Reactive oxygen species, endoplasmic reticulum stress and mitochondrial dysfunction: the link with cardiac arrhythmogenesis

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Angiotensin II type 1 receptor-dependent oxidative stress mediates endothelial dysfunction in type 2 diabetic mice

The mechanisms underlying the effect of the renin-angiotensin-aldosterone system (RAAS) inhibition on endothelial dysfunction in type 2 diabetes are incompletely understood. This study explored a causal relationship between RAAS activation and oxidative stress involved in diabetes-associated endothelial dysfunction. Daily oral administration of valsartan or enalapril at 10mg/kg/day to db/db mice for 6 weeks reversed the blunted acetylcholine-induced endothelium-dependent dilatations, suppressed the upregulated expression of angiotensin II type 1 receptor (AT1R) and NAD(P)H oxidase subunits (p22phox and p47phox), and reduced reactive oxygen species (ROS) production. Acute exposure to AT1R blocker losartan restored the impaired endothelium-dependent dilatations in aortas of db/db mice and also in renal arteries of diabetic patients (fasting plasma glucose level ≥7.0 mmol/l). Similar observations were also made with apocynin, diphenyliodonium, or tempol treatment in db/db mouse aortas. DHE fluorescence revealed an overproduction of ROS in db/db aortas which was sensitive to inhibition by losartan or ROS scavengers. Losartan also prevented the impairment of endothelium-dependent dilatations under hyperglycemic conditions that were accompanied by high ROS production. The present study has identified an initiative role of AT1R activation in mediating endothelial dysfunction of arteries from db/db mice and diabetic patients. © 2010 Mary Ann Liebert, Inc.published_or_final_versio

Autotaxin signaling facilitates β cell dedifferentiation and dysfunction induced by Sirtuin 3 deficiency

OBJECTIVE: β cell dedifferentiation may underlie the reversible reduction in pancreatic β cell mass and function in type 2 diabetes (T2D). We previously reported that β cell-specific Sirt3 knockout (Sirt3f/f;Cre/+) mice developed impaired glucose tolerance and glucose-stimulated insulin secretion after feeding with high fat diet (HFD). RNA sequencing showed that Sirt3-deficient islets had enhanced expression of Enpp2 (Autotaxin, or ATX), a secreted lysophospholipase which produces lysophosphatidic acid (LPA). Here, we hypothesized that activation of the ATX/LPA pathway contributed to pancreatic β cell dedifferentiation in Sirt3-deficient β cells. METHODS: We applied LPA, or lysophosphatidylcoline (LPC), the substrate of ATX for producing LPA, to MIN6 cell line and mouse islets with altered Sirt3 expression to investigate the effect of LPA on β cell dedifferentiation and its underlying mechanisms. To examine the pathological effects of ATX/LPA pathway, we injected the β cell selective adeno-associated virus (AAV-Atx-shRNA) or negative control AAV-scramble in Sirt3f/f and Sirt3f/f;Cre/+ mice followed by 6-week of HFD feeding. RESULTS: In Sirt3f/f;Cre/+ mouse islets and Sirt3 knockdown MIN6 cells, ATX upregulation led to increased LPC with increased production of LPA. The latter not only induced reversible dedifferentiation in MIN6 cells and mouse islets, but also reduced glucose-stimulated insulin secretion from islets. In MIN6 cells, LPA induced phosphorylation of JNK/p38 MAPK which was accompanied by β cell dedifferentiation. The latter was suppressed by inhibitors of LPA receptor, JNK, and p38 MAPK. Importantly, inhibiting ATX in vivo improved insulin secretion and reduced β cell dedifferentiation in HFD-fed Sirt3f/f;Cre/+ mice. CONCLUSIONS: Sirt3 prevents β cell dedifferentiation by inhibiting ATX expression and upregulation of LPA. These findings support a long-range signaling effect of Sirt3 which modulates the ATX-LPA pathway to reverse β cell dysfunction associated with glucolipotoxicity

Uncoupling Protein-2 Mediates DPP-4 Inhibitor-Induced Restoration of Endothelial Function in Hypertension Through Reducing Oxidative Stress

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Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin F2α impairs endothelial function in renovascular hypertensive rats

Abstract Aims: The role of endothelium-derived contracting factors (EDCFs) in regulating renovascular function is yet to be elucidated in renovascular hypertension (RH). The current study investigated whether oxidative stress-dependent cyclooxygenase (COX)-2-derived prostaglandin F(2alpha) (PGF(2alpha)) impairs endothelial function in renal arteries of renovascular hypertensive rats (RHR). Results: Renal hypertension was induced in rats by renal artery stenosis of both kidneys using the 2-kidney 2-clip model. Acute treatment with reactive oxygen species (ROS) scavengers, COX-2 inhibitors, and thromboxane-prostanoid receptor antagonists, but not COX-1 inhibitors, improved endothelium-dependent relaxations and eliminated endothelium-dependent contractions in RHR renal arteries. Five weeks of treatment with celecoxib or tempol reduced blood pressure, increased renal blood flow, and restored endothelial function in RHRs. Increased ROS production in RHR arteries was inhibited by ROS scavengers, but unaffected by COX-2 inhibitors; whereas increased PGF(2alpha) release was reduced by both ROS scavengers and COX-2 inhibitors. ROS also induced COX-2-dependent contraction in RHR renal arteries, which was accompanied by the release of COX-2-derived PGF(2alpha). Further, chronic tempol treatment reduced COX-2 and BMP4 upregulation, p38MAPK phosphorylation, and the nitrotyrosine level in RHR renal arteries. Conclusion: These findings demonstrate the functional importance of oxidative stress, which serves as an initiator of increased COX-2 activity, and that COX-2-derived PGF(2alpha) plays an important role in mediating endothelial dysfunction in RH. Innovation: The current study, thus, suggests that drugs targeting oxidative stress-dependent COX-2-derived PGF(2alpha) may be useful in the prevention and management of RH. Antioxid. Redox Signal. 16, 363-373.published_or_final_versio

In situ interface engineering for probing the limit of quantum dot photovoltaic devices.

Quantum dot (QD) photovoltaic devices are attractive for their low-cost synthesis, tunable band gap and potentially high power conversion efficiency (PCE). However, the experimentally achieved efficiency to date remains far from ideal. Here, we report an in-situ fabrication and investigation of single TiO2-nanowire/CdSe-QD heterojunction solar cell (QDHSC) using a custom-designed photoelectric transmission electron microscope (TEM) holder. A mobile counter electrode is used to precisely tune the interface area for in situ photoelectrical measurements, which reveals a strong interface area dependent PCE. Theoretical simulations show that the simplified single nanowire solar cell structure can minimize the interface area and associated charge scattering to enable an efficient charge collection. Additionally, the optical antenna effect of nanowire-based QDHSCs can further enhance the absorption and boost the PCE. This study establishes a robust 'nanolab' platform in a TEM for in situ photoelectrical studies and provides valuable insight into the interfacial effects in nanoscale solar cells

Urokinase plasminogen activator secreted by cancer-associated fibroblasts induces tumor progression via PI3K/AKT and ERK signaling in esophageal squamous cell carcinoma

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Small inhibitor of Bcl-2, HA14-1, selectively enhanced the apoptotic effect of cisplatin by modulating Bcl-2 family members in MDA-MB-231 breast cancer cells

Inhibition or downregulation of Bcl-2 represents a new therapeutic approach to by-pass chemoresistance in cancer cells. Therefore, we explored the potential of this approach in breast cancer cells. Cisplatin and paclitaxel induced apoptosis in a dose-dependent manner in MCF-7 (drug-sensitive) and MDA-MB-231 (drug-insensitive) cells. Furthermore, when we transiently silenced Bcl-2, both cisplatin and paclitaxel induced apoptosis more than parental cells. Dose dependent induction of apoptosis by drugs was enhanced by the pre-treatment of these cells with HA14-1, a Bcl-2 inhibitor. Although the effect of cisplatin was significant on both cell lines, the effect of paclitaxel was much less potent only in MDA-MB-231 cells. To further understand the distinct role of drugs in MDA-MB-231 cells pretreated with HA14-1, caspases and Bcl-2 family proteins were studied. The apoptotic effect of cisplatin with or without HA14-1 pre-treatment is shown to be caspase-dependent. Among pro-apoptotic Bcl-2 proteins, Bax and Puma were found to be up-regulated whereas Bcl-2 and Bcl-x(L) were down-regulated when cells were pretreated with HA14-1 followed by paclitaxel or cisplatin. Enforced Bcl-2 expression in MDA-MB-231 cells abrogated the sensitizing effect of HA14-1 in cisplatin induced apoptosis. These results suggest that the potentiating effect of HA14-1 is drug and cell type specific and may not only depend on the inhibition of Bcl-2. Importantly, alteration of other pro-apoptotic or anti-apoptotic Bcl-2 family members may dictate the apoptotic response when HA14-1 is combined with chemotherapeutic drugs

Molecular cloning and transcriptional activity of a new Petunia calreticulin gene involved in pistil transmitting tract maturation, progamic phase, and double fertilization

Calreticulin (CRT) is a highly conserved and ubiquitously expressed Ca2+-binding protein in multicellular eukaryotes. As an endoplasmic reticulum-resident protein, CRT plays a key role in many cellular processes including Ca2+ storage and release, protein synthesis, and molecular chaperoning in both animals and plants. CRT has long been suggested to play a role in plant sexual reproduction. To begin to address this possibility, we cloned and characterized the full-length cDNA of a new CRT gene (PhCRT) from Petunia. The deduced amino acid sequence of PhCRT shares homology with other known plant CRTs, and phylogenetic analysis indicates that the PhCRT cDNA clone belongs to the CRT1/CRT2 subclass. Northern blot analysis and fluorescent in situ hybridization were used to assess PhCRT gene expression in different parts of the pistil before pollination, during subsequent stages of the progamic phase, and at fertilization. The highest level of PhCRT mRNA was detected in the stigma–style part of the unpollinated pistil 1 day before anthesis and during the early stage of the progamic phase, when pollen is germinated and tubes outgrow on the stigma. In the ovary, PhCRT mRNA was most abundant after pollination and reached maximum at the late stage of the progamic phase, when pollen tubes grow into the ovules and fertilization occurs. PhCRT mRNA transcripts were seen to accumulate predominantly in transmitting tract cells of maturing and receptive stigma, in germinated pollen/growing tubes, and at the micropylar region of the ovule, where the female gametophyte is located. From these results, we suggest that PhCRT gene expression is up-regulated during secretory activity of the pistil transmitting tract cells, pollen germination and outgrowth of the tubes, and then during gamete fusion and early embryogenesis

Three-dimensional micromachining for microsystems by confined etchant layer technique

The micromachining of GaAs with three different truly three-dimensional (3D) molds were performed by the confined etchant layer technique (CELT). The etched patterns were found, approximately, to be the negative copy of the 3D molds. The general comparison of CELT with the existing micromachining techniques, such as two-dimensional (2D) projection lithography and electro-discharge machining, was made. The replication of the complex microstructures down to micrometer scale has been done by CELT in a single step. The photoresist layer, together with the procedures of exposure, developing and removal of resist, could be eliminated. The advantages of CELT over the existing lithography techniques and its potential applications are discussed briefly. It has been shown that CELT could be developed as a complementary technique to the existing micromachining techniques in fabricating microdevices for microsystems. (C) 2001 Elsevier Science Ltd. All rights reserved