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It has long been suspected that chronic stress can exacerbate, or even cause, disease. We now propose that the RCAN1 gene, which can generate several RCAN1 protein isoforms, may be at least partially responsible for this phenomenon. We review data showing that RCAN1 proteins can be induced by multiple stresses, and present new data also implicating psychosocial/emotional stress in RCAN1 induction. We further show that transgenic mice overexpressing the RCAN1-1L protein exhibit accumulation of hyperphosphorylated tau protein (AT8 antibody), an early precursor to the formation of neurofibrillary tangles and neurodegeneration of the kind seen in Alzheimer disease. We propose that, although transient induction of the RCAN1 gene might protect cells against acute stress, persistent stress may cause chronic RCAN1 overexpression, resulting in serious side effects. Chronically elevated levels of RCAN1 proteins may promote or exacerbate various diseases, including tauopathies such as Alzheimer disease. We propose that the mechanism by which stress can lead to these diseases involves the inhibition of calcineurin and the induction of GSK-3β by RCAN1 proteins. Both inhibition of calcineurin and induction of GSK-3β contribute to accumulation of phosphorylated tau, formation of neurofibrillary tangles, and eventual neurodegeneration.

Scope The cathelicidin antimicrobial peptide (CAMP) gene is induced by 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), lithocholic acid, curcumin, nicotinamide and butyrate. Discovering additional small molecules that regulate its expression will identify new molecular mechanisms involved in CAMP regulation and increase understanding of how diet and nutrition can improve immune function. Methods and results We discovered that two stilbenoids, resveratrol and pterostilbene, induced CAMP promoter-luciferase expression. Synergistic activation was observed when either stilbenoid was combined with 1α,25(OH)2D3. Both stilbenoids increased CAMP mRNA and protein levels in the monocyte cell line U937 and synergy was observed in both U937 and the keratinocyte cell line, HaCaT. Inhibition of resveratrol targets sirtuin-1, cyclic AMP production and the c-Jun N-terminal, phophoinositide 3 and AMP-activated kinases did not block induction of CAMP by resveratrol or synergy with 1α,25(OH)2D3. Nevertheless, inhibition of the extracellular signal-regulated 1/2 and p38 mitogen-activated protein kinases, increased CAMP gene expression in combination with 1α,25(OH)2D3 suggesting that inhibition of these kinases by resveratrol may explain, in part, its synergy with vitamin D. Conclusions Our findings demonstrate for the first time that stilbenoid compounds may have the potential to boost the innate immune response by increasing CAMP gene expression particularly in combination with 1α,25(OH)2D3.

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OBJECTIVE-Gestational diabetes type A1 (A1GDM), also known as diet-controlled gestational diabetes, is associated with an increase in adverse perinatal outcomes such as macrosomia and Erb's palsy. However, it remains unclear when to deliver these women because optimal timing of delivery requires balancing neonatal morbidities from early term delivery against the risk of IUFD. We sought to determine the optimal gestational age (GA) for women with A1GDM to deliver.STUDY DESIGN-A decision-analytic model was built to compare the outcomes of delivery at 37 through 41 weeks in a theoretical cohort of 100,000 women with A1GDM. Strategies involving expectant management until a later GA accounted for probabilities of spontaneous delivery, indicated delivery, and IUFD during each week. GA associated risks of neonatal complications included cerebral palsy, infant death, and Erb's palsy. Probabilities were derived from the literature, and total quality-adjusted life years (QALYs) were calculated. Sensitivity analyses were used to investigate the robustness of the baseline assumptions. RESULTS-Our model showed that induction at 38 weeks maximized QALYs. Within our cohort, delivery at 38 weeks would prevent 48 stillbirths but lead to 12 more infant deaths compared to 39 weeks. Sensitivity analysis revealed that 38 weeks remains the optimal timing of delivery until IUFD rates fall below 0.3-fold of our baseline assumption at which expectant management until 39 weeks is optimal. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.All authors report no conflict of interest. This paper was presented as a poster at the 34th Annual Society for Maternal-Fetal Medicine meeting in February, 2014. NIH Public Access CONCLUSION-By weighing the risks of IUFD against infant deaths and neonatal morbidities from early term delivery, the ideal GA for women with A1GDM to deliver is 38 weeks.