Protein kinase A-dependent substance P expression by pituitary adenylate cyclase-activating polypeptide in rat sensory neuronal cell line ND7/23 cells.

The neurotrophic effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on rat sensory neuronal cell line ND7/23 cells were investigated. PACAP caused a concentration-dependent increase in the number of neurite-bearing cells and the expression of the substance P precursor (PPT) mRNA in 24 h. The effects of PACAP were mimicked by vasoactive intestinal polypeptide with lower potency and dibutyryl-cyclic AMP, and inhibited by inhibitors of protein kinase A, ERK kinase or p38 kinase, KT5720, U0126, or SB203580, respectively. In a PPT promoter luciferase reporter assay, the increase of PPT mRNA was the result of an increase in PPT gene transcriptional activity by PACAP. The increasing effects of PACAP on PPT mRNA were similarly observed in primary cultured rat dorsal root ganglion cells. Thus, PACAP could induce differentiation-like phenomena in sensory neurons in a cAMP-, protein kinase A-, ERK kinase-, and p38 kinase-dependent manner. These results provide evidence of the neurotrophic action of PACAP, which may function to rescue damaged neurons or to switch the neuronal phenotype in injured or inflamed sensory neurons.The neurotrophic effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on rat sensory neuronal cell line ND7/23 cells were investigated. PACAP caused a concentration-dependent increase in the number of neurite-bearing cells and the expression of the substance P precursor (PPT) mRNA in 24 h. The effects of PACAP were mimicked by vasoactive intestinal polypeptide with lower potency and dibutyryl-cyclic AMP, and inhibited by inhibitors of protein kinase A, ERK kinase or p38 kinase, KT5720, U0126, or SB203580, respectively. In a PPT promoter luciferase reporter assay, the increase of PPT mRNA was the result of an increase in PPT gene transcriptional activity by PACAP. The increasing effects of PACAP on PPT mRNA were similarly observed in primary cultured rat dorsal root ganglion cells. Thus, PACAP could induce differentiation-like phenomena in sensory neurons in a cAMP-, protein kinase A-, ERK kinase-, and p38 kinase-dependent manner. These results provide evidence of the neurotrophic action of PACAP, which may function to rescue damaged neurons or to switch the neuronal phenotype in injured or inflamed sensory neurons

HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats.

Thrombin activates immunocompetent microglia and increases release of inflammatory cytokines under intracerebral hemorrhage (ICH) insults. Also, thrombin injection into the striatum evokes acute necrosis and delayed apoptosis of neurons. A nucleoprotein high-mobility group box 1 (HMGB1) that is released from necrotic cells has been suggested to behave like a cytokine and cause over-facilitation of immune functions. Here we examined the effect of glycyrrhizin, known as an inhibitor of HMGB1, on thrombin-induced injury in rat cortico-striatal slice cultures and in vivo rat ICH model. In slice cultures, thrombin-induced a drastic increase in propidium iodide fluorescence indicating necrotic cell death in the cortical region, and robust shrinkage of the striatal tissue. Glycyrrhizin (10-100 μM) attenuated thrombin-induced cortical injury in a concentration-dependent manner. The protective effect of glycyrrhizin was not mediated by glucocorticoid receptors or modulation of nitric oxide production, but was reversed by exogenous HMGB1 application. The injury induced by a high concentration of HMGB1 was suppressed by glycyrrhizin. In vivo, unilateral injection of type IV collagenase into rat striatum induced ICH associated with brain edema formation, contralateral paralysis and neuron death. Once daily intraperitoneal administration of glycyrrhizin attenuated ICH-induced edema in both the cortex and the basal ganglia, and improved behavioral performance of rats in forelimb placing. Moreover, glycyrrhizin partially but significantly ameliorated ICH-induced neuron loss inside hematoma. These findings suggest that an HMGB1 inhibitor glycyrrhizin is a potential candidate for a remedy for ICH.Thrombin activates immunocompetent microglia and increases release of inflammatory cytokines under intracerebral hemorrhage (ICH) insults. Also, thrombin injection into the striatum evokes acute necrosis and delayed apoptosis of neurons. A nucleoprotein high-mobility group box 1 (HMGB1) that is released from necrotic cells has been suggested to behave like a cytokine and cause over-facilitation of immune functions. Here we examined the effect of glycyrrhizin, known as an inhibitor of HMGB1, on thrombin-induced injury in rat cortico-striatal slice cultures and in vivo rat ICH model. In slice cultures, thrombin-induced a drastic increase in propidium iodide fluorescence indicating necrotic cell death in the cortical region, and robust shrinkage of the striatal tissue. Glycyrrhizin (10-100 μM) attenuated thrombin-induced cortical injury in a concentration-dependent manner. The protective effect of glycyrrhizin was not mediated by glucocorticoid receptors or modulation of nitric oxide production, but was reversed by exogenous HMGB1 application. The injury induced by a high concentration of HMGB1 was suppressed by glycyrrhizin. In vivo, unilateral injection of type IV collagenase into rat striatum induced ICH associated with brain edema formation, contralateral paralysis and neuron death. Once daily intraperitoneal administration of glycyrrhizin attenuated ICH-induced edema in both the cortex and the basal ganglia, and improved behavioral performance of rats in forelimb placing. Moreover, glycyrrhizin partially but significantly ameliorated ICH-induced neuron loss inside hematoma. These findings suggest that an HMGB1 inhibitor glycyrrhizin is a potential candidate for a remedy for ICH

Lrriq1 is an essential factor for fertility by suppressing apoptosis

Purpose Leucine-rich repeats and IQ motif containing 1 (LRRIQ1) gene is reportedly associated with plasma inhibin B levels. However, the function of LRRIQ1 remains unknown. In this study, we generated Lrriq1 knockout mice (Lrriq1-/- mice) and examined the effects of LRRIQ1 on inhibin B and fertility. Methods Lrriq1-/- mice were generated using CRISPR/Cas9 genome editing technology. The expression of Inhibin B was examined by Western blotting using a protein extracted from the testis of a 3-month-old male mouse. Mating experiments were conducted using 7-week-old Lrriq1-/-mice and wild-type (WT) mice to examine fertility. Sperm concentration and sperm motility were measured using 3-month-old male mice. Results Expression analysis of inhibin B revealed that Lrriq1-/- mice exhibited reduced mRNA and protein levels of inhibin alpha (Inha), which constitutes the α subunit. In the mating experiment, the litter size of Lrriq1-/- male mice was 4.3 ± 2.9, which was significantly lower than that of WT male mice (8.3 ± 1.3) (p < 0.001). No difference in sperm count was observed between Lrriq1-/- and WT male mice; however, sperm motility (%) was significantly reduced in Lrriq1-/- mice (48.4 ± 4.9) when compared with WT mice (70.2 ± 4.7) (p < 0.001). Based on TUNEL staining, the testes and epididymal sperm of Lrriq1-/- mice showed high numbers of apoptosis-positive cells. Conclusion Lrriq1 knockout reduced sperm motility and litter size by inducing apoptosis of testicular germ cells and epididymal sperm

Obesity, but not metabolic syndrome, as a risk factor for late-onset asthma in Japanese women

Background: Several cross-sectional studies have suggested an association between obesity and asthma. However, few studies have investigated this relationship longitudinally, especially in middle-aged subjects. Although metabolic syndrome is a well-known risk factor for many non-communicable diseases, its contribution to asthma remains controversial. Methods: From 2008, specific health checkups for metabolic syndrome have been conducted throughout Japan. To seek relationships of obesity and metabolic syndrome with late-onset asthma in Japan, we analyzed data collected from health insurance claims and specific health checkups for metabolic syndrome at three large health insurance societies. Among subjects aged 40–64 years (n = 9888), multivariate logistic regression analyses were performed to investigate the relationships of obesity and metabolic syndrome in fiscal year 2012 (from April 2012 to March 2013) with the incidence of late-onset asthma in the following two years (from April 2013 to March 2015). Results: In women, BMI 25–29.9 kg/m2 or ≥30 kg/m2, waist circumference ≥90 cm, and waist-to-height ratio ≥0.5 were shown to be significant risk factors for asthma, with adjusted odds ratios (95% CI) of 1.92 (1.35–2.75), 2.24 (1.23–4.09), 1.89 (1.30–2.75), and 1.53 (1.15–2.03), respectively. Significance was retained even after adjustment for metabolic syndrome, and there were no significant relationships between metabolic syndrome itself and the incidence of asthma in men or women. Conclusions: Only the obesity measures, not metabolic syndrome, were shown to be significant risk factors for the incidence of late-onset asthma but only in middle-aged Japanese women, and not in men. Keywords: Health insurance claims, Late-onset asthma, Metabolic syndrome, Obesity, Specific health checkup

Longitudinal changes in the prevalence of adult asthma: An epidemiological survey among Japanese salaried employees and their dependents using healthcare insurance claim from 1999 to 2019

Background: Information on changes in asthma prevalence and the treatment status for asthma is used as basic information for taking medical and administrative measures against asthma. However, this information among adults is relatively limited. Methods: To elucidate changes in the prevalence of asthma and treatment status over time among Japanese adults, health insurance claim data from some health insurance societies covering salaried employees and their dependents were studied longitudinally. Claim data from FY1999 to 2007 were obtained from two health insurance societies, and data from FY 2011 to 2019 were obtained from three different health insurance societies, and changes in standardized asthma prevalence among subjects aged 20–59 years, proportion of asthma patients prescribed ICS, leukotriene receptor antagonist (LTRA), and LABA, and the mean number of acute asthma exacerbations per year were analyzed. Results: The prevalence of asthma increased from 1.6% in 1999 to 3.0% in 2007 and 2.9% in 2011 to 4.6% in 2019. Increased trends in asthma prevalence from 2011 to 2019 were more noticeable in subjects in their 50s than those in their 20s for both sexes. The number of emergency visits related to asthma was 1.5 per year in 1999, which decreased to 0.8 per year in 2019. The proportion of people prescribed all anti-asthma medications (ICS, LTRA, and LABA) increased over time. Conclusions: The prevalence of adult asthma among Japanese salaried employees and their dependents has increased over the last 20 years, suggesting more attention should be paid to the prevention of this disease in adults

Association between Smoking Status and Obesity in a Nationwide Survey of Japanese Adults.

OBJECTIVE:A positive association between the number of cigarettes smoked per day and obesity has been reported, whereas how other smoking-related indices, such as pack-years and duration of smoking, are related with obesity has been less investigated. We analyzed the age-adjusted cross-sectional association between smoking and obesity in a general Japanese population. METHODS:We used data from a nationwide epidemiological study of Japanese adults (N = 23,106). We compared the prevalence of obesity (defined as body mass index ≥ 25kg/m2) among groups classified by smoking behavior, pack-years, number of cigarettes per day, duration of smoking, and duration and time of smoking cessation. RESULTS:In men, current smokers had a lower odds ratio (OR) for obesity of 0.80 (95% confidence interval (CI): 0.72-0.88) compared to non-smokers, whereas past smokers had a higher OR of 1.23 (95% CI: 1.09-1.37) compared to current smokers. In women, there were no differences in obesity between the three groups classified by smoking behavior. However, in both sexes, the prevalence of obesity tended to increase with pack-years and the number of cigarettes per day, but not with duration of smoking in current and past smokers. Further, in male smokers, the risks for obesity were markedly higher in short-term heavy smokers compared with long-term light smokers, even with the same number of pack-years. Regarding the impact of smoking cessation, female past smokers who quit smoking at an age > 55-years had an elevated OR of 1.60 (95% CI:1.05-2.38) for obesity. CONCLUSIONS:In a general Japanese population, obesity is progressively associated with pack-years and number of cigarettes per day, but not with the duration of smoking. When investigating the association between obesity and cigarette smoking, the daily smoking burden and the duration of smoking require to be independently considered