Search

Background and Purpose The pulmonary vascular remodeling (PVR), the pathological basis of pulmonary hypertension (PH), entails pulmonary artery smooth muscle cells (PASMCs) phenotypic switching, but appreciation of the underlying mechanisms is incomplete. Exosomes, a novel transfer machinery enabling delivery of its cargos to recipient cells, have been recently implicated in PH. The two critical questions of whether plasma-derived exosomes drive PASMCs phenotypic switching and what cargo the exosomes transport, however, remain unclear. Experimental Approach PH is induced by exposure of rats to chronic hypoxia (10% O2, 3 weeks). Exosomes were isolated and purified from rat plasma by ultracentrifugation. Exosomal LOX-1 was assessed by transmission electron microscopy and Western blotting. PASMCs phenotypic switching was determined by Western blotting, immunofluorescence staining and flow cytometry. Key Results We characterized lectin like oxidized low-density lipoprotein receptor-1 (LOX-1) as a novel cargo of plasma-derived exosomes in PH. With LOX-1 knockout (Olr1-/-) rats-derived exosomes, we demonstrated that exosomal LOX-1 could be transferred into PASMCs and thus elicited cell phenotypic switching. Of importance, Olr1-/- rats exhibited no cell phenotypic switching and developed less severe PH, but administration of wild type rather than Olr1-/- exosomes to Olr1-/- rats recapitulated the phenotype of PH with robust PASMCs phenotypic switching. We also revealed that exosomal LOX-1 triggered PASMCs phenotypic switching, PVR and ultimately PH via ERK1/2-KLF4 signaling axis. Conclusion and Implications This study has generated proof that plasma-derived exosomes confer PH by delivering LOX-1 into PASMCs. Hence, exosomal LOX-1 represents a novel exploitable target for PH prevention and treatment.

Multisystem inflammatory syndrome in children (MIS-C) is a type of hyperinflammatory symptoms similar to Kawasaki disease after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and is commonly observed in children aged 8-10 years. Primary therapeutic medications for MIS-C are intravenous immunoglobulins and glucocorticoids. It has been reported that biologics, such as IL-1 receptor antagonist anakinra, IL-6 receptor antagonist tocilizumab, and TNF-α receptor antagonist infliximab, can be used as an option for critically ill patients. This article elaborates on the mechanism of action of the above biologics and discusses the efficacy and safety biologics in the treatment of MIS-C after SARS-CoV-2 infection, in order to provide methods for the treatment of MIS-C with severe symptoms.儿童多系统炎症综合征（multisystem inflammatory syndrome in children，MIS-C）是儿童感染严重急性呼吸综合征冠状病毒2后出现的类似川崎病的过度炎症症状，多发于8~10岁儿童。首选治疗药物是静脉注射免疫球蛋白和糖皮质激素，文献报道危重症患者可选择生物制剂如白细胞介素1受体拮抗剂阿那白滞素、白细胞介素6受体拮抗剂托珠单抗、肿瘤坏死因子α受体拮抗剂英夫利昔单抗等治疗。该文通过阐述上述生物制剂的作用机制，结合案例具体分析生物制剂在治疗儿童感染严重急性呼吸综合征冠状病毒2后出现MIS-C中的安全性和有效性，以期对具有严重症状的MIS-C治疗提供方案。.

Endosomal sorting complex required for transport III (ESCRT-III) machinery is a key component to counteract the mixed lineage kinase domain-like pseudokinase (MLKL)-induced plasma membrane broken in cells undergoing necroptosis. Based on the bioinformatics analysis, polymyxin B, a polypeptide antibiotic, is predicted to simultaneously interact with ESCRT-III subunits and necroptosis-relevant proteins. This study aims to explore whether polymyxin B could reduce necroptosis in the stroke rat brain via enhancing the ESCRT-III machinery and/or suppressing the RIPK1/RIPK3/MLKL pathway. The stroke rats showed evident brain injury, concomitant with the downregulation of ESCRT-III subunits and the upregulation of necroptosis-relevant proteins. Post-ischemic administration of polymyxin B could alleviate the brain injury, accompanied by restoration of the levels of ESCRT-III subunits and suppression of necroptosis-relevant proteins. And, polymyxin B exerted similar effects in hypoxia-treated HT22 cells. We conclude that polymyxin B can reduce necroptosis in the stroke rat brain via enhancing the ESCRT-III machinery and suppressing the RIPK1/RIPK3/MLKL pathway simultaneously.

Continuous recruitment and inappropriate activation of platelets in pulmonary arteries contribute to pulmonary vascular remodeling in pulmonary hypertension (PH). Our previous study has demonstrated that lectin like oxidized low-density lipoprotein receptor-1 (LOX-1) regulates the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Phosphatidylserine exposed on the surface of activated platelets is a ligand for LOX-1. However, whether hypoxia-activated platelets stimulate the proliferation and migration of PASMCs by phosphatidylserine/LOX-1 signaling-impelled intercellular communication remains unclear. The present study found that rats treated with hypoxia (10% O2) for 21 days revealed PH with the activation of platelets and the recruitment of platelets in pulmonary arteries, and LOX-1 knockout inhibited hypoxia-induced PH and platelets activation. Notably, co-incubation of PASMCs with hypoxic PH rats-derived platelets up-regulated LOX-1 expression in PASMCs leading to the proliferation and migration of PASMCs, which was inhibited by the phosphatidylserine inhibitor annexin V or the LOX-1 neutralizing antibody. LOX-1 knockout led to decreased proliferation and migration of PASMCs stimulated by hypoxia-activated platelets. In rats, hypoxia up-regulated the phosphorylation of signal transducer and activator of transcription 3 (Stat3) and the expression of Pim-1 in pulmonary arteries. Hypoxia-activated platelets also up-regulated the phosphorylation of Stat3 and the expression of Pim-1 in PASMCs, which was inhibited by annexin V, the LOX-1 neutralizing antibody, the protein kinase C inhibitor and LOX-1 knockout. In conclusion, we for the first time demonstrated that hypoxia-activated platelets stimulated the proliferation and migration of PASMCs by phosphatidylserine/LOX-1/PKC/Stat3/Pim-1 signaling-impelled intercellular communication, thereby potentially contributing to hypoxic pulmonary vascular remodeling.

Aim Growing evidence suggests that endothelial-mesenchymal transition (EndMT) play key roles in pulmonary arterial remodeling during pulmonary arterial hypertension (PAH), but the underlying mechanisms have yet to be fully understood. miR-27a has been shown to promote proliferation of pulmonary arterial cells during PAH, but its role in EndMT remains unexplored. This study was designed to investigate the role and underlying mechanism of miR-27a in EndMT during PAH. Main methods Rats were exposed in hypoxia (10% O2) for 3 weeks to induce PAH, and human pulmonary artery endothelial cells (HPAECs) were exposed in hypoxia (1% O2) for 48 h to induce EndMT. Immunohistochemistry, in situ hybridization, immunofluorescence, real-time PCR and Western blot were conducted to detect the expressions of RNAs and proteins, and luciferase assay was used to verify the putative binding site of miR-27a. Key findings We found that hypoxia up-regulated miR-27a in the tunica intima of rat pulmonary arteries and HPAECs, and that inhibition of miR-27a suppressed hypoxia-induced EndMT. Furthermore, elevated expression of miR-27a suppressed bone morphogenetic protein (BMP) signaling by targeting Smad5, thereby lessening Id2-mediated repression of the 2 critical mediators of EndMT (Snail and Twist). Significance Our data unveiled a novel role of miR-27a in EndMT during hypoxia-induced PAH. Thus, targeting of miR-27a-related pathway may be therapeutically harnessed to treat PAH.

Pulmonary vascular remodeling (PVR) is the pathological basis of pulmonary hypertension (PH). Incomplete understanding of PVR etiology has hindered drug development for this devastating disease, which exhibits poor prognosis despite the currently available therapies. Endothelial-to-mesenchymal transition (EndMT), a process of cell transdifferentiation, has been recently implicated in cardiovascular diseases, including PH. But the questions of how EndMT occurs and how to pharmacologically target EndMT in vivo have yet to be further answered. Herein, by performing hematoxylin-eosin and immunofluorescence staining, transmission electron microscopy and Western blotting, we found that EndMT plays a key role in the pathogenesis of PH, and importantly that aspirin, a FDA-approved widely used drug, was capable of ameliorating PVR in a preclinical rat model of hypoxia-induced PH. Moreover, aspirin exerted its inhibitory effects on EndMT in vitro and in vivo by suppressing HIF-1α/TGF-β1/Smads/Snail signaling pathway. Our data suggest that EndMT represents an intriguing drug target for the prevention and treatment of hypoxic PH and that aspirin may be repurposed to meet the urgent therapeutic needs of hypoxic PH patients.

The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodeling in pulmonary hypertension (PH). It has been reported that miR-137 inhibits the proliferation of tumor cells. However, whether miR-137 is involved in PH remains unclear. In this study, male Sprague-Dawley rats were subjected to 10% O2 for 3 weeks to establish PH, and rat primary PASMCs were treated with hypoxia (3% O2) for 48 h to induce cell proliferation. The effect of miR-137 on PASMC proliferation and calpain-2 expression was assessed by transfecting miR-137 mimic and inhibitor. The effect of calpain-2 on PASMC proliferation was assessed by transfecting calpain-2 siRNA. The present study found for the first time that miR-137 was downregulated in pulmonary arteries of hypoxic PH rats and in hypoxia-treated PASMCs. miR-137 mimic inhibited hypoxia-induced PASMC proliferation and upregulation of calpain-2 expression in PASMCs. Furthermore, miR-137 inhibitor induced the proliferation of PASMCs under normoxia, and knockdown of calpain-2 mRNA by siRNA significantly inhibited hypoxia-induced proliferation of PASMCs. Our study demonstrated that hypoxia-induced downregulation of miR-137 expression promoted the proliferation of PASMCs by targeting calpain-2, thereby potentially resulting in pulmonary vascular remodeling in hypoxic PH.

Background Pulmonary hypertension (PH) is a proliferative disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMCs). Our lately study demonstrated that let-7g inhibited hypoxia-induced proliferation of PASMCs via repressing c-myc-Bmi-1-p16 signaling pathway. However, the upstream of let-7g has not yet been fully defined. Previous studies have shown that LOX-1, a target of let-7g, could also regulate the expression of let-7g in human aortic endothelial cells. In this present study, we aimed to investigate whether there is a negative feedback regulation between microRNA let-7g and LOX-1 in hypoxia-induced proliferation of PASMCs. Methods SD Rats were exposed to hypoxia (10% O2, 3 weeks) to induce PH. HE staining was used to evaluate pulmonary artery remodeling. in situ hybridization and immunohistochemistry were performed to assess the expression and distribution of let-7g and LOX-1, respectively. MTS, EDU and flow cytometry were performed to evaluate PASMCs proliferation. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were conducted to assess the expression of let-7g, LOX-1, calpain-1,-2,-4, and OCT-1. Results The expression of let-7g was significantly down-regulated in pulmonary arteries of hypoxia-induced PH rats accompanied by pulmonary vascular remodeling, whereas let-7g mimic inhibited hypoxia-induced proliferation of PASMCs and up-regulation of LOX-1 expression. LOX-1 blocking reversed hypoxia-induced down-regulation of let-7g expression. Calpains, protein kinase C and OCT-1 were involved in negative feedback regulation between let-7g and LOX-1. Conclusion Negative feedback regulation between let-7g and LOX-1 mediated hypoxia-induced proliferation of in PASMCs.

Background and objective Diabetic pulmonary fibrosis is a severe disease that increases mortality risk of diabetes. However, the molecular mechanisms leading to pulmonary fibrosis in diabetes are poorly understood. This study investigated the roles of epithelial-mesenchymal transition (EMT) and the associated molecular mechanisms in streptozotocin (STZ)-induced rat pulmonary fibrosis. Methods The rat model of diabetic pulmonary fibrosis was established by intraperitoneal injection of a single dose of STZ (35 mg/kg). Typical lesions of diabetic pulmonary fibrosis were observed 8 weeks after STZ injection by hematoxylin-eosin (HE) and Masson staining. Human bronchial epithelial cells (HBECs) and A549 cells were treated by high glucose. Gene or protein expression was measured by real-time PCR, Western blot, immunohistochemistry or immunofluorescence. The knockdown of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) or transforming growth factor-β1 (TGF-β1) was conducted by siRNA. Results Activation of EMT was observed in lung tissues of STZ-induced diabetic rats, exhibiting a loss in the epithelial cell marker E-cadherin and an increase in the mesenchymal marker Vimentin. The protein and mRNA levels of LOX-1, TGF-β1 and kruppel-like factor 6 (KLF6) in the lung tissues were increased. Incubation of HBECs and A549 cells with high glucose activated EMT and induced an increase in LOX-1, TGF-β1 and KLF-6 expression. LOX-1 siRNA inhibited high glucose-induced EMT in HBECs and A549 cells, which correlated with the reduction of TGF-β1. TGF-β1 siRNA decreased the expression of LOX-1 and KLF6. Conclusions EMT was involved in the pathological process of diabetic pulmonary fibrosis, which was activated by LOX-1/TGF-β1/KLF6 signaling pathway.

Aim Chronic hypoxia leads to right ventricular hypertrophy (RVH). RVH is believed to result from hypoxia-induced pulmonary hypertension. However, if hypoxia impacts RVH directly awaits clarification. Hypoxia triggers oxidative stress, and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mediates reactive oxygen species (ROS) generation in different cells. Therefore, this study aims to explore whether LOX-1-mediated oxidative stress accounts for hypoxia-induced RVH. Main methods Rats developed RVH after 3 weeks of hypoxia (10% O2). Immunofluorescence staining was performed to evaluate H9C2 cell hypertrophy induced by hypoxia (3% O2). Real-time PCR and Western-blot were performed to assess LOX-1, NADPH oxidases (NOX), collagen I/III, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) expression. DCFH-DA staining was performed to measure ROS generation. Key findings Hypoxia induced RVH and cardiac fibrosis in rats, as indicated by enlarged cardiomyocytes and deposition of extracellular matrix. Interestingly, hypoxia treatment directly induced H9C2 cardiomyocyte hypertrophy, implying direct effects of hypoxia on cell hypertrophy. Rat and H9C2 hypertrophy model revealed that cell hypertrophy was accompanied by marked increase in LOX-1 expression. Knockdown of LOX-1 significantly ameliorated H9C2 cell hypertrophy. Mechanistically, hypoxia induced prominent oxidative stress in rat right ventricles and H9C2 cells, most likely as a result from increased expression of NOX2/4, contributing to RVH. Knockdown of LOX-1 significantly attenuated H9C2 cell oxidative stress, with a concomitant decrease in NOX2/4 expression. Significance LOX-1/NOX/ROS pathway could represent a novel mechanism underlying hypoxia-induced RVH. Therapeutic targeting of LOX-1 would be exploited to treat RVH owing to chronic hypoxia exposure.

Recent studies revealed that sirtuin 1 (SIRT1) is involved in the regulation of energy metabolism and its agonist resveratrol showed anti-obesity effect. This study aims to determine whether BTM-0512, a novel derivative of resveratrol, acts as an antagonist of obesity and to explore its possible mechanisms. High-fat diet (HFD)-induced obese mice were intragastrically administered with BTM-0512 (5, 10, and 20 mg/kg/day) or resveratrol (10 mg/kg/day). It was found that the body weight, Lee's index, ratio of visceral adipose tissue (VAT) to body weight, and blood glucose were significantly reduced in BTM-0512-treated mice when compared with those in mice treated with resveratrol. BTM-0512 up-regulated the expressions of SIRT1, full length PRDM16 (fPRDM16), total PRDM16 (tPRDM16, including fPPRDM16 and other PRDM16 isoforms), and uncoupling protein 1 (UCP1) in both brown and subcutaneous adipose tissues. Although BTM-0512 and resveratrol also up-regulated SIRT1 and tPRDM16 levels in VAT of HFD-induced obese mice, the expressions of fPRDM16, UCP1, and TMEM26 were down-regulated. In mouse primary subcutaneous preadipocytes cultured with or without adipogenic medium, BTM-0512 up-regulated fPRDM16, tPRDM16, and UCP1 expressions, which was reversed by SIRT1 antagonists. But in cultured brown and visceral adipocytes, the UCP1 protein level showed no significant change after treatment with 1 μM of BTM-0512. Moreover, transfection with human SIRT1 plasmid reduced lipid deposit, as well as the mRNA levels of fPRDM16, UCP1, and TMEM26, in cultured human visceral adipose-derived stem cells. In conclusion, BTM-0512 has stronger anti-obesity effect than resveratrol, which might be associated with activation of beige remodeling in subcutaneous adipose tissue.

MicroRNAs (miRNAs), a large family of small and highly conserved non-coding RNAs, regulate gene expression through translational repression or mRNA degradation. Aberrant expression of miRNAs underlies a spectrum of diseases including organ fibrosis. Recent evidence suggests that miRNAs contribute to organ fibrosis through mediating epithelial-mesenchymal transition (EMT). Alleviation of EMT has been proposed as a promising strategy against fibrotic diseases given the key role of EMT in fibrosis. miRNAs impact the expression of specific ligands, receptors, and signaling pathways, thus modulating EMT and consequently influencing fibrosis. This review summarizes the current knowledge concerning how miRNAs regulate EMT and highlights the specific roles that miRNAs-regulated EMT plays in fibrotic diseases as diverse as pulmonary fibrosis, hepatic fibrosis, renal fibrosis and cardiac fibrosis. It is desirable that a more comprehensive understanding of the functions of miRNAs-regulated EMT will facilitate the development of novel diagnostic and therapeutic strategies for various debilitating organ fibrosis.

It has well been demonstrated that E3 ubiquitin ligase cullin7 plays important roles in cancer cell growth control via down-regulating p53 expression. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular remodeling. Therefore, whether cullin7 participates in hypoxia-induced pulmonary vascular remodeling deserves to be elucidated. The present study found that hypoxia up-regulated the expression of cullin7 mRNA and protein in pulmonary arteries and pulmonary artery smooth muscle cells, and knockdown of cullin7 inhibited hypoxia-induced proliferation and migration of pulmonary artery smooth muscle cells and reversed hypoxia-induced inhibition of p53 expression. Notably, administration of proteasome inhibitor MG132 significantly inhibited the expression of cullin7 and up-regulated the expression of p53 in pulmonary arteries concomitantly with improvement of hypoxia-induced pulmonary vascular remodeling. Our study demonstrated that hypoxia induced up-regulation of cullin7 expression resulting to the proliferation and migration of pulmonary artery smooth muscle cells via down-regulating p53 expression, which contributed to pulmonary vascular remodeling.

Pulmonary arterial remodeling is a crucial cause of increased pulmonary artery pressure during pulmonary hypertension (PH). Recently, growing evidence has upheld the contribution of endothelial-mesenchymal transition (EndMT) to pulmonary arterial remodeling, but the underlying mechanisms remain largely unaddressed. miR-204 has been implicated in PH, being anti-proliferative and pro-apoptotic in pulmonary artery smooth muscles cells (PASMCs), but its role in EndMT is still unknown. Here we found that miR-204 was down-regulated by hypoxia in rat pulmonary arterial intima and human pulmonary artery endothelial cells (HPAECs), and its further down-regulation by using miR-204 inhibitor suppressed hypoxia-induced EndMT. Moreover, autophagy, evoked by hypoxia in rat pulmonary arterial intima and HPAECs, suppressed hypoxia-induced EndMT via p62-dependent degradation of Snail and Twist. Additionally, autophagy was regulated by miR-204 targeting ATG7. While down-regulation of miR-204 in PASMCs reportedly promoted monocrotaline-induced pulmonary arterial hypertension via increased cell proliferation, our data suggested an important, albeit dichotomous, role of miR-204 down-regulation in endothelial cells in the process of EndMT that it attenuated EndMT by enhancing autophagy, thereby ameliorating hypoxia-induced PH to some extent.

Restoration of blood supply to ischemic myocardium causes cardiomyocyte damage, a process known as ischemia-reperfusion injury. Excess reactive oxygen species and intracellular calcium contribute to cell damage but the involvement of sirt1, a versatile protein deacetylase in reperfusion-induced cell damage remains unknown. Here, we found that hypoxia-reoxygenation, an in vitro model of ischemia-reperfusion injury, induced H9c2 cardiomyocyte apoptosis as revealed by caspase-3 assay, Hoechst 33258 staining, flow cytometric analysis and JC-1 staining. Molecular docking analysis showed that, pterostilbene, a natural dimethyl ether derivative of resveratrol, binds to the enzymatic active pocket of sirt1. Importantly, application of pterostilbene at low concentrations of 0.1-3.0 μM rescued H9c2 cells from apoptosis, an effect comparable with resveratrol at 20 μM. Mechanistically, pterostilbene exerted its cardioprotective effects via 1) stimulation of sirt1 activity, since pretreatment of H9c2 cells with splitomicin, an antagonist of sirt1, removed the effects of pterostilbene, and 2) enhancement of sirt1 expression. Therefore, the present study demonstrates that activation of sitr1 during ischemia-reperfusion is cardioprotective and that the natural compound-pterostilbene-could be used therapeutically to alleviate ischemia-reperfusion injury.

Aims Activation of hypoxia inducible factor-1 (HIF) is a hallmark in hypoxia-induced pulmonary hypertension (HPH). microRNAs play a significant role in regulating proliferation of pulmonary arterial smooth muscle cells (PASMCs) in pulmonary hypertension. Previous studies have shown that HIF-1β is a target of miR-103/107. In this present study, we aimed to investigate whether miR-103/107 regulate vascular remodeling in HPH via HIF-1β. Main methods The HPH model was built by hypoxia exposure in rats. Real-time PCR and Western blotting were used to determine the expression of miR-103/107 and HIF-1β. Proliferation of PASMCs was examined by 5-bromo-2′-deoxyuridine (BrdU) incorporation method. The functions of miR-103/107 on PASMCs proliferation, HIF-1α and HIF-1β expression were assessed by transfecting miR-103/107 mimics and inhibitors. Key findings Significant down-regulation of miR-103/107 was observed in remodeled intrapulmonary vascular in HPH rats and hypoxia-exposured PASMCs, whereas HIF-1α and HIF-1β expression were up-regulated. Hypoxia exposure induced significant proliferation of PASMCs, overexpression of miR-103/107 inhibited but miR-103/107 inhibitors exacerbated PASMCs proliferation. Gain-of-function and loss-of-function experiments showed that miR-103/107 expression was inversely correlated with HIF-1β level. No significant changes of HIF-1α expression were observed under miR-103/107 mimic treatment. Significance Loss of suppression on HIF-1β by miR-103/107 may contribute to excess proliferation of PASMCs and vascular remodeling in hypoxic pulmonary hypertension.

Aim Proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) are regarded as the primary factors resulting in pulmonary arterial remodeling in pulmonary hypertension (PH). Myeloid ecotropic viral integration site 1 (MEIS1) has been positioned as a negative cardiomyocyte cell cycle regulator and regulates proliferation of multiple kinds of cancer cells. Whether MESI1 is involved in the proliferation and migration of PASMCs deserves to be identified. Main methods Sprague Dawley rats were exposed to hypoxia condition (10% O2) for 4 weeks to induce PH and primary rat PASMCs were cultured in hypoxia condition (3% O2) for 48 h to induce proliferation and migration. Immunohistochemistry, immunofluorescence, reverse transcription PCR and Western blot analysis were performed to detect the expressions of target mRNAs and proteins. EDU, CCK8 and wound healing assays were conducted to measure the proliferation and migration of PASMCs. Key findings Hypoxia down-regulated the expression of MEIS1 (both mRNA and protein) in pulmonary arteries and PASMCs. Over-expression of MEIS1 inhibited the proliferation and migration of PASMCs afforded by hypoxia. In contrast, knockdown of MEIS1 under normoxia condition like hypoxia induced the proliferation and migration of PASMCs. MEIS1 mediated hypoxia-induced the proliferation and migration of PASMCs via METTL14/MEIS1/p21 signaling. Significance The present study revealed that MEIS1 regulated the proliferation and migration of PASMCs during hypoxia-induced PH. Thus, MEIS1 may be a potential target for PH therapy.

Aims Ionic perturbation in vascular smooth muscle cells contributes to cerebrovascular remodelling in the setting of hypertension, but the role of transient receptor potential (TRP) channel superfamily remains unknown. The present study was conducted to define the contribution of TRP channels to cerebrovascular remodelling. Methods and results By integrating quantitative PCR, western blotting, patch clamping, and Ca2+ imaging, we identified TRP channel, subfamily canonical, member 3 (TRPC3) as the channel subtype most considerably elevated in basilar arteries of two-kidney, two-clip stroke-prone hypertensive rats. Importantly, administration of pyrazole 3 (Pyr3), a TRPC3 channel blocker, attenuated cerebrovascular remodelling. During hypertension, epidermal growth factor receptor (EGFR) was transactivated, as evidenced by marked EGFR phosphorylation, increased pro-HB-EGF shedding, and elevated activity of ADAM17 (HB-EGF sheddase). ADAM17 activity was increased owing to enhanced activation rather than elevated expression. Remarkably, Pyr3 treatment suppressed EGFR transactivation in hypertension. In proliferating basilar artery smooth muscle cells or basilar arteries of hypertensive rats, co-immunoprecipitation assay revealed an interaction between TRPC3 and ADAM17 upon Ang II stimulation. Conclusion Collectively, we demonstrated that enhanced EGFR transactivation, due to increased TRPC3 expression and functional coupling of TRPC3/ADAM17, resulted in cerebrovascular remodelling. Therefore, TRPC3-induced EGFR transactivation may be therapeutically exploited to prevent hypertension-induced cerebrovascular remodelling.

Mammalian Target of Rapamycin (mTOR) is involved in the proliferation and survival of pulmonary artery smooth muscle cells (PASMCs) in human pulmonary hypertension (PH) and animal PH models, and miRNAs are reported to play a key role in modulation of the proliferation of PASMCs. The purposes of this study are to determine the functions of miR-100 and mTOR in cardiovascular remodeling of the hypoxic PH rats and to clarify the correlation between them. We established a rat model of hypoxic PH, which showed an increase in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, accompanied by an up-regulation of mTOR and a down-regulation of miR-100. Next, we established an in vitro model of hypoxia-induced proliferation of PASMCs. Consistent with the in vivo findings, hypoxia induced proliferation of PASMCs, accompanied by a down-regulation of miR-100 and an up-regulation of mTOR; these phenomena were reversed by miR-100 mimics or the antagonist of mTOR. Finally, the dual-luciferase reporter gene assay was utilized to reveal the direct interaction between miR-100 and the 3 '-UTR region of mTOR gene. Based on these observations, we conclude that miR-100 can modulate the proliferation of PASMCs in hypoxic PH rats through suppressing the mTOR expression.

It has also been shown that the decreased expression of eukaryotic translation initiation factor 3a (eIF3a) by L-mimosine caused cell cycle arrest. Our previous study has found that eIF3a is involved in bleomycin-induced pulmonary fibrosis. Whether the eIF3a/p27 signal pathway is involved in the inhibitory effect of L-mimosine on bleomycin-induced pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. The expression of eIF3a, p27, α-SMA, collagen I and collagen III was analyzed by qPCR and Western blot. In vivo, L-mimosine treatment significantly ameliorated the bleomycin-mediated histological fibrosis alterations and blocked collagen deposition concomitantly with reversing bleomycin-induced expression up-regulation of eIF3a, α-SMA, collagen I and collagen III (both mRNA and protein) and expression down- regulation of p27. In vitro, L-mimosine remarkably attenuated proliferation of pulmonary fibroblasts and expression of α-SMA, collagen I and collagen III induced by TGF-β1, and this inhibitory effect of L-mimosine was accompanied by inhibiting eIF3a expression and increasing p27 expression. Knockdown of eIF3a gene expression reversed TGF-β1-induced proliferation of fibroblasts, down-regulation of p27 expression and up-regulation of α-SMA, collagen I, and collagen III expression. These results suggest that L-mimosine inhibited the progression of bleomycin-induced pulmonary fibrosis in rats via the eIF3a/p27 pathway.

The risk of cardiovascular complications in diabetic patients is mainly associated with endothelial dysfunction. Reduced number of EPCs and impaired function of EPCs in diabetes result in imbalance of endothelial homeostasis and dysfunction of vessels. In patients with diabetes mellitus, plasma levels of asymmetric dimethylarginine (ADMA) were elevated, while the expression and activity of dimethylarginine dimethylaminohydrolase (DDAH) were reduced. In the present study, we investigated the role of the DDAH2/ADMA pathway in the senescence of EPCs in type 2 diabetic patients and cultured EPCs treated with high glucose. The results showed that the percentage of senescent EPCs increased while the expression of DDAH2 decreased concomitantly with an increase in the plasma levels of ADMA in patients with type 2 diabetes mellitus (T2DM). Similar results were seen in cultured EPCs treated with high glucose. Exogenous application of ADMA accelerated the senescence of EPCs in a dose-dependent manner, and overexpression of DDAH2 inhibited high glucose-induced EPCs senescence. In addition, it has also been reported that DDAH/ADMA pathway is regulated by silent information regulator 1 (SIRT1) in endothelial cell. In the present study, we found decreased expression of SIRT1 both in T2DM patients and EPCs pretreated with high glucose. And resveratrol (activating SIRT1) inhibited high glucose-induced EPCs senescence by upregulating the expression of DDAH2 and decreasing the levels of ADMA. Taken together, we concluded that DDAH2/ADMA is involved in the accelerated senescence of EPCs in diabetes, which is associated with the activation of SIRT1.

In order to distinguish the research focus between different Library and Information Science (LIS) research institutions in China, we use the Keyword Activity Index (KAI) to identify their institution-specific keywords. The KAI, whose idea is borrowed from the Activity Index, measures whether an institution has alternatively comparative advantage in a particular topic according to its share in publications. In this study, a total of 65,653 papers from 19 core LIS journals in China during the period of 2000---2013 are collected. The top 8 most prolific LIS research institutions in China are selected for further investigation of the utility of KAI. Their institution-specific keywords are extracted based on the KAI values to represent their research focus and then clustered using co-word analysis; the research advantages of each institution are analyzed and compared according to these clusters. The reasons of their research advantages are analyzed based on their research function and research background.

Eukaryotic translation initiation factor 3a (eIF3a) is a multifunctional protein and plays an important role in regulation of cellular function including proliferation and differentiation. In the present study, we tested the function of eIF3a in pulmonary fibrosis. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5mg/kg) in rats. Primary pulmonary fibroblasts were cultured for proliferation investigation by BrdU incorporation method and flow cytometry. The expression/level of eIF3a, TGF-β1, ERK1/2 and α-SMA were analyzed by ELISA, real-time PCR or western blot. Results showed that the expression of eIF3a was obviously increased in lungs of pulmonary fibrosis rats accompanied by up-regulation of α-SMA and collagens. In cultured pulmonary fibroblasts, application of exogenous TGF-β1 induced cell proliferation and differentiation concomitantly with up-regulation of eIF3a expression and ERK1/2 phosphorylation. The effects of TGF-β1-induced proliferation of fibroblasts and up-regulation of α-SMA were abolished by eIF3a siRNA. TGF-β1-induced eIF3a expression was reversed in the presence of PD98059, an inhibitor of ERK1/2. These findings suggest that eIF3a plays an important role in bleomycin-induced pulmonary fibrosis by regulating pulmonary fibroblasts׳ function, and up-regulation of eIF3a induced by TGF-β1 is mediated via the ERK1/2 pathway.

In pulmonary hypertension (PH), pulmonary arterial smooth muscle cells (PASMCs) are dedifferentiated, undergoing a contractile-to-synthetic phenotypic switching. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays diverse roles in the cardiovascular system, but its contribution to PH remains to be fully defined. The present study was undertaken to explore the role of LOX-1 in PASMCs dedifferentiation in hypoxia-induced pulmonary vascular remodeling and PH. In a rat model of hypoxic PH, pulmonary vascular remodeling was accompanied by increased expression of LOX-1 in pulmonary arteries. In primary rat PASMCs, hypoxia-induced PASMCs dedifferentiation occurred concomitantly with LOX-1 upregulation. Inhibition of LOX-1 by either siRNA knockdown or neutralizing antibody significantly ameliorated PASMCs dedifferentiation. Mechanistically, LOX-1 promotes PASMCs dedifferentiation under hypoxic conditions via ERK1/2-Elk-1/MRTF-A/SRF signaling pathway. In conclusion, our data uncovers an important role of LOX-1 in the maintenance of PASMCs phenotype. Therapeutic targeting of LOX-1/ERK1/2-Elk-1/MRTF-A/SRF signaling axis would be exploited to treat hypoxic PH.

We have previously reported that the long-term exposure of organophosphorus induces vascular dementia (VD) in rats. As a coenzyme, vitamin B6 is mainly involved in the regulation of metabolisms. Whether vitamin B6 improves VD remains unknown.The model of VD was induced by feeding rats with isocarbophos (0.5 mg/kg per two day, 12 weeks). The blood flow of the posterior cerebral artery (PCA) in rat was assessed by transcranial Doppler (TCD). The learning and memory were evaluated by the Morris Water Maze (MWM) test.Administration of vitamin B6 increased the blood flow in the right and left posterior cerebral arteries and improved the functions of learning and memory in isocarbophos-treated rats. Vitamin B6 increased the protein levels of N-methyl-D-aspartate receptor (NMDAR) 2B, postsynaptic densities (PSDs) protein 95, and calmodulin-dependent protein kinase II (CaMK-II) in the hippocampus, which were decreased by isocarbophos in rats. Morphological analysis by light microscope and electronic microscope indicated disruptions of the hippocampus caused by isocarbophos were normalized by vitamin B6. Importantly, the antagonist of NMDAR signaling by eliprodil abolished these beneficial effects produced by vitamin B6 on PCA blood flow, learning, memory, and hippocampus structure in rats, as well as the protein expression of NMDAR 2B, PSDs protein 95, and CaMK-II in the hippocampus.Vitamin B6 activates NMDAR signaling to prevent isocarbophos-induced VD in rats.

Pulmonary hypertension (PH) mainly results from excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and displays mitochondrial abnormalities such as mitochondrial fragmentation. Epigallocatechin-3-gallate (EGCG), an efficient antiproliferative compound in green tea, has recently been demonstrated to inhibit PASMCs proliferation. However, the pre-clinical issues as to whether EGCG attenuates PH and the underlying mechanisms have yet to be addressed. The present study was undertaken to investigate the therapeutic effects of EGCG on PH and its effects on mitochondrial fragmentation in PASMCs. Rats exposed to hypoxia (10% O2, 3 weeks) developed PH. EGCG (50, 100 or 200mg/kg/d, i.g.) dose-dependently attenuated right ventricular systolic pressure, pulmonary vascular remodeling and right ventricular hypertrophy, increased expression of mitochondrial fusion protein - mitofusin-2 (MFN-2), and promoted mitochondrial fusion as evidenced by decreased number and volume of mitochondria in PASMCs of pulmonary arteries. Notably, EGCG (50μM) downregulated hypoxia-induced (3% O2, 48h) PASMCs mitochondrial fragmentation and inhibited PASMCs proliferation via KLF-4/MFN-2/p-Erk signaling pathway. Collectively, our data demonstrated that EGCG exerts antiproliferative effects via regulating mitochondrial fragmentation of PASMCs and EGCG holds the promise as a drug against PH.

Studies of the resources and services provided through university digital libraries have focused on evaluation criteria which consider usability, content, technology, and context. The factors influencing user perception of university digital libraries have not been explored and discussed from the perspective of specific library service types. Structural equation modeling was used to explore influencing factors and the relationships among them, based on 353 responses to survey questionnaires regarding academic DLs in China. Findings show that information providing services, information retrieval services, and individual services are direct influencing factors, while information organizing services affect user perception indirectly through information retrieval services and individual services. Various services also demonstrate interactions.

This study is aimed at revealing the contributions of microblogging services to user satisfaction in China. An empirical investigation was conducted to analyse user experience on the 36 main microblogging service elements, using a sample of 216 users of Sina Weibo, which is the biggest microblog in China. The tetra-class model was then applied to identify the contribution of each service element to the overall satisfaction. Through correspondence analysis, we calculated, respectively, the contribution to dissatisfaction when the service element was negatively evaluated and that to satisfaction when it was positively evaluated. Based on these two contribution values, we classified the service elements into four categories: Basic, Secondary, Plus, and Key. In order to know the preferences of different users towards the microblogging service elements, we segmented the users into groups according to their microblogging characteristics and personal attributes and then discussed the variations of the service, c...

Objective To investigate the effect of lectin-like ox-LDL receptor-1 (LOX-1) on oxidized low-density lipoprotein (ox-LDL)-induced apoptosis and the involvement of the endoplasmic reticulum (ER) stress response pathway. Methods and results Human umbilical vein endothelial cells were treated with 50, 100, or 200 μg/ml ox-LDL and cultured for 12, 24, or 48 h for concentration- and time-dependent studies. Cells were transfected with LOX-1 or Nox-4 shRNAs, and target proteins were inhibited with the corresponding antibodies for mechanistic studies. Active proteins and mRNAs were analyzed by Western blotting and RT-PCR, respectively. Cell apoptosis was analyzed by Annexin and Hoechst staining assays. Ox-LDL induced both apoptosis and protein expression of LOX-1 and Nox-4 through activation of ER stress sensors IRE1 and PERK, and nuclear translocation of ATF6 and their subsequent pathways were indicated by JNK, eukaryotic initiation factor 2 phosphorylation, XBP-1, and chaperone GRP78 expression; up-regulation of proapoptotic proteins CHOP and Bcl-2; and caspase-12 activity. LOX-1 gene silencing and treatment with an anti-LOX-1 antibody attenuated the effects of ox-LDL. Pretreatment with irestatin 9389, salubrinal, or AEBSF also blocked ox-LDL-induced expression of CHOP and Bcl-2 and activation of caspase-12 activity, leading to an attenuation of endothelial cell apoptosis. Furthermore, Nox-4 siRNA attenuated the up-regulated expression of GRP78, PERK, IRE1, and XBP-1 to reduce ox-LDL-induced endothelial cell apoptosis. Conclusions LOX-1 plays a critical role in ox-LDL-induced endothelial cell apoptosis via the ER stress pathway.

Reactive oxygen species (ROS) contributes to endothelial dysfunction that is involved in the pathogeneses of hypertension. Vascular peroxidase 1 (VPO1) can utilize ROS to catalyze peroxidative reactions, possibly enhancing endothelial dysfunction. This study is to identify VPO1's involvement in endothelial dysfunction and hypertension. Sixty-four spontaneously hypertensive rats (SHRs) and 64 age-matched, bodyweight controlled normotensive Wistar-Kyoto rats (WKYs) were randomly grouped and studied at the age of 5, 8, 13 and 20 weeks (16 animals, each). Blood pressure and vasodilator responses to acetylcholine in aortic rings were observed. The expressions of VPO1 and endothelial NO synthase (eNOS) in aortas were assessed by quantitative reverse transcription-PCR and western blotting analysis. Plasma concentrations of hydrogen peroxide (H2O2) and NO, NOX activity, hypochlorous acid (HOCl) production, and 3-nitrotyrosine content in aortic homogenates were also determined in this study. Along with the development of hypertension in SHR rats, VPO1 expression was up-regulated together with a significant increase in NOX activity, HOCl production, 3-nitrotyrosine content, and plasma H2O2 level compared with WKYs at 8, 13 and 20 weeks of age. In contrast, blood NO levels were decreased and aortic relaxation to acetylcholine was deteriorated in SHRs. The over-expression of VPO1 during the development of hypertension, accompanied by the endothelial dysfunction, the decreased NO levels, the elevated NOX and ROS activities, indicates a clear connection between VPO1 gene and hypertension. VPO1 may pathogenetically contribute to hypertension via signal pathways involving NOX-H2O2-VPO1-HOCl or JNK/p38 MAPK although further studies are needed to determine the precise mechanisms.

This study aims to reveal the intellectual structure of Library and Information Science (LIS) in China during the period 2008---2012 utilizing co-word analysis. The status and trends of LIS in China are achieved by measuring the correlation coefficient of selected keywords extracted from relevant journals in the Chinese Journal Full-Text Database. In co-word analysis, multivariate statistical analysis and social network analysis are applied to obtain 13 clusters of keywords, a two-dimensional map, centrality and density of clusters, a strategic diagram and a relation network. Based on these results, the following conclusions can be drawn: (i) LIS in China has some established and well-developed research topics; (ii) a few emerging topics have a great potential for development; and (iii), the research topics in this LIS field are largely decentralized as a whole, where there are many marginal and immature topics.

We have found that eIF3a plays an important role in bleomycin-induced pulmonary fibrosis, and up-regulation of eIF3a induced by TGF-β1 is mediated via the ERK1/2 pathway. Whether ERK1/2 – eIF3a signal pathway is involved in calcitonin gene-related peptide (CGRP)-mediated pathogenesis of bleomycin-induced pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. Sensory CGRP depletion by capsaicin exacerbated bleomycin-induced pulmonary fibrosis in rats, as shown by a significant disturbed alveolar structure, marked thickening of the interalveolar septa and dense interstitial infiltration by inflammatory cells and fibroblasts, accompanied with increased expression of TGF-β1, eIF3a, phosphorylated ERK1/2, α-SMA, collagen I, and collagen III. Exogenous application of CGRP significantly inhibited TGF-β1-induced proliferation and differentiation of pulmonary fibroblasts concomitantly with decreased expression of eIF3a, phosphorylated ERK1/2, α-SMA, collagen I, and collagen III. These effects of CGRP were abolished in the presence of CGRP8-37. These results suggest that endogenous CGRP is related to the development of pulmonary fibrosis induced by bleomycin, and the inhibitory effect of CGRP on proliferation of lung fibroblasts involves the ERK1/2 – eIF3a signaling pathway.

Background Endothelial cell apoptosis contributes to cardiovascular diseases such as hypertension, atherosclerosis. MicroRNA regulates endothelial cell function but its role in endothelial cell apoptosis remains to be fully elucidated. This study aims to investigate the role of miR-590-5p in endothelial cell apoptosis and dissect the underlying mechanisms. Methods Flow cytometric analysis, Hoechst 33258 staining and Western blotting were performed to evaluate human umbilical vein endothelial cell (HUVEC) apoptosis induced by Angiotensin (Ang) II. Western blotting and real-time quantitative PCR were conducted to assess the expression of LOX-1. DCFH-DA staining was carried out to measure the generation of reactive oxygen species (ROS). Results Ang II-induced HUVEC apoptosis was accompanied by downregulation of miR-590-5p; administration of miR-590-5p mimics attenuated HUVEC apoptosis and decreased ROS generation, as indicated by reduced fraction of apoptotic HUVECs and decreased caspase-3 activity. LOX-1 expression was increased by Ang II, and miR-590-5p mimics reduced LOX-1 expression in HUVECs in the absence or presence of Ang II. Pharmacologic or genetic block of LOX-1 with small interference RNA or TS92 (LOX-1 neutralizing antibody) significantly ameliorated HUVEC apoptosis, as evidenced by reduced number of apoptotic HUVECs, inhibited caspase-3 activation and suppressed mitochondrial cytochrome C release. Moreover, LOX-1 siRNA or TS92 treatment dramatically reduced ROS production in HUVECs treated with Ang II. Conclusion Our data demonstrated that miR-590-5p downregulation promoted Ang II-induced endothelial cell apoptosis by elevating LOX-1 expression and consequently increasing ROS generation. Thus, restoration of miR-590-5p or block of LOX-1 could be therapeutically exploited to alleviate endothelial cell apoptosis.

Angiogenesis, the development of new capillaries from pre-existing vessels, requires the coordinate activation of endothelial cells, which migrate and proliferate to form functional vessels. Endothelial dysfunction and decreased nitric oxide bioavailability may underscore the impairment of angiogenesis. As such, the delivery of exogenous NO is an attractive therapeutic option that has been used to therapeutic angiogenesis. In this paper, a novel group of hybrid nitric oxide-releasing chrysin derivatives was synthesized. The results indicated that all these chrysin derivatives exhibited promotion of endothelial migration and tubulogenesis in vitro as well as stimulation angiogenesis in vivo.Furthermore, all compounds released NO upon incubation with phosphate buffer at pH 7.4 and enhanced VEGF secretion and VEGF mRNA expression of endothelial cells. These hybrid ester NO donor prodrugs offer a potential drug design concept for the development of therapeutic or preventive agents for angiogenesis deficiency due to ischemic diseases.

Profilin-1, a regulator of actin polymerization, has recently been linked to vascular hypertrophy and remodeling. Whether profilin-1 is involved in angiotensin (Ang) II-induced proliferation of vascular smooth muscle cells leading to vascular remodeling in hypertension remains unclear. The present study was designed to analyze the correlation of profilin-1 and vascular remodeling during hypertension and to evaluate the role of profilin-1 in proliferation of vascular smooth muscle cells and the underlying mechanisms. The vascular morphology and the expression of profilin-1 in arterial tissues of spontaneously hypertensive rats and Wistar-Kyoto rats were assessed. The profilin-1 expression was significantly increased concomitantly with definite vascular remodeling by evaluating the media thickness, lumen diameter, media thickness-to-lumen diameter ratio and mean nuclear area in artery media in spontaneously hypertensive rats, which was inhibited by treatment with losartan. In cultured rat aortic smooth muscle cells (RASMCs), Ang II induced profilin-1 expression in a dose- and time-dependent manner. Knockdown of profilin-1 using small hairpin RNA inhibited Ang II-induced proliferation of RASMCs. Moreover, blockade of JAK2/STAT3 signaling pathway also inhibited Ang II-induced proliferation of RASMCs and profilin-1 expression. These results suggest that profilin-1 mediates the proliferation of RASMCs induced by Ang II via activation of Ang II type 1 receptor/JAK2/STAT3 signaling pathway, which may contribute to vascular remodeling in hypertension.

This paper aims to reveal the relationship and structure of library and information science (LIS) journals in China. 24 core LIS journals in China are selected and the relevant data of journal co-citation are retrieved from Chinese Journal Full-Text Database constructed by China National Knowledge Infrastructure during the period of 1999---2009. By calculating mean co-citation frequencies and correlation coefficients, we find that there is a strong relationship among LIS journals in China. Utilizing the methods of cluster analysis, multidimensional scaling analysis and factor analysis, we analyze the data of journal co-citation. LIS journals in China are divided into four clusters. The relatedness among journals is shown manifestly through their locations in the two-dimensional map. A three-factor solution is obtained with the factor loading of each journal. Finally, we interpret and discuss the results to get some conclusions and also expect to describe the network characters of journal co-citation in future research.

1. It has been reported that resveratrol exerts the inhibitory effects on aging through activation of sirtuin 1 (SIRT1) and dimethylarginine dimethylaminohydrolase (DDAH)/asymmetric dimethylarginine (ADMA) pathway involved in the high glucose-induced endothelial cell senescence. 2. The aims of this work were to explore whether BTM-0512, a novel derivative of resveratrol, was able to exert the beneficial effect on high glucose-induced cellular senescence through regulating the DDAH/ADMA pathway and to explore whether the regulatory effect of BTM-0512 on DDAH/ADMA pathway was related to the activation of SIRT1. 3. The senescence model of endothelial cells was induced by high glucose and the cells were collected for the determination of beta-galactosidase and DDAH activity, ADMA level, DDAH and SIRT1 mRNA expression. 4. The results showed that high glucose significantly increased the ratio of senescent cells concomitantly with the decreased DDAH activity, the downregulated DDAH2 and SIRT1 mRNA expressions and the increased ADMA levels, which were attenuated by pretreatment with BTM-0512. 5. The beneficial effects of BTM-0512 on high glucose-induced senescence were blocked by splimtomicin, the specific inhibitor of SIRT1, or by silencing DDAH2 expression. 6. The results suggest that BTM-0512 was able to exert the beneficial effects on high glucose-induced cellular senescence through regulating the DDAH/ADMA pathway, and its regulatory effect on DDAH/ADMA pathway was related to the activation of SIRT1.

Vascular complications are major causes of disability and death in patients with diabetes mellitus. It is often characterized by endothelial dysfunction. Studies have shown that either the loss of nitric oxide bioactivity or the decreased biosynthesis of NO is a central mechanism in endothelial dysfunction. As such, the delivery of exogenous NO is an attractive therapeutic option that has been used to slow the progress of diabetic vascular complications. In this paper, a novel group of hybrid nitric oxide-releasing chrysin derivatives was synthesized. The results indicated that all these chrysin derivatives exhibited in vitro inhibitory activities against aldose reductase and advanced glycation end-products formation. And some of them were even found to increase the glucose consumption of HepG2 cells. Furthermore, all compounds released NO upon incubation with phosphate buffer at pH 7.4. These hybrid ester NO donor prodrugs offer a potential drug design concept for the development of therapeutic or preventive agents for vascular complications due to diabetes.

This paper describes the introduction of an open-access preprint server in China covering 43 disciplines. The system includes mandatory deposit for state-funded research and reports on the repository and its effectiveness and outlines a novel process of peer-review of preprints in the repository, which can be incorporated into the established system of promotion and tenure. This state-initiated innovation is considered to have been well incorporated into the established scientific communication system despite the sociological differences between the various disciplines served by the repository.

L-glutamate plays a key role in neuronal cell death associated with many neurodegenerative conditions such as cerebral ischemia, hypoxia, Alzheimer's, Huntington's, and Parkinson's diseases. Selaginellin, a component extracted from Saussurea pulvinata (Hook.et Grev.) Maximo, was assessed for its ability to protect rat pheochromocytoma (PC12) cells against oxidative toxicity induced by glutamate. The differentiated PC12 cells were pretreated with various concentrations (10(-7), 3 x 10(-7), or 10(-6) M) of selaginellin for 1 h prior to exposure to L-glutamate. Selaginellin was shown to protect PC12 cells against glutamate toxicity, as determined by characteristic morphological features, lactate dehydrogenase release and cell viability, and apoptosis as evaluated by Hoechst 33342 staining assay and caspase-3 activity. In addition, the increase in levels of reactive oxygen species and decrease in klotho gene expression induced by glutamate were significantly reversed by selaginellin. Our study suggests that selaginellin has a neuroprotective effect against L-glutamate-induced neurotoxicity through mechanisms related to anti-oxidation and anti-apoptosis via scavenging reactive oxygen species and up-regulating the expression of klotho gene.

Monocyte adhesion to activated vascular endothelial cells is the critical event in the initiation of atherosclerosis. Adhesion molecules are inflammatory markers, which are upregulated by oxidized low-density lipoprotein (ox-LDL) and play a pivotal role in atherogenesis. In present study, the effect of reinioside C, a major compound of Polygala fallax Hemsl., on adhesion of monocytes to endothelial cells induced by ox-LDL was investigated. The results showed that incubation of endothelial cells with ox-LDL (100 microg/mL) for 24 h markedly increased the expression of ICAM-1 and P-selectin and enhanced the adhesion of monocytes to endothelial cells. Pretreatment with reinioside C (1, 3, or 10 microM) dose-dependently decreased ox-LDL-induced upregulation of expression of ICAM-1 and P-selectin and the enhanced adhesion of monocytes to endothelial cells. To determine the role of NADPH oxidase/reactive oxygen species (ROS)/nuclear factor-kappaB (NF-kappaB) pathway, endothelial cells were treated with ox-LDL (100 microg/mL) for 2 h, and NADPH oxidase subunit (Nox 2 and p22phox) mRNA expression, intracellular ROS level, and NF-kappaB activity were measured. The results showed that reinioside C attenuated ox-LDL-induced NADPH oxidase subunit (Nox 2 and p22phox) mRNA expression, generation of ROS, and activation of NF-kappaB in endothelial cells in a dose-dependent manner; the two latter effects were inhibited by pyrollidine dithiocarbamate, the inhibitor of NF-kappaB. These findings suggest that reinioside C attenuates ox-LDL-induced expression of adhesion molecules (P-selectin and ICAM-1) and the adhesion of monocytes to endothelial cells by inhibiting NADPH oxidase/ROS/NF-kappaB pathway.

Atherosclerosis is associated with oxidative stress and inflammation, and upregulation of LOX-1, an endothelial receptor for oxidized LDL (oxLDL). Here, we describe generation of LOX-1 knockout (KO) mice in which binding of oxLDL to aortic endothelium was reduced and endothelium-dependent vasorelaxation preserved after treatment with oxLDL ( P P P

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a receptor for oxidized-LDL, is up-regulated in activated endothelial cells, and it plays a role in atherothrombosis. However, its role in platelet aggregation is unclear. Both aspirin and HMG CoA reductase inhibitors (statins) reduce LOX-1 expression in endothelial cells. In this study, we investigated the effect of aspirin and pravastatin on LOX-1 expression on plate-lets. After ADP stimulation, mean fluorescence intensity of LOX-1 expression on platelets increased 1.5- to 2.0-fold. Blocking LOX-1 inhibited ADP-induced platelet aggregation in a concentration- and time-dependent manner. We also established that LOX-1 is important for ADP-stimulated inside-out activation of platelet alpha(IIb)beta(3) and alpha(2)beta(1) integrins (fibrinogen receptors). The specificity of this interaction was determined by arginine-glycine-aspartate-peptide inhibition. Furthermore, we found that LOX-1 inhibition of integrin activation is mediated by inhibition of protein kinase C activity. In other experiments, treatment with aspirin (1-10 mM) and pravastatin (1-5 microM) reduced platelet LOX-1 expression, with a synergistic effect of the combination of aspirin and pravastatin. Aspirin and pravastatin both reduced reactive oxygen species (ROS) released by activated platelets measured as malonyldialdehyde (MDA) release and nitrate/nitrite ratio. Aspirin and pravastatin also enhanced nitric oxide (NO) release measured as nitrite/nitrite + nitrate (NOx) ratio in platelet supernates. Small concentrations of aspirin and pravastatin had a synergistic effect on the inhibition of MDA release and enhancement of nitrite/NOx. Thus, LOX-1 is important for ADP-mediated platelet integrin activation, possibly through protein kinase C activation. Furthermore, aspirin and pravastatin inhibit LOX-1 expression on platelets in part by favorably affecting ROS and NO release from activated platelets.

Asymmetric dimethylarginine (ADMA), a major endogenous nitric oxide (NO) synthase inhibitor, is thought to be a key contributor for endothelial dysfunction. Decrease in activity of dimethylarginine dimethylaminohydrolase (DDAH), a major hydrolase of ADMA, causes accumulation of ADMA in some risk factors of atherosclerosis, including hypercholesterolemia. Taurine is a semi-essential amino acid that has previously been shown to have endothelial protective effects. The present study was to test whether the protective effect of taurine on endothelial function is related to modulation of the DDAH/ADMA pathway. A single injection of native LDL (4 mg/kg, i.v.) markedly reduced endothelium-dependent vasorelaxation and the plasma level of NO, and increased plasma concentrations of ADMA, malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-alpha). Treatment with taurine in vivo (60 or 180 mg/kg) significantly attenuated the inhibition of endothelium-dependent vasorelaxation and the reduced level of NO, and decreased the elevated levels of ADMA, MDA, and TNF-alpha. Incubation human umbilical vein endothelial cells (HUVECs) with ox-LDL (100 microg/ml) for 24 h markedly increased the medium levels of lactate dehydrogenase (LDH), ADMA, TNF-alpha and MDA, and decreased the level of NO in the medium and the intracellular activity of DDAH. Taurine (1 or 5 microg/ml) significantly attenuated the increases in the levels of LDH, ADMA, TNF-alpha and MDA, and the decrease in the level of NO and the activity of DDAH induced by ox-LDL in HUVECs. The present results suggested that taurine protected against endothelial dysfunction induced by native LDL in vivo or by ox-LDL in endothelial cells, and the protective effect of taurine on the endothelium is related to decrease in ADMA level by increasing of DDAH activity.

Background Previous investigations have indicated that the level of asymmetric dimethylarginine (ADMA) is increased in diabetic patients and animals, and rosiglitazone has a protective effect on the endothelium. In the present study, we tested the relationship between protective effects of rosiglitazone and ADMA in streptozotocin (STZ)-induced diabetic rats and cultured endothelial cells. Methods Blood samples were collected from carotid artery. Vasodilator responses to acetylcholine (ACh) in the isolated aortic rings were measured, and serum concentrations of glucose, lipid, nitrite/nitrate, ADMA and tumour necrosis factor-α (TNF-α) were determined. Cultured endothelial cells were treated with ADMA, and the concentrations of intercellular adhesion molecule (ICAM-1), TNF-α, and the activity of nuclear factor-κB (NF-κB) were determined. Results Vasodilator responses to ACh were decreased markedly and the serum concentrations of TNF-α, nitrite/nitrate and ADMA were increased significantly in diabetic rats. Rosiglitazone (3, 10 or 30 mg/kg) produced a significant reduction of the inhibition of vasodilator responses to ACh, but had no effect on the serum concentrations of glucose, lipid, nitrite/nitrate and ADMA in diabetic rats. ADMA (30 µM) significantly increased the activity of NF-κB and elevated the levels of ICAM-1 and TNF-α, and pre-treatment with rosiglitazone (10 or 30 µM) markedly inhibited the increased activity of NF-κB and reduced the elevated levels of TNF-α and ICAM-1 induced by ADMA in cultured endothelial cells. Conclusions Rosiglitazone improves endothelial function in diabetic rats, which is related to the reduction of the inflammatory response induced by ADMA. Copyright © 2006 John Wiley & Sons, Ltd.

Long non-coding RNA (lncRNA) is a type of DNA transcript that is longer than 200 nucleotides (nt). They do not encode proteins, but they control gene expression on various levels. Long non-coding RNA metastasis-associated urothelial carcinoma associated 1 (UCA1) was confirmed to play an important role in the occurrence and development of many tumor and non-tumor diseases. UCA1 mainly interacts with proteins in the nucleus, regulating gene expression in transcription and post-transcription. UCA1 is highly expressed in tumor tissue, and therefore can be related to clinical parameters. It may regulate tumor cell proliferation, invasion, apoptosis, and migration, so UCA1 can be applied in clinical prognosis and targeted therapy. This review mainly elaborates the roles of UCA1 in tumor diseases of the respiratory, digestive, reproductive, and urinary systems; and in non-tumor diseases.