Project description:Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects females three times more frequently than males. A potential role for hormones, such as prolactin (PRL), may in part explain this phenomenon. The risk of developing RA is increased in women who are lactating after the first pregnancy, which might be related to breastfeeding and the release of PRL. Other studies found a protective effect of PRL on RA development. Some studies have reported that hyperprolactinemia is more common in RA and serum PRL levels are correlated with several disease parameters, although others could not confirm these findings. Overall the plasma PRL levels are on average not elevated in RA. Previously, a small number of open-label clinical trials using bromocriptine, which indirectly decreases PRL levels, were performed in RA patients and showed clinical benefit, although others found the opposite effect. Locally produced PRL at the site of inflammation may have a crucial role in RA as well, as it has been shown that PRL can be produced by synovial macrophages. Locally produced PRL has both pro-inflammatory and anti-inflammatory effects in arthritis. Psoriatic arthritis (PsA) is also an autoinflammatory disease, in which the prolactin receptor is also expressed in macrophages. The aim of this review is to provide an overview of the potential role of PRL signaling in inflammatory joint diseases (RA and PsA) and its potential as a therapeutic target.
Project description:Reproductive system diseases pose prominent threats to human physical and mental well-being. Besides being influenced by genetic material regulation and changes in lifestyle, the occurrence of these diseases is closely connected to exposure to harmful substances in the environment. Endocrine disrupting chemicals (EDCs), characterized by hormone-like effects, have a wide range of influences on the reproductive system. EDCs are ubiquitous in the natural environment and are present in a wide range of industrial and everyday products. Currently, thousands of chemicals have been reported to exhibit endocrine effects, and this number is likely to increase as the testing for potential EDCs has not been consistently required, and obtaining data has been limited, partly due to the long latency of many diseases. The ability to avoid exposure to EDCs, especially those of artificially synthesized origin, is increasingly challenging. While EDCs can be divided into persistent and non-persistent depending on their degree of degradation, due to the recent uptick in research studies in this area, we have chosen to focus on the research pertaining to the detrimental effects on reproductive health of exposure to several EDCs that are widely encountered in daily life over the past six years, specifically bisphenol A (BPA), phthalates (PAEs), polychlorinated biphenyls (PCBs), parabens, pesticides, heavy metals, and so on. By focusing on the impact of EDCs on the hypothalamic-pituitary-gonadal (HPG) axis, which leads to the occurrence and development of reproductive system diseases, this review aims to provide new insights into the molecular mechanisms of EDCs' damage to human health and to encourage further in-depth research to clarify the potentially harmful effects of EDC exposure through various other mechanisms. Ultimately, it offers a scientific basis to enhance EDCs risk management, an endeavor of significant scientific and societal importance for safeguarding reproductive health.
Project description:Vitamin D along with its active metabolite calcitriol and its metabolic and signaling system, known as the vitamin D endocrine system, have been widely recognized as a pivotal regulator of calcium homeostasis in addition to non-calcemic antitumoral effects in a variety of human cancers, including cervical cancer. Several studies have found an inverse relationship between the incidence of cervical neoplasia and vitamin D levels. This narrative review updates the current evidence supporting the notion that the vitamin D endocrine system has a preventive role on cervical cancer, mainly in the early phases of the disease, acting at the level of suppressing cell proliferation, promoting apoptosis, modulating inflammatory responses, and probably favoring the clearance of human papillomavirus-dependent cervical lesions. Although an optimal vitamin D status helps in the prevention and regression of low-grade squamous intraepithelial lesions of the cervix, it appears that vitamin D alone or combined with chemotherapeutic agents has little effectivity once advanced cervical cancer is established. These observations suggest that an optimal vitamin D status might exert beneficial actions in the early phases of cervical cancer by preventing its onset and progression.
Project description:The physiological role of the osteocyte, the most numerous of the three bone cell types, was significantly underestimated until recently. It is now known that they not only coordinate bone remodeling but also have an endocrine function as part of the regulatory network for calcium and phosphate homeostasis. Vitamin D and osteocytes interact in numerous ways to accomplish these activities. The major source of active vitamin D (1,25(OH)2D3) is the kidney but there is evidence that osteocytes can produce it as well. Renal 1,25(OH)2D3 regulates osteocyte production of fibroblast growth factor 23 (FGF23), a powerful phosphaturic factor with far-reaching physiological effects. The function of 1,25(OH)2D3 produced by osteocytes themselves is poorly understood and is an area of active research. Osteocytes affect local bone remodeling by producing regulatory factors for osteoblasts and osteoclasts in response to mechanical loading and to endocrine signals such as serum 1,25(OH)2D3. In addition, 1,25(OH)2D3 may inhibit mineralization in osteocyte lacunae. Whether 1,25(OH)2D3 has a role in osteocytic perilacunar remodeling is currently unknown. This short review presents the current state of our knowledge about the physiologically and clinically significant roles of vitamin D signaling in osteocytes.
Project description:Vitamin D was discovered as an anti-rachitic agent preventing a failure in bone mineralization, but it is now established that the active form of vitamin D3 (1α,25(OH)2D3) induces bone resorption. Discovery of the receptor activator of nuclear factor -κB ligand (RANKL) uncovered the molecular mechanism by which 1α,25(OH)2D3 stimulates bone resorption. Treating osteoblastic cells with 1α,25(OH)2D3 stimulates RANKL expression, which in turn induces osteoclastogenesis. Nevertheless, active vitamin D compounds such as calcitriol (1α,25(OH)2D3), alfacalcidol (1α(OH)D3) and eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropoxy) vitamin D3) have been used as therapeutic drugs for osteoporosis, as they increase bone mineral density (BMD) in osteoporotic patients. Paradoxically, the increase in BMD is caused by the suppression of bone resorption. Several studies have been performed to elucidate the mechanism by which active vitamin D compounds suppress bone resorption in vivo. Our study showed that daily administration of eldecalcitol to mice suppressed neither the number of osteoclast precursors in the bone marrow nor the number of osteoclasts formed in ex vivo cultures. Eldecalcitol administration suppressed RANKL expression in osteoblasts. This review discusses how the difference between in vitro and in vivo effects of active vitamin D compounds on bone resorption is induced.
Project description:Chronic consumption of a large amount of alcohol disrupts the communication between nervous, endocrine, and immune system and causes hormonal disturbances that lead to profound and serious consequences at physiologic and behavioral levels. These alcohol-induced hormonal dysregulations affect the entire body and can result in various disorders such as stress abnormalities, reproductive deficits, body growth defect, thyroid problems, immune dysfunction, cancers, bone disease, and psychological and behavioral disorders. This review summarizes the findings from human and animal studies that provide consistent evidence on the various effects of alcohol abuse on the endocrine system.
Project description:CC chemokine receptor 2 (CCR2) plays important roles in extravasation and transmigration of monocytes under inflammatory conditions. CCR2 and its ligands have been extensively studied in a range of inflammatory diseases in the central nervous system (CNS), including multiple sclerosis, Alzheimer's disease and ischemic stroke. This brief review summarizes our current understanding of the physiologic and pathologic roles of CCR2, focusing on its involvement in CNS inflammatory diseases. There appears to be a rationale for exploring therapies involving CCR2 inhibition in multiple sclerosis and ischemic stroke, but there is also evidence for immunomodulatory and protective effects of CCR2 activity during CNS inflammation. The critical balance between protective and detrimental roles of CCR2-dependent recruitment of leukocytes must therefore be carefully examined to guide safe and effective development of any therapies involving CCR2 modulation.
Project description:Calcium and phosphate regulate numerous biological processes and they are essential for bone mass and bone quality. The calcium and phosphate balance largely depends on intestinal absorption, and the dietary content of these ions determines the type of transport. High dietary intake of calcium and phosphate enables absorption by passive transport, but often the dietary content of these ions is in the low-normal range, especially for calcium. In this condition, the contribution of active intestinal calcium transport will increase to maintain normal serum levels. This adaptation is mainly regulated by the active form of vitamin D, 1,25 dihydroxyvitamin D, and requires normal concentrations of the precursor 25-hydroxyvitamin D. When intestinal calcium absorption is insufficient, hormonal adaptations will release calcium from bones to secure normocalcemia, not only by increasing bone loss but also by decreasing bone mineralization. These data underline the fact that adequate calcium intake is critical to secure skeletal integrity. Despite the insights that sufficient dietary calcium intake and normal 25-hydroxyvitamin D levels are critical for calcium and bone homeostasis, surprisingly little is known on the proteins that mediate intestinal calcium transport. Also, the interaction between the intestine and the kidney to control serum phosphate levels is still incompletely understood.
Project description:In several central nervous system diseases, it has been reported that inflammation may be related to the etiologic process, therefore, therapeutic strategies are being implemented to control inflammation. As the nervous system and the immune system maintain close bidirectional communication in physiological and pathological conditions, the modulation of inflammation through the cholinergic anti-inflammatory reflex has been proposed. In this review, we summarized the evidence supporting chemical stimulation with cholinergic agonists and vagus nerve stimulation as therapeutic strategies in the treatment of various central nervous system pathologies, and their effect on inflammation.
Project description:Nonverbal intelligence represents one of the components of brain cognitive functions, which uses visual images and nonverbal approaches for solving required tasks. Interaction between the nervous and immune systems plays a specif ic role in individual differences in brain cognitive functions. Therefore, the genes encoding pro- and antiinflammatory cytokines are prospective candidate genes in the study of nonverbal intelligence. Within the framework of the present study, we conducted the association analysis of six SNPs in the genes that encod proteins involved in inf lammatory response regulation in the central nervous system (CRP rs3093077, IL1А rs1800587, IL1B rs16944, TNF/ LTA rs1041981, rs1800629, and P2RX7 rs2230912), with nonverbal intelligence in mentally healthy young adults aged 18- 25 years without cognitive decline with inclusion of sex, ethnicity and the presence of the "risky" APOE ε4 allele as covariates. Considering an important role of environmental factors in the development of brain cognitive functions in general and nonverbal intelligence in particular, we conducted an analysis of gene-by-environment (G × E) interactions. As a result of a statistical analysis, rs1041981 and rs1800629 in the tumor necrosis factor gene (TNF) were shown to be associated with a phenotypic variance in nonverbal intelligence at the haplotype level (for АА-haplotype: βST = 1.19; p = 0.033; pperm = 0.047) in carriers of the "risky" APOE ε4 allele. Gene-by-environment interaction models, which determined interindividual differences in nonverbal intelligence, have been constructed: sibship size (number of children in a family) and smoking demonstrated a modulating effect on association of the TNF/LTA (rs1041981) (β = 2.08; βST = 0.16; p = 0.001) and P2RX7 (rs2230912) (β = -1.70; βST = -0.10; p = 0.022) gene polymorphisms with nonverbal intelligence. The data obtained indicate that the effect of TNF/LTA on the development of cognitive functions is evident only in the presence of the "unfavorable" APOE ε4 variant and/or certain environmental conditions.