Sildenafil for pulmonary hypertension

OBJECTIVE: To evaluate the efficacy of sildenafil for treatment of pulmonary hypertension. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1977-March 2005), Cochrane Library, and International Pharmaceutical Abstracts (1977-March 2005) using the terms sildenafil and pulmonary hypertension. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles in English identified from the data sources were evaluated. Studies including >5 patients with primarily adult populations were included in the review. DATA SYNTHESIS: The treatment of pulmonary hypertension is challenging. Sildenafil has recently been studied as monotherapy and in combination with other vasodilators in the management of pulmonary hypertension. Eight hemodynamic studies and 12 clinical trials were reviewed (1 retrospective, 3 double-blind, 8 open-label). Sildenafil reduced pulmonary arterial hypertension and pulmonary vascular resistance/peripheral vascular resistance index and tended to increase cardiac output/cardiac index compared with baseline. Sildenafil was comparable to nitric oxide and at least as effective as iloprost or epoprostenol in terms of its pulmonary vasoreactivity. Combination therapy with iloprost, nitric oxide, or epoprostenol resulted in enhanced and prolonged pulmonary vascular effects. Clinical trials suggest that sildenafil improves exercise tolerance and New York Heart Association functional class, but large, randomized controlled trials are needed to confirm these findings. Overall, sildenafil was well tolerated. CONCLUSIONS: Overall, sildenafil is a promising and well-tolerated agent for management of pulmonary hypertension. Further well-designed trials are warranted to establish its place in the treatment of pulmonary hypertension.     

Amelioration of collagen‐induced arthritis in rats by nanogold

Objective

Angiogenesis plays a part in the pathogenesis of rheumatoid arthritis (RA), and nanogold inhibits the activity of an angiogenic factor, vascular endothelial growth factor (VEGF). We therefore investigated whether intraarticular delivery of nanogold ameliorates collagen‐induced arthritis (CIA) in rats.

Methods

Binding of 13‐nm nanogold to VEGF in human RA synovial fluid (SF) and its effects on RA SF–induced endothelial cell proliferation and migration were assessed. Nanogold was administered intraarticularly to rats with CIA before the onset of arthritis. Progression of CIA was monitored by measures of clinical, radiologic, and histologic changes. In addition, the microvessel density and extent of infiltrating macrophages as well as levels of tumor necrosis factor α (TNFα) and interleukin‐1β (IL‐1β) in the ankle joints were determined.

Results

Nanogold bound to VEGF in RA SF, resulting in inhibition of RA SF–induced endothelial cell proliferation and migration. Significant reductions in ankle circumference, articular index scores, and radiographic scores were observed in the nanogold‐treated rats with CIA compared with their control counterparts. In addition, the histologic score (of synovial hyperplasia, cartilage erosion, and leukocyte infiltration), microvessel density, macrophage infiltration, and levels of TNFα and IL‐1β were also significantly reduced in the ankle joints of nanogold‐treated rats.

Conclusion

Our results are the first to demonstrate that intraarticular administration of nanogold ameliorates the clinical course of CIA in rats. Nanogold exerted antiangiogenic activities and subsequently reduced macrophage infiltration and inflammation, which resulted in attenuation of arthritis. These results demonstrate proof of principle for the use of nanogold as a novel therapeutic agent for the treatment of RA.

     

Hepatitis B virus surface antigen interacts with acid alpha‐glucosidase and alters glycogen metabolism

Aim: Hepatitis B virus (HBV) infection is highly correlated with hepatocellular carcinoma. Previous studies have reported that expression of hepatitis B virus pre‐S2 mutant surface antigen is related to hepatoma development. An aberrant carbohydrate metabolism is a hallmark of malignant transformation. Methods: We performed yeast two‐hybrid screening with HBV pre‐S2‐del large surface protein (pre‐S2Δ) by using human liver cDNA library, and identified the acid alpha‐glucosidase (acid α‐glucosidase) as the novel cellular interacting protein of pre‐S2Δ. The association of pre‐S2Δ with the acid α‐glucosidase was confirmed by confocal immunofluorescence and co‐immunoprecipitation assay. Further, the acid α‐glucosidase activity and glycogen content were analyzed in ML‐1 cells expressing pre‐S2Δ. Results: The interaction between HBV large surface protein and acid α‐glucosidase was demonstrated with co‐immunoprecipitation in vitro and in vivo, and the binding was mediated through c‐terminal region 889‐952 amino acid of acid α‐glucosidase. On the other hand, HBV large surface protein interacted with acid α‐glucosidase through N‐terminal region 1–157 amino acid of HBV large surface protein. Expression of HBV large surface protein enhanced acid α‐glucosidase activity and resulted in decrease of cellular glycogen. Conclusion: Our result demonstrates that HBV large surface protein interacts with acid α‐glucosidase which plays an important role in glycogen balance. Together, these data suggest a novel pathway by which HBV large surface protein affects carbohydrate metabolism.     

Smoking Behavior Changes in the Early Rheumatoid Arthritis Period and Risk of Mortality During Thirty‐Six Years of Prospective Followup

Objective

To investigate whether rheumatoid arthritis (RA) diagnosis influences smoking behavior changes and whether these changes were associated with mortality.

Methods

We identified an incident RA cohort in the Nurses' Health Study (NHS; 1976–2012). Behavioral data were collected through biennial questionnaires. We created a comparison cohort, matching RA cases to women without RA by age and calendar year at the index date of RA diagnosis. To investigate smoking behavior changes in the early RA period, sustained cessation was defined as permanently quitting within 4 years of the RA/index date. We used Cox regression to obtain hazard ratios (HRs) for mortality, comparing sustained smoking cessation to continued smoking.

Results

Among 121,700 women in the NHS, we identified 938 with incident RA matched to 8,951 non‐RA comparators. Among current smokers, 40.0% with RA permanently quit smoking in the early RA period, compared to 36.1% of comparators (odds ratio for sustained cessation 1.18 [95% confidence interval (95% CI) 0.88, 1.58]). There were 313 deaths (33.4%) in the RA cohort and 2,042 (22.8%) among comparators. Compared to continued smoking, sustained cessation was associated with similarly decreased mortality in both the RA (HR 0.58 [95% CI 0.33, 1.01]) and comparison (HR 0.47 [95% CI 0.39, 0.58]) cohorts. Women with RA had higher mortality for >5 post‐RA pack‐years (HR 3.67 [95% CI 2.80, 4.81]) than comparators with >5 post‐index pack‐years (HR 1.88 [95% CI 1.62, 2.17]; P < 0.001 for interaction; reference: ever‐smoker non‐RA women with 0 post‐index pack‐years).

Conclusion

Sustained smoking cessation within 4 years of RA diagnosis reduced mortality risk, with a similar effect observed among non‐RA comparators. Smoking >5 pack‐years after RA diagnosis significantly increased mortality beyond the risk of non‐RA comparators.     

Leptin receptor-induced STAT3-independent signaling pathways are protective against atherosclerosis in a murine model of obesity and hyperlipidemia

AimsLeptin is an adipocyte-derived hormone that has been shown to exert both beneficial metabolic effects and potentially adverse vascular effects in preclinical studies. The primary aim of this study was to determine the effects of leptin receptor signaling pathways on atherosclerosis in the setting of obesity and hyperlipidemia.Methods and resultsMice were generated with deficiency of apolipoprotein E (ApoE^?/?) and either wild-type leptin receptor expression (Lepr^+/+, ApoE^?/?), mutant leptin receptor expression defective in all leptin receptor signaling pathways (Lepr^db/db, ApoE^?/?), or mutant leptin receptor expression with selective deficiency of leptin receptor-STAT3 signaling (Lepr^s/s, ApoE^?/?). At 27 weeks of age (including 7 weeks on a Western diet), Lepr^db/db, ApoE^?/? developed severe obesity, hypercholesterolemia, and increased atherosclerosis compared to Lepr^+/+, ApoE^?/? mice. Despite similar obesity and hyperlipidemia to Lepr^db/db, ApoE^?/? mice, Lepr^s/s, ApoE^?/? developed less atherosclerosis than Lepr^db/db, ApoE^?/? mice. Adipose tissue macrophage content, monocyte chemoattractant protein-1 and fatty-acid-binding protein 4 levels were also reduced in Lepr^s/s, ApoE^?/? mice compared to Lepr^db/db, ApoE^?/? mice.ConclusionsIn a mouse model of obesity and hyperlipidemia, leptin receptor-mediated STAT3-independent signaling pathways confer protection against atherosclerosis. These differences occur independently of leptin effects on energy balance.     

Effects of evodiamine on the secretion of testosterone in rat testicular interstitial cells

Evodiamine, a bioactive component isolated from the Chinese medicine Wu-chu-yu, exhibits vasodilative and antianoxic action. Although evodiamine indeed has many biological effects, its effects on the endocrine system are not clear. The present study explored the effects of evodiamine on testosterone secretion in vitro. Rat collagenase-dispersed testicular interstitial cells (TICs) were incubated with evodiamine (0 to 10(-4) mol/L) in the presence or absence of human chorionic gonadotropin (hCG), forskolin, 8-bromo-adenosine 3':5'-cyclic monophosphate (8-Br-cAMP), or steroidogenic precursors (including 25-hydroxycholesterol, pregnenolone, progesterone, 17alpha-hydroxyprogesterone, and androstenedione) at 34 degrees C for 1 hour. The testosterone concentration in the media samples was measured by radioimmunoassay. Evodiamine 10(-4) mol/L was effective to reduce both basal and hCG-stimulated testosterone secretion in rat TICs after 1, 2, or 4 hours of incubation. The stimulatory effect of forskolin on testosterone release in TICs was prevented by administration of evodiamine. Evodiamine 10(-4) mol/L also decreased 8-Br-cAMP- and androstenedione-stimulated testosterone secretion. These results suggest that evodiamine reduces testosterone secretion in rat TICs via a mechanism involving reduced activity of cAMP-related pathways and 17beta-hydroxysteroid dehydrogenase (17beta-HSD).     

Association between TNF-a and IL-1β genotypes vs Helicobacter pylori infection in Indonesia

AIM:To investigate the correlation between the Helicobacter pylori(H.pylori)infection and host genetic background of healthy populations in Indonesia.METHODS:In March 2007,epidemiological studies were undertaken on the general population of a city in Indonesia(Mataram,Lombok).The participants included 107 men and 187 women,whose ages ranged from6 to 74 years old,with an average age of 34.0(±14.4)(±SD).The H.pylori of subject by UBT method determination,and through the polymerase chain reaction with confronting two-pair primers(PCR-CTPP)method parsing the single nucleotide polymorphism of interleukin(IL)-8,IL-4,IL-1β,CD14,tumor necrosis factor(TNF-a)and tyrosine-protein phosphates non-receptor type 11(PTPN11)genotypes.The experimental data were analyzed by the statistical software SAS.RESULTS:The H.pylori infection rates in the healthy Indonesian population studied were 8.4%for men and12.8%for women;no obvious differences were noted for H.pylori infection rates by sex or age.TC genotypes of IL-4,TC and CC genotypes of TNF-a,and GA genotypes of PTPN11,were higher in frequency.Both CC and TC genotype of TNF-a T-1031C loci featured higher expressions in the healthy Indonesian population Indonesia studied of(OR=1.99;95%CI:0.67-5.89)and(OR=1.66;95%CI:0.73-3.76),respectively.C allele of IL-1βT-31C gene locus was at a higher risk(OR=1.11;95%CI:0.70-1.73)of H.pylori infection,but no statistical significance was found in our study.CONCLUSION:We reveal that the association between the TNF-a and IL-1βgenotypes may be the susceptibility of H.pylori in the studied population.     

Paradoxical protection from atherosclerosis and thrombosis in a mouse model of sickle cell disease

Sickle cell disease (SCD) is associated with vascular complications including premature stroke. The role of atherothrombosis in these vascular complications is unclear. To determine the effect of SCD on atherosclerosis and thrombosis, mice with SCD along with controls were generated by transplantation of bone marrow from mice carrying the homozygous sickle cell mutation (Hbb^hβs/hβs) or wild‐type mice (Hbb^+/+) into C57BL6/J or apolipoprotein E deficient (Apoe^?/?) recipient mice. At the time of sacrifice, 23–28 weeks following bone marrow transplantation, anaemia, reticulocytosis, and splenomegaly were present in mice receiving Hbb^hβs/hβs bone marrow compared with control mice. Analysis of atherosclerosis involving the aortic root revealed reduced atherosclerotic lesion area with reduced macrophage content and increased collagen content in Apoe^?/?, Hbb^hβs/hβs mice compared to Apoe^?/?, Hbb^+/+ mice. In a carotid thrombosis model, the time to thrombosis was prolonged in Hbb^hβs/hβs mice compared to Hbb^+/+ mice. This apparent protective effect of SCD on atherosclerosis and thrombosis was diminished by inhibition of heme oxygenase‐1 (HMOX1) using zinc protoporphyrin IX. We conclude that SCD in mice is paradoxically protective against atherosclerosis and thrombosis, highlighting the complexity of vascular events in SCD. This protective effect is at least partially mediated by induction of HMOX1.