Estrogen-receptor status determines differential regulation of α1- and α2-adrenoceptor-mediated cell survival, angiogenesis, and intracellular signaling responses in breast cancer cell lines.

Psychosocial stress promotes cancer pathogenesis involving angiogenesis through alterations in neuroendocrine-immune functions that may involve adrenoceptor (AR)-dependent signaling mechanisms in the brain, lymphoid organs, and cancerous cells. Various concentrations of α1- and α2- AR-specific agonists and antagonists were incubated in vitro with estrogen receptor-positive (ER +) MCF-7, and ER (-) MDA MB-231 cells to examine the secretions of VEGF-A, VEGF-C, and nitric oxide (NO), and expression of signaling molecules- p-ERK, p-CREB, and p-Akt on the proliferation of breast cancer cell lines. Cellular proliferation, VEGF-A and NO secretion, expression of p-ERK, p-CREB, and p-Akt were enhanced in MCF-7 cells treated with α1-AR agonist while VEGF-C secretion alone was enhanced in MDA MB-231 cells. Treatment of MCF-7 and MDA MB-231 cells with α2- AR agonist similarly enhanced proliferation and decreased NO production and p-CREB expression while VEGF-C secretion was decreased in MCF-7 cells and p-Akt expression was decreased in MDA MB-231 cells. α1-AR inhibition reversed cellular proliferation and VEGF-A secretion by MCF-7 cells while α2-AR inhibition reversed the proliferation of MCF-7 and MDA MB-231 cells and VEGF-C secretion by MCF-7 cells. Taken together, breast cancer pathogenesis may be influenced by distinct α-AR-mediated signaling mechanisms on angiogenesis and lymphangiogenesis that are dependent on estrogen receptor status.

Exploring the Effects of Endocrine-Disrupting Chemicals and miRNA Expression in the Pathogenesis of Endometriosis by Unveiling the Pathways: a Systematic Review.

Endometriosis, characterized by endometrial-like mucosal tissue outside the uterine cavity, is a reproductive disorder afflicting about 10% of women within the reproductive age. The pathogenesis of endometriosis has been attributed to factors like genetics, environmental particles, and hormones. A comprehensive review of studies from July 2010 to July 2023 across multiple databases was done to aid in a better understanding of the same. The investigation focused on studies delineating the correlation between endocrine disruptors, microRNAs, and endometriosis. To optimize the search scope, keywords and subject headings were used as search terms. Then, two authors rigorously assessed studies using criteria, selecting 27 studies from various databases. Notably, dioxins, organochlorine pesticides, and polychlorinated biphenyls exhibited a solid connection for endometriosis, while bisphenol A and phthalates yielded conflicting results. The heightened presence of bisphenol A, polychlorinated biphenyls, and phthalates was linked to altered gene expression, including genes like AKR1B10, AKR1C3, and FAM49B. MicroRNAs like miRNA-31, miRNA-144, and miRNA-145 emerged as vital factors in the onset of endometriosis and progression. Furthermore, elevated expression of miR-1304-3p, miR-544, and miR-3684 and reduced expression of miR-3935 and miR-4427 exert substantial influence on signaling pathways like NF-κB, MAPK, and Wnt/ß-catenin. Currently, literature shows an independent link between endocrine disruptor exposure and endometriosis and between microRNA dysregulation and endometriosis. However, research lacks the combination of all three factors. The review delves into the effects of endocrine disruptors and microRNAs on the pathogenesis of endometriosis to improve our understanding of the disorder and in finding therapies.

Alterations in Immune Responses Are Associated with Dysfunctional Intracellular Signaling in Peripheral Blood Mononuclear Cells of Men and Women with Mild Cognitive Impairment and Alzheimer's disease.

Deficits in the neuroendocrine-immune network in the periphery associated with the onset and progression of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have not been extensively studied. The present study correlatively examines the association between cell-mediated immune responses, stress hormones, amyloid precursor protein (APP) expression, peripheral blood mononuclear cells (PBMC), and intracellular signaling molecules in the pathophysiology of MCI and AD compared to adults. Serum APP, lymphocyte proliferation, total cholinesterase (TChE), butyrylcholinesterase (BChE) activities, cytokines (IL-2, IFN-γ, IL-6, and TNF-α), and intracellular signaling molecules (p-ERK, p-CREB, and p-Akt) were measured in the PBMCs of adult, old, MCI, and AD men and women initially and after 3 years in the same population. An age- and disease-associated decline in mini-mental state examination (MMSE) scores and lymphocyte proliferation of MCI and AD men and women were observed. An age- and disease-related increase in serum APP, cortisol levels, and TChE activity were observed in men and women. Enhanced production of Th1 cytokine, IL-2, pro-inflammatory cytokines, and suppressed intracellular transcription factors may promote the inflammatory environment in MCI and AD patients. The expression of CREB and Akt was lower in MCI and AD men, while the expression of p-ERK was higher, and p-CREB was lower in MCI and AD women after 3 years. These results suggest that changes in specific intracellular signaling pathways may influence alterations in cell-mediated immunity to promote disease progression in MCI and AD patients.

Endocrine-Disrupting Chemicals Exposure Alter Neuroendocrine Factors, Disrupt Cardiac Functions and Provokes Hypoxia Conditions in Zebrafish Model.

Zebrafish (Danio rerio) is an increasingly popular vertebrate model used for assessing the toxicity of endocrine-disrupting chemicals (EDCs) on living beings. The zebrafish features high genetic homology to mammals, because of its rapid embryonic development, optical transparency of phenotypic screening embryos, high throughput genetic and chemical screening which make them a powerful toxicological model. This systematic review aimed to assess the recent literature on the use of zebrafish model in EDCs toxicity studies. We capture the data on the types of EDCs used, zebrafish life stages associated with the toxicity, and its effects on the alterations in neuroendocrine factors and cardiac hypoxia in zebrafish. A total of 17 articles published between 2010 and 2020 were curated. The information gathered highlighted the association of EDCs with cardiological outcomes and neurobehavioral effects and distorted expression of genes. The genes that were highlighted in the paper include bdnf, ntrk2a, grin2cb, VTG-1, HIF-1α, tnnt2, ntrk1, and pax6b. The effect of EDCs on cardiac hypoxia and neurodevelopmental and behavioral factors of zebrafish were described in all the papers chosen for this review. The involvement of EDCs in altered regulation of gene expression can be studied further to identify the potential EDC compounds on its toxicological and endocrine disruption function at the molecular level.

Age-associated decline in neural, endocrine, and immune responses in men and women: Involvement of intracellular signaling pathways.

The aim of this study was to investigate the alterations in the neuroendocrine-immune functions by using human peripheral blood mononuclear cells (hPBMCs) from three age groups (young, middle-aged, and old) of men and women for the analyses of lymphocyte proliferation and cytokine production, expression of cell signaling molecules, nitric oxide (NO) production, and expression of p-tyrosine hydroxylase (TH). Serum was examined for levels of testosterone in men, 17-ß-estradiol in women, and cortisol in both sexes. Lymphoproliferation, expression of p-ERK, p-CREB, p-Akt, and p-TH, and levels of serum sex steroid hormones declined with age in men and women. However, TNF-α production and serum cortisol level increased with age in men and women. mTOR expression was higher in older men while it was lower in older women. IFN-γ and IL-6 production and expression of p-TH and p-mTOR were differentially regulated in men and women. These results suggest that intracellular signaling mediators may be involved in the age-related alterations in the neuroendocrine-immune interactions in men and women.

Sex-Based Differences in the Cytokine Production and Intracellular Signaling Pathways in Patients With Rheumatoid Arthritis.

OBJECTIVES: This study aims to investigate lymphoproliferation, cytokine production, and intracellular signaling molecules in peripheral blood mononuclear cells (PBMCs) isolated from healthy individuals and rheumatoid arthritis (RA) patients to understand the extent of the involvement of these pathways in the pathogenesis of RA. PATIENTS AND METHODS: The study included 65 participants (29 males, 36 females; mean age 51.8±10.3 years; range, 37 to 71 years) who were categorized into four groups as healthy males (n=22, mean age 49.8±10.6 years; range, 39 to 65 years), male RA patients (n=7, mean age 51.8±13.9 years; range, 37 to 68 years), healthy females (n=20, mean age 53.7±8.8 years; range, 42 to 67 years), and female RA patients (n=16, mean age 52.9±10.4 years; range, 40 to 71 years). PBMCs were collected from the participants and analyzed for Concanavalin A (Con A)-induced lymphoproliferation using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cytokine production, and phospho-signal transducer and activator of transcription 3 (p-STAT-3), phospho-extracellular-signal-regulated kinase (p-ERK), phospho-cAMP response element binding (p-CREB), and phospho-protein kinase B expressions using enzyme-linked immunosorbent assay. Short form of the Arthritis Impact Measurement Scales 2 and multidimensional health assessment questionnaire were used to measure the level of disability and the quality of life. RESULTS: In RA patients, production of Con A-induced interleukin (IL)-2 and IL-17 was higher in both sexes while interferon-gamma levels decreased in RA females alone. Expression of p-STAT-3 in PBMCs increased in RA males while it was unaltered in RA females. p-ERK expression was not altered while p-CREB expression was enhanced in RA males and females. Protein-protein interaction analyses demonstrated that these and other key signaling molecules were dysregulated in RA patients. CONCLUSION: Our results suggest that sex-based differences in RA pathogenesis result from differential alterations in signaling pathways to influence the inflammatory process.

Virgin coconut oil supplementation in diet modulates immunity mediated through survival signaling pathways in rats.

Background Virgin coconut oil (VCO), a cold processed form of coconut oil, is traditionally consumed in Asian countries owing to its nutritional and medicinal properties. The aim of this study was to investigate whether the health benefits of VCO involve alterations in immune responses that are regulated by intracellular signaling molecules in the spleens of rats. Methods Young male Wistar rats were fed with three doses of VCO in diet for 30 days. At the end of the treatment period, spleens were isolated and in vitro effects on immune responses (Concanavalin A [Con A]-induced lymphoproliferation and cytokine production), and direct effects of VCO treatment on intracellular signaling molecules and antioxidant status were examined. Serum was collected to measure glucose, lipid levels, and leptin. Results VCO supplementation in diet enhanced Con A-induced splenocyte proliferation and Th1 cytokine production while it suppressed the proinflammatory cytokine production. VCO increased the expression of mechanistic target of rapamycin (p-mTOR), sirtuin1 (SIRT1), liver kinase B1 (p-LKB1) p-ERK, and p-CREB in spleen. Similarly, VCO increased the activities of antioxidant enzymes while it suppressed lipid peroxidation in the spleen. VCO diet had hypolipidemic effects on the rats: an increase in high density lipoprotein cholesterol (HDL-C) levels while lowering triacylglycerol (TAG) levels. Conclusion The health benefits of VCO may be mediated through enhanced Th1 immunity through the upregulation of survival signaling pathways and inhibition of free radical generation in the spleen besides its capacity to induce hypolipidemia.

Estrogen-induced neuroimmunomodulation as facilitator of and barrier to reproductive aging in brain and lymphoid organs.

Reproductive aging in females is marked by alterations in gonadal hormones, estrogen and progesterone, that facilitate cessation of reproductive cycles and onset of female-specific diseases such as autoimmune and neurodegenerative diseases, hormone-dependent cancers, and osteoporosis. Bidirectional communication between the three homeostatic systems, nervous system, endocrine system, and immune system, is essential for the maintenance of health and any dysfunction in the cross-talk promotes the development of diseases and cancer. The pleiotropic effects of estrogen on neural-immune interactions may promote either neuroprotection or inflammatory conditions depending on the site of action, dose and duration of treatment, type of estrogen receptors and its influence on intracellular signaling pathways, etc. Our studies involving treatment of early middle-aged female rats with low and high doses of estrogen and examining the brain areas, thymus, spleen, and lymph nodes revealed that estrogen-induced changes in neural-immune interactions are markedly affected in thymus followed by spleen and lymph nodes while it confers neuroprotection in the brain areas. These alterations are determined by antioxidant enzyme status, growth factors, intracellular signaling pathways involved in cell survival and inflammation, and metabolic enzymes and thus, may regulate the various stages in female reproductive aging. It is imperative that detailed longitudinal studies are carried out to understand the mechanisms of neuroendocrine-immune interactions in reproductive aging to facilitate healthy aging and for the development of better treatment strategies for female-specific diseases.

Interrelationship between Mini-Mental State Examination scores and biochemical parameters in patients with mild cognitive impairment and Alzheimer's disease.

AIM: The aim of the present study was to provide first-hand information about the prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) in Tamil Nadu, a southern state in India, and examine if there exists a relationship between cognitive functions and biochemical parameters in these patients. METHODS: Surveys were collected from adults, older men and women (n = 3126) from different regions of Tamil Nadu, which were followed up after 12 months for 1337 participants. Mini-Mental State Examination (MMSE) scores, lipid profile, and liver function tests were carried out in the elderly, MCI and AD patients. Based on the MMSE scores, the elderly population was classified into old control (28.97 ± 1.49; n = 1868), MCI (19.58 ± 1.17; n = 734) and AD (7.18 ± 1.38; n = 304) groups. Peripheral blood samples were collected after overnight fast from both male and female volunteers (n = 40 per group) who were categorized as young adult control, old control, MCI and AD. RESULTS: AD patients showed lower MMSE scores compared with the young adults, old and MCI groups, and MMSE further decreased at follow-up examination a year later. In the serum of AD patients, high-density lipoprotein, alkaline phosphatase activity and bilirubin levels were lower, whereas low-density lipoprotein, total cholesterol and triglycerides levels were higher. MMSE was positively correlated with high-density lipoprotein, and negatively correlated with other lipid parameters in AD. CONCLUSIONS: Hypercholesterolemia is a risk factor for AD that might result in neurotoxicity and cognitive impairment. Dysfunction of lipoprotein and heme metabolism might also provide additional targets for AD diagnosis. Geriatr Gerontol Int 2017; 17: 1737-1745.