Evaluating telehealth lifestyle therapy versus telehealth psychotherapy for reducing depression in adults with COVID-19 related distress: the curbing anxiety and depression using lifestyle medicine (CALM) randomised non-inferiority trial protocol.

BACKGROUND: There is increasing recognition of the substantial burden of mental health disorders at an individual and population level, including consequent demand on mental health services. Lifestyle-based mental healthcare offers an additional approach to existing services with potential to help alleviate system burden. Despite the latest Royal Australian New Zealand College of Psychiatrists guidelines recommending that lifestyle is a 'first-line', 'non-negotiable' treatment for mood disorders, few such programs exist within clinical practice. Additionally, there are limited data to determine whether lifestyle approaches are equivalent to established treatments. Using an individually randomised group treatment design, we aim to address this gap by evaluating an integrated lifestyle program (CALM) compared to an established therapy (psychotherapy), both delivered via telehealth. It is hypothesised that the CALM program will not be inferior to psychotherapy with respect to depressive symptoms at 8 weeks. METHODS: The study is being conducted in partnership with Barwon Health's Mental Health, Drugs & Alcohol Service (Geelong, Victoria), from which 184 participants from its service and surrounding regions are being recruited. Eligible participants with elevated psychological distress are being randomised to CALM or psychotherapy. Each takes a trans-diagnostic approach, and comprises four weekly (weeks 1-4) and two fortnightly (weeks 6 and 8) 90-min, group-based sessions delivered via Zoom (digital video conferencing platform). CALM focuses on enhancing knowledge, behavioural skills and support for improving dietary and physical activity behaviours, delivered by an Accredited Exercise Physiologist and Accredited Practising Dietitian. Psychotherapy uses cognitive behavioural therapy (CBT) delivered by a Psychologist or Clinical Psychologist, and Provisional Psychologist. Data collection occurs at baseline and 8 weeks. The primary outcome is depressive symptoms (assessed via the Patient Health Questionnaire-9) at 8 weeks. Societal and healthcare costs will be estimated to determine the cost-effectiveness of the CALM program. A process evaluation will determine its reach, adoption, implementation and maintenance. DISCUSSION: If the CALM program is non-inferior to psychotherapy, this study will provide the first evidence to support lifestyle-based mental healthcare as an additional care model to support individuals experiencing psychological distress. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12621000387820 , Registered 8 April 2021.

Repurposing With Purpose: Creating a Collaborative Learning Space to Support Institutional Interprofessional Initiatives.

When the University of Mississippi Medical Center embraced a didactic shift to patient-centered, interprofessional education of its medical, dental, nursing, pharmacy, and allied health students, the Rowland Medical Library repurposed space to support the cause and created a collaborative learning space designated for campus-wide utility.

Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes.

The mechanisms through which hematopoietic cytokines accelerate revascularization are unknown. Here, we show that the magnitude of cytokine-mediated release of SDF-1 from platelets and the recruitment of nonendothelial CXCR4+ VEGFR1+ hematopoietic progenitors, 'hemangiocytes,' constitute the major determinant of revascularization. Soluble Kit-ligand (sKitL), thrombopoietin (TPO, encoded by Thpo) and, to a lesser extent, erythropoietin (EPO) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induced the release of SDF-1 from platelets, enhancing neovascularization through mobilization of CXCR4+ VEGFR1+ hemangiocytes. Although revascularization of ischemic hindlimbs was partially diminished in mice deficient in both GM-CSF and G-CSF (Csf2-/- Csf3-/-), profound impairment in neovascularization was detected in sKitL-deficient Mmp9-/- as well as thrombocytopenic Thpo-/- and TPO receptor-deficient (Mpl-/-) mice. SDF-1-mediated mobilization and incorporation of hemangiocytes into ischemic limbs were impaired in Thpo-/-, Mpl-/- and Mmp9-/- mice. Transplantation of CXCR4+ VEGFR1+ hemangiocytes into Mmp9-/- mice restored revascularization, whereas inhibition of CXCR4 abrogated cytokine- and VEGF-A-mediated mobilization of CXCR4+ VEGFR1+ cells and suppressed angiogenesis. In conclusion, hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4+ VEGFR1+ hemangiocytes, whereas VEGFR1 is essential for their angiogenic competency for augmenting revascularization. Delivery of SDF-1 may be effective in restoring angiogenesis in individuals with vasculopathies.

Post-Prandial Cognitive and Blood Pressure Effects of a DHA-Rich Omega-3 Powder in Middle-Aged Males: A Pilot Study.

The use of omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplements is increasingly common among middle-aged and older adults. Users of ω-3 PUFA supplements often report using such supplements to support cognitive health, despite mixed findings reported within the ω-3 PUFA literature. To date, very few studies have explored cognitive effects in distinctly middle-aged (40 to 60 years) adults, and none have examined the acute effects (in the hours following a single dose) on cognitive performance. The current study evaluated whether a single dose of ω-3 PUFA (4020 mg docosahexaenoic acid and 720 mg eicosapentaenoic acid) influences cognitive performance and cardiovascular function in middle-aged males. Cognitive performance and cardiovascular function were assessed before and 3.5-4 h after consumption of a high dose of ω-3 PUFA (DHA + EPA) or placebo, incorporated into a standardized meal (i.e., single serve of Greek yogurt). In this study of middle-aged males, no significant differential treatment effects were observed for cognitive performance. However, a significant reduction in aortic systolic blood pressure (pre-dose to post-dose) was apparent following consumption of the ω-3 PUFA (DHA + EPA) treatment (mean difference = -4.11 mmHg, p = 0.004) but not placebo (mean difference = -1.39 mmHg, p = 0.122). Future replication in a sample comprising females, as well as patients with hypertension, is merited.

Corrigendum: The association between diet and cardio-metabolic risk on cognitive performance: A cross-sectional study of middle-aged Australian adults.

[This corrects the article DOI: 10.3389/fnut.2022.862475.].

The association of dietary and nutrient patterns on neurocognitive decline: A systematic review of MRI and PET studies.

BACKGROUND: As the global population ages, there has been a growing incidence of neurodegenerative diseases such as Alzheimer's. More recently, studies exploring the relationship between dietary patterns and neuroimaging outcomes have received particular attention. This systematic literature review provides a structured overview of the association between dietary and nutrient patterns on neuroimaging outcomes and cognitive markers in middle-aged to older adults. A comprehensive literature search was conducted to find relevant articles published from 1999 to date using the following databases Ovid MEDLINE, Embase, PubMed, Scopus and Web of Science. The inclusion criteria for the articles comprised studies reporting on the association between dietary patterns and neuroimaging outcomes, which includes both specific pathological hallmarks of neurodegenerative diseases such as Aß and tau and nonspecific markers such as structural MRI and glucose metabolism. The risk of bias was evaluated using the Quality Assessment tool from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The results were then organized into a summary of results table, collated based on synthesis without meta-analysis. After conducting the search, 6050 records were extracted and screened for eligibility, with 107 eligible for full-text screening and 42 articles ultimately being included in this review. The results of the systematic review indicate that there is some evidence suggesting that healthy dietary and nutrient patterns were associated with neuroimaging measures, indicative of a protective influence on neurodegeneration and brain ageing. Conversely, unhealthy dietary and nutrient patterns showed evidence pointing to decreased brain volumes, poorer cognition and increased Aß deposition. Future research should focus on sensitive neuroimaging acquisition and analysis methods, to study early neurodegenerative changes and identify critical periods for interventions and prevention. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no, CRD42020194444).

Dietary patterns in middle age: effects on concurrent neurocognition and risk of age-related cognitive decline.

CONTEXT: Diet plays a critical role in cognitive integrity and decline in older adults. However, little is known about the relationship between diet and cognitive integrity in middle age. OBJECTIVE: To investigate the relationship between dietary patterns in healthy middle-aged adults and neurocognition both in middle age and later in life. DATA SOURCES: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, the following electronic databases were searched: Web of Science, Scopus, PubMed, and PsychInfo. DATA EXTRACTION: Data from eligible articles was extracted by 2 reviewers. DATA ANALYSIS: Articles included in the systematic review were synthesized (based on the synthesis without meta-analysis reporting guidelines) and assessed for quality (using the Joanna Briggs Institute checklist for randomized controlled trials, cohort studies, and cross-sectional studies) by 2 reviewers. RESULTS: Of 1558 studies identified, 34 met the eligibility criteria for inclusion. These comprised 9 cross-sectional studies, 23 longitudinal or prospective cohort studies, and 2 randomized controlled trials. Findings were mixed, with some studies reporting a significant positive relationship between adherence to various "healthy" dietary patterns and neurocognition, but others reporting no such relationship. CONCLUSION: This systematic review demonstrated that adherence to the Mediterranean diet and other healthy dietary patterns in middle age can protect neurocognition later in life. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42020153179.

The Association Between Diet and Cardio-Metabolic Risk on Cognitive Performance: A Cross-Sectional Study of Middle-Aged Australian Adults.

Adherence to different dietary patterns has been linked to the development of cognitive decline; yet little is known about whether this relationship is present in middle age. The current study aimed to explore the relationship between different dietary patterns, cognitive performance, and potential cardio-metabolic mechanisms for this relationship. Participants were recruited using a diet screening tool to ensure that the cohort had a range of diet quality ranging from relatively poor to relatively healthy. In a sample of 141 middle-aged adults (age: M = 52.84 years, SD = 6.87 years), multiple 24 h diet recalls were collected and used to score adherence to the Mediterranean diet, dietary approaches to stop hypertension (DASH) diet, and Mediterranean-DASH diet intervention for neurodegenerative delay (MIND) diet. Metabolic risk was assessed using the metabolic syndrome severity score (MetSSS) and arterial stiffness. Cognitive performance was assessed using the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB). Adherence to the MIND diet was significantly related to Stroop Processing domain (ß = 0.19, p = 0.035). None of the dietary patterns were significantly related to MetSSS or arterial stiffness. However, adherence to the DASH diet was significantly associated with two cardio-metabolic measures including lower augmentation index (ß = -0.17, p = 0.032) and lowered cholesterol (ß = -0.18, p = 0.041). Interestingly, two cardio-metabolic risk factors were also associated with better cognitive performance: MetSSS (ß = 0.21, p = 0.010) and waist circumference (ß = 0.22, p = 0.020). Together these findings suggest that diet in middle age may be important for cognitive functioning and cardio-metabolic risk. However, more research is needed in the form of randomized controlled trials to confirm the direction of these relationships.

Diet May Moderate the Relationship Between Arterial Stiffness and Cognitive Performance in Older Adults.

BACKGROUND: Cognitive decline is influenced by various factors including diet, cardiovascular disease, and glucose control. However, the combined effect of these risk factors on cognitive performance is yet to be fully understood. OBJECTIVE: The current study aimed to explore the inter-relationship between these risk factors and cognitive performance in older adults at risk of future cognitive decline. METHODS: The sample comprised 163 (Age: M = 65.23 years, SD = 6.50) participants. Food Frequency Questionnaire data was used to score diet quality and adherence to the Western Style Diet (WSD) and Prudent Style Diet (PSD). Glucose control was gauged by serum levels of glycated hemoglobin (HbA1c) and arterial stiffness was measured using carotid to femoral pulse wave velocity. Cognitive performance was assessed using two subtests of the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB) and Rey's Verbal Learning Test (RVLT). RESULTS: Diet quality, adherence to the WSD or PSD, and glucose control were not significantly related to cognitive outcomes. However, a significant negative association was found between arterial stiffness and the spatial working memory subtest of SUCCAB (ß= -0.21, p < 0.05). Arterial stiffness also significantly interacted with the PSD to impact total recall (F change (1,134) = 5.37, p < 0.05) and the composite score of RVLT (F change (1,134) = 4.03, p < 0.05). CONCLUSION: In this sample of older adults at risk of cognitive decline, diet alone was not found to predict cognitive performance; however, it was found to moderate the relationship between arterial stiffness and cognition.

Investigating the Effects of a Multinutrient Supplement on Cognition, Mood and Biochemical Markers in Middle-Aged Adults with 'Optimal' and 'Sub-Optimal' Diets: A Randomized Double Blind Placebo Controlled Trial.

Background: Previous randomized controlled trials examining cognitive and mood effects of combination multivitamin supplements in healthy, non-clinical adults have reported mixed results. One purported explanation for this is that the dietary status of participants at the start of supplement interventions may influence the magnitude of the effect of supplementation. Methods: In this study, we evaluated the effect of a multinutrient formula containing B group vitamins, Bacopa monniera and Ginkgo biloba on memory, attention, mood and biochemical markers of nutrient status in middle-aged adults (M = 52.84 years, n = 141) with 'optimal' and 'sub-optimal' diets over 12 weeks. We hypothesised that active supplementation would differentially improve memory and attention in those with a 'sub-optimal' diet. Results: Mixed model, repeated measures analysis revealed that, in comparison to placebo, active treatment was associated with significant increases in B vitamin status (B1, B6, B12). Regarding behavioural outcomes there was no significant benefit to memory (F(1, 113.51) = 0.53, p = 0.470) nor attention (F(1,113.77) = 1.89, p = 0.171) in the whole cohort. Contrary to our hypothesis, there was a significant beneficial effect of supplementation on attentional performance in individuals with an 'optimal' diet prior to supplementation (F(1,57.25) = 4.94, p = 0.030). In the absence of a main effect of supplementation across the entire cohort, there were also a number of significant three-way interactions (treatment by time by diet group) detected in secondary outcomes including lower state anxiety and mental fatigue in those with an 'optimal' diet. Conclusion: These findings suggest that the cognitive benefit of B vitamin and herbal supplementation may be dependent on diet quality, supporting the concepts of 'co-nutrient optimisation' and interdependency of nutrients. This warrants further investigation. This study advocates characterising the diet of participants prior to supplementation as it may influence the effect of a nutraceutical intervention.

The Moo'D Study: protocol for a randomised controlled trial of A2 beta-casein only versus conventional dairy products in women with low mood.

BACKGROUND: Beta-casein is a major protein in cow's milk, of which A1 and A2 are the most frequent variants. Recent evidence implicates A1 beta-casein consumption in mechanisms that are of potential importance to mental health, yet its possible effects on psychological endpoints remains unknown. The primary aim of the study is to evaluate the comparative effects of consumption of dairy products containing A2 beta-casein versus conventional dairy (i.e. containing both A1 and A2 beta-casein) on symptoms of psychological distress in women with low mood. METHODS: 'The Moo'D Study' is a 16-week, superiority, 1:1 parallel group, triple-blinded, randomised controlled trial. Ninety women with low mood (Patient Health Questionnaire score ≥ 5) will be randomised to consume either A2 beta-casein only or conventional dairy products. The primary outcome, symptoms of psychological distress, will be measured by the 21-item Depression, Anxiety and Stress Scale. Secondary outcomes will include symptoms of depression, anxiety and stress, severity of low mood, cognition, gut microbiota composition, gut symptomatology, markers of immune function, gut inflammation, systemic metabolites, endothelial integrity and oxidative stress, body composition, perceived wellbeing, sleep, quality of life, resource use and cost-effectiveness. DISCUSSION: This study will advance our understanding of the possible impact of milk proteins on psychological distress in women as well as elucidate mechanisms underpinning any association. Given dairy products form a substantial component of traditional and Western diets, the implications of these findings are likely to be of clinical and public health importance. TRIAL REGISTRATION: The trial protocol has been prospectively registered with the Australia and New Zealand Clinical Trials Registry, ACTRN12618002023235 . Registered on 17 December 2018.

Self-Selection Bias: An Essential Design Consideration for Nutrition Trials in Healthy Populations.

Many researchers have identified the issue of self-selection bias hindering the ability to detect nutrient effects in healthy populations. However, it appears that no effort has been made to mitigate this potential design flaw. By recruiting individuals on the basis of pre-trial dietary intake, the Memory and Attention Supplementation Trial aimed to capture a cohort of participants with a wide variety of dietary intake, thus increasing the likelihood of a diverse range of nutrient status. This perspective specifically examines the profile of these trial volunteers and in doing so, we present the first empirical evidence of self-selection bias when recruiting healthy volunteers for a randomized controlled trial of a nutrient-based supplement. These findings support the anecdotal proposal that traditional recruitment methods inherently attract trial volunteers who are vastly unrepresentative of the population and threatens the generalizability of this field of research. Alternative approaches to recruitment, including a-priori screening for baseline diet quality and nutrient status, are discussed as essential design recommendations to ensure accurate interpretation of nutrient effects within the context of baseline participant characteristics.

How polypharmacologic is each chemogenomics library?

AIM: High-throughput phenotypic screens have emerged as a promising avenue for small-molecule drug discovery. The challenge faced in high-throughput phenotypic screens is target deconvolution once a small molecule hit is identified. Chemogenomics libraries have emerged as an important tool for meeting this challenge. Here, we investigate their target-specificity by deriving a 'polypharmacology index' for broad chemogenomics screening libraries. METHODS: All known targets of all the compounds in each library were plotted as a histogram and fitted to a Boltzmann distribution, whose linearized slope is indicative of the overall polypharmacology of the library. RESULTS & CONCLUSION: Comparison of libraries clearly distinguished the most target-specific library, which might be assumed to be more useful for target deconvolution in a phenotypic screen.

Self-Reported Diet Quality Differentiates Nutrient Intake, Blood Nutrient Status, Mood, and Cognition: Implications for Identifying Nutritional Neurocognitive Risk Factors in Middle Age.

Evidence for diet quality representing a modifiable risk factor for age-related cognitive decline and mood disturbances has typically come from retrospective, cross-sectional analyses. Here a diet screening tool (DST) was used to categorize healthy middle-aged volunteers (n = 141, 40-65 years) into "optimal" or "sub-optimal" diet groups to investigate cross-sectional associations between diet quality, cognitive function, and mood. The DST distinguished levels of nutrient intake as assessed by Automated Self-Administered 24-h dietary recall and nutrient status, as assessed by blood biomarker measures. Compared with the "sub-optimal" group, the "optimal" diet group showed significantly higher intake of vitamin E (p = 0.007), magnesium (p = 0.001), zinc (p = 0.043) and fiber (p = 0.015), higher circulating levels of vitamin B6 (p = 0.030) and red blood cell folate (p = 0.026) and lower saturated fatty acids (p = 0.012). Regarding psychological outcomes, the "optimal" diet group had significantly better Stroop processing than those with a "sub-optimal" diet (p = 0.013). Regression analysis revealed that higher DST scores were associated with fewer mood disturbances (p = 0.002) and lower perceived stress (p = 0.031), although these differences were not significant when comparing "optimal" versus "sub-optimal" as discrete groups. This study demonstrates the potential of a 20-item diet screen to identify both nutritional and psychological status in an Australian setting.

A Systematic Review and Meta-Analysis of B Vitamin Supplementation on Depressive Symptoms, Anxiety, and Stress: Effects on Healthy and 'At-Risk' Individuals.

A systematic review and meta-analysis was undertaken to examine and quantify the effects of B vitamin supplementation on mood in both healthy and 'at-risk' populations. A systematic search identified all available randomised controlled trials (RCTs) of daily supplementation with ≥3 B group vitamins with an intervention period of at least four weeks. Random effects models for a standardized mean difference were used to test for overall effect. Heterogeneity was tested using the I2 statistic. Eighteen articles (16 trials, 2015 participants) were included, of which 12 were eligible for meta-analysis. Eleven of the 18 articles reported a positive effect for B vitamins over a placebo for overall mood or a facet of mood. Of the eight studies in 'at-risk' cohorts, five found a significant benefit to mood. Regarding individual facets of mood, B vitamin supplementation benefited stress (n = 958, SMD = 0.23, 95% CI = 0.02, 0.45, p = 0.03). A benefit to depressive symptoms did not reach significance (n = 568, SMD = 0.15, 95% CI = -0.01, 0.32, p = 0.07), and there was no effect on anxiety (n = 562, SMD = 0.03, 95% CI = -0.13, 0.20, p = 0.71). The review provides evidence for the benefit of B vitamin supplementation in healthy and at-risk populations for stress, but not for depressive symptoms or anxiety. B vitamin supplementation may particularly benefit populations who are at risk due to (1) poor nutrient status or (2) poor mood status.

Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling.

The molecular and cellular pathways that support the maintenance and stability of tumor neovessels are not well defined. The efficacy of microtubule-disrupting agents, such as combretastatin A4 phosphate (CA4P), in inducing rapid regression of specific subsets of tumor neovessels has opened up new avenues of research to identify factors that support tumor neoangiogenesis. Herein, we show that CA4P selectively targeted endothelial cells, but not smooth muscle cells, and induced regression of unstable nascent tumor neovessels by rapidly disrupting the molecular engagement of the endothelial cell-specific junctional molecule vascular endothelial-cadherin (VE-cadherin) in vitro and in vivo in mice. CA4P increases endothelial cell permeability, while inhibiting endothelial cell migration and capillary tube formation predominantly through disruption of VE-cadherin/beta-catenin/Akt signaling pathway, thereby leading to rapid vascular collapse and tumor necrosis. Remarkably, stabilization of VE-cadherin signaling in endothelial cells with adenovirus E4 gene or ensheathment with smooth muscle cells confers resistance to CA4P. CA4P synergizes with low and nontoxic doses of neutralizing mAbs to VE-cadherin by blocking assembly of neovessels, thereby inhibiting tumor growth. These data suggest that the microtubule-targeting agent CA4P selectively induces regression of unstable tumor neovessels, in part through disruption of VE-cadherin signaling. Combined treatment with anti-VE-cadherin agents in conjunction with microtubule-disrupting agents provides a novel synergistic strategy to selectively disrupt assembly and induce regression of nascent tumor neovessels, with minimal toxicity and without affecting normal stabilized vasculature.

Chemical probes of Skp2-mediated p27 ubiquitylation and degradation.

Skp2 is a member of the F-box family of proteins that serve as substrate-specific adaptors in Skp1-CUL1-ROC1-F-box (SCF) E3 ubiquitin ligases. Skp2 (Fbxl1) directly binds to the tumor suppressor p27 in the context of the SCFSkp2 E3 ubiquitin ligase to ubiquitylate and target-phosphorylated p27 for proteasomal degradation. As p27 is a powerful suppressor of growth in a variety of cells, and as Skp2 is also overexpressed in many human cancers, Skp2 is considered an oncogene and an intriguing drug target. However, despite 20 years of investigation, a valid chemical inhibitor of Skp2-mediated degradation of p27 has not been identified. Recently, an increasing number of compounds designed to have this bioactivity have been reported. Here, we conduct a meta-analysis of the evidence regarding bioactivity, structure, and medicinal chemistry in order to evaluate and compare these Skp2 inhibitor compounds. Despite chemically diverse compounds with a wide array of Skp2-mediated p27 ubiquitylation inhibition properties reported by several independent groups, no current chemical probe formally qualifies as a validated pharmaceutical hit compound. This finding suggests that our knowledge of the structural biochemistry of the Skp2-p27 complex remains incomplete and highlights the need for novel modes of inquiry.

Molecular basis of atypicality of bupropion inferred from its receptor engagement in nervous system tissues.

Despite decades of clinical use and research, the mechanism of action (MOA) of antidepressant medications remains poorly understood. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly prescribed antidepressants-atypical antidepressants such as bupropion have also proven effective, while exhibiting a divergent clinical phenotype. The difference in phenotypic profiles presumably lies in the differences among the MOAs of SSRIs/SNRIs and bupropion. We integrated the ensemble of bupropion's affinities for all its receptors with the expression levels of those targets in nervous system tissues. This "combined target tissue" profile of bupropion was compared to those of duloxetine, fluoxetine, and venlafaxine to isolate the unique target tissue effects of bupropion. Our results suggest that the three monoamines-serotonin, norepinephrine, and dopamine-all contribute to the common antidepressant effects of SSRIs, SNRIs, and bupropion. At the same time, bupropion is unique in its action on 5-HT3AR in the dorsal root ganglion and nicotinic acetylcholine receptors in the pineal gland. These unique tissue-specific activities may explain unique therapeutic effects of bupropion, such as pain management and smoking cessation, and, given melatonin's association with nicotinic acetylcholine receptors and depression, highlight the underappreciated role of the melatonergic system in bupropion's MOA.

Adenovirus vector E4 gene regulates connexin 40 and 43 expression in endothelial cells via PKA and PI3K signal pathways.

Connexins (Cxs) provide a means for intercellular communication and play important roles in the pathophysiology of vascular cardiac diseases. Infection of endothelial cells (ECs) with first-generation E1/E3-deleted E4+ adenovirus (AdE4+) selectively modulates the survival and angiogenic potential of ECs by as of yet unrecognized mechanisms. We show here that AdE4+ vectors potentiate Cx expression in ECs in vitro and in mouse heart tissue. Infection of ECs with AdE4+, but not AdE4-, resulted in a time- and dose-dependent induction of junctional Cx40 expression and suppression of Cx43 protein and mRNA expression. Treatment of ECs with PKA inhibitor H89 or PI3K inhibitor LY294002 prevented the AdE4+-mediated regulation of Cx40 and Cx43 that was associated with diminished AdE4+-mediated survival of ECs. Moreover, both PKA activity and cAMP-response element (CRE)-binding activity were enhanced by treatment of ECs with AdE4+. However, there is no causal evidence of a cross-talk between the 2 modulatory pathways, PKA and PI3K. Remarkably, Cx40 immunostaining was markedly increased and Cx43 was decreased in the heart tissue of mice treated with intra-tracheal AdE4+. Taken together, these results suggest that AdE4+ may play an important role in the regulation of Cx expression in ECs, and that these effects are mediated by both the PKA/CREB and PI3K signaling pathways.