Search Results (355)

Background/Objectives: Adequate vitamin D levels are essential for various physiological functions, including cell growth, immune modulation, metabolic regulation, DNA repair, and overall health span. Despite its proven cost-effectiveness, widespread deficiency persists due to inadequate supplementation and limited sunlight exposure. Methods: This systematic review (SR) examines the relationship between vitamin D and the reduction of cancer risk and mortality, and the mechanisms involved in cancer prevention. This SR followed the PRISMA and PICOS guidelines and synthesized evidence from relevant studies. Results: Beyond genomic actions via calcitriol [1,25(OH)₂D]-receptor interactions, vitamin D exerts cancer-protective effects through mitigating inflammation, autocrine, paracrine, and membrane signaling. The findings reveal a strong inverse relationship between serum 25(OH)D levels and the incidence, metastasis, and mortality of several cancer types, including colon, gastric, rectal, breast, endometrial, bladder, esophageal, gallbladder, ovarian, pancreatic, renal, vulvar cancers, and both Hodgkin’s and non-Hodgkin’s lymphomas. While 25(OH)D levels of around 20 ng/mL suffice for musculoskeletal health, maintaining levels above 40 ng/mL (100 nmol/L: range, 40–80 ng/mL) significantly lowers cancer risks and mortality. Conclusions: While many observational studies support vitamin D’s protective role in incidents and deaths from cancer, some recent mega-RCTs have failed to demonstrate this. The latter is primarily due to critical study design flaws, like recruiting vitamin D sufficient subjects, inadequate dosing, short durations, and biased designs in nutrient supplementation studies. Consequently, conclusions from these cannot be relied upon. Well-designed, adequately powered clinical trials using appropriate methodologies, sufficient vitamin D₃ doses, and extended durations consistently demonstrate that proper supplementation significantly reduces cancer risk and markedly lowers cancer mortality. Full article

Arginine vasopressin (AVP) and oxytocin (OXT) are neuropeptides traditionally recognized for their roles in the control of osmoregulation, blood pressure, lactation, and parturition in mammals. However, growing evidence suggests that AVPand OXT also regulate gonadal functions in teleost fish. Their expression in both male and female gonads, the presence of their receptors in ovaries and testes, and their interactions with steroids and other gonadal factors indicate a role in modulating gametogenesis and steroidogenesis via autocrine and paracrine mechanisms. Here, we review the current findings on AVP and OXT in teleost gonads, compared to the observed functions in mammals, emphasizing their systemic interactions within the hypothalamic–pituitary–gonadal (HPG) axis. While highlighting the roles of gonadal AVP and OXT in fish reproduction, we underscore the need for further research to unravel their complex multifactorial regulatory networks. Insights into the vasopressinergic system could enhance aquaculture practices by improving spawning success and reproductive efficiency. Full article

Androgenetic alopecia (AGA) is a common form of hair loss characterized by androgen-driven tissue remodeling, including progressive follicular miniaturization and dermal fibrosis, which is accompanied by low-grade immune activation. However, the molecular mechanisms underlying this fibroimmune dysfunction remain poorly understood. Dermal fibroblasts (DFs) have been suggested as androgen-responsive stromal cells and a potential source of CXCL12, a chemokine implicated in fibroimmune pathology, but their precise role in AGA has not been fully established. In this study, we performed single-cell transcriptomic profiling of a testosterone-induced mouse model of AGA, with or without treatment of CXCL12-neutralizing antibody, to elucidate the pathological role of CXCL12 in mediating stromal-immune interactions. Our analysis suggested that DFs are the primary androgen-responsive population driving CXCL12 expression. Autocrine CXCL12-ACKR3 signaling in DFs activated TGF-β pathways and promoted fibrotic extracellular matrix deposition. In parallel, paracrine CXCL12-CXCR4 signaling reprogrammed Sox2⁺Twist1⁺ dermal papilla cells (DPCs) and promoted the accumulation of pro-fibrotic Trem2⁺ macrophages, contributing to impaired hair follicle regeneration. Notably, CXCL12 blockade attenuated these stromal and immune alterations, restored the regenerative capacity of DPCs, reduced pro-fibrotic macrophage infiltration, and promoted hair regrowth. Together, these findings identify CXCL12 as a central mediator of androgen-induced fibroimmune remodeling and highlight its potential as a therapeutic target in AGA. Full article

The incidence of Hashimoto’s disease (HD) increases with age and in people who have other autoimmune diseases. It is characterized by lymphocytic infiltration, fibrosis, and atrophy of the thyroid parenchyma with the simultaneous presence of thyroid peroxidase antibodies (ATPO) and/or thyroglobulin antibodies (ATG). Eicosanoids are formed via the cyclooxygenase (COX), lipoxygenase (LOX), and monooxygenase (CYP450) pathways with arachidonic acid (ARA), resulting in the production of epoxyeicosatrienoic acids (EETs) or hydroxyeicosatetraenoic acids (HETEs). These eicosanoids can act in an autocrine or paracrine manner on target cells. This study aimed to examine whether a gluten-free diet (GFD) can modulate the enzymatic pathways of the pro-inflammatory ARA cascade. The study material consisted of serum samples from Caucasian female patients with HD aged 18–55 years. Participants were enrolled in the study based on the presence of an ultrasound characteristic of HD, and elevated serum levels of anti-thyroid peroxidase antibodies and anti-thyroglobulin antibodies. Patients with confirmed celiac disease did not participate in the study. A total of 78 samples were analyzed, with 39 collected after 3 months of following a GFD. Eicosanoids (thromboxane B2, prostaglandin E2, leukotriene B4, and 16R-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid (16-RS HETE)) were extracted using high-performance liquid chromatography. The contribution of leukotriene (LTB) was analyzed in the LOX pathway, prostaglandins (PGE2) and thromboxane (TXB2) were selected for the involvement of the COX pathway, and 16RS HETE was used for the CYP450 pathway. All parameters were analyzed before and after a 3-month dietary intervention that included a gluten-free diet. In the obtained results, only one mediator, leukotriene B4, was significant (p < 0.05). The mean level on the initial visit was 0.202 ± 0.11 (SD), while it was 0.421 ± 0.27 (SD) on the subsequent visit, indicating a significant increase in its level after implementing a GFD. Although there was a trend in the CYP 450 pathway of decreased 16-RS HETE, the presented correlations show that thromboxane B4 and 16RS-HETE were positively correlated with the body mass and body fat mass of the examined patients. There was a trend in the CYP 450 pathway of decreased 16-RS HETE after GFD. Thromboxane B4 and 16RS-HETE levels before GFD were positively correlated with the body mass and body fat mass of the examined patients. A gluten-free diet in HD does not suppress the synthetic pathways of LOX, COX, or cytochrome P450 (CYP450). The level of adipose tissue has a greater impact on the inflammatory processes in HD than a gluten-free diet. This study does not confirm the suppressive effect of a gluten-free diet on the pro-inflammatory arachidonic acid cascade in any of the three analyzed mediator synthesis LOX, COX, CYP450 pathways. Full article

One of the most common malignant tumors worldwide is lung cancer, and it is associated with the highest death rate among all cancers. Traditional treatment options for lung cancer include radiation, chemotherapy, targeted therapy, and surgical resection. However, the survival rate is low, and the outlook is still dreadfully dire. The pursuit of a paradigm change in treatment approaches is, therefore, imperative. Tyrosine kinases (TKs), a subclass of protein kinases, regulate vital cellular function by phosphorylating tyrosine residues in proteins. Mutations, overexpression, and autocrine paracrine stimulation can transform TKs into oncogenic drivers, causing cancer pathogenesis. Tyrosine kinase inhibitors (TKIs) have emerged as an attractive targeted therapy option, especially for non-small cell lung cancer (NSCLC). However, resistance to TKIs, and adverse cardiovascular effects such as heart failure, atrial fibrillation, hypertension, and sudden death, are among the most common adverse effects of TKIs. There is increasing interest in plant-derived natural products in the hunt for powerful chemosensitizer and pathway modulators for enhancing TKI activity and/or overcoming resistance mechanisms. This highlights the mechanism of TKs’ activation in cancer, the role of TKIs in NSCLC mechanisms, and the challenges posed by TKI-acquired resistance. Additionally, we explored various plant-derived natural products’ bioactive compounds with the chemosensitizer and pathway-modulating potential with TKs’ inhibitory and anticancer effects. Our review suggests that a combination of natural products with TKIs may provide a novel and promising strategy for overcoming resistance in lung cancer. In future, further preclinical and clinical studies are advised. Full article

Glioblastoma (GBM) is the most aggressive form of malignant gliomas, with the eicosanoid-synthesizing enzyme cyclooxygenase-2 (COX-2) playing a pivotal role in its progression via the COX-2/prostaglandin E2/4 axis. COX-2 upregulations in tumor cells induces a pro-inflammatory tumor microenvironment (TME), affecting the behavior of invading bone marrow-derived macrophages (Mϕ) and brain-resident microglia (MG) through unclear autocrine and paracrine mechanisms. Using CRISPR/Cas9 technology, we generated COX-2 knockout U87 glioblastoma cells. In spheroids and in vivo xenografts, this resulted in a significant inhibition of tumorigenic properties, while not observed in standard adherent monolayer culture. Here, the knockout induced a G1 cell cycle arrest in adherent cells, accompanied by increased ROS, mitochondrial activity, and cytochrome c-mediated apoptosis. In spheroids and xenograft models, COX-2 knockout led to notable growth delays and increased cell death, characterized by features of both apoptosis and autophagy. Interestingly, these effects were partially reversed in subcutaneous xenografts after co-culture with Mϕ, while co-culture with MG enhanced the growth-suppressive effects. In an orthotopic model, COX-2 knockout tumors displayed reduced proliferation (fewer Ki-67 positive cells), increased numbers of GFAP-positive astrocytes, and signs of membrane blebbing. These findings highlight the potential of COX-2 knockout and suppression as a therapeutic strategy in GBM, particularly when combined with suppression of infiltrating macrophages and stabilization of resident microglia populations to enhance anti-tumor effects. Full article

Skeletal muscle, traditionally recognized for its motor function, has emerged as a key endocrine organ involved in metabolic regulation and interorgan communication. This narrative review addresses the dual role of muscle as a target tissue for classical hormones—such as growth hormone (GH), insulin-like growth factor type 1 (IGF-1), thyroid hormones, and sex steroids—and as a source of myokines, bioactive peptides released in response to muscle contraction that exert autocrine, paracrine, and endocrine effects. Several relevant myokines are discussed, such as irisin and Metrnl-like myokines (Metrnl), which mediate exercise-associated metabolic benefits, including improved insulin sensitivity, induction of thermogenesis in adipose tissue, and immunometabolic modulations. It also examines how muscle endocrine dysfunction, caused by chronic inflammation, hormone resistance, or sedentary lifestyle, contributes to the development and progression of metabolic diseases such as obesity, type 2 diabetes, and sarcopenia, highlighting the importance of muscle mass in the prognosis of these pathologies. Finally, the therapeutic potential of interventions aimed at preserving or enhancing muscle function—through physical exercise, hormone therapy and anabolic agents—is highlighted, together with the growing research on myokines as biomarkers and pharmacological targets. This review expands the understanding of muscle in endocrinology, proposing an integrative approach that recognizes its central role in metabolic health and its potential to innovate the clinical management of endocrine–metabolic diseases. Full article

The unique secondary messenger 2′3′-cGAMP, produced by cGAS in response to cytosolic dsDNA, plays a critical role in activating innate immunity by binding to and activating STING via cell-intrinsic, autocrine, or paracrine mechanisms. Recently, we identified Rab18 as a novel, STING-independent binder of 2′3′-cGAMP. Binding of 2′3′-cGAMP to Rab18 promotes Rab18 activation and induces cell migration. However, the downstream mechanisms by which 2′3′-cGAMP-induced Rab18 activation regulates cell migration remain largely unclear. Herein, using phospho-profiling analysis, we identify MAPK signaling as a key downstream effector of the 2′3′-cGAMP/Rab18 axis that promotes the expression of FosB2 and drives cell migration. Furthermore, we identify MMP3 as a major transcriptional target of FosB2, through which the 2′3′-cGAMP/Rab18/MAPK/FosB2 signaling pathway positively regulates cell migration. Together, our findings provide new mechanistic insights into how 2′3′-cGAMP signaling controls cell migration and suggest the potential of MAPK inhibitors to block 2′3′-cGAMP-induced migratory responses. Full article

Extracellular vesicles (EVs) play pivotal roles in tumor progression and metastasis by mediating intercellular communication within the tumor microenvironment. In this study, we identified two novel EX cargo proteins—UBE2NL and HIST2H3PS2—derived from highly aggressive epithelial ovarian cancer (EOC) cells and mesenchymal-type ovarian stromal progenitor cells (MSC-OCSPCs) but absent in less aggressive SKOV3 cells. Quantitative proteomic profiling via LC-MS/MS and TCGA-integrated analysis revealed that high expression of these genes correlated with advanced tumor stages and poor overall survival in EOC, and high HIST2H3PS2 expression predicted poor survival in endometrial cancer (EC). Functionally, UBE2NL and HIST2H3PS2 overexpression promoted EOC cell invasiveness, which was further enhanced by EX-mediated autocrine and paracrine effects. In contrast, the knockdown of UBE2NL reduced cell invasiveness and prolonged mouse survival in vivo. Moreover, HIST2H3PS2-enriched EXs significantly increased peritoneal dissemination and ascites in murine models. These findings suggest that EX-packaged UBE2NL and HIST2H3PS2 drive tumor aggressiveness and metastasis in gynecologic cancers, highlighting their potential as prognostic biomarkers and therapeutic targets. Full article

Background/Objectives: The amino acid γ-aminobutyric acid (GABA) is the primary neurotransmitter in the central nervous system (CNS) and acts as an autocrine and/or paracrine signaling molecule in various types of non-neuronal cells. On the other hand, GABA is a nutrient found in a variety of foods and is marketed as a health supplement based on a growing number of studies reporting health benefits in humans and recuperations in animal models of diseases. The present study sought to examine whether supplementation of GABA to young mice regulates their growth as well as glucose and lipid metabolism during physiological adolescence. Methods: Mice were supplemented with GABA over a 16-week period with subsequent anthropometric, metabolic, and endocrine measurements. Results: Results showed that 16-week oral supplementation of GABA increased food consumption and body length while attenuating weight gain in male mice but not females. In addition, GABA treatment lowered the index of body fat (Lee index) and increased the expression of lipolytic enzymes in adipose and liver tissues of male mice without affecting blood glucose levels. Remarkably, supplementation of GABA significantly increased the protein expression of growth hormone (GH) in the pituitary gland of both male and female mice. However, it only substantially increased GH levels in the sera of male mice but not females. Moreover, GABA significantly increased the expression of the GH secretagogue peptide ghrelin in the stomachs of male mice only. Conclusions: Together these novel findings suggest that long-term GABA supplementation fundamentally influences the growth and lipid metabolism of males during adolescent development by stimulating ghrelin–GH production and secretion. The mechanisms of GABA-induced sex-dependent upregulations of ghrelin and GH, as well as lipid metabolism in adolescence, await further studies. Full article

The specific pathogenesis of osteoarthritis (OA) remains not fully understood. As a transmembrane heparan sulfate proteoglycan, syndecan-4 (SDC4) has been proven to play an important role in the development of OA. Notably, the extracellular domain of SDC4 can be cleaved by proteolytic enzymes, leading to the release of shed SDC4 (sSDC4), which subsequently regulates various biological processes in an autocrine or paracrine manner. This review analyzed 97 publications (1987–2025) from Pubmed and the Web of Science Core Collection using specific key words (syndecan-4, shed syndecan-4, and osteoarthritis), providing a comprehensive overview of the current research on sSDC4, including its shedding enzymes and specific cleavage sites, as well as the factors and mechanisms that influence SDC4 shedding. Furthermore, it summarizes the functions of both sSDC4 and its remaining membrane-bound domain. Finally, the roles of sSDC4 in OA are discussed to identify potential therapeutic targets and explore new strategies for the treatment of OA. Full article

Background: Hodgkin lymphoma (HL) is a B-cell-derived malignancy and one of the most frequent types of lymphoma. The tumour cells typically exhibit multiple genomic alterations together with aberrantly activated signalling pathways, driven by paracrine and/or autocrine modes. SPP1 (alias osteopontin) is a cytokine acting as a signalling activator and has been connected with relapse in HL patients. To understand its pathogenic role, here, we investigated the mechanisms and function of deregulated SPP1 in HL. Methods: We screened public patient datasets and cell lines for aberrant SPP1 expression. HL cell lines were stimulated with SPP1 and subjected to siRNA-mediated knockdown. Gene and protein activities were analyzed by RQ-PCR, ELISA, Western blot, and immuno-cytology. Results: SPP1 expression was detected in 8.3% of classic HL patients and in HL cell line SUP-HD1, chosen to serve as an experimental model. The gene encoding SPP1 is located at chromosomal position 4q22 and is genomically amplified in SUP-HD1. Transcription factor binding site analysis revealed TALE and HOX factors as potential regulators. Consistent with this finding, we showed that aberrantly expressed PBX1 and HOXB9 mediate the transcriptional activation of SPP1. RNA-seq data and knockdown experiments indicated that SPP1 signals via integrin ITGB1 in SUP-HD1. Accordingly, SPP1 activated NFkB in addition to MAPK/ERK which in turn mediated the nuclear import of ETS2, activating oncogenic JUNB expression. Conclusions: SPP1 is aberrantly activated in HL cell line SUP-HD1 via genomic copy number gain and by homeodomain transcription factors PBX1 and HOXB9. SPP1-activated NFkB and MAPK merit further investigation as potential therapeutic targets in affected HL patients. Full article

Spermatogenesis is a process of self-renewal of spermatogonial stem cells and their proliferation and differentiation to generate mature sperm. This process involves interactions between testicular somatic (mainly Sertoli cells) and spermatogonial cells at their different stages of development. The functionality of Sertoli cells is regulated by hormones and testicular autocrine/paracrine factors. In this study, we investigated the effects of follicle-stimulating hormone (FSH) and testosterone addition on Sertoli cell cultures that undergo hypotonic shock, with a primary focus on Sertoli cell activity. Cells were enzymatically isolated from testicular seminiferous tubules of 7-day-old mice. These cells were cultured in vitro for 3 days. Thereafter, some cultures were treated with hypotonic shock to remove germ cells. After overnight, fresh media without (control; CT) or with FSH, testosterone (Tes), or FSH+T were added to the hypotonic shock-treated or untreated (CT) cultures for 24 h. The morphology of the cultures and the presence of Sertoli cells and germ cells were examined. The expression of growth factors (CSF-1, LIF, SCF, GDNF) or other specific Sertoli cell factors [transferrin, inhibin b, androgen receptor (AR), androgen binding protein (ABP), FSH receptor (FSHR)] was examined by qPCR. Our immunofluorescence staining showed depletion/major reduction in VASA-positive germ cells in Sertoli cell cultures following hypotonic shock (HYP) treatment compared to untreated cultures (WO). Furthermore, the expression of the examined growth factors and other factors was significantly increased in HYP cultures compared to WO (in the CT). However, the addition of hormones significantly decreased the expression levels of the growth factors in HYP cultures compared to WO cultures under the same treatment. In addition, the expression of all other examined Sertoli cell factors significantly changed following HYP treatment compared to WO and following treatment with FSH and or T. However, the expression levels of some factors remained normal following the treatment of Sertoli cell cultures with one or both hormones (transferrin, Fsh-r, Abp, Ar). Thus, our results demonstrate the crucial role of germ cells in the functionality of Sertoli cells and the possible role of FSH and T in maintaining, at least partially, the normal activity of Sertoli cells following germ cell depletion in vitro by hypotonic shock treatment. Full article

Nerve growth factor (NGF) plays a critical role in reproduction through paracrine and endocrine mechanisms. However, its autocrine effects on uterine receptivity and inflammatory pathways remain unknown. This study is the first to demonstrate NGF’s direct autocrine action on sheep endometrial luminal epithelial cells (SELECs), primary cultures treated with NGF for 12, 24, and 48 h, with or without the NTRK1 antagonist. NGF significantly increased PGE2 (p < 0.0001) and PGF2α (p < 0.0001) levels only at 12 h, with no significant changes at 24 and 48 h. NGF also upregulated the expression of NGF, COX2, and NTRK1 (p < 0.0001), and p75NTR and STAR (p < 0.001), at 12 h, with the effects reversed by NTRK1 inhibition, while no significant changes were observed for TLR4 (p > 0.05). Western blot (WB) analysis was performed exclusively to confirm the presence of NGF protein, revealing no significant differences (p > 0.05) across experimental conditions. These findings highlight NGF’s role in directly regulating SELEC activity through autocrine mechanisms, emphasizing its importance in uterine receptivity and reproductive readiness. This study provides novel insights into NGF’s role in sheep reproduction and its potential applications in fertility treatments. Full article

Fibroblast growth factors (FGFs) have diverse functions in the regulation of cell proliferation and differentiation in development, tissue maintenance, wound repair, and angiogenesis. The goal of this review paper is to (i) deliberate on the role of FGFs and FGF receptors (FGFRs) in different cancers, (ii) present advances in FGF-targeted cancer therapies, and (iii) explore cell signaling mechanisms that explain how FGF expression becomes dysregulated during cancer development. FGF is often mutated and overexpressed in cancer and the different FGF and FGFR isoforms have unique expression patterns and distinct roles in different cancers. Among the FGF members, the FGF 15/19 subfamily is particularly interesting because of its unique protein structure and role in endocrine function. The abnormal expression of FGFs in different cancer types (breast, colorectal, hepatobiliary, bronchogenic, and others) is examined and correlated with patient prognosis. The classification of FGF ligands based on their mode of action, whether autocrine, paracrine, endocrine, or intracrine, is illustrated, and an analysis of the binding specificity of FGFs to FGFRs is also provided. Moreover, the latest advances in cancer therapeutic strategies involving small molecules, ligand traps, and monoclonal antibody-based FGF inhibitors are presented. Lastly, we discuss how the dysregulation of FGF and FGFR expression affects FGF signaling and its role in cancer development. Full article