Search Results (27)

Lipedema is a chronic, estrogen-sensitive adipose tissue disorder characterized by disproportionate subcutaneous fat accumulation, fibrosis, inflammation, and resistance to fat mobilization. Despite its high prevalence, lipedema remains poorly understood and frequently misdiagnosed. This narrative review proposes a novel pathophysiological model in which menopause acts as a critical turning point in the progression of lipedema, driven by estrogen receptor imbalance (ERβ predominance over ERα), intracrine estrogen excess, and adipose tissue dysfunction. We demonstrate how menopause amplifies adipose tissue dysfunction by suppressing ERα signaling; enhancing ERβ activity; and disrupting mitochondrial function, insulin sensitivity, and lipid oxidation. Concurrently, the upregulation of aromatase and 17β-HSD1, combined with the suppression of 17β-HSD2, sustains localized estradiol excess, perpetuating inflammation, fibrosis, and immune dysregulation. The molecular signature observed in lipedema closely mirrors that of other estrogen-driven gynecological disorders, such as endometriosis, adenomyosis, and uterine fibroids. Understanding these molecular mechanisms highlights the pivotal role of menopause as a catalyst for disease progression and provides a rationale for targeted therapeutic strategies, including hormonal modulation and metabolic interventions. This review reframes lipedema as an estrogen receptor-driven gynecological disorder, offering a new perspective to improve clinical recognition, diagnosis, and management of this neglected condition. Full article

The fibroblast growth factor (FGF) family includes 22 proteins in humans. Based on their mode of action, there are three families of FGFs: paracrine FGFs (FGF 1–10, 16, 17, 18, 20, and 22), intracrine FGFs (FGF 11–14), and endocrine FGFs (FGF 19, 21, and 23). FGF signaling plays critical roles in embryonic development, tissue repair, regeneration, angiogenesis, and metabolic regulation. They exert their cellular functions by binding, dimerization, and activation of transmembrane FGF receptors (FGFRs). Aberrant FGF signaling is associated with various human diseases. Thus, understanding the unique properties of FGF signaling will help to explore new therapeutic interventions against FGF-mediated pathological conditions. This review will discuss the differential expression and regulation of each FGF under normal human physiological and pathological conditions. Moreover, we will outline current therapeutics and treatment strategies that have been developed against FGF-related pathology. Full article

Peripheral tissues such as skin and adipose tissue play a crucial role in the intracrine formation of sex steroid hormones, complementing the endocrine and paracrine systems. These mechanisms involve the conversion of dehydroepiandrosterone (DHEA) and its sulfated form—DHEAS—into potent androgenic and estrogenic hormones. In vitro studies using tissue-specific cell lines are essential for unraveling the complex intracrine synthesis of these hormones. This study examined the formation of DHEA, androstenedione (A4), testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) from DHEAS in four cell lines: MCF-7 breast cancer cells, HaCaT keratinocytes, human dermal fibroblasts (HDF), and 3T3-L1 preadipocytes and mature adipocytes, using liquid chromatography–mass spectrometry (LC-MS/MS). MCF-7 cells converted DHEAS to DHEA, A4, T, E2, and DHT, while HaCaT cells produced all these steroids except DHT. Mature 3T3-L1 adipocytes produced DHEA, A4, T, and DHT. By contrast, HDF and 3T3-L1 preadipocytes converted DHEAS only to DHEA and A4. This study highlights the vital role of peripheral tissues, such as skin and adipose tissue, for the intracrine formation of sex hormones and underlines the crucial role of in vitro cell culture models to analyze such effects. The data shed light on the significant impact of androgen metabolism in skin and adipose tissue, which is of great relevance for aging, wound healing, obesity, and lipid metabolism. 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

Background/Objectives: Vitamin D is essential for bone health, immune function, and overall well-being. Numerous ecological, observational, and prospective studies, including randomized controlled clinical trials (RCTs), report an inverse association between higher serum 25-hydroxyvitamin D [25(OH)D; calcifediol] levels in various conditions, including cardiovascular disease, metabolic disorders such as diabetes and obesity, susceptibility to infection-related complications, autoimmune diseases, and all-cause mortality. Results: Vitamin D operates through two distinct systems. The endocrine system comprises the renal tubular cell-derived circulatory calcitriol, which primarily regulates calcium homeostasis and muscular functions. In contrast, intracellularly generated calcitriol in peripheral target cells is responsible for intracrine/paracrine system signaling and calcitriol–vitamin D receptor-mediated genomic effects. Government-appointed committees and health organizations have developed various clinical practice guidelines for vitamin D supplementation and management. However, these guidelines heavily relied on the 2011 Institute of Medicine (IoM) report, which focused solely on the skeletal effects of vitamin D, ignoring other body systems. Thus, they do not represent maintaining good overall health and aspects of disease prevention. Additionally, the IoM report was intended as a public health recommendation for the government and is not a clinical guideline. Discussion: New country- and regional-specific guidelines must focus on healthy nations through disease prevention and reducing healthcare costs. They should not be restricted to bone effect and must encompass all extra-skeletal benefits. Nevertheless, due to misunderstandings, medical societies and other governments have used faulty IoM report as a foundation for creating vitamin D guidelines. Consequently, they placed disproportionate emphasis on bone health while largely overlooking its benefits for other bodily systems, making current guidelines, including 2024, the Endocrine Society less applicable to the public. As a result, the utility of published guidelines has been significantly reduced for clinical practice and RCTs that designed on bone-centric are generate misleading information and remain suboptimal for public health and disease prevention. Conclusions: This review and its recommendations address the gaps in current vitamin D clinical practice guidelines and propose a framework for developing more effective, country and region-specific recommendations that capture the extra-skeletal benefits of vitamin D to prevent multiple diseases and enhance public health. Full article

Dehydroepiandrosterone and its sulfate are the most abundant steroids in humans. The metabolism of dehydroepiandrosterone can differ significantly depending on the organ or tissue and the subtype of steroid receptors expressed in it. For dehydroepiandrosterone, as a precursor of all steroid hormones, intracrine hormonal activity is inherent. This unique feature could be beneficial for the medicinal application, especially for the local treatment of various pathologies. At present, the clinical use of dehydroepiandrosterone is limited by its Intrarosa^® (Quebec city, QC, Canada) prasterone) 6.5 mg vaginal suppositories for the treatment of vaginal atrophy and dyspareunia, while the dehydroepiandrosterone synthetic derivatives Triplex, BNN 27, and Fluasterone have the investigational status for the treatment of various diseases. Here, we discuss the molecular targets of dehydroepiandrosterone, which open future prospects to expand its indications for use. Dehydroepiandrosterone, as an oral drug, is surmised to have promise in the treatment of osteoporosis, cachexia, and sarcopenia, as does 10% unguent for skin and muscle regeneration. Also, 5-androstenediol, a metabolite of dehydroepiandrosterone, is a promising candidate for the treatment of acute radiation syndrome and as an immunostimulating agent during radiopharmaceutical therapy. The design and synthesis of new 5-androstenediol derivatives with increased bioavailability may lead to the appearance of highly effective cytoprotectors on the pharmaceutical market. The argumentations for new clinical applications of these steroids and novel insights into their mechanisms of action are discussed. Full article

In recent years, numerous approaches have been developed to comprehend the molecular alterations underlying thyroid cancer (TC) oncogenesis and explore novel therapeutic strategies for TC. It is now well established that the neurokinin-1 receptor (NK-1R) is overexpressed in cancer cells and that NK-1R is essential for the viability of cancer cells. The binding of substance P (SP) to NK-1R in neoplastic cells plays a pivotal role in cancer progression by promoting neoplastic cell growth, protecting tumor cells from apoptosis, triggering invasion and metastasis through the enhanced migration of cancer cells, and stimulating endothelial cell proliferation for tumor angiogenesis. Remarkably, all types of human TC (papillary, follicular, medullary, anaplastic), as well as metastatic lesions, exhibit the overexpression of SP and NK-1R compared to the normal thyroid gland. TC cells synthesize and release SP, which exerts its multiple functions through autocrine, paracrine, intracrine, and neuroendocrine processes, including the regulation of tumor burden. Consequently, the secretion of SP from TC results in increased SP levels in plasma, which are significantly higher in TC patients compared to controls. Additionally, NK-1R antagonists have demonstrated a dose-dependent antitumor action. They impair cancer cell proliferation on one side and induce apoptosis of tumor cells on the other side. Furthermore, it has been demonstrated that NK-1R antagonists inhibit neoplastic cell migration, thereby impairing both invasiveness and metastatic abilities, as well as angiogenesis. Given the consistent overexpression of NK-1R in all types of TC, targeting this receptor represents a promising therapeutic approach for TC. Therefore, NK-1R antagonists, such as the drug aprepitant, may represent novel drugs for TC treatment. Full article

Periodontal ligament fibroblasts (PdLFs) exert important functions in oral tissue and bone remodeling following mechanical forces, which are specifically applied during orthodontic tooth movement (OTM). Located between the teeth and the alveolar bone, mechanical stress activates the mechanomodulatory functions of PdLFs including regulating local inflammation and activating further bone-remodeling cells. Previous studies suggested growth differentiation factor 15 (GDF15) as an important pro-inflammatory regulator during the PdLF mechanoresponse. GDF15 exerts its effects through both intracrine signaling and receptor binding, possibly even in an autocrine manner. The extent to which PdLFs are susceptible to extracellular GDF15 has not yet been investigated. Thus, our study aims to examine the influence of GDF15 exposure on the cellular properties of PdLFs and their mechanoresponse, which seems particularly relevant regarding disease- and aging-associated elevated GDF15 serum levels. Therefore, in addition to investigating potential GDF15 receptors, we analyzed its impact on the proliferation, survival, senescence, and differentiation of human PdLFs, demonstrating a pro-osteogenic effect upon long-term stimulation. Furthermore, we observed altered force-related inflammation and impaired osteoclast differentiation. Overall, our data suggest a major impact of extracellular GDF15 on PdLF differentiation and their mechanoresponse. Full article

The sodium-dependent organic anion transporter (SOAT, gene symbol SLC10A6) specifically transports 3′- and 17′-monosulfated steroid hormones, such as estrone sulfate and dehydroepiandrosterone sulfate, into specific target cells. These biologically inactive sulfo-conjugated steroids occur in high concentrations in the blood circulation and serve as precursors for the intracrine formation of active estrogens and androgens that contribute to the overall regulation of steroids in many peripheral tissues. Although SOAT expression has been detected in several hormone-responsive peripheral tissues, its quantitative contribution to steroid sulfate uptake in different organs is still not completely clear. Given this fact, the present review provides a comprehensive overview of the current knowledge about the SOAT by summarizing all experimental findings obtained since its first cloning in 2004 and by processing SOAT/SLC10A6-related data from genome-wide protein and mRNA expression databases. In conclusion, despite a significantly increased understanding of the function and physiological significance of the SOAT over the past 20 years, further studies are needed to finally establish it as a potential drug target for endocrine-based therapy of steroid-responsive diseases such as hormone-dependent breast cancer. Full article

The current prevailing paradigm in the renin-angiotensin system dictates that most, if not all, biological, physiological, and pathological responses to its most potent peptide, angiotensin II (Ang II), are mediated by extracellular Ang II activating its cell surface receptors. Whether intracellular (or intracrine) Ang II and its receptors are involved remains incompletely understood. The present study tested the hypothesis that extracellular Ang II is taken up by the proximal tubules of the kidney by an AT₁ (AT_1a) receptor-dependent mechanism and that overexpression of an intracellular Ang II fusion protein (ECFP/Ang II) in mouse proximal tubule cells (mPTC) stimulates the expression of Na⁺/H⁺ exchanger 3 (NHE3), Na⁺/HCO₃^- cotransporter, and sodium and glucose cotransporter 2 (Sglt2) by AT_1a/MAPK/ERK1/2/NF-kB signaling pathways. mPCT cells derived from male wild-type and type 1a Ang II receptor-deficient mice (Agtr1a^-/-) were transfected with an intracellular enhanced cyan fluorescent protein-tagged Ang II fusion protein, ECFP/Ang II, and treated without or with AT₁ receptor blocker losartan, AT₂ receptor blocker PD123319, MEK1/MEK2 inhibitor U0126, NF-кB inhibitor RO 106-9920, or p38 MAP kinase inhibitor SB202196, respectively. In wild-type mPCT cells, the expression of ECFP/Ang II significantly increased NHE3, Na⁺/HCO₃^-, and Sglt2 expression (p < 0.01). These responses were accompanied by >3-fold increases in the expression of phospho-ERK1/2 and the p65 subunit of NF-кB (p < 0.01). Losartan, U0126, or RO 106-9920 all significantly attenuated ECFP/Ang II-induced NHE3 and Na⁺/HCO₃^- expression (p < 0.01). Deletion of AT₁ (AT_1a) receptors in mPCT cells attenuated ECFP/Ang II-induced NHE3 and Na⁺/HCO₃^- expression (p < 0.01). Interestingly, the AT₂ receptor blocker PD123319 also attenuated ECFP/Ang II-induced NHE3 and Na⁺/HCO₃^- expression (p < 0.01). These results suggest that, similar to extracellular Ang II, intracellular Ang II may also play an important role in Ang II receptor-mediated proximal tubule NHE3, Na⁺/HCO₃^-, and Sglt2 expression by activation of AT_1a/MAPK/ERK1/2/NF-kB signaling pathways. Full article

Parathyroid-hormone-related protein (PTHrP) is a protein with a long history of association with bone metastatic cancers. The paracrine signaling of PTHrP through the parathyroid hormone receptor (PTHR1) facilitates tumor-induced bone destruction, and PTHrP is known as the primary driver of humoral hypercalcemia of malignancy. In addition to paracrine signaling, PTHrP is capable of intracrine signaling independent of PTHR1 binding, which is essential for cytokine-like functions in normal physiological conditions in a variety of tissue types. Pre-clinical and clinical studies evaluating the role of PTHrP in breast cancer have yielded contradictory conclusions, in some cases indicating the protein is tumor suppressive, and in other studies, pro-growth. This review discusses the possible molecular basis for the disharmonious prognostic indications of these studies and highlights the implications of the paracrine, intracrine, and nuclear functions of the protein. This review also examines the current understanding of the functional domains of PTHrP and re-evaluates their role in the unique context of the breast cancer environment. This review will expand on the current understanding of PTHrP by attempting to reconcile the functional domains of the protein with its intracrine signaling in cancer. Full article

PTHrP exerts its effects by binding to its receptor, PTH1R, a G protein-coupled receptor (GPCR), activating the downstream cAMP signaling pathway. As an autocrine, paracrine, or intracrine factor, PTHrP has been found to stimulate cancer cell proliferation, inhibit apoptosis, and promote tumor-induced osteolysis of bone. Despite these findings, attempts to develop PTHrP and PTH1R as drug targets have not produced successful results in the clinic. Nevertheless, the efficacy of blocking PTHrP and PTH1R has been shown in various types of cancer, suggesting its potential for therapeutic applications. In light of these conflicting data, we conducted a comprehensive review of the studies of PTHrP/PTH1R in cancer progression and metastasis and highlighted the strengths and limitations of targeting PTHrP or PTH1R in cancer therapy. This review also offers our perspectives for future research in this field. Full article

Tissue-resident macrophages (Mø) play tissue/organ-specific roles, and the physiological/pathological implications of uterine Mø in fertility and infertility are not yet fully understood. Herein, we report a simple propagation method for tissue-resident Mø by mixed culture with the respective tissue/organ-residing cells as the niche. We successfully propagated mouse uterine Mø by mixed culture with fibroblastic cells that exhibited properties of endometrial stromal cells. Propagated mouse uterine Mø were CD206- and arginase-1-positive; iNOS- and MHC-II-negative, indicating M2 polarization; and highly phagocytic, similar to endometrial Mø. Furthermore, uterine Mø were observed to express steroidogenic molecules including SRD5A1 and exhibited gap junction formation, likely with endometrial stromal cells. Accordingly, uterine Mø propagated by mixed culture may provide a new tool for studying immune–endocrine interactions related to fertility and infertility, particularly androgen’s intracrine actions in preparing the uterine tissue environment to support implantation and pregnancy as well as in the etiology of endometriosis. Full article

Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of MET and HGF genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention. Full article

Cardiovascular disease (CVD) is the leading cause of death in the world. Hypertension is a serious medical problem not only in adults but also in children and adolescents. The renin-angiotensin-aldosterone system (RAAS) is one of the most important mechanisms regulating blood pressure and the balance of water and electrolytes. According to the latest reports, RAAS acts not only on endocrine but also on paracrine, autocrine, and intracrine. Moreover, RAAS has a component associated with hypotension and cardioprotective effects. These components are called alternative pathways of RAAS. The most important peptide of the alternative pathway is Ang 1–7, which is related to the Mas receptor. Mas receptors have widely known antihypertension properties, including vasodilatation, the release of nitric oxide, and increased production of anti-inflammatory cytokines. Another interesting peptide is angiotensin A, which combines the properties of the classical and alternative pathways. No less important components of RAAS are the proteolytic enzymes angiotensin convertase enzyme type 1 and 2. They are responsible for the functioning of the RAAS system and are a hypertension therapeutic target. Also involved are tissue-specific enzymes that form a local renin-angiotensin system. Currently, a combination of drugs is used in hypertension treatment. These drugs have many undesirable side effects that cannot always be avoided. For this reason, new treatments are being sought, and the greatest hope comes from the ACE2/ang 1–7/MasR axis. Full article