Role of p38 mitogen-activated protein kinase pathway on heart failure in the infant rat after burn injury

We examined the hypothesis that post-burn activation of the p38 mitogen-activated protein kinase (MAPK) pathway is one aspect of the signalling cascade culminating in post-burn secretion of tumour necrosis factor (TNF)-alpha which contributes to post-burn myocardial apoptosis. Studies were designed to determine the time course of the induction of p38MAPK, TNF-alpha and myocardial apoptosis after burn injury. Our quantitative bacterial culture data demonstrated that viable bacteria reached the heart, and Western blotting data identified the increase in the phosphorylation of p38MAPK at an early time after burn. The peak incidence of myocardial apoptosis was also seen at an early time after burn. The expression of TNF-alpha mRNA, infiltrated neutrophils and serum creatine phosphokinase myocardial band data peaked at a late time after burn. FR167653, a specific inhibitor of p38MAPK, prevented the induction of myocardial apoptosis, TNF-alpha expression and myocardial injury after burn. Presumably, the bacterial LPS-induced activation of p38MAPK pathway occurring at an early time after burn induced the subsequent myocardial apoptosis. The p38MAPK-induced activation of pro-inflammatory cytokine appeared to promote the degenerative myocardial injury at a late time after burn. Our present data provided evidence for the hypothesis that the p38MAPK pathway controls both myocardial apoptosis and the pro-inflammatory mediator.     

A study of factors in medical insurance records associated with participation in health examinations

Factors in medical insurance records of two groups classified as participants and nonparticipants in a multiphasic health examination (MHE) conducted in a rural town in Kyoto prefecture were compared. The purpose of this study was to clarify how the conditions of medical care influenced the participation in the MHE. The factors were days of consultation, total insurance points and days of consultation classified by specific disease and the area of the medical facility. Participants were examined at least once in 1987-1988 and nonparticipants were never examined in the corresponding period. The data were obtained from the medical insurance records of outpatients for the period from April 1986 thru March 1987. The medical care bills of 170 males and 201 females aged 30-69 were randomly sampled from National Health Insurance records (unit = family), and those of 55 males and 88 females aged 70 and over were from the Medical Service for the Aged (unit = person). These samples were about one forth of target population respectively. Both older participants and older nonparticipants of both sexes had more consultation days and more total insurance points than the corresponding younger subjects. Nonparticipants of both sexes aged 70 and over had more consultation days and more total insurance points than participants; female nonparticipants aged 50-69 had slightly more consultation days and those aged 30-49 also had more insurance points. Nonparticipants tended to have previous medical care for hypertension or ischemic heart disease, which the MHE is responsible for discovering.(ABSTRACT TRUNCATED AT 250 WORDS)     

NGF Increases Brain Astrocyte Number in Culture

Nerve growth factor (NGF) promotes survival and maintenance of peripheral and central neurons. In previous studies, we found that low-affinity NGF binding sites were associated with flat nonneuronal cells dissociated and cultured from the embryonic septum. These cells were also labeled with a monoclonal antibody to the NGF receptor, 192 IgG, suggesting that low-affinity NGF receptors are associated with a nonneuronal population. To define the potential effect of NGF on these nonneuronal cells, rat Embryonic Day 17 (E17) septa were dissociated and cultured in fully defined medium in the presence of NGF. Glial fibrillary acidic protein (GFAP) was used as a marker for the astrocyte population. NGF elicited a dramatic ninefold increase in the number of GFAP-positive cells after 7 days. NGF similarly increased astrocyte number in cultures grown from E18 hippocampi and E16 substantia nigra, suggesting that NGF acts on glia from multiple brain regions. To begin defining the mechanism of NGF action on astrocytes, we examined [³H]thymidine incorporation, which increased significantly, but by only 50%, upon exposure to the trophic factor. We tentatively conclude that NGF increases astrocyte number in culture by stimulating mitosis as well as enhancing survival or differentiation.     

A case-control study of ulcerative colitis

In order to evaluate the epidemiological characteristics of ulcerative colitis, we conducted a matched case-control study of ulcerative colitis. Fifty patients with ulcerative colitis diagnosed at three hospitals in Kyoto, Osaka and Hyogo Prefectures in Japan during 1984 and 1987 were interviewed about their habitual and pre-illness diets, personal habits, past histories and family histories. The results were compared to those for fifty healthy controls who were matched for sex and age (+/- 2 years) and participated in health-screening examinations in Kyoto or Osaka during the same period. Frequent intake of rice (4 or more bowls a day), bread (3 or more times a week), and green tea (7 or more cups a day) significantly increased the relative risk of ulcerative colitis. However, a past history of appendectomy was negatively correlated with the disease. There were no relationships between ulcerative colitis and consumption of animal foods and tobacco.     

Adenoviral expression of protein-L-isoaspartyl methyltransferase (PIMT) partially attenuates the biochemical changes in PIMT-deficient mice

Protein-L-isoaspartyl methyltransferase (PIMT) is a putative protein repair enzyme, which methylates the alpha-carboxyl group of atypical L-isoaspartyl residues in aged proteins and converts them to normal L-aspartyl residues. Two splicing variants, PIMT-I and PIMT-II, have been reported, although their biological functions and specific subcellular substrates are still to be defined. We and another group have previously showed that PIMT-deficient mice succumbed to fatal epileptic seizures associated with an abnormal accumulation of isoaspartate (IsoAsp) in the brain. In the present study, we prepared two recombinant adenovirus vectors that contained PIMT-I or PIMT-II, respectively, in order to investigate the differential biological roles of PIMT-I and PIMT-II. These recombinant viruses differentially conferred PIMT-I or PIMT-II expressions in cultured neurons. Biochemical analyses showed that either of PIMT-I or PIMT-II effectively repaired the damaged proteins in PIMT-deficient neurons, but the concomitant expression failed to show an additive effect in the repair of IsoAsp. These results suggested that PIMT-I and PIMT-II might share a common biological function and/or subcellular substrates. In addition, we administered an adeno-PIMT-I vector into the brain of PIMT-deficient mice at embryonic day 14.5 by an exo-utero method to assess the biological effects in vivo. The result showed that recombinant adeno-PIMT improved the symptoms of PIMT-deficient mice in vivo, but only partially repaired IsoAsp in damaged proteins. The gene therapy presented in this report provided a better prognosis for the survival of PIMT-deficient mice than the previously reported anti-epileptic drug therapy. The results suggested a new reagent for gene therapy applicable to ageing-associated neurodegenerative disorders.     

Angiotensin II-induced insulin resistance is associated with enhanced insulin signaling

Angiotensin II (AII) is involved in the pathogenesis of both hypertension and insulin resistance, though few studies have examined the relationship between the two. We therefore investigated the effects of chronic AII infusion on blood pressure and insulin sensitivity in rats fed a normal (0.3% NaCl) or high-salt (8% NaCl) diet. AII infusion for 12 days significantly elevated blood pressure and significant insulin resistance, assessed by a hyperinsulinemic-euglycemic clamp study and glucose uptake into isolated muscle and adipocytes. High-salt loading exacerbated the effects of AII infusion significantly. Despite the insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol (PI) 3-kinase, and phosphorylation of Akt were all enhanced by AII infusion. Subsequently, to investigate whether oxidative stress induced by AII contributes to insulin resistance, the membrane-permeable superoxide dismutase mimetic, tempol, was administered to AII-infused rats. Chronic AII infusion induced an accumulated plasma cholesterylester hydroperoxide levels, indicating the increased oxidative stress, whereas the treatment with tempol normalized plasma cholesterylester hydroperoxide levels in AII-infused rats. In addition, the treatment with tempol normalized insulin resistance in AII-infused rats, shown as a decreased glucose infusion rate in the hyperinsulinemic euglycemic clamp study and a decreased insulin-induced glucose uptake into isolated skeletal muscle, as well as enhanced insulin-induced PI 3-kinase activation to those in the control rats. These results strongly suggest that AII-induced insulin resistance cannot be attributed to impairment of early insulin-signaling steps and that increased oxidative stress, possibly through impaired insulin signaling located downstream from PI 3-kinase activation, is involved in AII-induced insulin resistance.     

Expression of mitogen-activated protein kinases in human renal dysplasia

BACKGROUND: We previously reported that the expression of mitogen-activated protein kinases (MAPKs) is developmentally regulated. Dysregulation of MAPKs may lead to kidney malformation. Thus, we investigated the expression of MAPKs in human renal dysplasia, one of the most common kidney malformations. METHODS: Prenatal (gestational ages 20 to 36 weeks, N = 6) and postnatal (2 years old, N = 1) dysplastic kidneys, and normal kidneys (gestational ages 19 to 34 weeks, N = 4) were examined. Immunohistochemical studies were performed using antibodies against extracellular signal-regulated kinase (ERK), p38 MAPK (p38), c-Jun N-terminal kinase (JNK), phospho-MAPKs (P-MAPKs), and proliferating cell nuclear antigen (PCNA). Apoptosis was detected by the TUNEL method. RESULTS: In dysplastic kidneys, proliferation was prominent in dysplastic tubules and also found in cyst epithelia. TUNEL staining was detected in dysplastic tubules and cysts, and occasionally in undifferentiated cells. p38 and anti-phospho-p38 (P-p38) were strongly expressed in dysplastic epithelia, but not detected in normal kidneys at any stage examined. On the other hand, JNK and P-JNK were positive in tubular epithelia of normal kidneys, whereas their expression was barely detectable in dysplastic tubules and cysts. ERK was expressed in all tubular segments, and P-ERK was detected in distal tubules and collecting ducts of normal kidneys. Dysplastic kidney epithelia stained exclusively positive for ERK and P-ERK. CONCLUSIONS: p38 is ectopically expressed, and JNK is down-regulated in dysplastic kidney epithelia. Furthermore, dysplastic epithelia are exclusively positive for ERK and P-ERK. Activated p38 and ERK may mediate hyperproliferation of dysplastic tubules resulting in cyst formation, whereas down-regulated JNK expression may be the cause or the result of an undifferentiated state of dysplastic epithelia.