Oxidative Stress-Induced Diseases via the ASK1 Signaling Pathway

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK) kinase kinase that activates the downstream MAPKs, c-Jun N-terminal kinase (JNK) and p38. ASK1 is activated by various types of stress, such as oxidative stress, endoplasmic reticulum stress, and infection, and regulates various cellular functions. Recently, it has been reported that ASK1 is associated with various diseases induced by oxidative stress. In this review, we introduce recent findings of the regulatory mechanisms of ASK1 and the oxidative stress-induced diseases mediated by the ASK1 signaling pathway

Pathophysiological Investigation of the Gastric Surface Mucous Gel Layer of Patients with Helicobacter pylori Infection by Using Immunoassays for Trefoil Factor Family 2 and Gastric Gland Mucous Cell-Type Mucin in Gastric Juice

Background The trefoil factor family (TFF) 2 protein is produced by gastric gland mucous cells (GMCs), and the secreted TFF2 shares a mucosal barrier function with GMC-type mucin. Recently, we presented an enzyme-linked immunosorbent assay (ELISA) method for measurement of GMC-type mucin in the gastric juice. Aims We aimed to develop an ELISA for TFF2 and to assess pathophysiological changes in the gastric surface mucous gel layer (SMGL) of patients with Helicobacter pylori infection. Methods The distribution of TFF2 and GMC-type mucin in the SMGL was immunohistochemically determined. The ELISA for TFF2 was based on a polyclonal goat antibody. Recombinant TFF2 was employed to prepare the calibrators. TFF2 and GMC-type mucin in the gastric juice in healthy individuals (n = 33) and patients with gastritis (n = 37), gastric ulcer (n = 16), and duodenal ulcer (n = 10) were assayed using ELISA. Results TFF2 and GMC-type mucin were immunohistochemically co-localized in the gastric SMGL and GMCs. The TFF2 levels in the patients were significantly higher than those in the healthy individuals. Further, the TFF2 levels in the H. pylori-positive patients were significantly higher than those in the H. pylori-negative patients, and decreased after the eradication of the infection. GMC-type mucin levels showed a tendency similar to that of TFF2 levels. Conclusions The upregulation of TFF2 and GMC-type mucin secretion may reflect the response of the gastric mucosa to H. pylori-induced injuries. TFF2 and GMC-type mucin secreted into the SMGL may protect the gastric mucosa against H. pylori.ArticleDIGESTIVE DISEASES AND SCIENCES. 56(12):3498-3506 (2011)journal articl

ASK1-dependent recruitment and activation of macrophages induce hair growth in skin wounds

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein 3-kinase family that activates both c-Jun NH2-terminal kinase and p38 pathways in response to inflammatory cytokines and physicochemical stress. We report that ASK1 deficiency in mice results in dramatic retardation of wounding-induced hair regrowth in skin. Oligonucleotide microarray analysis revealed that expression of several chemotactic and activating factors for macrophages, as well as several macrophage-specific marker genes, was reduced in the skin wound area of ASK1-deficient mice. Intracutaneous transplantation of cytokine-activated bone marrow-derived macrophages strongly induced hair growth in both wild-type and ASK1-deficient mice. These findings indicate that ASK1 is required for wounding-induced infiltration and activation of macrophages, which play central roles in inflammation-dependent hair regrowth in skin

Association of Habitual Physical Activity Measured by an Accelerometer with High-Density Lipoprotein Cholesterol Levels in Maintenance Hemodialysis Patients

After confirming the relationship between high-density lipoprotein cholesterol (HDL-C) levels and mortality in hemodialysis patients for study 1, we investigated the effect of physical activity on their HDL-C levels for study 2. In study 1, 266 hemodialysis patients were monitored prospectively for five years, and Cox proportional hazard regression confirmed the contribution of HDL-C to mortality. In study 2, 116 patients were recruited after excluding those with severe comorbidities or requiring assistance from another person to walk. Baseline characteristics, such as demographic factors, physical constitution, primary kidney disease, comorbid conditions, smoking habits, drug use, and laboratory parameters, were collected from patient hospital records. An accelerometer measured physical activity as the number of steps per day over five consecutive days, and multiple regression evaluated the association between physical activity and HDL-C levels. Seventy-seven patients died during the follow-up period. In study 1, we confirmed that HDL-C level was a significant predictor of mortality (P=0.03). After adjusting for patient characteristics in study 2, physical activity was independently associated with HDL-C levels (adjusted R2=0.255; P=0.005). In conclusion, physical inactivity was strongly associated with decreased HDL-C levels in hemodialysis patients

Utility of Regular Management of Physical Activity and Physical Function in Hemodialysis Patients

Background/Aims: Several clinical practice guidelines recommend regular assessment of physical activity and physical function as part of routine care in hemodialysis patients. However, there is no clear evidence to support these recommendations. We investigated whether the proportion of attendance at a regular program for management of physical activity and physical function can predict all-cause mortality and cardiovascular events in hemodialysis patients. Methods: This retrospective cohort study consisted of 266 hemodialysis patients participating in the management program at least once. Participants were tracked for 3 years after their first attendance at the management program to determine their attendance proportion. The main study outcomes included all-cause mortality and a composite of fatal and nonfatal cardiovascular events. Results: Median patient age was 64.5 (interquartile range, 56.8 – 72.0) years, 45% were women, and the median time on hemodialysis was 35.5 (interquartile range, 12.0 – 114.3) months at baseline. Sixty-five patients died over a median follow-up of 79 months. The incidence of cardiovascular events was 60 over a median follow-up of 68 months. Even after adjusting for any of the prognostic models, participants who attended ≤ 75% of sessions (n = 140) had higher risks of mortality (hazard ratio (HR), 1.79; 95% confidence interval (CI): 1.00 – 3.36; P = 0.049) and cardiovascular events (HR, 1.84; 95% CI: 1.07 – 3.48; P = 0.03) than those attending > 75% of sessions (n = 126). Conclusion: Hemodialysis patients in whom physical activity and physical function could be assessed more regularly had better prognosis than those with only intermittent assessment