Resveratrol Effects on Astrocyte Function: Relevance to Neurodegenerative Diseases

Inflammatory molecules have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis. Resveratrol is an antifungal compound found in the skins of red grapes and other fruits and nuts. We examined the ability of resveratrol to inhibit lipopolysaccharide (LPS)-induced production of inflammatory molecules from primary mouse astrocytes. Resveratrol inhibited LPS-induced production of nitric oxide (NO); the cytokines tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), and IL-6; and the chemokine monocyte chemotactic protein-1 (MCP-1), which play critical roles in innate immunity, by astrocytes. Resveratrol also suppressed astrocyte production of IL-12p40 and IL-23, which are known to alter the phenotype of T cells involved in adaptive immunity. Finally resveratrol inhibited astrocyte production of C-reactive protein (CRP), which plays a role in a variety of chronic inflammatory disorders. Collectively, these studies suggest that resveratrol may be an effective therapeutic agent in neurodegenerative diseases initiated or maintained by inflammatory processes

MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease

Hyperproliferation of bile duct epithelial cells due to cell-cycle dysregulation is a key feature of cystogenesis in polycystic liver diseases (PCLDs). Recent evidence suggests a regulatory role for microRNAs (miRNAs) in a variety of biological processes, including cell proliferation. We therefore hypothesized that miRNAs may be involved in the regulation of selected components of the cell cycle and might contribute to hepatic cystogenesis. We found that the cholangiocyte cell line PCK-CCL, which is derived from the PCK rat, a model of autosomal recessive polycystic kidney disease (ARPKD), displayed global changes in miRNA expression compared with normal rat cholangiocytes (NRCs). More specific analysis revealed decreased levels of 1 miRNA, miR15a, both in PCK-CCL cells and in liver tissue from PCK rats and patients with a PCLD. The decrease in miR15a expression was associated with upregulation of its target, the cell-cycle regulator cell division cycle 25A (Cdc25A). Overexpression of miR15a in PCK-CCL cells decreased Cdc25A levels, inhibited cell proliferation, and reduced cyst growth. In contrast, suppression of miR15a in NRCs accelerated cell proliferation, increased Cdc25A expression, and promoted cyst growth. Taken together, these results suggest that suppression of miR15a contributes to hepatic cystogenesis through dysregulation of Cdc25A

Deepwater Horizon Oil Spill Exposure, Industry Sector, and Child Health

The historic 2010 BP Deepwater Horizon Oil Spill (DHOS) led to public distress regarding potential impacts on children in nearby Gulf Coast communities. Using a community-based South Louisiana panel study of households with children, we examined the effect of fishing industry employment on changes in a subjective measure of general child health and whether economic and physical DHOS exposures played a mediating role. Fishing industry employment had a negative effect on child health compared to other industries. Economic exposure and physical exposure both mediated the effects of the fishing industry on child health, with economic exposure mediating a larger share (49.3%) of the relationship compared to physical exposure (40.5%). The importance of economic oil spill exposure in these findings highlights the significance of social determinants of health at the intersection of disasters and child vulnerability

Supplemental Material - Age Changes in Religious Service Attendance in Mexican American Older Adults: A Growth Curve Analysis

Supplemental Material for Age Changes in Religious Service Attendance in Mexican American Older Adults: A Growth Curve Analysis by Samuel Stroope and Rhiannon A. Kroeger in Journal of Aging and Health</p

Sociodemographic Correlates of Vaccine Hesitancy in the United States and the Mediating Role of Beliefs About Governmental Conspiracies

Objective: Vaccine hesitancy remains a significant public health challenge, and one that is socially patterned. This study examined whether the vaccine hesitancy effects of identifying as female, race–ethnicity, the number of children, educational attainment, and political conservatism were mediated by governmental conspiracy beliefs. Methods: Linear mediation models controlling for potential confounders were employed to analyze data from a national survey of adults (2019 Chapman University Survey of American Fears; n = 1,209). Results: Effects on vaccine hesitancy were significant and negative for educational attainment, and significant and positive for the other focal predictors. Governmental conspiracy beliefs significantly mediated each of these effects; the percent mediated was largest for Hispanic identity (79 percent), followed by female identification (69 percent), educational attainment (69 percent), number of children (55 percent), black identification (34 percent), and political conservatism (30 percent). Conclusion: This study underscores the importance of nonvaccine-related conspiracy beliefs for future interventions aimed at reducing sociodemographic disparities in vaccine hesitancy

Disparate effects of BP Deepwater Horizon oil spill exposure on psychological resilience.

A growing body of research has demonstrated links between exposure to the BP Deepwater Horizon oil spill (DHOS) and negative consequences for well-being in the impacted region. We contribute to this literature by investigating the relationship between exposure to the DHOS (i.e., physical and economic) and subsequent perceptions of the ability to cope with adverse events (i.e., psychological resilience) among adults with children. Doing so advances prior research by (a) providing a direct test of psychological resilience (i.e., the 10-item Connor-Davidson Resilience Scale) rather than relying on proxy measures and (b) improving on cross-sectional studies by using prospective cohort data to establish temporal ordering between spill exposure and psychological resilience. Data were obtained from the 2014 Gulf Coast Population Impact study and the 2018 wave of the Resilient Children, Youth, and Communities study (N = 481). The analysis used descriptive statistics and linear regression models with adult psychological resilience (10-item Connor-Davidson Resilience Scale) as the outcome of interest. Results showed that economic DHOS exposure held a significant negative relationship with later levels of psychological resilience, whereas physical DHOS exposure did not. These findings inform policy and practice by underscoring links between socioeconomic disaster impacts and psychological resilience in the aftermath of such events. (PsycInfo Database Record (c) 2021 APA, all rights reserved

Parental Education and Child Physical Health Following the BP Deepwater Horizon Oil Spill

Purpose: To assess whether trajectories of children’s physical health problems differ by parental college degree attainment in Louisiana areas highly impacted by the 2010 BP Deepwater Horizon oil spill (BP-DHOS). Design: Three waves of panel data (2014, 2016, and 2018) from the Gulf Coast Population Impact / Resilient Children, Youth, and Communities studies. Setting: BP-DHOS-impacted communities in coastal Louisiana. Participants: Parents of children aged 4-18 in a longitudinal probability sample (n = 392). Measures: Reported child physical health problems from the BP-DHOS, parental college degree attainment, and covariates. Analysis: Linear growth curve models are used to assess initial levels of and the rate of change in child physical unknown. The current study uses 3 waves physical health problems by parental college degree attainment. Explanatory variables are measured at baseline and the outcome variable is measured at all 3 waves. Results: Compared to children of parents without college degrees, children of college graduates had fewer initial health problems in 2014 (b = −.33; p = .02). Yet, this health advantage decreased over time, as indicated by their positive rate of change (b = .22; p = .01), such that the higher education health advantage was not statistically significant by 2018. Conclusion: Children of college graduates experienced a physical health advantage following the BP-DHOS, but this gap closed over time. The closure of the gap was due to the children of college graduates experiencing significant increases in reported health problems over the study period

Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors

Cholangiocytes, the epithelial cells lining intrahepatic bile ducts, contain primary cilia, which are mechano- and osmosensory organelles detecting changes in bile flow and osmolality and transducing them into intracellular signals. Here, we asked whether cholangiocyte cilia are chemosensory organelles by testing the expression of P2Y purinergic receptors and components of the cAMP signaling cascade in cilia and their involvement in nucleotide-induced cAMP signaling in the cells. We found that P2Y12 purinergic receptor, adenylyl cyclases (i.e., AC4, AC6, and AC8), and protein kinase A (i.e., PKA RI-β and PKA RII-α regulatory subunits), exchange protein directly activated by cAMP (EPAC) isoform 2, and A-kinase anchoring proteins (i.e., AKAP150) are expressed in cholangiocyte cilia. ADP, an endogenous agonist of P2Y12 receptors, perfused through the lumen of isolated rat intrahepatic bile ducts or applied to the ciliated apical surface of normal rat cholangiocytes (NRCs) in culture induced a 1.9- and 1.5-fold decrease of forskolin-induced cAMP levels, respectively. In NRCs, the forskolin-induced cAMP increase was also lowered by 1.3-fold in response to ATP-γS, a nonhydrolyzed analog of ATP but was not affected by UTP. The ADP-induced changes in cAMP levels in cholangiocytes were abolished by chloral hydrate (a reagent that removes cilia) and by P2Y12 siRNAs, suggesting that cilia and ciliary P2Y12 are involved in nucleotide-induced cAMP signaling. In conclusion, cholangiocyte cilia are chemosensory organelles that detect biliary nucleotides through ciliary P2Y12 receptors and transduce corresponding signals into a cAMP response

MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease

Hyperproliferation of bile duct epithelial cells due to cell-cycle dysregulation is a key feature of cystogenesis in polycystic liver diseases (PCLDs). Recent evidence suggests a regulatory role for microRNAs (miRNAs) in a variety of biological processes, including cell proliferation. We therefore hypothesized that miRNAs may be involved in the regulation of selected components of the cell cycle and might contribute to hepatic cystogenesis. We found that the cholangiocyte cell line PCK-CCL, which is derived from the PCK rat, a model of autosomal recessive polycystic kidney disease (ARPKD), displayed global changes in miRNA expression compared with normal rat cholangiocytes (NRCs). More specific analysis revealed decreased levels of 1 miRNA, miR15a, both in PCK-CCL cells and in liver tissue from PCK rats and patients with a PCLD. The decrease in miR15a expression was associated with upregulation of its target, the cell-cycle regulator cell division cycle 25A (Cdc25A). Overexpression of miR15a in PCK-CCL cells decreased Cdc25A levels, inhibited cell proliferation, and reduced cyst growth. In contrast, suppression of miR15a in NRCs accelerated cell proliferation, increased Cdc25A expression, and promoted cyst growth. Taken together, these results suggest that suppression of miR15a contributes to hepatic cystogenesis through dysregulation of Cdc25A

Activation of Trpv4 reduces the hyperproliferative phenotype of cystic cholangiocytes from an animal model of ARPKD

BACKGROUND & AIMS: In polycystic liver diseases, cyst formation involves cholangiocyte hyperproliferation. In polycystic kidney (PCK) rats, an animal model of autosomal-recessive polycystic kidney disease (ARPKD), decreased intracellular calcium [Ca(2+)](i) in cholangiocytes is associated with hyperproliferation. We recently showed transient receptor potential vanilloid 4 (Trpv4), a calcium-entry channel, is expressed in normal cholangiocytes and its activation leads to [Ca(2+)](i) increase. Thus, we hypothesized that pharmacologic activation of Trpv4 might reverse the hyperproliferative phenotype of PCK cholangiocytes. METHODS: Trpv4 expression was examined in liver of normal and PCK rats, normal human beings, and patients with autosomal-dominant polycystic kidney disease or ARPKD. Trpv4 activation effect on cell proliferation and cyst formation was assessed in cholangiocytes derived from normal and PCK rats. The in vivo effects of Trpv4 activation on kidney and liver cysts was analyzed in PCK rats. RESULTS: Trpv4 was overexpressed both at messenger RNA (8-fold) and protein (3-fold) levels in PCK cholangiocytes. Confocal and immunogold electron microscopy supported Trpv4 overexpression in the livers of PCK rats and ARPKD or autosomal-dominant polycystic kidney disease patients. Trpv4 activation in PCK cholangiocytes increased [Ca(2+)](i) by 30%, inhibiting cell proliferation by approximately 25%-50% and cyst growth in 3-dimensional culture (3-fold). Trpv4-small interfering RNA silencing blocked effects of Trpv4 activators by 70%. Trpv4 activation was associated with Akt phosphorylation and beta-Raf and Erk1/2 inhibition. In vivo, Trpv4 activation induced a significant decrease in renal cystic area and a nonsignificant decrease in liver cysts. CONCLUSIONS: Taken together, our in vitro and in vivo data suggest that increasing intracellular calcium by Trpv4 activation may represent a potential therapeutic approach in PKD