Search Results (60)

Vitamin D is a secosteroid hormone traditionally recognized for its role in bone and mineral metabolism, but it is increasingly understood to also function as an important immunomodulator influencing susceptibility to and outcomes of infectious diseases. This narrative review summarizes current evidence on the immunological, clinical, and preventive effects of vitamin D in the context of novel coronavirus disease (COVID-19), post-acute sequelae of SARS-CoV-2 infection (long COVID), and influenza. Mechanistically, vitamin D enhances innate immune defenses through the induction of antimicrobial peptides, including cathelicidin and defensins, and modulates adaptive immunity by suppressing maladaptive Th1/Th17 responses while promoting regulatory T-cell activity. Observational studies have frequently associated vitamin D deficiency with more severe COVID-19 outcomes; however, these associations may be influenced by confounding factors and reverse causality. Some meta-analyses suggest that vitamin D supplementation reduced rates of intensive care unit admission and ventilatory support, particularly among older adults and individuals with low baseline serum 25-hydroxyvitamin D concentrations. Emerging evidence also indicates that inadequate vitamin D status may be associated with an increased risk and symptom burden of long COVID, although causality has not been established. In the case of influenza, a limited number of randomized controlled trials (RCTs) and meta-analyses report a modest but statistically significant reduction in infection risk, especially with daily or weekly vitamin D supplementation in populations with low baseline vitamin D levels. Clinical guidelines consistently recommend maintaining adequate vitamin D status for general health but do not endorse high-dose vitamin D as a treatment for COVID-19 due to inconsistent trial findings. Overall, vitamin D should not be considered a standalone therapeutic agent; rather, maintaining sufficient vitamin D levels represents a low-risk, potentially beneficial strategy to support immune resilience against respiratory viral infections. Full article

Vitamin D, a fat-soluble secosteroid traditionally recognized for skeletal health, exerts pleiotropic effects on cardiovascular physiology and disease. Circulating 25-hydroxyvitamin D [25(OH)D], the principal biomarker of vitamin D status, is frequently suboptimal worldwide, particularly in older adults, individuals with darker skin pigmentation, and populations at higher latitudes. Observational studies consistently associate low 25(OH)D concentrations with increased risk of hypertension, atherosclerosis, myocardial infarction, heart failure, arrhythmias, stroke, and cardiovascular mortality. Mechanistic investigations have revealed that vitamin D modulates cardiomyocyte calcium handling, endothelial function, vascular smooth muscle proliferation, inflammation, oxidative stress, and renin–angiotensin–aldosterone system activity, establishing biologically plausible links to cardiovascular outcomes. Despite these associations, large randomized trials of vitamin D supplementation have failed to demonstrate reductions in major cardiovascular events, likely due to heterogeneity in baseline status, dosing regimens, intervention timing, genetic variability, and underlying comorbidities. Vitamin D may function more effectively as a biomarker of cardiovascular risk rather than a universal therapeutic agent, with deficiency reflecting systemic vulnerability rather than acting as a dominant causal factor. Emerging evidence supports precision approaches targeting individuals with severe deficiency, high renin activity, early endothelial dysfunction, or specific genetic profiles, potentially in combination with lifestyle or pharmacologic interventions. Future research should focus on defining optimal dosing strategies, intervention timing, and mechanistic biomarkers to identify subpopulations most likely to benefit, integrating vitamin D therapy into multifaceted cardiovascular prevention frameworks. This systematic review synthesizes molecular, observational, and clinical trial evidence, critically evaluating the current understanding of vitamin D in cardiovascular medicine and highlighting opportunities for targeted, personalized interventions. Vitamin D represents a complex, context-dependent modulator of cardiovascular health, offering both prognostic insight and potential therapeutic value when appropriately applied. Full article

Broodstock nutrition is a key determinant of reproductive output in marine fishes because lipids support yolk formation, embryonic development, and early larval viability. However, the allocation of lipid classes between fertilized eggs and the egg envelope (chorion) remains poorly characterized for many tropical species. In this study, we performed a comparative lipidomic analysis of dechorionated fertilized egg contents and isolated chorion from three tropical marine fishes (Trachinotus ovatus, Platax teira, and Plectropomus leopardus) using UHPLC–Q Exactive Orbitrap MS/MS. Multivariate analyses revealed clear tissue- and species-specific lipid patterns. Dechorionated eggs were enriched in energy-storage lipids, dominated by triacylglycerols and essential polyunsaturated fatty acids, whereas chorion tissues contained higher levels of structural and signaling lipids, including phosphatidylinositols and sphingolipids. Each species exhibited a distinct lipid signature, with T. ovatus characterized by higher secosteroids and free fatty acids, P. teira by glycerophosphoethanolamines and phosphoinositols, and P. leopardus by abundant triradylglycerols. Pathway enrichment highlighted glycerophospholipid metabolism and sphingolipid signaling as prominent processes during early development. These findings clarify lipid partitioning between dechorionated fertilized egg contents and the chorion and provide a biochemical rationale for optimizing species-specific broodstock diets to enhance egg quality in tropical marine aquaculture. Full article

Upon RNA virus infection, viral RNA is sensed by the RIG-I-like receptors (RLRs), which signal through the adaptor protein VISA/MAVS to induce an innate antiviral response. How the VISA-mediated innate antiviral response is regulated and whether it can be targeted for drug development against diseases caused by RNA virus infection needs to be further investigated. Here we report that physalin F, a natural secosteroid isolated from Physalis angulata L., inhibits innate immune response to RNA virus. Mechanistically, physalin F binds to and promotes the activation of the mitochondrial m-AAA protease AFG3L2, which subsequently mediates the degradation of VISA. Knockdown of AFG3L2 promotes RLR-mediated innate antiviral signaling, whereas physalin F inhibits innate immune response to RNA virus both in cells and mice. Our study discovers physalin F as an inhibitor of VISA-mediated innate antiviral response as well as a candidate compound for the treatment of related diseases. More importantly, our findings suggest that AFG3L2 constitutively mediates degradation of VISA under physiological conditions, which represents a novel negative regulatory mechanism of RLR-mediated innate antiviral response. Full article

Microorganisms have emerged as prolific and versatile producers of steroidal natural products, displaying a remarkable capacity for structural diversification that extends far beyond classical sterol frameworks. This review critically examines steroidal metabolites isolated from microbial sources, with a particular emphasis on marine-derived and endophytic fungi belonging to the genera Aspergillus and Penicillium, alongside selected bacterial and lesser-studied fungal taxa. Comparative analysis reveals that these organisms repeatedly generate distinctive steroid scaffolds, including highly oxygenated ergostanes, secosteroids, rearranged polycyclic systems, and hybrid architectures arising from oxidative cleavage, cyclization, and Diels–Alder-type transformations. While many reported compounds exhibit cytotoxic, anti-inflammatory, antimicrobial, or enzyme-inhibitory activities, the biological relevance of these metabolites varies considerably, highlighting the need to distinguish broadly recurring bioactivities from isolated or strain-specific observations. By integrating structural classification with biosynthetic considerations and bioactivity trends, this review identifies key steroidal frameworks that recur across taxa and appear particularly promising for further pharmacological investigation. In addition, current gaps in mechanistic understanding and compound prioritization are discussed. Finally, emerging strategies such as genome mining, biosynthetic gene cluster analysis, co-culture approaches, and synthetic biology are highlighted as powerful tools to unlock the largely untapped potential of microbial genomes for the discovery of novel steroidal scaffolds. Together, this synthesis underscores the importance of microorganisms as a dynamic and expandable source of structurally unique and biologically relevant steroids, and provides a framework to guide future discovery-driven and mechanism-oriented research in the field. Full article

Vitamin D, traditionally regarded as a nutrient, is increasingly recognized as a pharmacologically active secosteroid with pleiotropic effects extending beyond calcium homeostasis and bone integrity. Together with vitamin K2, it participates in the fine-tuning of mineral metabolism and vascular health, potentially modulating cardiometabolic risk through intertwined endocrine and paracrine pathways. Despite widespread fortification and supplementation, vitamin D deficiency remains a major global health concern, driven by limited sun exposure, obesity, and metabolic dysfunction. Observational and mechanistic studies consistently link low serum 25(OH)D concentrations with hypertension, insulin resistance, heart failure, and increased cardiovascular mortality. At the molecular level, vitamin D exerts pharmacological actions—modulating the renin–angiotensin–aldosterone system, exerting anti-inflammatory and antifibrotic effects, and influencing endothelial and cardiomyocyte signaling. While experimental and epidemiological evidence suggests potential cardiovascular benefits, large randomized controlled trials (RCTs) provide conflicting results, particularly regarding hypertension and heart failure. However, these often-neutral results do not preclude a targeted action. On the contrary, clinical efficacy is strongly dependent on baseline deficiency status and the presence of metabolic cofactors. In this context, high-dose supplementation of Vitamin D, in combination with Vitamin K2 to prevent vascular calcification, elevates the supplement to a genuine pharmacological agent, with a distinct therapeutic potential for modulating cardiometabolic risk in selected patient subgroups. Emerging evidence supports the concept that vitamin D, when appropriately dosed and combined with K2, may act more as a low-potency pharmacological modulator than a simple nutritional supplement. This review synthesizes current mechanistic, observational, and interventional evidence, aiming to clarify whether vitamin D should be reclassified—from a micronutrient to a pharmacologically relevant agent—in cardiometabolic prevention and therapy, proposing a paradigm shift toward personalized and targeted dosing strategies, characteristic of precision pharmacology. Full article

Background/Objectives: Breast cancer remains one of the most prevalent and life-threatening malignancies worldwide. This study describes the design and biological evaluation of a series of secosteroid–2-pyrazoline hybrids as novel antitumor agents against ERα-positive breast cancer cell lines MCF-7 and T47D. Methods: A simple and efficient method for synthesizing secosteroid–2-pyrazoline hybrids was developed starting from 13α-hydroxy-3-methoxy-13,17-secoestra-1,3,5(10)-triene-17-oic acid hydrazide and 1,3-diketones. The resulting secosteroid derivatives were evaluated against hormone-dependent MCF-7 and T47D breast cancer cells. Furthermore, the selectivity and effects of three lead compounds on signaling pathways in MCF-7 cells were examined. Flow cytometry was used to assess the cell-cycle distribution of MCF-7 cells treated with the lead compound. Results: Among the synthesized hybrids, compounds 3f, 3j, and 3k exhibited potent antiproliferative activity with IC₅₀ values of 0.2–0.5 μM against breast cancer cells, while demonstrating very low cytotoxicity towards normal cells (IC₅₀ > 25 μM), indicating a favorable safety profile. The antitumor activity of lead compound 3j was additionally investigated in combination with standard chemotherapeutics, docetaxel and doxorubicin, yielding synergistic effects. The lead compounds showed a dual mechanism of action by inhibiting S6 kinase and promoting Bcl-2 phosphorylation at 0.9 μM, without significantly affecting hormonal breast cancer targets such as ERα, GREB1, and AR. Compound 3j induced apoptosis accompanied by a reduction of the G1/G0 phase in MCF-7 cells. Conclusions: These findings highlight secosteroid–2-pyrazoline hybrids as promising candidates for the development of next-generation breast cancer therapeutics targeting apoptosis and S6K signaling pathways. Full article

Vitamin D (VD) is a vital lipophilic secosteroid hormone known for its essential role in maintaining skeletal health and regulating calcium and phosphate metabolism. Recent evidence has begun to illuminate its significance beyond bone health, particularly in relation to thrombosis—a condition characterized by blood clot formation within the vascular system that can lead to serious cardiovascular events such as myocardial infarction and stroke. VD deficiency, defined as a plasma 25-hydroxyVD level below 25 nmol/L, affects a substantial portion of the global population, with prevalence rates ranging from 8% to 18%. This study systematically explores the relationships between VD levels and the risk of thrombosis, investigating the underlying mechanisms including VD’s anticoagulant properties, influence on inflammatory pathways, and interactions with endothelial cells. Epidemiological data suggest that low serum levels of VD correlate with an increased risk of venous thromboembolism (VTE), although the reported findings remain inconsistent. Mechanisms that potentially link VD to thrombotic risk include modulation of thrombomodulin and tissue factor expression, as well as enhancement of anti-inflammatory cytokines. Given the prevalence of VD insufficiency, particularly among populations with limited exposure to sunlight, this research highlights the urgent need for strategies to increase VD levels through dietary modifications and supplementation in order to prevent thrombotic events. Full article

Despite the recent development of improved methods of treating melanoma such as targeted therapy, immunotherapy or combined treatment, the number of new cases worldwide is increasing. It is well known that active metabolites of vitamin D₃ and lumisterol (L₃) exert photoprotective and antiproliferative effects on the skin, while UV radiation is a major environmental risk factor for melanoma. Thus, many natural metabolites and synthetic analogs of steroidal and secosteroidal molecules have been tested on various cancer cells and in animal models. In this study, we tested the anti-melanoma properties of several natural derivatives of vitamin D₃ and L₃ in comparison to 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). A significant decrease in melanoma cell proliferation and cell mobility was observed for selected derivatives, with (25R)-27-hydroxyL₃ showing the highest potency (lowest IC50) in A375 cells but lower potency in SK-MEL-28 cells, whereas the parent L₃ failed to inhibit proliferation. The efficacy (% inhibition) by 1,24,25(OH)₃D₃ and 1,25(OH)₂D₃ were similar in both cell types. 1,25(OH)₂D₃ showed higher potency than 1,24,25(OH)₃D₃ in SK-MEL-28 cells, but lower potency in A375 cells for the inhibition of proliferation. As for 1,25(OH)₂D₃, but not the other derivatives tested, treatment of melanoma cells with 1,24,25(OH)₃D₃ markedly increased the expression of CYP24A1, enhanced translocation of the vitamin D receptor (VDR) from the cytoplasm to the nucleus and also decreased the expression of the proliferation marker Ki67. The effects of the other compounds tested were weaker and occurred only under certain conditions. Our data indicate that 1,24,25(OH)₃D₃, which has undergone the first step in 1,25(OH)₂D₃ inactivation by being hydroxylated at C24, still shows anti-melanoma properties, displaying higher potency than 1,25(OH)₂D₃ in SK-MEL-28 cells. Furthermore, hydroxylation increases the potency of some of the lumisterol hydroxy-derivatives, as in contrast to L₃, (25R)-27(OH)L₃ effectively inhibits proliferation and migration of the human malignant melanoma cell line A375. Full article

Background and Objectives: Vitamin D is a secosteroid hormone essential for calcium homeostasis and skeletal health, but established evidence highlights its significant roles also in muscle health and in the modulation of immune response. This review aims to explore the impact of impaired vitamin D status on outcomes of muscle function and involvement in inflammatory and autoimmune rheumatic diseases damaging the skeletal muscle efficiency both with direct immune-mediated mechanisms and indirect processes such as sarcopenia. Methods: A comprehensive literature search was conducted on PubMed and Medline using Medical Subject Headings (MeSH) terms: “vitamin D, muscle, rheumatic diseases.” Additionally, conference abstracts from The European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) (2020–2023) were reviewed, and reference lists of included papers were scanned. The review emphasizes the evidence published in the last five years, while also incorporating significant studies from earlier years, structured by the extent of evidence linking vitamin D to muscle health in the most commonly inflammatory and autoimmune rheumatic diseases encountered in clinical practice. Results: Observational studies indicate a high prevalence of vitamin D serum deficiency (mean serum concentrations < 10 ng/mL) or insufficiency (<30 ng/mL) in patients with idiopathic inflammatory myopathies (IIMs) and polymyalgia rheumatica, as well as other autoimmune connective tissue diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Of note, vitamin D insufficiency may be associated with reduced muscle strength (2 studies on RA, 2 in SLE and 1 in SSc), increased pain (1 study on SLE), fatigue (2 studies on SLE), and higher disease activity (3 studies on IIMs and 1 on SLE) although there is much heterogeneity in the quality of evidence and different associations for the different investigated diseases. Therefore, linked to the multilevel biological intervention exerted by vitamin D, several translational and clinical studies suggest that active metabolites of this secosteroid hormone, play a role both in reducing inflammation, but also in enhancing muscle regeneration, intra-cellular metabolism and mitochondrial function, although interventional studies are limited. Conclusions: Altered serum vitamin D status is commonly observed in inflammatory and autoimmune rheumatic diseases and seems to be associated with adverse muscle health outcomes. While maintaining adequate serum vitamin D concentrations may confer muscle-protective effects, further research is needed to confirm these findings and establish optimal supplementation strategies to obtain a safe and efficient serum threshold. Full article

Vitamin D is a group of seco-steroidal fat-soluble compounds. The two basic forms, vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol), do not have biological activity. They are converted in the body by a two-step enzymatic hydroxylation into biologically active forms, 1α,25-dihydroxyvitamin D₂ [ercalcitriol, 1,25(OH)₂D₂] and 1α,25-dihydroxyvitamin D₃ [calcitriol, 1,25(OH)₂D₃], which act as classical steroid hormones. 1,25(OH)₂D₃ exerts most of its physiological functions by binding to the nuclear vitamin D receptor (VDR), which is present in most body tissues to provide support to a broad range of physiological processes. Vitamin D-liganded VDR controls the expression of many genes. High levels of 1,25(OH)₂D₃ cause an increase in calcium in the blood, which can lead to harmful hypercalcemia. Several analogs of 1,25(OH)₂D₃ and 1,25(OH)₂D₂ have been designed and synthesized with the aim of developing compounds that have a specific therapeutic function, for example, with potent anticancer activity and a reduced toxic calcemic effect. Particular structural modifications to vitamin D analogs have led to increased anticancer activity and reduced calcemic action with the prospect of extending work to provide future innovative therapies. Full article

We investigated multiple signaling pathways activated by CYP11A1-derived vitamin D3 hydroxymetabolites in human skin fibroblasts by assessing the actions of these molecules on their cognate receptors and by investigating the role of CYP27B1 in their biological activities. The actions of 20(OH)D3, 20,23(OH)₂D3, 1,20(OH)₂D3 and 1,20,23(OH)₃D3 were compared to those of classical 1,25(OH)₂D3. This was undertaken using wild type (WT) fibroblasts, as well as cells with VDR, RORs, or CYP27B1 genes knocked down with siRNA. Vitamin D3 hydroxymetabolites had an inhibitory effect on the proliferation of WT cells, but this effect was abrogated in cells with silenced VDR or RORs. The collagen expression by WT cells was reduced upon secosteroid treatment. This effect was reversed in cells where VDR or RORs were knocked down where the inhibition of collagen production and the expression of anti-fibrotic genes in response to the hydroxymetabolites was abrogated, along with ablation of their anti-inflammatory action. The knockdown of CYP27B1 did not change the effect of either 20(OH)D3 or 20,23(OH)₂D3, indicating that their actions are independent of 1α-hydroxylation. In conclusion, the expression of the VDR and/or RORα/γ receptors in fibroblasts is necessary for the inhibition of both the proliferation and fibrogenic activity of hydroxymetabolites of vitamin D3, while CYP27B1 is not required. Full article

Matrix metalloproteinases (MMPs), which are proteolytic enzymes, promote blood–brain barrier (BBB) disruption, leading to neuronal damage and neuroinflammation. Among them, MMP-9 upregulation serves as an inflammatory biomarker in the central nervous system (CNS). Currently, the development of marine organism-derived bioactive compounds or metabolites as anti-inflammatory drugs has received considerable attention. The 9,11-secosteroid, 3β,11-dihydroxy-9,11-secogorgost-5-en-9-one (4p3f), is a novel sterol compound extracted from the soft coral Sinularia leptoclado with potential anti-inflammatory activity. However, the effect of and potential for brain protection of 4p3f on brain astrocytes remain unclear. Herein, we used rat brain astrocytes (RBAs) to investigate the effects and signaling mechanisms of 4p3f on lipopolysaccharide (LPS)-induced MMP-9 expression via zymographic, quantitative reverse transcription–polymerase chain reaction (qRT-PCR), Western blot, immunofluorescence staining, promoter–reporter, and cell migration analyses. We first found that 4p3f blocked LPS-induced MMP-9 expression in RBAs. Next, we demonstrated that LPS induced MMP-9 expression via the activation of ERK1/2, p38 MAPK, and JNK1/2, which is linked to the STAT3-mediated NF-κB signaling pathway. Finally, 4p3f effectively inhibited LPS-induced upregulation of MMP-9-triggered RBA cell migration. These data suggest that a novel sterol from soft coral, 4p3f, may have anti-inflammatory and brain-protective effects by attenuating these signaling pathways of MMP-9-mediated events in brain astrocytes. Accordingly, the soft coral-derived sterol 4p3f may emerge as a potential candidate for drug development or as a natural compound with neuroprotective properties. Full article

This article explores the diverse array of biologically active compounds derived from microbial symbionts, particularly focusing on the isolation and characterization of diepoxides, highly oxygenated triterpenoids, secosteroids, ergostane-type steroids, and meroterpenoids from various marine and plant-derived fungi. We highlight significant discoveries such as vitamin D variants from fungal species, unique sesterterpenoids from mangrove endophytic fungi, and secosteroids with potential medicinal applications. The study delves into the structural uniqueness and bioactivities of these compounds, including their anti-inflammatory, antibacterial, antifungal, antiviral, and cytotoxic effects. Notable findings include the isolation of compounds with significant activity against cancer cell lines, the inhibition of acetylcholinesterase, and promising antifouling properties. This work underscores the potential of microbial symbionts as a rich source of novel bioactive compounds with diverse therapeutic applications, highlighting the importance of marine and fungal biodiversity in drug discovery and development. Full article

The genomic activity of 1,25(OH)₂D₃ is mediated by vitamin D receptor (VDR), whilst non-genomic is associated with protein disulfide isomerase family A member 3 (PDIA3). Interestingly, our recent studies documented that PDIA3 is also involved, directly or indirectly, in the modulation of genomic response to 1,25(OH)₂D₃. Moreover, PDIA3 was also shown to regulate cellular bioenergetics, possibly through the modulation of STAT signaling. Here, the role of VDR and PDIA3 proteins in membrane response to 1,25(OH)₂D₃ and calcium signaling was investigated in squamous cell carcinoma A431 cell line with or without the deletion of VDR and PDIA3 genes. Calcium influx was assayed by Fura-2AM or Fluo-4AM, while calcium-regulated element (NFAT) activation was measured using a dual luciferase assay. Further, the levels of proteins involved in membrane response to 1,25(OH)₂D₃ in A431 cell lines were analyzed via Western blot analysis. The deletion of either PDIA3 or VDR resulted in the decreased baseline levels of Ca²⁺ and its responsiveness to 1,25(OH)₂D₃; however, the effect was more pronounced in A431∆PDIA3. Furthermore, the knockout of either of these genes disrupted 1,25(OH)₂D₃-elicited membrane signaling. The data presented here indicated that the VDR is essential for the activation of calcium/calmodulin-dependent protein kinase II alpha (CAMK2A), while PDIA3 is required for 1,25(OH)₂D₃-induced calcium mobilization in A431 cells. Taken together, those results suggest that both VDR and PDIA3 are essential for non-genomic response to this powerful secosteroid. Full article