Search Results (130)

Global demand for sustainable protein has intensified amid environmental, public health, and ethical concerns surrounding conventional animal agriculture. Edible mushrooms have emerged as promising next-generation protein sources, delivering 19–35% protein (dry weight) with complete essential amino acid profiles and digestibility rates of 60–80%. Beyond protein, mushrooms provide bioactive compounds, including β-glucans, ergothioneine, phenolic acids, and vitamin D₂, supporting immunomodulatory, antioxidant, and anti-inflammatory functions. Enzymatically derived bioactive peptides further demonstrate antihypertensive and antimicrobial activity. This review systematically examines mushroom protein properties, processing technologies, and product performance across three application categories: meat analogs, functional snacks, and beverages. Advanced processing technologies including high-moisture extrusion, ultrasonic-assisted extraction, and microencapsulation have improved bioactive preservation and digestibility. From an environmental perspective, mushroom cultivation requires 85–90% less water and land than animal agriculture, with 80% fewer greenhouse gas emissions. However, critical gaps remain: extraction efficiency varies 3-fold across studies, only 15–23% of commercial products are supported by clinical trials, and techno-economic analyses are largely absent. Standardized processing protocols, large-scale clinical validation, and harmonized quality standards are essential to establish mushrooms as viable, commercially scalable protein alternatives. Full article

Vitamin D signaling via the vitamin D receptor (VDR) regulates calcium–phosphate homeostasis and extensive gene programs controlling cell proliferation, differentiation, immune tone, and metabolism. However, systemic use of the natural agonist 1α,25-dihydroxyvitamin D₃ (calcitriol) for extraskeletal indications is limited by dose-limiting hypercalcemia. This review summarizes VDR biology and the structural basis of ligand action, emphasizing how ligand-induced repositioning of helix 12 and altered coregulator recruitment can be exploited to engineer selective VDR modulators. We highlight medicinal chemistry strategies spanning secosteroidal analogs with side-chain or ring modifications and emerging non-seco scaffolds and discuss clinically established agents (e.g., calcipotriol and paricalcitol) alongside experimental “super-agonists”, partial agonists, and antagonists designed to widen the therapeutic window. Finally, we discuss current evidence for VDR targeting across cancer, metabolic disease, fibrosis, and immune-inflammatory disorders, including mechanisms of resistance such as dysregulated vitamin D metabolism and epigenetic repression. Structural and epigenomic insights are positioning next-generation VDR ligands as tissue- and pathway-biased therapeutics that may enable safer, mechanism-guided translation beyond bone and mineral indications. Full article

Vitamin D (VD), a fat-soluble prohormone, exerts diverse effects on cellular proliferation, differentiation, and immune modulation, with accumulating evidence supporting its role in pancreatic ductal adenocarcinoma (PDAC) biology. Experimental studies demonstrate that VD and its analogs can inhibit PDAC cell growth and remodel the tumor microenvironment, potentially contributing to tumor suppression. Epidemiological data indicate that VD deficiency is prevalent among PDAC patients and is associated with increased inflammatory biomarkers and reduced overall survival, particularly in early-stage disease. However, meta-analyses reveal inconsistent associations between circulating 25-hydroxyvitamin D levels and PDAC incidence, while higher levels may be linked to improved survival but not reduced risk of disease onset. The clinical utility of VD supplementation for PDAC prevention or treatment remains uncertain, with ongoing debate regarding optimal dosing, timing, and patient selection. This narrative review synthesizes current evidence on the mechanistic, epidemiological, and clinical relevance of VD in PDAC. Particular emphasis is placed on existing knowledge gaps and the need for well-designed clinical trials to clarify the potential therapeutic and prognostic role of VD in pancreatic cancer. Full article

Vitamin D, a fat-soluble vitamin functioning as a hormone via the vitamin D receptor (VDR), is critical for calcium homeostasis and bone health. Vitamin D deficiency is linked to nutritional rickets, osteomalacia, and increased risk of non-communicable diseases such as cancer and diabetes. While serum 25(OH)D₃ is used to assess vitamin D status, its active form, 1α,25(OH)₂D₃, exerts context-dependent effects on calcium metabolism. Nonetheless, the therapeutic utility of native vitamin D is limited in certain pathologies. In chronic kidney disease (CKD), the renal conversion of 25(OH)D₃ to active 1α,25(OH)₂D₃ is compromised, necessitating the use of active synthetic analogs to bypass this metabolic defect. Furthermore, for dermatological and oncological disorders requiring supraphysiological dosing, synthetic analogs have been designed to dissociate beneficial anti-proliferative effects from the severe hypercalcemia induced by high-dose 1α,25(OH)₂D₃. VDR mediates transcriptional responses, modulated by co-regulators and chromatin remodeling complexes. Recent discoveries include non-genomic VDR pathways and SCAP (SREBP cleavage-activating protein)-dependent signaling that modulate lipid metabolism. Despite promising preclinical results, most synthetic VDR agonists fail to show efficacy in cancer therapy due to calcemic toxicity. However, compounds like eldecalcitol are effective in osteoporosis, especially in low-calcium-intake populations. Selective VDR modulators, akin to SERMs, exhibit tissue-specific effects. Moreover, novel VDR antagonists such as ZK168281 demonstrate potential to suppress hypercalcemia and vitamin D toxicity by inhibiting transcriptional activity and altering VDR localization. These agents may enable anti-inflammatory or anti-proliferative actions without calcemic risks. Understanding the nuanced biology of vitamin D and its analogs offers new avenues for therapeutic intervention beyond bone metabolism, including managing hyperparathyroidism, granulomatous diseases, and inflammation-associated disorders. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of cartilage, as well as by extra-articular manifestations. Rheumatoid nephropathy is a common complication of RA and its principal target is the renal corpuscle. Vitamin D and its analogs exert immunomodulatory actions throughout the body due to the widespread of their receptors. Our study aimed to compare the effects of cholecalciferol (vitamin D3) and alfacalcidol on renal corpuscle changes in pristane-induced RA model following a 28-day treatment, using geometric morphometrics. Forty female Wistar rats (190–210 g; 12–13 weeks old) were randomly assigned to four groups: the control (Cont) group (n = 10) received saline i.c., the PIA group (n = 10) was administered pristane i.c., PIA-ALF group (n = 10) was administered pristane i.c. and alfacalcidol orally, and the PIA-CH group (n = 10) was injected i.c. with pristane and received cholecalciferol orally. Pristane administration was used for RA induction. At the end of the experiment, the left kidneys were removed and processed by standard histological procedures for geometric morphometric analysis. Geometric morphometric analysis demonstrated that, compared with the control group, the architecture of the renal corpuscles was altered in the PIA (p < 0.0001) and PIA-CH (p = 0.0065) groups. In contrast, no statistically significant differences were observed in the PIA-ALF group (p = 0.3011). Geometric morphometric analysis demonstrated that alfacalcidol, but not cholecalciferol, exertedaprotective effect on the renal corpuscle architecture in pristane-induced rheumatoid arthritis in rats. Full article

Management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) has evolved dramatically over the past five decades, driven by discoveries that have fundamentally reshaped our understanding of the vitamin D endocrine system and its role in disease progression. This review synthesizes the key pathophysiological insights and clinical evidence underlying three critical paradigm shifts. The first shift moved beyond simple calcitriol replacement with the development of selective vitamin D receptor activators (VDRAs) designed to minimize hypercalcemia while maximizing PTH suppression. Crucially, these analogs revealed unexpected survival benefits, suggesting protective VDR actions extending beyond mineral metabolism. The second shift recognized the profound prevalence and independent mortality risk associated with nutritional vitamin D (25(OH)D) deficiency in CKD. This highlighted the kidney’s complex role in maintaining systemic 25(OH)D supply and the importance of extrarenal vitamin D activation, although optimal assessment, targets, and supplementation strategies remain highly controversial due to CKD-specific pathophysiology (e.g., megalin loss, impaired uptake, obesity effects) and complex dosing paradoxes. The third, and most impactful, shift centers on the FGF23-Klotho axis. Pathologically high FGF23 is now established as a direct cardiovascular and skeletal toxin, acting via Klotho-independent pathways in CKD, while the profound deficiency of the protective, anti-aging hormone Klotho exacerbates systemic damage (inflammation, oxidative stress, impaired autophagy). This creates a major therapeutic dilemma, as VDRAs induce protective Klotho but worsen toxic FGF23, while calcimimetics do not increase FGF23 but offer no Klotho benefit. Furthermore, this complex interplay is obscured by significant limitations in accurately measuring FGF23 isoforms, soluble Klotho, and true vitamin D status. These paradigm shifts reveal a complex pathophysiology far beyond simple PTH control, demanding a move towards nuanced, potentially combined therapeutic strategies that balance FGF23 burden with Klotho preservation. Overcoming the profound diagnostic limitations to accurately monitor this axis and guide personalized therapy represents the critical next frontier in improving outcomes for patients with CKD. Full article

Hyperparathyroidism is a serious complication of chronic kidney disease (CKD) and can occur in patients not on renal replacement therapy, during dialysis therapy, or after kidney transplantation. The disease leads to an increased risk of cardiovascular events, bone loss, and fractures. Cinacalcet is a widely used drug, but its effectiveness in treating hyperparathyroidism in selected stages of chronic kidney disease remains unclear. This critical review aims to integrate findings from meta-analyses and clinical trials to assess optimal therapeutic strategies in patients suffering from CKD, who are non-dialysis-dependent, dialysis-dependent, and after kidney transplantation. The authors reviewed eligible studies, including meta-analyses, randomized controlled trials, and observational studies assessing biochemical outcomes, cardiovascular, bone, and survival outcomes with cinacalcet. Cinacalcet effectively reduced serum parathyroid hormone (PTH), calcium, and phosphorus across all CKD stages, particularly in hemodialysis patients. Combination therapy with vitamin D analogs enhanced biochemical control without increasing adverse events, although mild, transient hypocalcemia and gastrointestinal symptoms were common. In kidney transplant recipients, parathyroidectomy achieved greater normalization of PTH and calcium. Cinacalcet has been shown to reduce mortality in patients on hemodialysis and peritoneal dialysis. Full article

Acute myeloid leukemia (AML) is an aggressive and often fatal hematopoietic malignancy, diagnosed predominantly in the elderly. The five-year survival of patients with AML is as low as 30%. Differentiation therapy of a subtype of AML, named acute promyelocytic leukemia (APL), using all-trans retinoic acid (ATRA) was the most successful example of a targeted therapy against AML. Epigenetic-based differentiation therapies for other subtypes of AML are also showing improvements in response and in survival rates. Thus, in this study, we investigated a potential differentiation therapy with a combination of 1,25-dihydroxyvitamin D (1,25D) analog (named PRI5202) and low concentration of Fludarabine. We show that such a combination elicits immunostimulatory and pro-differentiation effects in AML cells, specifically in those with activating mutations in fibroblast growth factor receptor (FGFR) and Janus kinase (JAK) pathways. We show here that both PRI5202 and Fludarabine are potent activators of the transcription of many innate immunity-related genes, and that, in combination, their effects are in many aspects synergistic. We propose that such a low-intensity regimen may be suitable for older patients with AML, who are unfit for intensive chemotherapy. We also present data indicating that PRI5202 induces myeloid differentiation in blasts from patients with myelodysplastic syndrome (MDS), and we propose to further investigate PRI5202 as a differentiation therapy for patients suffering from MDS. Full article

Rare diseases are conditions that affect up to 65 people per 100,000 individuals. They are also known as “orphan diseases”, because they attract limited interest from researchers and pharmaceutical industries. Epidermolysis bullosa (EB), ichthyosis, Hailey–Hailey disease (HHD), Darier disease (DD), erythrokeratoderma, porokeratosis, inflammatory linear verrucous epidermal nevus (ILVEN) and piebaldism are examples of rare genetic skin diseases with few approved treatments. Topical treatments are the principal approach for rare dermatological diseases, and it can be useful to manage the symptoms or the patophysiology of these diseases. This study aimed to conduct a comprehensive review of the topical treatments of EB, ichthyosis, HHD, DD, erythrokeratodermias, porokeratosis, ILVEN, and piebaldism. The search was performed across the SciELO, MEDLINE^®/PubMed^®, Embase and Cochrane databases. This review identified porokeratosis, EB, and congenital ichthyosis as the rare genodermatoses with the highest number of reported studies and topical treatment options. In contrast, conditions such as piebaldism, erythrokeratodermia, and HHD have fewer reported topical interventions. For most rare genetic dermatological diseases, treatment aims to improve quality of life and control clinical signals and symptoms. Creams, gels, and ointments are frequently used as the main pharmaceutical approaches, and several pharmacological classes are employed, including keratolytics, retinoids, vitamin D analogs, topical corticosteroids, calcineurin inhibitors, and cytotoxic or antiproliferative agents. This review highlights the potential of off-label use of topical therapies as cost-effective alternatives in the treatment of rare genetic skin disorders. It also reinforces the critical role of compounded medicines in allowing for dose optimization, drug repurposing, and formulation adjustments, personalizing treatment to achieve improved therapeutic outcomes. Full article

Introduction: Transient osteoporosis of the hip (TOH) is a rare, self-limiting disorder characterized by acute hip pain and reversible osteopenia. The aim of this study was to evaluate clinical outcomes following treatment with Neridronate, Clodronic Acid, Cholecalciferol, and pulsed electromagnetic field therapy (PEMF). Materials and Methods: A total of 45 patients presenting with non-traumatic hip pain were screened using a standardized diagnostic protocol. Magnetic resonance imaging (MRI) identified 8 patients (17.8%) with transient osteoporosis of the hip (TOH), who were subsequently enrolled in this analysis. Pain was evaluated using the Visual Analog Scale (VAS). Patients received a three-phase therapeutic protocol, including pharmacological therapy and PEMF. Clinical evaluations using the Harris Hip Score (HHS) were performed monthly, and follow-up MRI was conducted at the end of treatment. Results: We identified 8 cases of TOH (17.8%); the mean baseline HHS for these patients was 68.5 (range 51–83, SD 10.36). Pain reduction became evident within the first month of treatment. At the end of treatment, clinical improvement was observed in 7 patients, with mean HHS increasing to 88.0 (range 67–95, SD 8.84). Post-treatment MRI demonstrated complete resolution of bone marrow edema in all patients. One patient developed avascular necrosis despite therapy and required surgical intervention. Conclusions: TOH remains a controversial condition in terms of diagnosis and treatment. Early diagnosis and timely intervention are essential to progression to osteonecrosis. A combined therapeutic approach using bisphosphonates, vitamin D, and PEMF appears effective in reducing symptoms, promoting bone healing, and ensuring good patient compliance. Full article

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease in which environmental factors modulate genetically determined immune dysregulation. Vitamin D has emerged as a plausible modifier of disease expression because its active metabolite signals through the vitamin D receptor on innate and adaptive immune cells and influences antigen presentation, cytokine balance, and lymphocyte differentiation. This narrative review synthesizes current evidence on vitamin D status and supplementation in SLE with attention to organ-specific domains. Observational studies consistently report high rates of hypovitaminosis D in SLE and associations with less favorable clinical profiles, including higher global and renal disease activity, adverse cardiometabolic features, greater infection vulnerability, and neuropsychiatric manifestations. Preclinical models demonstrate neuroprotective and barrier-stabilizing actions of vitamin D analogs, supporting biological plausibility. Interventional trials indicate that supplementation safely corrects deficiency and shows signals of benefit for selected outcomes (e.g., modest activity reductions or fatigue in specific contexts), although effects on interferon signatures, complement, and autoantibodies are heterogeneous and often limited. Overall, current evidence supports optimization of vitamin D status as a low-risk adjunct in comprehensive SLE care while highlighting the need for adequately powered, organ-focused randomized trials using standardized measurements and prespecified endpoints to define causality, therapeutic targets, and long-term safety. Full article

Background/Objectives: Systemic toxicities to key organs like the heart, liver, and kidneys impair the efficacy of chemotherapy in cancer treatment. These toxicities are caused by oxidative stress, inflammation, mitochondrial malfunction and ferroptosis, causing clinical morbidity and possibly impaired adherence to treatment. This review, also, examines how magnesium, selenium, zinc and vitamin D protect against chemotherapy-induced cardiotoxicity, hepatotoxicity and nephrotoxicity. Methodology: A complete literature search of PubMed (MEDLINE), Scopus, Cochrane Library and Embase was used to synthesize data till 29 June 2025. Studies included randomized and non-randomized trials, cohort studies, case series (≥3 patients), and relevant systematic reviews. To contextualize pathways, preclinical in vivo and in vitro studies were studied independently. Patients undergoing systemic chemotherapy and magnesium, selenium, zinc or vitamin D therapies were eligible. Supplementation’s safety and organ-specific toxicity were investigated. Results: Magnesium protected against cisplatin-induced nephrotoxicity via modulating renal transporters and oxidative defenses across chemotherapy regimens. Selenium supplementation has strong antioxidant and anti-inflammatory characteristics, especially in avoiding cardiac and hepatic injury, although its nephroprotective potential was formulation-dependent. Zinc’s activity was connected to metallothionein-mediated redox stabilization, inflammatory regulation, and cardiac and hepatic resilience. Vitamin D and its analogs reduced cardiotoxicity and nephrotoxicity through mitochondrial preservation and immunomodulatory signaling. Conclusions: To date, magnesium, selenium, zinc, and vitamin D have been shown to reduce chemotherapy-related organ toxicities. Preclinical studies are promising, but randomized clinical trials are needed to prove therapeutic effectiveness and oncologic safety. Full article

The clinical use of 1,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D₃, is limited by its calcemic side effects and rapid metabolic degradation. To overcome these limitations, we designed novel vitamin D analogs with extended, rigidified, and branched side chains. Among them, PRI-1938, featuring a 5,6-trans triene system and 22,24-all-trans side-chain geometry, demonstrated markedly enhanced resistance to enzymatic catabolism. In vitro assays revealed that metabolic conversion of PRI-1938 by the nonselective cytochrome P450 3A4 (CYP3A4) enzyme was ca. 4-fold lower than that of the previously obtained PRI-1906 and over 9-fold lower than 1,25D3. All new analogs, including PRI-1927 and PRI-1937, exhibited significantly higher stability toward mitochondrial cytochrome P450 24A1 (CYP24A1), the vitamin D-selective catabolic enzyme, than that of 1,25D3. Molecular modeling and quantum mechanical calculations indicated that PRI-1938 adopts a highly stable conformation in the CYP24A1 active site, stabilized by four hydrogen bonds and multiple hydrophobic interactions. The spatially optimized interaction network reduces access to the catalytic heme, resulting in the lowest observed metabolic conversion. These findings highlight the critical role of the side-chain geometry in modulating metabolic stability and support the further development of PRI-1938 as a promising anticancer vitamin D analog. Full article

Plastic pollution is one of the leading global problems of modern society. The growing demand for and production of plastic polymers has caused bisphenol A (BPA) and its emergent substitute molecules bisphenol S and F (BPS and BPF) to be present in water, food, and soil worldwide, exposing humans to endocrine disruptors. Exposure to these compounds has been associated with pathologies such as diabetes, obesity, hypertension, and psychiatric disorders. Interestingly, hypovitaminosis D (or low 25(OH)D) is also associated with this class of diseases. Therefore, the present work, for the first time, explores the relationship patterns between urinary bisphenols (BPs) and low 25(OH)D in a large general cohort (NHANES 13–16). Descriptive statistical analyses, comparative analyses, linear regressions, and binomial and multinomial logistic regressions were performed. Descriptive and comparative analysis, and simple linear regressions, showed different trends between BPs, and binomial logistic regressions showed that only BPS is a risk factor of low 25(OH)D, independently of age, BMI, gender, diabetes, dyslipidemia, smoking, and vitamin supplements consumption; odds ratio (95% confidence interval) of 1.10 (1.04–1.17). The different trend patterns observed in urinary bisphenols show that, despite being structurally similar molecules and potential analogs, they may affect the body in different ways. From an integrated perspective, this could represent an even greater potential threat than that posed by BPA alone. Future integrated studies will be required to further explore and clarify this emerging paradigm. Full article

Vitiligo is a chronic autoimmune dermatosis defined by selective melanocyte depletion and patchy depigmentation. IFN–γ-driven recruitment of autoreactive CD8⁺ T cells and induction of melanocyte apoptosis are central to its pathogenesis. Current therapies—including UVB phototherapy, tacrolimus, vitamin D3 analogs, and surgical methods—show limited and inconsistent efficacy. Emerging treatments like JAK inhibitors and WNT activators offer potential but require further validation. Translational progress is hindered by a lack of scalable human models. Here, we describe a tunable in vitro vitiligo platform in which human iPSC-derived melanocytes (iMc) are co-cultured with keratinocytes on Matrigel and exposed to precise graded IFN-γ concentrations. Our data revealed dose-dependent decreases in iMc survival and dendritic structure, faithfully mirroring derived melanocyte pathology. Leveraging this platform, we first evaluated the short-term efficacy of the ROCK inhibitor Y27632 under early-stage patient IFN-γ concentrations representative of patient lesional thresholds. At three days, Y27632 significantly upregulated adhesion molecules E-cadherin and DDR1, and two central factors—ET1 and bFGF. Importantly, ROCK inhibition reversed dendritic retraction and improved overall viability of iMc-keratinocytes. These findings position ROCK blockade as a promising adjunctive strategy and establish a pre-clinical platform for evaluating combination therapies for durable pigment restoration. Full article