A Prospective Study of Aspirin Use and the Risk of Gastrointestinal Bleeding in Men

Data regarding the influence of dose and duration of aspirin use on risk of gastrointestinal bleeding are conflicting.We conducted a prospective cohort study of 32,989 men enrolled in the Health Professionals Follow-up Study (HPFS) in 1994 who provided biennial aspirin data. We estimated relative risk of major gastrointestinal bleeding requiring hospitalization or a blood transfusion.During 14 years of follow-up, 707 men reported an episode of major gastrointestinal bleeding over 377,231 person-years. After adjusting for risk factors, regular aspirin use (≥2 times/week) had a multivariate relative risk (RR) of gastrointestinal bleeding of 1.32 (95% confidence interval [CI], 1.12-1.55) compared to non-regular use. The association was particularly evident for upper gastrointestinal bleeding (multivariate RR, 1.49; 95% CI, 1.16-1.92). Compared to men who denied any aspirin use, multivariate RRs of upper gastrointestinal bleeding were 1.05 (95% CI 0.71-1.52) for men who used 0.5-1.5 standard tablets/week, 1.31 (95% CI 0.88-1.95) for 2-5 aspirin/week, 1.63 (95% CI, 1.15-2.32) for 6-14 aspirin/week and 2.40 (95% CI, 1.10-5.22) for >14 aspirin/week (P(trend)<0.001). The relative risk also appeared to be dose-dependent among short-term users <5 years; P(trend)<.001) and long-term users (≥5 years; P(trend) = 0.015). In contrast, after controlling for dose, increasing duration of use did not appear to be associated with risk (P(trend) = 0.749).Regular aspirin use increases the risk of gastrointestinal bleeding, especially from the upper tract. However, risk of bleeding appears to be more strongly related to dose than to duration of use. Risk of bleeding should be minimized by using the lowest effective dose among short-term and long-term aspirin users

Down-regulation of HSP70 sensitizes gastric epithelial cells to apoptosis and growth retardation triggered by H. pylori

<p>Abstract</p> <p>Background</p> <p><it>H. pylori </it>infection significantly attenuated the expression of HSP70 in gastric mucosal cells. However, the role of HSP70 cancellation in <it>H. pylori</it>-associated cell damages is largely unclear.</p> <p>Methods</p> <p>Small interfering RNA (siRNA) was used to down-regulate HSP70 in gastric epithelial cell lines AGS. The transfected cells were then incubated with <it>H. pylori </it>and the functions of HSP70 suppression were observed by viability assay, cell cycle analyses and TUNEL assay. HSP70 target apoptotic proteins were further identified by Western blot.</p> <p>Results</p> <p>The inhibition of HSP70 has further increased the effect of growth arrest and apoptosis activation triggered by <it>H. pylori </it>in gastric epithelial cells. The anti-proliferation function of HSP70 depletion was at least by up-regulating p21 and cell cycle modulation with S-phase accumulation. An increase of apoptosis-inducing factor (AIF) and cytosolic cytochrome C contributes to the activation of apoptosis following down-regulation of intracellular HSP70. Extracellular HSP70 increased cellular resistance to apoptosis by suppression the release of AIF and cytochrome c from mitochondria, as well as inhibition of p21 expression.</p> <p>Conclusions</p> <p>The inhibition of HSP70 aggravated gastric cellular damages induced by <it>H. pylori</it>. Induction of HSP70 could be a potential therapeutic target for protection gastric mucosa from <it>H. pylori</it>-associated injury.</p

Nitric oxide-an endogenous inhibitor of gastric acid secretion in isolated human gastric glands

BACKGROUND: Endothelial nitric oxide synthase (eNOS) has previously been detected in the glandular part of the human gastric mucosa. Furthermore, nitric oxide (NO) has been shown to influence gastric secretion in various animal models. The present study was conducted to investigate the influence of exogenously and endogenously derived NO on histamine- and cAMP-stimulated gastric acid secretion in isolated human oxyntic glands. METHODS: Oxyntic glands were isolated from human gastric biopsies and were subsequently pre-treated with NO donors and nitric oxide synthase inhibitors and then exposed to histamine or dibutyryl-cAMP (db-cAMP). The secretory response of the glands was determined as accumulation of [(14)C]aminopyrine. RESULTS: The histamine- or db-cAMP-induced acid secretion was attenuated by L-arginine, a known source of endogenous NO, and also by the NO-donors sodium nitroprusside (SNP) and S-nitroso-N-acetyl-penicillamine (SNAP). Pre-treatment with either of the NOS inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) or N(G)-nitro-L-arginine (L-NNA) enhanced the secretory response. CONCLUSION: Our results show that NO inhibits gastric acid secretion in isolated human gastric glands, and that there is endogenous formation of NO within the glandular epithelium in the vicinity of the parietal cells

Differential expression of HSPA1 and HSPA2 proteins in human tissues; tissue microarray-based immunohistochemical study

In the present study we determined the expression pattern of HSPA1 and HSPA2 proteins in various normal human tissues by tissue-microarray based immunohistochemical analysis. Both proteins belong to the HSPA (HSP70) family of heat shock proteins. The HSPA2 is encoded by the gene originally defined as testis-specific, while HSPA1 is encoded by the stress-inducible genes (HSPA1A and HSPA1B). Our study revealed that both proteins are expressed only in some tissues from the 24 ones examined. HSPA2 was detected in adrenal gland, bronchus, cerebellum, cerebrum, colon, esophagus, kidney, skin, small intestine, stomach and testis, but not in adipose tissue, bladder, breast, cardiac muscle, diaphragm, liver, lung, lymph node, pancreas, prostate, skeletal muscle, spleen, thyroid. Expression of HSPA1 was detected in adrenal gland, bladder, breast, bronchus, cardiac muscle, esophagus, kidney, prostate, skin, but not in other tissues examined. Moreover, HSPA2 and HSPA1 proteins were found to be expressed in a cell-type-specific manner. The most pronounced cell-type expression pattern was found for HSPA2 protein. In the case of stratified squamous epithelia of the skin and esophagus, as well as in ciliated pseudostratified columnar epithelium lining respiratory tract, the HSPA2 positive cells were located in the basal layer. In the colon, small intestine and bronchus epithelia HSPA2 was detected in goblet cells. In adrenal gland cortex HSPA2 expression was limited to cells of zona reticularis. The presented results clearly show that certain human tissues constitutively express varying levels of HSPA1 and HSPA2 proteins in a highly differentiated way. Thus, our study can help designing experimental models suitable for cell- and tissue-type-specific functional differences between HSPA2 and HSPA1 proteins in human tissues

Protective effects of N-acetylcysteine on acetic acid-induced colitis in a porcine model

BACKGROUND: Ulcerative colitis is a chronic inflammatory disease and involves multiple etiological factors. Acetic acid (AA)-induced colitis is a reproducible and simple model, sharing many characteristics with human colitis. N-acetylcysteine (NAC) has been widely used as an antioxidant in vivo and in vitro. NAC can affect several signaling pathways involving in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and inflammatory response. Therefore, NAC may not only protect against the direct injurious effects of oxidants, but also beneficially alter inflammatory events in colitis. This study was conducted to investigate whether NAC could alleviate the AA-induced colitis in a porcine model. METHODS: Weaned piglets were used to investigate the effects of NAC on AA-induced colitis. Severity of colitis was evaluated by colon histomorphology measurements, histopathology scores, tissue myeloperoxidase activity, as well as concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon. The protective role of NAC was assessed by measurements of antioxidant status, growth modulator, cell apoptosis, and tight junction proteins. Abundances of caspase-3 and claudin-1 proteins in colonic mucosae were determined by the Western blot method. Epidermal growth factor receptor, amphiregulin, tumor necrosis factor-alpha (TNF-α), and toll-like receptor 4 (TLR4) mRNA levels in colonic mucosae were quantified using the real-time fluorescent quantitative PCR. RESULTS: Compared with the control group, AA treatment increased (P < 0.05) the histopathology scores, intraepithelial lymphocyte (IEL) numbers and density in the colon, myeloperoxidase activity, the concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon, while reducing (P < 0.05) goblet cell numbers and the protein/DNA ratio in the colonic mucosa. These adverse effects of AA were partially ameliorated (P < 0.05) by dietary supplementation with NAC. In addition, NAC prevented the AA-induced increase in caspase-3 protein, while stimulating claudin-1 protein expression in the colonic mucosa. Moreover, NAC enhanced mRNA levels for epidermal growth factor and amphiregulin in the colonic mucosa. CONCLUSION: Dietary supplementation with NAC can alleviate AA-induced colitis in a porcine model through regulating anti-oxidative responses, cell apoptosis, and EGF gene expression