Roles of pigment epithelium-derived factor in exercise-induced suppression of senescence and its impact on lung pathology in mice.

Senescent cells contribute to tissue aging and underlie the pathology of chronic diseases. The benefits of eliminating senescent cells have been demonstrated in several disease models, and the efficacy of senolytic drugs is currently being tested in humans. Exercise training has been shown to reduce cellular senescence in several tissues; however, the mechanisms responsible remain unclear. We found that myocyte-derived factors significantly extended the replicative lifespan of fibroblasts, suggesting that myokines mediate the anti-senescence effects of exercise. A number of proteins within myocyte-derived factors were identified by mass spectrometry. Among these, pigment epithelium-derived factor (PEDF) exerted inhibitory effects on cellular senescence. Eight weeks of voluntary running increased Pedf levels in skeletal muscles and suppressed senescence markers in the lungs. The administration of PEDF reduced senescence markers in multiple tissues and attenuated the decline in respiratory function in the pulmonary emphysema mouse model. We also showed that blood levels of PEDF inversely correlated with the severity of COPD in patients. Collectively, these results strongly suggest that PEDF contributes to the beneficial effects of exercise, potentially suppressing cellular senescence and its associated pathologies.

Impact of mindfulness tendency and physical activity on brain-gut interactions.

BACKGROUND: Irritable bowel syndrome (IBS) is a disorder of brain-gut interactions characterized by abdominal pain and bowel dysfunction. Exercise and mindfulness have been reported to be effective on IBS, but there has been no study of their interaction. In this study, we hypothesized that exercise and mindfulness interactively affect the severity of IBS symptoms. METHODS: Subjects were 703 adolescents with 590 women and 113 men. Their IBS status was evaluated with Rome III Diagnostic Questionnaire and IBS Severity Index (IBS-SI). They also fulfilled past exercise experience, athletic performance and exercise enthusiasm, International Physical Activity Questionnaire (IPAQ), Mindful Attention Awareness Scale (MAAS), Kessler 6 Scale (K6), and Perceived Stress Scale (PSS). Statistical analysis was performed using SPSS v25. RESULTS: In this population, 184 (158 women and 26 men, 14.1%) subjects had Rome III IBS symptoms. IBS subjects scored significantly less in exercise enthusiasm at high school (p = 0.017) and MAAS (p < 0.001) and significantly more K6 (p < 0.001) and PSS (p < 0.001) than non-IBS. The two-way ANOVA on IBS-SI showed a significant main effect of MAAS (p < 0.001) and interaction between MAAS and IPAQ (p = 0.008). CONCLUSION: It is suggested that mindfulness per se decreases IBS severity, but that mindfulness and physical activity interactively affect the severity. Further studies on how to design interventional trials for IBS patients with mindfulness and physical exercise are warranted.

The immunosenescence-related factor DOCK11 is involved in secondary immune responses of B cells.

BACKGROUND: Memory B cells are an antigen-experienced B-cell population with the ability to rapidly differentiate into antibody-producing cells by recall responses. We recently found that dedicator of cytokinesis 11 (DOCK11) contributes to the expansion of antigen-specific populations among germinal center B cells upon immunization. In comparison, limited information is available on the contribution of DOCK11 to secondary humoral immune responses. RESULTS: In this study, effects of the DOCK11 deficiency in B cells were examined on secondary immune responses to protein antigen. The lack of DOCK11 in B cells resulted in the impaired induction of antibody-producing cells upon secondary immunization with protein antigen. DOCK11 was dispensable for the recall responses of antigen-experienced B cells, as demonstrated by the comparable induction of antibody-producing cells in mice given transfer of antigen-experienced B cells with no DOCK11 expression. Instead, the lack of DOCK11 in B cells resulted in the impaired secondary immune responses in a B cell-extrinsic manner, which was recovered by the adoptive transfer of cognate T cells. CONCLUSIONS: We addressed that intrinsic and extrinsic effects of DOCK11 expression in B cells may contribute to secondary humoral immune responses in manner of the induction of cognate T-cell help.

Oxytocin antagonist induced visceral pain and corticotropin-releasing hormone neuronal activation in the central nucleus of the amygdala during colorectal distention in mice.

Activation of neurons containing oxytocin and corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus, the anterior cingulate cortex (ACC), and the central nucleus of the amygdala (CeA) during colorectal distention (CRD) is likely to play a crucial role in animal models of irritable bowel syndrome (IBS). Earlier studies in rodents showed that the microbiome is involved in social behavior via oxytocin expression in the brain. However, the detailed mechanism of visceral sensation and oxytocin is largely unknown. We tested the following hypotheses: (1) that oxytocin neurons in the PVN are activated by CRD, and (2) that the activation of oxytocin neurons by CRD is related to anxiety-like behavior, visceral perception, and an activation of CRH CeA neurons or ACC neurons. Oxytocin antagonist caused visceral hypersensitivity and anxiety-like behavior. In the PVN, oxytocin neurons were activated by CRD. Noxious CRD activated the CeA, basolateral nucleus of the amygdala (BLA), and ACC. High-dose oxytocin antagonist suppressed ACC activity and activated CRH CeA neurons. These results support our hypotheses. Oxytocin likely regulates CRH CeA neurons in an inhibitory manner and the ACC in an excitatory manner. Further research into the interaction of oxytocin and CRH in visceral pain and anxiety is warranted.

Leucine-Rich Repeat Kinase 2 Is Associated With Activation of the Paraventricular Nucleus of the Hypothalamus and Stress-Related Gastrointestinal Dysmotility.

Leucine-rich repeat kinase 2 (LRRK2) is a molecule associated with familial and sporadic Parkinson's disease. It regulates many central neuronal functions, such as cell proliferation, apoptosis, autophagy, and axonal extension. Recently, it has been revealed that LRRK2 is related to anxiety/depression-like behavior, implying an association between LRRK2 and stress. In the present study, we investigated for the first time the stress pathway and its relationship to gastrointestinal motility in LRRK2-knockout (KO) mice. The mice were subjected to acute restraint stress, and analyzed for activation of the paraventricular nucleus of the hypothalamus (PVN) using an immunohistochemical approach. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) was assessed by Western blotting. The KO mice showed a lower number of c-Fos-positive cells and disruption of the ERK signaling pathway in the PVN in the presence of restraint stress. Stress responses in terms of both upper and lower gastrointestinal motility were alleviated in the mice, accompanied by lower c-Fos immunoreactivity in enteric excitatory neurons. Our present findings suggest that LRRK2 is a newly recognized molecule regulating the stress pathway in the PVN, playing a role in stress-related gastrointestinal dysmotility.

LRRK2: An Emerging New Molecule in the Enteric Neuronal System That Quantitatively Regulates Neuronal Peptides and IgA in the Gut.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) is a recently discovered molecule associated with familial and sporadic Parkinson's disease. It regulates many central neuronal functions such as cell proliferation, apoptosis, autophagy, and axonal extension. However, in contrast to the well-documented function of LRRK2 in central neurons, it is unclear whether LRRK2 is expressed in enteric neurons and affects the physiology of the gut. AIMS: By examining LRRK2-KO mice, this study investigated whether enteric neurons express LRRK2 and whether intestinal neuronal peptides and IgA are quantitatively changed. METHODS: Intestinal protein lysates and sections prepared from male C57BL/6 J mice were analyzed by Western blotting and immunostaining using anti-LRRK2 antibody, respectively. Intestinal neuronal peptide-mRNAs were quantified by real-time PCR in wild-type mice and LRRK2-KO mice. Intestinal IgA was quantified by ELISA. Lamina propria mononuclear cells (LPMCs) were analyzed by flow cytometry to evaluate the ratio of B1 to B2 B cells. RESULTS: Western analysis and immunostaining revealed that LRRK2 is expressed in enteric neurons. The amounts of mRNA for vasoactive intestinal peptide, neuropeptide Y, and substance P were increased in LRRK2-KO mice accompanied by an increment of IgA. However, the intestinal B cell subpopulations were not altered in LRRK2-KO mice. CONCLUSIONS: For the first time, we have revealed that LRRK2 is expressed in enteric neurons and related to quantitative alterations of neuronal peptide and IgA. Our study highlights the importance of LRRK2 in enteric neurons as well as central neurons.