6392; P

// Hong Jiang 1 , Shuhong Huang 2 , Xinyun Li 1 , Xian Li 2 , Shanying Huang 1 , Yun Zhang 1 and Zhe-Yu Chen 2 1 Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong, China 2 Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, China Correspondence to: Zhe-Yu Chen, email: // Yun Zhang, email: // Keywords : atherosclerosis, endothelial barrier dysfunction, brain-derived neurotrophic factor, tyrosine kinase receptor B, vascular endothelial cadherin, Pathology Section Received : June 30, 2015 Accepted : September 06, 2015 Published : September 28, 2015 Abstract Tyrosine kinase receptor B (TrkB) is a high-affinity receptor for brain-derived neurotrophic factor (BDNF). In addition to its nervous system functions, TrkB is also expressed in the aortic endothelium. However, the effects of endothelial TrkB signaling on atherosclerosis remained unknown. Immunofluorescence analysis revealed that TrkB expression is downregulated in the endothelium of atherosclerotic lesions from ApoE-/- mice compared with the atheroma-free aorta of WT mice. Endothelial TrkB knockdown led to increased lesion size, lipid deposition and inflammatory responses in the atherosclerotic lesions of the ApoE-/- mice compared with the control mice. Mechanistic studies showed that TrkB activation prevented VE-cadherin shedding by enhancing the interaction between vascular endothelial protein tyrosine phosphatase and VE-cadherin, maintaining VE-cadherin in a dephosphorylated state. Our data demonstrate that TrkB is an endothelial injury-response molecule in atherogenesis. Endothelial BDNF/TrkB signaling reduces VE-cadherin shedding and protects against atherosclerotic lesion development in ApoE−/− mice.

Macrophage migration inhibitory factor (MIF) involves the pathogenesis of atherosclerosis (AS) and increased plasma MIF levels in diabetes mellitus (DM) patients are associated with AS. Here, we have been suggested that MIF could be a critical contributor for the pathological process of diabetes-associated AS by using adenovirus-mediated RNA interference. First, streptozotocin (STZ)-induced diabetic animal model was constructed in 114 apolipoprotein E-deficient mice (apoE−/− mice) fed on a regular chow diet. Then, the animals were randomly divided into three groups: Adenovirus-mediated MIF interference (Ad-MIFi), Ad-enhanced green fluorescent protein (EGFP) and normal saline (NS) group (n ≈ 33/group). Non-diabetic apoE−/− mice (n = 35) were served as controls. Ad-MIFi, Ad-EGFP and NS were, respectively, injected into the tail vein of mice from Ad-MIFi, Ad-EGFP and NS group, which were injected repeatedly 4 weeks later. Physical, biochemical, morphological and molecular parameters were measured. The results showed that diabetic apoE−/− mice had significantly aggravated atherosclerotic lesions. MIF gene interference attenuated atherosclerotic lesions and stabilized atheromatous plaque, accompanied by the decreased macrophages and lipids deposition and inflammatory cytokines production, improved glucose intolerance and plasma cholesterol level, the decreased ratio of matrix matalloproteinase-2/tissue inhibitor of metalloproteinase-1 and plaque instability index. An increased expression of MIF and its ligand CD74 was also detected in the diabetic patients with coronary artery disease. The results suggest that MIF gene interference is able to inhibit atherosclerotic lesions and increase plaque stability in diabetic apoE−/−mice. MIF inhibition could be a novel and promising approach to the treatment of DM-associated AS.

Programmed cell death 5 (PDCD5) is a novel apoptosis-related gene with potent antitumor effects which can interact with the histone acetyltransferase Tip60 and induce DNA damage-induced apoptosis. Reduced PDCD5 expression has been found in a few types of human tumors and is also associated with the progression and prognosis of the tumors. However, the expression status and clinical significance of PDCD5 in gastrointestinal stromal tumors has not yet been analyzed. In our study, we examined PDCD5 expression in 63 tumor samples of gastrointestinal stroma at both mRNA and protein levels by RT-PCR, western blotting and immunohistochemistry. We found that 57% (16/28) of the tumor samples had a decreased PDCD5 expression at the mRNA level and 53% (35/66) of the samples were found to have decreased PDCD5 expression at the protein level, whereas PDCD5 was highly expressed in all adjacent normal gastrointestinal tissues at the mRNA or protein level. Moreover, decreased PDCD5 expression was significantly associated with clinicopathological characteristics including tumor size and mitosis. Our results suggest that PDCD5 expression plays a significant role in the malignant progression of human gastrointestinal stromal tumors and may be a key inhibitory factor.

The inflammatory responses accompanying stroke are recognized to contribute to secondary ischemic injury. TIPE2 is a very recently identified negative regulator of inflammation that maintains immune homeostasis. However, it is unknown whether TIPE2 is expressed in the brain and contributes to the regulation of cerebral diseases. In this study, we explored the potential roles of TIPE2 in cerebral ischemia/reperfusion injury. TIPE2(-/-) mice were used to assess whether TIPE2 provides neuroprotection following cerebral ischemia/reperfusion induced by middle cerebral artery occlusion (MCAO), and in vitro primary cerebral cell cultures were used to investigate the expression and regulation of TIPE2. Our results show that genetic ablation of the Tipe2 gene significantly increased the cerebral volume of infarction and neurological dysfunction in mice subjected to MCAO. Flow cytometric analysis revealed more infiltrating macrophages, neutrophils, and lymphocytes in the ischemic hemisphere of TIPE2(-/-) mice. The responses to inflammatory cytokines and chemokines were significantly increased in TIPE2(-/-) mouse brain after MCAO. We further observed that TIPE2 was highly induced in WT mice after cerebral ischemia and was expressed mainly in microglia/macrophages, but not in neurons and astrocytes. Finally, we found that regulation of TIPE2 expression was associated with NADPH oxidase activity. These findings demonstrate, for the first time, that TIPE2 is involved in the pathogenesis of stroke and suggest that TIPE2 plays an essential role in a signal transduction pathway that links the inflammatory immune response to specific conditions after cerebral ischemia. Targeting TIPE2 may be a new therapeutic strategy for stroke treatment.

The two-pore domain potassium (K2P) channel TREK-1 is recognized as a new and major candidate of cardiac stretch-activated potassium current and play a key role in the pathogenesis of human cardiac arrhythmias and heart failure. However, there is little study about the effect of antiarrhythmic drugs

// Lianyue Ma 1, 2 , Mei Ni 1 , Panpan Hao 1 , Huixia Lu 1 , Xiaoyan Yang 1 , Xingli Xu 1 , Cheng Zhang 1 , Shanying Huang 1 , Yuxia Zhao 1 , Xiaoling Liu 1, 2 , Yun Zhang 1, 2 1 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Shandong 250012, P.R. China 2 The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Shandong University, Shandong 250012, P.R. China Correspondence to: Xiaoling Liu, e-mail: xiaolingliusdu@163.com Yun Zhang, e-mail: zhangyun@sdu.edu.cn Keywords: atherogenesis, vasa vasorum, neovascularization, Tongxinluo Received: November 12, 2015 Accepted: February 08, 2016 Published: February 18, 2016 ABSTRACT Vasa vasorum (VV) neovascularization contributes to atherogenesis and its expansion and distribution is correlated with intraplaque expression of angiogenic factors. The present study investigated the roles of Tongxinluo (TXL), a traditional Chinese medication, on VV proliferation and atherogenesis. In vitro , TXL pre-treatment reversed the tumor necrosis factor-a (TNF-a) induced expression of vascular endothelial growth factor A (VEGF-A) and angiopoietin-1 (ANGPT-1) but not ANGPT-2, leading to increased ratio of ANGPT-1 to ANGPT-2. Consistently, TXL treatment (at a dosage of 0.38, 0.75, 1.5 g/kg/d, respectively) decreased the expression of VEGF-A while increased that of ANGPT-1 in early atherosclerotic lesions of apolipoprotein E deficient (apoE-/-) mice. On aortic ring assay, microvessels sprouting from aortas were significantly inhibited in TXL-treated mice. Moreover, VV neovascularization in plaques was markedly reduced with TXL treatment. Histological and morphological analysis demonstrated that TXL treatment reduced plaque burden, plaque size and changed the plaque composition. These data suggest that TXL inhibits early atherogenesis through regulating angiogenic factor expression and inhibiting VV proliferation in atherosclerotic plaque. Our study shed new light on the anti-atherosclerotic effect of TXL.

Sirtuin 1 (SIRT1) is a class III histone/protein deacetylase, and its activation status has been well documented to have physiologic benefits in human health. However, the function of SIRT1 in cancer remains controversial. Here, the expression and role of SIRT1 in gastric cancer is delineated. SIRT1 was present in all normal gastric mucosa specimens; however, it was only present in a portion of the matched gastric cancer tumor specimens. In SIRT1-positive tumors, both mRNA and protein levels were downregulated as compared with the corresponding nonneoplastic tissue. Ectopic expression of SIRT1 inhibited cell proliferation, diminished clonogenic potential, and induced a G1-phase cell-cycle arrest, the effects of which were not apparent when a catalytic-domain mutant form of SIRT1 was introduced, suggesting that SIRT1 functions in gastric cancer are dependent on its deacetylase activity. Further evidence was obtained from depletion of SIRT1. At the molecular level, SIRT1 inhibited the transcription of Cyclin D1 (CCND1), and inhibition of NF-κB in SIRT1-depleted cells rescued Cyclin D1 expression. Furthermore, inhibition of either NF-κB or Cyclin D1 in SIRT1-depleted cells reversed the inhibitory effects of SIRT1. The inhibitory role of SIRT1 was also verified in vivo using xenografts. This work characterizes SIRT1 status and demonstrates its inhibitory function in gastric cancer development, which involves NF-κB/Cyclin D1 signaling, offering a therapeutic role for SIRT1 activators. Implications: The inhibitory functions of SIRT1, which involve NF-κB/Cyclin D1 signaling, suggest the utility of SIRT1 activators in the prevention and therapy of gastric cancer. Mol Cancer Res; 11(12); 1497–507. ©2013 AACR.