Search Results (567)

Insulin is a key anabolic hormone traditionally considered to be exclusively produced by pancreatic β-cells. Insulin exerts several systemic effects involved in glucose uptake and metabolism. In the retina, insulin signaling acts as a regulator of photoreceptor- retinal pigment epithelium (RPE) metabolic coupling as well as of neuronal survival via the PI3K/Akt and MAPK/ERK pathways. Impaired insulin signaling contributes to diabetic retinopathy, retinitis pigmentosa, and age-related degeneration by disrupting energy homeostasis and trophic support. However, growing evidence suggests that the retina, particularly RPE, locally synthesizes and secretes insulin. Although the role of local insulin production in the retina remains to be clarified, this discovery introduces a paradigm shift in retinal physiology, suggesting a self-sustaining insulin signaling system that supports glucose uptake, lipid metabolism, and neurovascular integrity. Emerging data indicate that RPE-derived insulin is stimulated by photoreceptor outer segment (POS) phagocytosis and may act through autocrine and paracrine mechanisms to maintain retinal function, even under conditions of systemic insulin deficiency. Understanding this extra-pancreatic insulin source opens new therapeutic perspectives aimed at enhancing local insulin signaling to preserve vision and prevent retinal degeneration. Thus, the objective of this review is to summarize current evidence on RPE-derived insulin and to discuss its potential implications for retinal homeostasis and disease. Full article

The carotid body is a peripheral chemoreceptor that consists of clusters of chemoreceptive type I cells, glia-like type II cells, afferent and efferent nerves, and sinusoidal capillaries and arterioles. Cells and nerves communicate through reciprocal chemical synapses and electrical coupling that form a “tripartite synapse,” which allows for the process of sensory stimuli within the carotid body involving neurotransmission, autocrine, and paracrine pathways. In this network there are a variety of neurotransmitters and neuromodulators including adenosine 5′-triphosphate (ATP). Carotid body cells and nerve fibre terminals express ATP receptors, i.e., purinergic receptors. Here we used double immunofluorescence associated with laser confocal microscopy to detect the ATP receptor P2X7 and pannexin 1 (an ATP permeable channel) in the human carotid body, as well as the petrosal and cervical sympathetic ganglia. Immunofluorescence for P2X7r and pannexin 1 forms a broad cellular network within the glomeruli of the carotid body, whose pattern corresponds to that of type II cells. Moreover, both P2X7r and pannexin 1 were also detected in nerve profiles. In the petrosal ganglion, the distribution of P2X7r was restricted to satellite glial cells, whereas in the cervical sympathetic ganglion, P2X7r was found in neurons and glial satellite cells. The role of this purinergic receptor in the carotid body, if any, remains to be elucidated, but it probably provides new evidence for gliotransmission. Full article

Objectives: Oral candidiasis is commonly caused by Candida albicans, which possesses virulence factors and shows cytotoxic activity that affects oral keratinocytes. On the other hand, oral keratinocytes are known to induce immune responses against C. albicans infection. The aim of the present study was to investigate the relationships of various cytokines produced from oral keratinocytes with virulence factor activities and cytotoxicity of C. albicans strains. Methods: Following the determination of the amounts of cytokines (IL-1β, IL-8, TNF-α, CCL20, CXCL1, GM-CSF) produced by oral keratinocytes when exposed to 87 different C. albicans strains, relationships of the amounts of those cytokines from oral keratinocytes with biofilm formation, phospholipase production, and C. albicans cytotoxicity were examined using Spearman correlation analysis. Results: Positive correlations of the amount of IL-8 with CXCL1 (r_s = 0.295, p = 0.0055) and IL-1β (r_s = 0.35, p = 0.0009) were noted, while a positive correlation was also found between amounts of GM-CSF and IL-8 (r_s = 0.306, p = 0.004), as well as IL-1β (r_s = 0.38, p = 0.0003). In contrast, there were no significant correlations among biofilm formation, phospholipase production, or amounts of various cytokines produced by oral keratinocytes. Furthermore, a positive correlation was noted between cytotoxicity to oral keratinocytes and amounts of IL-1β (r_s = 0.736, p < 0.0001) and IL-8 (r_s = 0.371, p = 0.0004). Conclusions: The differential cytotoxicity of various C. albicans strains has an influence on the production of specific cytokines from oral keratinocytes. Additionally, cytokines produced by oral keratinocytes may be mutually involved with similar signaling activation and/or autocrine/paracrine functions. Full article

The cholinergic system is one of the most ancient and widespread signaling systems in the body, implicated in a range of pathological conditions—from neurodegenerative disorders to cancer. Given its broad relevance, there is growing interest in characterizing this system across diverse cellular models to enable drug screening, mechanistic studies, and exploration of new therapeutic avenues. In this study, we investigated four cancer cell lines: one of neuroblastoma origin previously used in cholinergic signaling studies (SH-SY5Y), one non-small cell lung adenocarcinoma line (A549), and two small cell lung carcinoma lines (H69 and H82). We assessed the expression and localization of key components of the cholinergic system, along with the cellular capacity for acetylcholine (ACh) synthesis and release. Whole-cell flow cytometry following membrane permeabilization revealed that all cell lines expressed the ACh-synthesizing enzyme choline acetyltransferase (ChAT). HPLC-MS analysis confirmed that ChAT was functionally active, as all cell lines synthesized and released ACh into the conditioned media, suggesting the presence of autocrine and/or paracrine ACh signaling circuits, consistent with previous reports. The cell lines also demonstrated choline uptake, indicative of functional choline and/or organic cation transporters. Additionally, all lines expressed the ACh-degrading enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), as well as the alfa seven (α7) nicotinic and M1 muscarinic ACh receptor subtypes. Notably, flow cytometry of intact SH-SY5Y cells revealed two novel findings: (1) ChAT was localized to the extracellular membrane, a feature not observed in the lung cancer cell lines, and (2) BChE, rather than AChE, was the predominant membrane-bound ACh-degrading enzyme. These results were corroborated by both whole-cell and surface-confocal microscopy. In conclusion, our findings suggest that a functional cholinergic phenotype is a shared feature of several carcinoma cell lines, potentially serving as a survival checkpoint that could be therapeutically explored. The discovery of extracellular membrane-bound ChAT uniquely in neuroblastoma SH-SY5Y cells points to a novel form of in situ ACh signaling that warrants further investigation. Full article

Immune checkpoint inhibitors (ICIs), including PD-L1 inhibitors, have been approved by the FDA for the treatment of cancers; however, only a small number of cancer patients benefit from these ICIs. Furthermore, the development of drug resistance to this type of treatment is often inevitable. The mechanisms of resistance to PD-L1 inhibitors can be attributed, in part, to an incomplete understanding of the regulation of PD-L1 protein expression. In this study, we identified the role of the E3 ligase GP78, also known as the Autocrine Motility Factor Receptor (AMFR), in the regulation of PD-L1 protein levels. We show that GP78 physically interacts with PD-L1, which is confirmed by IP and Western blotting and is supported by molecular modelling using AlphaFold2. Our modeling studies predict that the interface amino acids of the Ig1 domain of PD-L1 interact with the RING domain and a β-hairpin preceding the CUE domain of GP78. The crystal structure of the PD-1/PD-L1 complex reveals that the interaction with PD-1 is mediated by the Ig1 domain of PD-L1. Furthermore, proteasomal degradation of PD-L1 has been observed via GP78-mediated K48-linked ubiquitination, indicating a key regulatory role for GP78 in the downregulation of PD-L1. Because GP78 expression is inversely correlated with PD-L1 levels in cancer, these findings may have clinical implications for predicting tumor immune evasion and patient response to PD-1/PD-L1 blockade therapies. Taken together, these findings identify a previously unknown mechanism by which GP78 targets PD-L1 for ubiquitination and subsequent degradation in cancer cells, and suggest that blocking the interaction between PD-L1 and PD-1 by an E3 ligase is a novel strategy to improve immunotherapies for cancer patients. Full article

Insulin-like growth factor 1 (IGF-1) is an important endocrine and autocrine/paracrine factor that regulates various cellular responses in multiple biological systems. Its actions are mediated mainly via its binding to the type 1 IGF receptor (IGF-1R), while its bioactivity is also modulated by the IGF-binding proteins (IGFBPs). The IGF-1 system regulates cell growth, differentiation and energy metabolism and thus plays a crucial role in the modulation of key aspects of cancer biology, such as cancer cell growth, survival, transformation and invasion. The synthesis of IGF-1 is regulated, among other factors, by microRNAs (miRNAs), and it has been shown that the miRNA-induced regulation of IGF-1 is implicated in various stages of tumor development and/or progression in different types of cancer. The aim of this review was to identify and characterize the miRNA-induced regulation of the IGF-1 system in various types of cancer. It was revealed that many miRNAs can be used as potential biomarkers, while others may contribute to metastasis regulation, targeting components of the IGF-1 bioregulation system and being implicated in cancer staging and/or progression. Additional miRNAs and their role in IGF-1’s effects on other types of cancer have also been identified. Nevertheless, future studies are needed to expand the current knowledge on the role of miRNAs in the regulation of other components of the IGF-1 bioregulation system and in various types of cancer, contributing further to the characterization of the role of miRNAs and their target genes as pathogenic, therapeutic and diagnostic molecules for cancer in clinical practice. Full article

Adenosine triphosphate (ATP) is readily released into the extracellular space as an autocrine and paracrine purinergic signaling molecule. We originally reported a genetically encoded, fluorescent protein-based Förster Resonance Energy Transfer (FRET) biosensor that can detect micromolar levels of extracellular ATP. Through mutagenesis of the ATP binding site and optimization of cell-surface display, here we report the development of a second-generation biosensor called ECATS2 with greater than three-fold higher affinity for extracellular ATP. We found that the tether length between the FRET biosensor and the cell surface anchor is critical to optimization of its performance. Furthermore, we demonstrate that the improved sensor can detect extracellular ATP release upon hypoosmotic stress in cultured astrocytes. This new sensor contributes an improved tool for the ratiometric detection of extracellular ATP dynamics and purinergic signaling. Full article

Thyroid hormones are fundamental regulators of cellular differentiation, development, and metabolism. Their receptors are expressed in reproductive tissues, including the ovary, and dysregulation of thyroid hormone homeostasis has been associated with menstrual disturbances, infertility, and adverse pregnancy outcomes. Bone morphogenetic protein (BMP) ligands and their receptors are functionally involved in gonadotropin-induced ovarian steroidogenesis in an autocrine or paracrine manner. In this study, we examined the effects of thyroid hormones on steroidogenesis and their interplay with BMP signaling by using human granulosa-like KGN cells and primary rat granulosa cells (GCs). In KGN cells, triiodothyronine (T3) enhanced forskolin-induced expression of key steroidogenic enzymes involved in both estradiol biosynthesis and progesterone synthesis/metabolism, whereas thyroxine (T4) exerted minimal effects. In rat GCs, T3 treatment increased follicle-stimulating hormone (FSH)-stimulated estradiol production without altering progesterone output. T3 pretreatment attenuated BMP-6-induced phosphorylation of Smad1/5/9 in KGN cells, accompanied by upregulation of inhibitory Smad6 and downregulation of the BMP type II receptor. Conversely, BMP-6 stimulation elevated thyroid hormone receptor β expression, indicating reciprocal regulatory interactions between thyroid hormone and BMP pathways. Collectively, these findings suggest that thyroid hormones modulate steroidogenesis, at least in part, through suppression of endogenous BMP-6 signaling in granulosa cells. Full article

Schwann cells (SCs) are central players in peripheral nerve repair, facilitating axonal regrowth, remyelination, and modulation of the regenerative microenvironment. A pivotal driver of these functions is intracellular Ca²⁺ signaling, regulated by both endogenous Ca²⁺-permeable ion channels and engineered optogenetic actuators. Recent developments in optogenetics, particularly the application of Ca²⁺-permeable channelrhodopsins such as CapChR2, have enabled precise, light-controlled activation of SCs, allowing for targeted investigation of Ca²⁺-dependent pathways in non-neuronal cells. This review synthesizes emerging evidence demonstrating that optogenetically or endogenously induced Ca²⁺ influx in SCs leads to the release of a diverse set of neurotrophic and regulatory factors. These Ca²⁺-triggered secretomes modulate SC phenotypes and surrounding neurons, orchestrating axon regeneration and myelin repair via autocrine and paracrine mechanisms. We further discuss the roles of key endogenous Ca²⁺ channels—including transient receptor potential (TRP) channels and store-operated Ca²⁺ entry (SOCE; STIM/Orai)—in orchestrating SC activation under physiological and injury-induced conditions. By integrating insights from optogenetic manipulation and intrinsic signaling biology, this review proposes a conceptual framework in which Ca²⁺-triggered SC secretomes act as structural and functional scaffolds for nerve repair. We highlight how SC-derived factors shape the regenerative niche, influence adjacent neurons and glia, and modulate repair processes in peripheral and autonomic nerves. Full article

Vitamin D is converted to a steroid hormone by 25-hydroxylation in the liver and then by 1-hydroxylation in the kidney to produce the circulating hormone 1,25-dihydroxy vitamin D [1,25(OH₂D]. This hormone then functions in cells of the intestinal mucosa and in bone to maintain whole-body calcium homeostasis. Classical vitamin D deficiency thus results in defective calcium homeostasis. Yet vitamin D deficiency is often reported in people with various diseases not associated with whole-body calcium homeostasis. Because of these associations with vitamin D deficiency, clinical trials have been undertaken to determine whether raising vitamin D status could be an effective treatment for such diseases. However, the results of such clinical trials have largely been inconclusive. The steroidal autocrine or paracrine role of locally produced 1,25(OH)₂D in many nonrenal cells throughout the body is protective against a range of pathological changes. In vitamin D deficiency such protection becomes defective. A disease process may thus be initiated, and then progress, while vitamin D status is inadequate, as in the months of winter in temperate regions of the world. The subsequent correction of vitamin D deficiency may no longer be able to protect patients when the disease process has already become established. To maintain the many protective roles of vitamin D against disease, it is important that public health strategies aim to maintain adequate vitamin D status throughout the year. Full article

Atherosclerosis (AS) is directly linked to the aging and damage of endothelial cells (ECs). As ECs and vascular smooth muscle cells (VSMCs) age, more autocrine and paracrine signals are released, extending a vicious cycle of tissue aging and physiological dysfunction. The recruitment of immune cells to inflamed arteries, including coronary arteries, and an increase in the uptake of oxidised low-density lipoprotein (ox-LDL) by macrophages (foam cells) onto the tunica intima (intima) of coronary arteries restrict blood flow. The inability of aging and damaged ECs to accommodate vast changes in signalling molecules, many produced by gut microbiota, leads to a range of anatomical and physiological arterial anomalies. These include degradation of cardiovascular membranes, fibrosis, calcification, plaque formation, and an increasingly dysfunctional immune system. Changes in the gut microbiome of the elderly have a direct effect on the immune response, as the signalling molecules produced by gut microbiota target specific receptors on inflamed arteries. This review summarizes the anatomical and physiological changes associated with the aging of coronary arteries and emphasizes the conditions leading to AS. The importance of butyrate-producing gut microbiota in preventing AS, especially in the elderly, is discussed. Full article

Cancer-associated cachexia is a multifaceted wasting syndrome characterized by progressive loss of skeletal muscle mass, systemic inflammation, and metabolic dysfunction and is particularly prevalent in gastrointestinal cancers. Physical activity has emerged as a promising non-pharmacological intervention capable of attenuating key drivers of cachexia. Exercise modulates inflammatory signaling (e.g., IL-6/STAT3 and TNF-α/NF-κB), enhances anabolic pathways (e.g., IGF-1/Akt/mTOR), and preserves lean body mass and functional capacity. Exercise-induced signaling molecules, known as exerkines, are key mediators of these benefits, which are released during physical activity and act in an autocrine, paracrine, and endocrine manner. However, many of these molecules also exhibit context-dependent effects. While they exert protective, anti-inflammatory, or anabolic actions when transiently elevated after exercise, the same molecules may contribute to cachexia pathogenesis when chronically secreted by tumors or in systemic disease states. The biological effects of a given factor depend on its origin, timing, concentration, and physiological milieu. This review presents recent evidence from clinical and experimental studies to elucidate how physical activity and exerkines may be harnessed to mitigate cancer cachexia, with particular emphasis on gastrointestinal malignancies and their unique metabolic challenges. Full article

Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus that establishes lifelong latent infection in CD34⁺ haematopoietic stem and progenitor cells. A unique subset of viral genes is expressed during latency, which functions to modulate cellular mechanisms without supporting viral replication. One potential function of these genes is to regulate the differentiation state of latently infected CD34⁺ cells, thereby preventing their progression into antigen-presenting cells, e.g., dendritic cells. In this study, we first compared CD34⁺ cells that supported productive and latent infections using the RV-TB40-BAC_KL7-SE-EGFP virus. Over a seven-day time course, the proportion of latently infected CD34⁺ cell subsets within the myeloid progenitor population remained similar to that in the mock-infected control. However, starting from day 3 post-infection, there was an increase in the proportion of the early progenitor subsets, including haematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). In contrast, productively infected cells, which constituted less than 1% of the population, only accounted for a small portion of the myeloid progenitors. Importantly, our data revealed that the innate immune STING/p-TBK1/p-IRF3 pathway was activated in latently infected CD34⁺ cells, yet type I interferon (IFN) expression was decreased. This decrease was attributed to impaired p-IRF3 nuclear translocation, limiting the induction of an autocrine type I IFN response. However, treatment with IFN-β could induce myelopoiesis in latently infected cells. In summary, HCMV modulates a key component of the STING pathway to inhibit antiviral immune responses by decreasing the type I IFN-mediated cell differentiation of CD34⁺ progenitor cells. This study uncovered a new mechanism of latent HCMV-mediated regulation of the host cell differentiation response. Full article

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