Activation of eNOS in rat portal hypertensive gastric mucosa is mediated by TNF-alpha via the PI 3-kinase-Akt signaling pathway

Activation of endothelial nitric oxide synthase (eNOS) in portal hypertensive (PHT) gastric mucosa leads to hyperdynamic circulation and increased susceptibility to injury. However, the signaling mechanisms for eNOS activation in PHT gastric mucosa and the role of TNF-alpha in this signaling remain unknown. In PHT gastric mucosa we studied (1) eNOS phosphorylation (at serine 1177) required for its activation; (2) association of the phosphatidylinositol 3-kinase (PI 3-kinase), and its downstream effector Akt, with eNOS; and, (3) whether TNF-alpha neutralization affects eNOS phosphorylation and PI 3-kinase-Akt activation. To determine human relevance, we used human microvascular endothelial cells to examine directly whether TNF-alpha stimulates eNOS phosphorylation via PI 3-kinase. PHT gastric mucosa has significantly increased (1) eNOS phosphorylation at serine 1177 by 90% (P <.01); (2) membrane translocation (P <.05) and phosphorylation (P <.05) of p85 (regulatory subunit of PI 3-kinase) by 61% and 85%, respectively; (3) phosphorylation (P <.01) and activity (P <.01) of Akt by 40% and 52%, respectively; and (4) binding of Akt to eNOS by as much as 410% (P <.001). Neutralizing anti-TNF-alpha antibody significantly reduced p85 phosphorylation, phosphorylation and activity of Akt, and eNOS phosphorylation in PHT gastric mucosa to normal levels. Furthermore, TNF-alpha stimulated eNOS phosphorylation in human microvascular endothelial cells. In conclusion, these findings show that in PHT gastric mucosa, TNF-alpha stimulates eNOS phosphorylation at serine 1177 (required for its activation) via the PI 3-kinase-Akt signal transduction pathway.     

High Electrochemical Performance Silicon Thin-Film Free-Standing Electrodes Based on Buckypaper for Flexible Lithium-Ion Batteries

Recently, applications for lithium-ion batteries (LIBs) have expanded to include electric vehicles and electric energy storage systems, extending beyond power sources for portable electronic devices. The power sources of these flexible electronic devices require the creation of thin, light, and flexible power supply devices such as flexile electrolytes/insulators, electrode materials, current collectors, and batteries that play an important role in packaging. Demand will require the progress of modern electrode materials with high capacity, rate capability, cycle stability, electrical conductivity, and mechanical flexibility for the time to come. The integration of high electrical conductivity and flexible buckypaper (oxidized Multi-walled carbon nanotubes (MWCNTs) film) and high theoretical capacity silicon materials are effective for obtaining superior high-energy-density and flexible electrode materials. Therefore, this study focuses on improving the high-capacity, capability-cycling stability of the thin-film Si buckypaper free-standing electrodes for lightweight and flexible energy-supply devices. First, buckypaper (oxidized MWCNTs) was prepared by assembling a free stand-alone electrode, and electrical conductivity tests confirmed that the buckypaper has sufficient electrical conductivity (10⁻⁴(S m⁻¹) in LIBs) to operate simultaneously with a current collector. Subsequently, silicon was deposited on the buckypaper via magnetron sputtering. Next, the thin-film Si buckypaper freestanding electrodes were heat-treated at 600 °C in a vacuum, which improved their electrochemical performance significantly. Electrochemical results demonstrated that the electrode capacity can be increased by 27/26 and 95/93 μAh in unheated and heated buckypaper current collectors, respectively. The measured discharge/charge capacities of the USi_HBP electrode were 108/106 μAh after 100 cycles, corresponding to a Coulombic efficiency of 98.1%, whereas the HSi_HBP electrode indicated a discharge/charge capacity of 193/192 μAh at the 100th cycle, corresponding to a capacity retention of 99.5%. In particular, the HSi_HBP electrode can decrease the capacity by less than 1.5% compared with the value of the first cycle after 100 cycles, demonstrating excellent electrochemical stability.     

Sexually transmitted infections among pregnant women attending antenatal clinics in Mongolia: potential impact on the Mongolian HIV epidemic

We conducted Mongolia's first nation-wide cross-sectional survey of sexually transmitted infections (STIs) among pregnant women attending prenatal care. Among our 2000 participants, 386 (19.3%) were infected with Chlamydia trachomatis, 133 (6.7%) with Trichomonas vaginalis, 121 (6.1%) with Neisseria gonorrhoeae, and 128 (6.4%) were seropositive for Treponemal antibodies. None of our participants were seropositive for HIV infection. Additionally, 605 (30.3%) of the women had at least one STI, 133 (6.7%) had a double infection, and 15 (0.8%) had a triple infection. Our results suggest that STIs are a serious problem in Mongolia. Pregnant women represent a lower-risk general population; these high STI rates suggest that at this nascent stage, the identification, treatment, and prevention of STIs as risk factors for HIV transmission are crucial in the prevention of the emerging Mongolian HIV epidemic.     

Collagen/Chitosan Gels Cross-Linked with Genipin for Wound Healing in Mice with Induced Diabetes

Diabetes mellitus continues to be one of the most common diseases often associated with diabetic ulcers. Chitosan is an attractive biopolymer for wound healing due to its biodegradability, biocompatibility, mucoadhesiveness, low toxicity, and hemostatic effect. A panel of hydrogels based on chitosan, collagen, and silver nanoparticels were produced to treat diabetic wounds. The antibacterial activity, cytotoxicity, swelling, rheological properties, and longitudinal sections of hydrogels were studied. The ability of the gels for wound healing was studied in CD1 mice with alloxan-induced diabetes. Application of the gels resulted in an increase in VEGF, TGF-b1, IL-1b, and TIMP1 gene expression and earlier wound closure in a comparison with control untreated wounds. All gels increased collagen deposition, hair follicle repair, and sebaceous glands formation. The results of these tests show that the obtained hydrogels have good mechanical properties and biological activity and have potential applications in the field of wound healing. However, clinical studies are required to compare the efficacy of the gels as animal models do not reproduce full diabetes pathology.     

Independence of the appearance of HBsAg in the saliva and blood serum

HBsAg has been revealed in the saliva of 5 (20%) out of 25 HBsAg carriers in serum by RIA, but the appearance of HBsAg in the saliva was not correlated with the occult blood in saliva and with the HBsAg titer in the serum.     

Inducible NOS inhibition, eicosapentaenoic acid supplementation, and angiotensin II-induced renal damage

BACKGROUND: Cytochrome P450(CYP)-dependent hydroxylation and epoxygenation metabolites of arachidonic acid (AA) influence renal vascular tone, salt excretion, and inflammation. Transgenic rats over expressing both human renin and angiotensinogen genes (dTGR) feature angiotensin II (Ang II)-induced organ damage, increased expression of inducible nitric oxide synthase (iNOS), decreased AA hydroxylation, and epoxygenation. As nitric oxide production via iNOS can inhibit CYP AA metabolism, we tested the hypothesis that by blocking iNOS or by supplementing eicosapentanoic acid (EPA), which can serve as an alternative CYP substrate, Ang II-induced vasculopathy could be ameliorated. METHODS: We treated dTGR with the iNOS inhibitor L-N(6)-(1-iminoethyl) lysine (L-NIL), EPA, and the combination of both treatments from week 4 to 7. RESULTS: Immunohistochemistry showed that L-NIL and EPA reduced glomerular iNOS toward control levels. L-NIL-treated dTGR showed cardiac hypertrophy and albuminuria similar to untreated dTGR. EPA and the combination of EPA + L-NIL, ameliorated organ damage without lowering blood pressure. EPA and EPA + L-NIL reduced cardiac hypertrophy, albuminuria, renal fibronectin expression, and infiltration of monocytes/macrophages, compared to L-NIL and untreated dTGR. Reactive oxygen species were detected in glomeruli of untreated and L-NIL-treated dTGR, but was reduced in the EPA groups. EPA treatment reduced activator protein-1 (AP-1) activation and partially inhibited nuclear factor-kappaB (NF-kappaB) activity in kidneys of dTGR. CONCLUSION: These results demonstrate that iNOS inhibition does not protect against Ang II-induced end-organ damage, while EPA treatment does. Our electromobility shift assay experiments revealed that EPA protection may involve inhibition of AP-1- and NF-kappaB-dependent pathways.     

Tregs utilize β-galactoside-binding protein to transiently inhibit PI3K/p21 activity of human CD8 T cells to block their TCR-mediated ERK activity and proliferation

Regulatory T cells (Tregs) and beta-galactoside-binding protein (βGBP), a regulatory protein often found expressed at sites of immunological privilege, have similar functions. Their presence affects the outcome of harmful autoimmunity and cancers, including experimental autoimmune encephalomyelitis and malignant gliomas. Here we report a novel pathway by which Tregs express and utilize βGBP to control CD8⁺ T cell responses partially activating TCR signaling but blocking PI3K activity. As a result, this leads to a loss of p21^ras, ERK and Akt activities despite activation of TCR proximal signals, such as phosphorylation of CD3ζ, Zap70, Lat and PKCθ. Although non-processive TCR signaling often leads to cell anergy, Tregs/βGBP did not affect cell viability. Instead, βGBP/Tregs transiently prevented activation of CD8⁺ T cells with self-antigens, while keeping their responses to xenogeneic antigens unaffected.     

Protective role of CXC receptor 4/CXC ligand 12 unveils the importance of neutrophils in atherosclerosis

The CXC ligand (CXCL)12/CXC receptor (CXCR)4 chemokine-receptor axis controls hematopoiesis, organ development, and angiogenesis, but its role in the inflammatory pathogenesis of atherosclerosis is unknown. Here we show that interference with Cxcl12/Cxcr4 by a small-molecule antagonist, genetic Cxcr4 deficiency, or lentiviral transduction with Cxcr4 degrakine in bone marrow chimeras aggravated diet-induced atherosclerosis in apolipoprotein E-deficient (Apoe-/-) or LDL receptor-deficient (Ldlr-/-) mice. Chronic blockade of Cxcr4 caused leukocytosis and an expansion of neutrophils and increased neutrophil content in plaques, associated with apoptosis and a proinflammatory phenotype. Whereas circulating neutrophils were recruited to atherosclerotic lesions, depletion of neutrophils reduced plaque formation and prevented its exacerbation after blocking Cxcr4. Disrupting Cxcl12/Cxcr4 thus promotes lesion formation through deranged neutrophil homeostasis, indicating that Cxcl12/Cxcr4 controls the important contribution of neutrophils to atherogenesis in mice.     

Laparoscopic cholecystectomy in patients undergoing anticoagulant therapy

(Received for publication on Aug. 1, 1996; accepted on Mar. 4, 1997)