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A vitamin D 3 metabolite 1α,25-dihydroxyvitamin D 3 exhibits numerous hormonal actions to various tissues and cells such as induction of calcium ion absorption, bone metabolism, activation of innate immune system. Because hormonal actions of 1α,25-dihydroxyvitamin D 3 are too complex, it is difficult to better understand overall views of intermolecular networks on the cell activation by 1α,25-dihydroxyvitamin D 3 . In this review we concisely outline the most fundamental molecular mechanisms for the cell activation by 1α,25-dihydroxyvitamin D 3 based on the previous and recent studies. In addition, we expound biological activity of 25-hydroxyvitamin D 3 and 1α,25-dihydroxyvitamin D 3 that differs from hormonal actions. In addition, recent studies by our group revealed that vitamin D decomposition products confer extremely selective bactericidal action to Helicobacter pylori, a pathogen causative gastritis, peptic ulcers and gastric cancers in human. Vitamin D decomposition products induce the bacteriolysis as targeting of characteristic glycerophospholipids composed of the bacterial biomembranes. In the future we will expect to be capable of developing novel antibacterial agents targeting a characteristic glycerophospholipid of the pathogenic bacteria using vitamin D decomposition products as fundamental structures., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: Not applicable., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Several nutrients are crucial in enhancing the immune system and preserving the structural integrity of bodily tissue barriers. Vitamin D (VD) and zinc (Zn) have received considerable interest due to their immunomodulatory properties and ability to enhance the body's immune defenses. Due to their antiviral, anti-inflammatory, antioxidative, and immunomodulatory properties, the two nutritional powerhouses VD and Zn are crucial for innate and adaptive immunity. As observed with COVID-19, deficiencies in these micronutrients impair immune responses, increasing susceptibility to viral infections and severe disease. Ensuring an adequate intake of VD and Zn emerges as a promising strategy for fortifying the immune system. Ongoing clinical trials are actively investigating their potential therapeutic advantages. Beyond the immediate context of the pandemic, these micronutrients offer valuable tools for enhancing immunity and overall well-being, especially in the face of future viral threats. This analysis emphasizes the enduring significance of VD and Zn as both treatment and preventive measures against potential viral challenges beyond the current health crisis. The overview delves into the immunomodulatory potential of VD and Zn in combating viral infections, with particular attention to their effects on animals. It provides a comprehensive summary of current research findings regarding their individual and synergistic impacts on immune function, underlining their potential in treating and preventing viral infections. Overall, this overview underscores the need for further research to understand how VD and Zn can modulate the immune response in combatting viral diseases in animals., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The pressing issues of climate change and environmental degradation call for a reevaluation of how we approach economic activities. Both leaders and corporations are now shifting their focus, toward adopting practices and embracing the concept of circular economy (CE). Within this context, the Food and Beverage (F&B) sector, which significantly contributes to greenhouse gas (GHG) emissions, holds the potential for undergoing transformations. This study aims to explore the role that Artificial Intelligence (AI) can play in facilitating the adoption of CE principles, within the F&B sector. Design/methodology/approach: This research employs the Best Worst Method, a technique in multi-criteria decision-making. It focuses on identifying and ranking the challenges in implementing AI-driven CE in the F&B sector, with expert insights enhancing the ranking's credibility and precision. Findings: The study reveals and prioritizes barriers to AI-supported CE in the F&B sector and offers actionable insights. It also outlines strategies to overcome these barriers, providing a targeted roadmap for businesses seeking sustainable practices. Social implications: This research is socially significant as it supports the F&B industry's shift to sustainable practices. It identifies key barriers and solutions, contributing to global climate change mitigation and sustainable development. Originality/value: The research addresses a gap in literature at the intersection of AI and CE in the F&B sector. It introduces a system to rank challenges and strategies, offering distinct insights for academia and industry stakeholders. [ABSTRACT FROM AUTHOR]

Lower intramuscular fat (IMF) and excessive abdominal fat reduce carcass quality in broilers. The study aimed to investigate the effects of dietary VD3 on growth performance, lipid metabolism and cecal microbiota in broilers over an 84-d feeding experiment. One-day-old male Luhua broilers (210) were randomly assigned to control (basal diet) and VD group (basal diet supplemented with 3,750 IU/kg VD3). Samples were collected after a 12-h fasted feeding on days 28, 56, and 84. Supplementary VD3 significantly enhanced average daily gain (ADG) in broilers aged 57-84 d and 1-84 d, and increased leg muscle rate and fat content in breast and leg muscles and reduced abdominal fat rate of broilers at 84 d. VD3 increased TG and glycogen content in the liver of 28- and 84-d-old broilers, serum TG and VLDL-C content at 56 and 84 d, and TC, HDL-C and LDL-C at 84 d. VD3 increased mRNA expressions of genes related to de novo lipogenesis (DNL) (mTOR , SREBP-1c , FAS and ACC), lipid oxidation (AMPK , PPARα , CPT-1α and ACO) and lipid transport (ApoB and MTTP), and FAS, ACC and CPT1 enzyme activities in the liver. However, mRNA levels of genes involved in DNL and cellular lipid uptake (LPL and FATP1) and LPL activity were decreased in abdominal adipose tissue, and that of genes involved in lipid oxidation and lipolysis (HSL and ATGL) was increased by VD3. LPL and FATP1 expression in breast and leg muscles was increased by VD3. Moreover, VD3 increased the abundance of cecum Bacteroides at 28 and 84 d, Rikenellaceae_RC9_gut_group and Faecalibacterium at 56 and 84 d, and Lachnoclostridium at 84 d. These bacteria were correlated with increased DNL, lipid oxidation and lipid transport in liver, and cellular lipid uptake in muscle, as well as decreased DNL and cellular lipid uptake, and increased lipid oxidation and lipolysis in abdominal adipose tissue. Altogether, supplementary VD3 in basal diet improved growth performance, increased IMF, and reduced abdominal fat rate, which is significant for enhancing feed utilization and improving the carcass quality of broilers. The regulation of VD3 on lipid metabolism could was associated with variation in cecal microbiota composition. [ABSTRACT FROM AUTHOR]

Background: Lifestyle changes have meant that it is problematic for many people across the globe to maintain adequate vitamin D concentrations. As UV-catalysed production in the skin, which uses vitamin D-binding protein to facilitate systemic absorption, is the primary source of vitamin D, it is questionable if oral supplementation of this vitamin is the optimal means to replace it. However, supplementing an oil-soluble vitamin via the skin is problematic as it gets stuck in the stratum corneum after topical application. This clinical study will test if a new vitamin D ester, vitamin D phosphate, which is more water-soluble compared to vitamin D, administered via a transdermal patch, can be used to improve vitamin D status. Method: This is a two-part study comprising a dose-escalation with the vitamin D phosphate transdermal patch followed by a randomised, double-blind, placebo-controlled, multiarmed, multistage clinical trial. It is a single-centred, 12-week study that will enrol a maximum of 100 participants. The dose escalation study will monitor safety and tolerability using serum calcium and 25(OH)D3 levels. The blinded, randomised trial will test different dose frequencies for 4 weeks compared to a placebo. Then, after an interim analysis, the best dosing frequency will be assessed against a placebo. The primary outcome for the multistage clinical study will be the percentage change in 25(OH)D3 concentration in the serum (ng/mL) at weeks 4 and 8 compared to baseline. The secondary outcome measures include percentage change in serum vitamin D-binding protein levels, skin interstitial fluid biomarker concentrations, and nail appearance after 4 and 8 weeks compared to baseline. Discussion: This study will determine if a vitamin D phosphate transdermal patch can improve vitamin D status. In addition, it could provide a better understanding of how vitamin D is absorbed directly into the skin after application by measuring the serum vitamin D-binding protein and skin biomarker responses to transdermal supplementation. Trial registration: Clinical Trials.gov NCT06098846, registered on 23rd October 2023. [ABSTRACT FROM AUTHOR]

Nuclear Receptors (NRs) comprise a superfamily of proteins with essential roles in cell signaling, survival, proliferation, and metabolism. They act as transcription factors and are subclassified into families based on their ligands, DNA-binding sequences, tissue specificity, and functions. Evidence indicates that in infectious diseases, cancer, and autoimmunity, NRs modulate immune and endocrine responses, altering the transcriptional profile of cells and organs and influencing disease progression. Chronic infectious diseases, characterized by pathogen persistence, are particularly notable for an exaggerated inflammatory process. Unlike acute inflammation, which helps the host respond to pathogens, chronic inflammation leads to metabolic disorders and a dysregulated neuro-immuno-endocrine response. Over time, disturbances in cytokine, hormone, and other compound production foster an unbalanced, detrimental defensive response. This complexity underscores the significant role of ligand-dependent NRs. Tuberculosis and Chagas Disease are two critical chronic infections. The causative agents, Mycobacterium tuberculosis and Trypanosoma cruzi , have developed evasion strategies to establish chronic infections. Their clinical manifestations are associated with disrupted immuno-endocrine responses, pointing to a potential involvement of NRs. This review explores the current understanding of NRs in regulating immune-endocrine interactions within the context Tuberculosis and Chagas Disease. These diseases remain significant global health concerns, particularly in developing countries, highlighting the importance of understanding the molecular mechanisms underlying host-pathogen interactions mediated by NRs. [ABSTRACT FROM AUTHOR]

The importance of vitamin D for a well-functioning immune system is becoming increasingly evident. Nevertheless, the other fat-soluble vitamins A, E and K also seem to play a central role regarding the adequate function of immune cells and to counteract excessive immune reactions and inflammatory processes. However, recognizing hidden hunger, particularly micronutrient deficiencies in vulnerable groups like the elderly, is crucial because older adults often lack sufficient micronutrients for various reasons. This review summarizes the latest findings on the immune modulating functions of fat-soluble vitamins in a physiological and pathophysiological context, provides a graphical comparison of the Recommended Daily Allowances between Deutschland, Austria, Confoederatio Helvetica (D-A-CH; eng. GSA, Germany, Switzerland, Austria), Deutsche Gesellschaft für Ernährung (DGE; eng. German Nutrition Society) and National Institutes of Health (NIH) across all age groups and, in particular, addresses the question regarding the benefits of supplementation of the respective micronutrients for the aging population of industrialized nations to strengthen the immune system. The following review highlights the importance of fat-soluble vitamins A, D, E and K which play critical roles in maintaining immune system function and, in some cases, in preventing excessive immune activation. Therefore, a better understanding of the relevance of adequate blood levels and consequently potential supplementation strategies may contribute to the prevention and management of infectious diseases as well as better overall health of the elderly. [ABSTRACT FROM AUTHOR]

Seasonal molting in mammals is a crucial survival strategy, yet the underlying molecular mechanisms have not been fully characterized. Melatonin, serving as a bridge for the transmission of photoperiod signals, plays a significant regulatory role in animals' seasonal molting, and the physiological regulatory effects of melatonin signaling are highly dependent on the retinoic-acid-related orphan receptor alpha (Rorα). Hair follicle stem cells (HFSCs) are the most essential cell type in the process of hair follicle regeneration and seasonal replacement. Therefore, this study aims to discuss the regulatory effects of melatonin and its nuclear receptor RORA on HFSCs. This research found that RORA can downregulate cellular proliferation levels by inhibiting the cell cycle of HFSCs, while simultaneously promoting apoptosis in HFSCs and affecting the expression of some genes involved in ferroptosis. RORA can directly bind to the promoter regions of the cyclin genes Ccna2 and Ccne1 to regulate their transcription. Melatonin may enhance the viability of HFSCs by downregulating RORA levels. In this study, the impact of melatonin and its nuclear receptor RORA on the viability of HFSCs, along with some of the underlying molecular mechanisms, is characterized. These findings provide a theoretical foundation for research on the regulation of animal hair follicle development. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, characterized by impairments in cognition, memory, and movement, are becoming increasingly prevalent due to population aging, posing a significant threat to public health. Extensive evidence suggests that neuroinflammation, mediated by microglia, plays a crucial role in the development of these diseases. Notably, the vitamin D receptor (VDR) has been shown to regulate microglia activation by controlling the function of neuroprotective vitamin D. This study aims to elucidate the potential of VDR in modulating neuroinflammation. To mimic neuroinflammation, BV2 cells were treated with lipopolysaccharide (LPS) for 12 h. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the release of cytokines, including IL-1β, IL-2, IL-6, IL-10, IL-12, MCP-1, and TNF-α. Western blot assays were performed to assess relative protein expressions and succinylation modifications. Co-immunoprecipitation (Co-IP) experiments were conducted to determine the interaction between VDR and carnitine palmitoyltransferase 1A (CPT1A). Immunofluorescence staining was used to analyze the localization of VDR, CPT1A, COX-2, and CD11b. Our findings demonstrated that VDR expression was upregulated in BV2 cells exposed to LPS. Ectopic expression of VDR attenuated the inflammatory response and microglia activation. We discovered that carnitine palmitoyltransferase 1A (CPT1A) promoted VDR succinylation. Further investigations revealed that CPT1A enhanced VDR stability by binding to VDR, with lysine K117 being the primary succinylation site. Importantly, depletion of CPT1A abrogated the protective effects of VDR overexpression on microglia-mediated neuroinflammation. Our study highlighted that CPT1A functioned as a suppressor in neuroinflammation by facilitating VDR succinylation, offering potential therapeutic targets for the management of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Introduction: Vitamin D3 (cholecalciferol) has demonstrated potential anticancer properties, but its clinical application is limited by associated toxicity at effective doses. This study investigated the use of liposomal encapsulation to increase the therapeutic efficacy of vitamin D3 while mitigating its toxicity. Methods: Liposomal vitamin D3 (VD-LP) was prepared via the film-hydration method and characterized for particle size, polydispersity index, encapsulation efficiency, and long-term stability. In vitro gene expression modulation was evaluated in monocytic THP-1 cells, and antiproliferative effects were assessed in HT29 (colorectal), BT474 (breast), and TRAMP-C1 (prostate) cancer cell lines. In vivo antitumor efficacy and toxicity were tested in a mouse model with subcutaneously implanted MC38 tumors. Tumor growth, survival rates, and serum calcium and phosphate levels were analyzed. Results: VD-LP demonstrated high encapsulation efficiency and stability over 90 days, with a consistent particle size of approximately 83 nm. VD-LP modulated immune-related and metabolic gene expression in THP-1 cells, including upregulation of antimicrobial peptides and vitamin D receptor genes. VD-LP showed superior antiproliferative effects compared to free vitamin D3 in all tested cancer cell lines. In vivo , VD-LP delayed tumor growth and improved survival without causing hypercalcemia, highlighting its favorable toxicity profile. Discussion: Liposomal encapsulation of vitamin D3 significantly improves its anticancer efficacy while mitigating toxicity, making it a promising strategy for future cancer therapies. VD-LP shows potential for enhanced therapeutic applications with reduced adverse effects, warranting further clinical exploration. [ABSTRACT FROM AUTHOR]

Childhood obesity has profound effects on puberty in boys and girls, altering its timing, progression, and associated hormonal changes. Also, later male fertility could be impaired by childhood and pubertal obesity in light of the impact of inflammatory markers on semen quality. The aim of this narrative review is to explore the intricate relationship between childhood obesity and its impact on pubertal development and fertility, with a specific focus on boys. Such a relationship between obesity and pubertal timing in males is highly influenced by metabolic, hormonal, genetic, epigenetic, and environmental factors. While many studies suggest that obesity accelerates pubertal onset in boys, some studies do not confirm these findings, especially in cases of severe obesity. In fact, delayed puberty has also been reported in certain instances. Obesity influences fertility through different central and peripheral processes, including an altered endocrine milieu, inflammatory environment, and epigenetic modifications that alter semen quality and vitality, leading to subfertility or infertility. The early identification and management of potential issues associated with obesity are crucial for ensuring optimal reproductive health in adulthood. Further research is essential to clarify these associations and to develop targeted interventions aimed at preventing the negative health outcomes associated with obesity-related disruptions in puberty and fertility. [ABSTRACT FROM AUTHOR]

Clinical trials consistently demonstrate an inverse correlation between serum 25-hydroxyvitamin D [25(OH)D; calcifediol] levels and the risk of symptomatic SARS-CoV-2 disease, complications, and mortality. This systematic review (SR), guided by Bradford Hill's causality criteria, analyzed 294 peer-reviewed manuscripts published between December 2019 and November 2024, focusing on plausibility, consistency, and biological gradient. Evidence confirms that cholecalciferol (D3) and calcifediol significantly reduce symptomatic disease, complications, hospitalizations, and mortality, with optimal effects above 50 ng/mL. While vitamin D requires 3–4 days to act, calcifediol shows effects within 24 h. Among 329 trials, only 11 (3%) showed no benefit due to flawed designs. At USD 2/patient, D3 supplementation is far cheaper than hospitalization costs and more effective than standard interventions. This SR establishes a strong inverse relationship between 25(OH)D levels and SARS-CoV-2 vulnerability, meeting Hill's criteria. Vitamin D3 and calcifediol reduce infections, complications, hospitalizations, and deaths by ~50%, outperforming all patented, FDA-approved COVID-19 therapies. With over 300 trials confirming these findings, waiting for further studies is unnecessary before incorporating them into clinical protocols. Health agencies and scientific societies must recognize the significance of these results and incorporate D3 and calcifediol for prophylaxis and early treatment protocols of SARS-CoV-2 and similar viral infections. Promoting safe sun exposure and adequate vitamin D3 supplementation within communities to maintain 25(OH)D levels above 40 ng/mL (therapeutic range: 40–80 ng/mL) strengthens immune systems, reduces hospitalizations and deaths, and significantly lowers healthcare costs. When serum 25(OH)D levels exceed 70 ng/mL, taking vitamin K2 (100 µg/day or 800 µg/week) alongside vitamin D helps direct any excess calcium to bones. The recommended vitamin D dosage (approximately 70 IU/kg of body weight for a non-obese adult) to maintain 25(OH)D levels between 50–100 ng/mL is safe and cost-effective for disease prevention, ensuring optimal health outcomes. [ABSTRACT FROM AUTHOR]

Vitamin D is activated into 1α,25(OH)2D through two hydroxylation steps that are primarily catalyzed by 25-hydroxylase in the liver and 1α-hydroxylase in the kidneys. The active form of vitamin D regulates myriads of cellular functions through its nuclear receptor, vitamin D receptor (VDR). Vitamin D metabolizing enzymes and VDR are expressed in adipose tissues and vitamin D regulates multiple aspects of adipose biology including the recruitment and differentiation of adipose stem cells into adipocytes and metabolic, endocrine, and immune properties. Obesity is associated with low vitamin D status, which is thought to be explained by its sequestration in large mass of adipose tissues as well as dysregulated vitamin D metabolism. Low vitamin D status in obesity may negatively impact adipose biology leading to adipose tissue dysfunctions, the major pathological factors for cardiometabolic diseases in obesity. In this review, the current understanding of vitamin D metabolism and its molecular mechanisms of actions, focusing on vitamin D–VDR regulation of adipose biology with their implications on obesity-associated diseases, is discussed. Whether improving vitamin D status leads to reductions in adiposity and risks for cardiometabolic diseases is also discussed. [ABSTRACT FROM AUTHOR]

Urolithiasis represents one of the most common urologic diseases, and its incidence demonstrates, globally, an increasing trend. The application of preventive measures is an established strategy to reduce urolithiasis-related morbidity, and it is based mostly on the adaptation of lifestyle factors and pharmacotherapy. Furthermore, other research areas demonstrate promising results, such as the research on the microbiome. In the current review, we searched for the latest data on lifestyle–based prevention and microbiome alterations in urolithiasis patients. The majority of the proposed lifestyle measures are already included in the urological guidelines, while additional factors, such as vitamin D supplementation, seem to have a putative positive effect. From the microbiome studies, several microbial composition patterns and metabolic pathways demonstrated an inhibiting or promoting role in lithogenesis. Up to the present, stone prevention has not shown satisfying results, which suggests that lifestyle measures are not adequate. Moreover, microbiome studies are prone to bias, since microbes are strongly affected by numerous clinical factors, while the analysis procedures are not standardized yet. Analysis standardization and data pooling from extensive registration of clinical and microbiome data are essential steps in order to improve the existing prevention strategy with targeted microbiome manipulations. [ABSTRACT FROM AUTHOR]

Sunlight exposure plays an important role in human health, impacting processes such as mood, blood pressure regulation, and vitamin D3 production. Solar ultraviolet B radiation initiates vitamin D3 synthesis in the skin, which is subsequently metabolized into its biologically active form. UVB exposure plays a key role in enabling vitamin D3 synthesis, but it can also contribute to skin carcinogenesis, creating a complex interplay between its beneficial and harmful effects. Vitamin D deficiency, affecting over half the global population, is linked to a range of chronic diseases, including cancers, cardiovascular conditions, and autoimmune disorders. Simultaneously, excessive solar UVB exposure increases the risk of non-melanoma and melanoma skin cancers through mechanisms involving DNA damage and oxidative stress. This review examines the dual role of UVB radiation in health and disease, focusing on the mechanisms of cutaneous vitamin D3 synthesis, the epidemiology of skin cancer, and the protective roles of vitamin D3's photoproducts and its active metabolite, 1,25-dihydroxyvitamin D3. Understanding these interconnections is critical for developing strategies that balance adequate sun-induced vitamin D3 production with skin cancer prevention. [ABSTRACT FROM AUTHOR]

Bee pollen is characterized by an exceptional diversity and abundance of micronutrients and bioactive phytochemicals. This richness remains very sparsely investigated, but accumulating evidence strongly supports a promising future for bee pollen in human nutrition and medicine. Epigenetic regulation is among the most compelling biomedical topics that remain completely untapped in bee pollen and bee derivative research. In our current research, we identified numerous ubiquitous compounds that are consistently present in this matrix, regardless of its botanical and geographical origins, and that have been well studied and documented as epigenetic regulators in recent years. Given the relative newness of both bee pollen biomedical research and epigenetic studies within nutritional, pharmaceutical, and medical sciences, this review aims to bridge these valuable fields and advance related experimental investigations. To the best of our knowledge, this is the first work that has aimed to comprehensively investigate the epigenetic modulatory potential of bee pollen compounds. Our findings have also unveiled several intriguing phenomena, such as a dual effect of the same compound depending on the cellular context or the effect of some compounds on the cross-generational heritability of epigenetic traits. Although experimental studies of epigenetic regulation by bee pollen as a whole or by its extract are still lacking, our current study clearly indicates that this research avenue is very promising and worth further investigations. We hope that our current work constitutes a foundational cornerstone of future investigations for this avenue of research. [ABSTRACT FROM AUTHOR]

Background: Obesity is an emerging health problem worldwide as it is associated with increased risk of cardiovascular, metabolic, mental disorders, and cancer. Therapeutic weight management remains one of the options for the treatment of excess weight and associated comorbidities. In this study, the therapeutic potential of elocalcitol, a fluorinated derivative of vitamin D, was studied on the model of high-fat diet (HFD)-induced obesity in mice. Results: It was demonstrated that co-administration of elocalcitol in the doses 15 ug/kg (i.p.) twice a week for 16 weeks prevented body weight gain by approximately 15%. The significant retardation in the body weight gain was observed already on the second week of elocalcitol treatment. Administration of elocalcitol also reduced visceral and epididymal fat accumulation by 55% and 35%, respectively, metabolic syndrome development, and lipid droplets accumulation in the liver of mice exposed to HFD. In contrast, the administration of cholecalciferol (vitamin D)—a precursor to calcitriol, the biologically active form of vitamin D, did not affect significantly the signs of obesity and metabolic syndrome, suggesting that the anti-obese effects of elocalcitol are not related to the canonical vitamin D receptor (VDR). Further studies have demonstrated that the preventive effect of elocalcitol is associated with the decreased levels of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and upregulation insulin-inducing gene-1 (Insig1) mRNA expression suggesting that the anti-obese effect of elocalcitol is mediated via inhibition of SREBP-mediated lipogenesis. We also demonstrated that elocalcitol prevents an increase in the expression of proinflammatory cytokines such as interleukin-1 beta (Il1b), tumor necrosis factor-alpha (Tnf), and interleukin-18 (Il18), and this effect was associated with upregulation of microRNA-146a (miR-146a). Deletion of the miR-146a gene reduced the anti-obese effects of elocalcitol and prevented its actions on the SCAP levels. The data indicate that elocalcitol's reduction of SCAP is at least partly mediated by miR-146a modulation. Conclusion: The study demonstrates that elocalcitol prevents HFD-induced obesity and metabolic syndrome in mice, likely by inhibiting SREBP-mediated lipogenesis and upregulating miR-146a. These findings provide valuable insights into the anti-obesity mechanisms of fluorinated D-vitamin analogs and suggest potential therapeutic strategies for obesity prevention. [ABSTRACT FROM AUTHOR]

Vitamin D is a lipid soluble steroid hormone, which plays a critical role in the calcium homeostasis, neuronal development, cellular differentiation, and growth by binding to vitamin D receptor (VDR). Associations between VDR gene polymorphism and Alzheimer's disease (AD), Parkinson's disease (PD), and mild cognitive impairment (MCI) risk has been investigated extensively, but the results remain ambiguous. The aim of this study was to comprehensively assess the correlations between four VDR polymorphisms (Fok I, Bsm I, Taq I, and Apa I) and susceptibility to AD, PD, and MCI. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the relationship of interest. Pooled analyses suggested that the Apa I polymorphism decreased the overall AD risk, and the Taq I increased the overall PD susceptibility. In addition, the Bsm I and Apa I polymorphisms were significantly correlated with the overall MCI risk. Stratified analysis by ethnicity further showed that the Taq I and Apa I genotypes reduced the AD predisposition among Caucasians, while the Taq I polymorphism enhanced the PD risk among Asians. Intriguingly, carriers with the BB genotype significantly decreased the MCI risk in Asian descents, and the Apa I variant elevated the predisposition to MCI in Caucasians and Asians. Further studies are need to identify the role of VDR polymorphisms in AD, PD, and MCI susceptibility. [ABSTRACT FROM AUTHOR]

Background/Objectives: The DNA methylation of neonatal cord blood can be used to accurately estimate gestational age. This is known as epigenetic gestational age. The greater the difference between epigenetic and chronological gestational age, the greater the association with an inappropriate perinatal fetal environment and development. Maternal vitamin D deficiency is common in Japan. The aim of this study was to investigate the associations between maternal serum vitamin D levels and epigenetic gestational age acceleration at birth in Japan. Methods: The data were obtained from the hospital-based birth cohort study conducted at the National Center for Child Health and Development in Tokyo, Japan. Maternal blood was collected in the second trimester to measure the serum vitamin D concentration. Cord blood was collected at birth to measure serum vitamin D and to extract DNA. DNA methylation was assessed using an Illumina methylation EPIC array. Epigenetic gestational age was calculated using the "methylclock" R package. Linear regression analysis was performed to see associations. Results: Maternal serum vitamin D levels in the second trimester were negatively associated with epigenetic gestational age acceleration at birth when calculated by Bohlin's method (regression coefficient [95% CI]: −0.022 [−0.039, −0.005], n = 157), which was still significant after considering infants' sex (−0.022 [−0.039, −0.005]). Cord blood serum vitamin D levels were not associated with epigenetic age acceleration. Maternal age at delivery and birth height were associated in positive and negative ways with epigenetic gestational age acceleration, respectively (0.048 [0.012, 0.085] and −0.075 [−0.146, −0.003]). Conclusions: Maternal vitamin D deficiency was related to an infant's epigenetic gestational age acceleration at birth. These findings suggest that the association between fetal development and maternal vitamin D levels may involve the fetal epigenetic regulation of the fetus. [ABSTRACT FROM AUTHOR]

Background: Calcitriol, beyond its well-established role in calcium and phosphate homeostasis, contributes to immunological processes. No known vitamin D dosage regimen effectively corrects the deficiency while accounting for immunoregulatory effects. Therefore, the purpose of this assessment was to determine whether regular administration of low doses of vitamin D might correct deficiency and have immunoregulatory effects. Methods: A total of 35 healthy volunteers were asked to supplement with vitamin D daily at a dosage of 500 or 1000 IU, depending on the degree of deficiency, for 12 months. At the beginning of the study and after the end of the supplementation period, concentrations of 25(OH)D; PTH; total calcium; inorganic phosphorus; and the inflammatory cytokines IL-17, IL-10, TGF-β, and IFN-γ were determined in all participants. Results: Correction of vitamin D deficiency was achieved with accompanying decreases in PTH and pro-inflammatory cytokine concentrations, while the concentration of anti-inflammatory cytokines remained stable. Conclusions: Therefore, regular vitamin D supplementation, even in small doses, effectively corrected the deficiency and had immunomodulatory effects. [ABSTRACT FROM AUTHOR]

Vitamin D offers numerous under-recognized health benefits beyond its well-known role in musculoskeletal health. It is vital for extra-renal tissues, prenatal health, brain function, immunity, pregnancy, cancer prevention, and cardiovascular health. Existing guidelines issued by governmental and health organizations are bone-centric and largely overlook the abovementioned extra-skeletal benefits and optimal thresholds for vitamin D. In addition, they rely on randomized controlled trials (RCTs), which seldom show benefits due to high baseline 25-hydroxyvitamin D [25(OH)D] concentrations, moderate supplementation doses, and flawed study designs. This review emphasizes the findings from prospective cohort studies showing that higher 25(OH)D concentrations reduce the risks of major diseases and mortality, including pregnancy and birth outcomes. Serum concentrations > 30 ng/mL (75 nmol/L) significantly lower disease and mortality risks compared to <20 ng/mL. With 25% of the U.S. population and 60% of Central Europeans having levels <20 ng/mL, concentrations should be raised above 30 ng/mL. This is achievable through daily supplementation with 2000 IU/day (50 mcg/day) of vitamin D3, which prevent diseases and deaths. Furthermore, a daily dose between 4000 and 6000 IU of vitamin D3 to achieve serum 25(OH)D levels between 40 and 70 ng/mL would provide greater protection against many adverse health outcomes. Future guidelines and recommendations should integrate the findings from observational prospective cohort studies and well-designed RCTs to improve public health and personalized care. [ABSTRACT FROM AUTHOR]

In addition to conventional treatments, there is growing interest in preventive and complementary therapies. Proper nutrition can prevent the manifestation of several chronic diseases such as obesity, diabetes, cardiovascular disease, and cancer, and can attenuate the severity of these diseases. Edible mushrooms have been used as nutrition and medicine for thousands of years. The spectrum and quantity of their medicinal compounds made them a widely investigated target both in basic research and clinical trials. The most abundant and medically important components are polysaccharides, terpenoids, phenols, and heterocyclic amines, but bioactive proteins, vitamins, including vitamin D, polyunsaturated fatty acids, and essential minerals are also important ingredients with noteworthy health benefits. Mushroom extracts have anti-diabetic, anti-hyperlipidemic, anti-inflammatory, antioxidant, cardioprotective, anti-osteoporotic, and anti-tumor effects and are well tolerated, even by cancer patients. In our previous review we detailed the molecular aspects of the development of type 2 diabetes, discussing the role of physical activity and diet, but we did not detail the role of medicinal mushrooms as part of nutrition. In this review, we aimed to summarize the most important medical mushrooms, along with their natural habitats, growing conditions, and components, that are presumably sufficient for the prevention and treatment of insulin resistance. [ABSTRACT FROM AUTHOR]

Featured Application: The utilization and beneficial roles of vitamin D as a bioactive ingredient with applications in health-promoting functional cosmetics and skincare products, offering anti-inflammatory and anti-aging protection against psoriasis; dermatitis; acne; and other inflammation-related skin disorders. Vitamin D, also called the "sunshine" vitamin, has gained great attention recently due to the observed high percentage of the worldwide population being deficient in this essential bioactive vitamin. Primarily, vitamin D was known for its important role in bone health. Nevertheless, recent research has shown its importance for the brain, heart, muscles, immune system, and skin health, due to its distinct bio-functionality in almost every tissue in the human body. Therefore, its deficiency has been highly correlated with multiple diseases, including skin and dermatologically associated ones. Moreover, different methodologies are applied to synthesize vitamin D, while the main vitamin D sources in human plasma levels and the factors that can cause adverse modifications are multiple. Further research upon vitamin D has exhibited its notable role against skin diseases, such as psoriasis, atopic dermatitis, vitiligo, acne, and rosacea. In this article, a critical review of the most relevant and significant information regarding the relationship between vitamin D and skin health is thoroughly conducted, while emphasis is given to its potential uses and benefits in several cosmetic applications. Current status, limitations, and future perspectives of such a potent bioactive are also extensively discussed. [ABSTRACT FROM AUTHOR]

Background: Previous studies have indicated that retinol and vitamin D may be associated with the oncogenesis of tongue cancer. Therefore, we aimed to assess the causal relationships of retinol and vitamin D with the risk of tongue cancer using the two-sample Mendelian randomization (MR) method. Methods: Single nucleotide polymorphisms (SNPs) related to retinol, vitamin D and tongue cancer were obtained from the up-to-date genome-wide association study (GWAS) catalogue, which was screened for instrumental variables (IVs). We performed two-sample MR analyses and used inverse-variance weighted (IVW) as the primary method. Additionally, we used the MR-pleiotropy residual sum and outlier (MR-PRESSO) method, MR-Egger intercept analysis, Cochran's Q test and leave-one-out analysis to evaluate the sensitivity of MR. Results: The IVW method revealed that retinol was not significantly correlated with the risk of tongue cancer (OR = 0.8602; 95% CI = 0.4453–1.6617; P = 0.654). However, the causal relationship between vitamin D and the risk of tongue cancer was significant according to IVW (OR = 0.4003; 95% CI = 0.1868–0.8577; P = 0.019). The sensitivity analysis did not detect any significant horizontal pleiotropy or heterogeneity. Conclusions: Given the limitations of this study, our MR study suggests that retinol is unlikely to influence the risk of tongue cancer, but vitamin D may decrease the risk of tongue cancer. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with no definitive trigger. However, epidemiological studies indicate that environmental factors, such as infection with Epstein-Barr virus (EBV) and low vitamin D (Vit D) levels in genetically predisposed individuals, are important risk factors. One leading proposal is that EBV triggers MS via mechanisms such as molecular mimicry, where activated autoreactive B and T lymphocytes mistakenly target self-antigens. In line with other risk factors, low serum Vit D level, genetic polymorphism of Vit D receptor, and higher incidence of MS in countries in the northern hemisphere, suggest that Vit D also plays a role in MS pathology. Vitamin D, known for its neuroprotective and immunomodulatory effects, helps maintain a balance between pro-inflammatory and anti-inflammatory immune cells. Studies and ongoing clinical trials indicate that hypovitaminosis D is associated with an increased risk of MS, and Vit D supplement can help to reduce the disease severity. Moreover, hypovitaminosis D has also been associated with a dysregulated immune system and an increased risk of developing MS. This review explores how these three well-recognized risk factors - EBV infection, hypovitaminosis D, and dysregulated immune system - interact in the pathogenesis of MS. Understanding these interactions and their consequences could provide new insights into novel therapeutic approaches for treating this devastating disease. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is a crucial factor in the progression of obesity-related type 2 diabetes (diabesity), contributing to skeletal muscle (SKM) dysfunction, calcium imbalance, metabolic inflexibility, and muscle atrophy. The ER and mitochondria together regulate intracellular calcium levels, and melatonin, a natural compound with antioxidant properties, may alleviate these challenges. Our previous research showed that melatonin raises intracellular calcium and preserves muscle structure by enhancing mitochondrial function in obese diabetic rats. This study further explores melatonin's potential to reduce ER stress in the vastus lateralis (VL) muscle by modulating the unfolded protein response (UPR) and restoring calcium levels disrupted by diabesity. Five-week-old Zücker diabetic fatty (ZDF) rats and lean littermates of both sexes were divided into control and melatonin-treated groups (10 mg/kg/day for 12 weeks). Flame atomic absorption spectrometry results showed that melatonin restored VL intraorganellar calcium homeostasis, increasing calcium levels in mitochondria and reducing them in the ER by raising the activity and expression of calcium transporters in both sexes of ZDF rats. Melatonin also decreased ER stress markers (GRP78, ATF6, IRE1α, and PERK) and reduced pro-apoptosis markers (Bax, Bak, P-JNK, cleaved caspase 3 and 9) while increasing Bcl2 levels and melatonin receptor 2 (MT2) expression. These findings suggest that melatonin may protect against muscle atrophy in obese and diabetic conditions by mitigating ER stress and calcium imbalance, highlighting its therapeutic potential. [ABSTRACT FROM AUTHOR]

Inorganic nitrate (NO3−) has been proposed to be of therapeutic use as a dietary supplement in obesity and related conditions including the metabolic syndrome (MetS), type II diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Administration of NO3− to endothelial nitric oxide synthase-deficient mice reversed aspects of MetS; however, the impact of NO3− supplementation in diet-induced obesity is not well understood. Here we investigated the whole body metabolic phenotype and cardiac and hepatic metabolism in mice fed a high-fat, high-sucrose (HFHS) diet for up to 12 mo of age, supplemented with 1 mM NaNO3 (or NaCl) in their drinking water. HFHS feeding was associated with a progressive obesogenic and diabetogenic phenotype, which was not ameliorated by NO3−. Furthermore, HFHS-fed mice supplemented with NO3− showed elevated levels of cardiac fibrosis and accelerated progression of MASLD including development of hepatocellular carcinoma in comparison with NaCl-supplemented mice. NO3− did not enhance mitochondrial β-oxidation capacity in any tissue assayed and did not suppress hepatic lipid accumulation, suggesting it does not prevent lipotoxicity. We conclude that NO3− is ineffective in preventing the metabolic consequences of an obesogenic diet and may instead be detrimental to metabolic health against the background of HFHS feeding. This is the first report of an unfavorable effect of long-term nitrate supplementation in the context of the metabolic challenges of overfeeding, warranting urgent further investigation into the mechanism of this interaction. NEW & NOTEWORTHY: Inorganic nitrate has been suggested to be of therapeutic benefit in obesity-related conditions, as it increases nitric oxide bioavailability, enhances mitochondrial β-oxidation, and reverses metabolic syndrome in eNOS−/− mice. However, we here show that over 12 months nitrate was ineffective in preventing metabolic consequences in high fat, high sucrose-fed mice and worsened aspects of metabolic health, impairing cholesterol handling, increasing cardiac fibrosis, and exacerbating steatotic liver disease progression, with acceleration to hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Melatonin is vital in human circadian rhythm and infant development. This scoping review summarized the current knowledge about melatonin's presence and effects in human milk to promote better understanding of its secretion pattern and clinical advancement of maternal-infant health. The review followed the Joanna Briggs Institute guideline and answered the question: What is the current knowledge about melatonin hormone in human milk? The databases searched were PubMed, CINAHL, SCOPUS, Web of Science, LILACS, Scielo, EMBASE, Science Direct, Eric, Cochrane, in addition to grey literature and reference lists of included sources. Research papers included English, Spanish, or Portuguese languages, regardless of study type or publication date. The study selection and data extraction involved two independent reviewers. Twenty-nine studies met inclusion criteria. The studies, conducted between 1993 and 2023, employed diverse designs, with cross-sectional studies being the most prevalent. Melatonin concentration exhibited a consistent pattern, being higher at night, and elevated in colostrum. The analysis methods for melatonin concentration evolved, with recent advancements contributing to more accurate measurements. Factors influencing melatonin levels, such as delivery type, maternal age, and health conditions, demonstrated a complex relationship, potentially impacting the health and development of infants. The dynamic nature of melatonin in human milk calls for continued interdisciplinary research, bridging gaps between clinical, biochemical, and epidemiological perspectives. Standardizing melatonin analysis methods are needed. Nurses should assess factors influencing melatonin levels in milk to promote interventions and guidance aimed at enhancing the regulation of the circadian cycle during the perinatal period and its benefits. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated retinal microvasculature changes in children with chronic kidney disease (CKD) using optical coherence tomography angiography (OCTA). It aimed to identify associations between OCTA parameters and serum levels of vitamin D, asymmetric dimethyl arginine (ADMA), vascular endothelial growth factor-A (VEGF-A), and angiopoietin-2 (Ang-2), and to examine their relationship with CKD progression as measured by estimated glomerular filtration rate (eGFR). Patients and methods: A single-center, cross–sectional, prospective correlation study used OCTA to compare retinal vessel density (VD) and foveal avascular zone area in 105 children: 35 on dialysis, 35 with nondialysis CKD, and 35 controls. Blood tests assessed kidney function and microvascular markers including ADMA, VEGF-A, and Ang-2. Results: Compared with controls, both CKD groups showed significantly lower VD in the macula. Additionally, both CKD groups had a larger foveal avascular zone area. In the dialysis group, vitamin D levels positively correlated with VD, while ADMA and Ang-2 levels negatively correlated. In the nondialysis group, albumin and vitamin D levels positively correlated with VD, while ADMA, VEGF, and Ang-2 levels were negatively correlated. Conclusion: Our findings suggest that OCTA is a valuable tool for monitoring microvascular health in children with CKD and highlights the potential roles of vitamin D, ADMA, Ang-2, and VEGF in CKD progression and microvascular damage. [ABSTRACT FROM AUTHOR]

Definitive chemoradiotherapy (CRT) is a cornerstone of treatment for locoregionally advanced head and neck cancer (HNC). Research is ongoing on how to improve the tumor response to treatment and limit normal tissue toxicity. A major limitation in that regard is the growing occurrence of intrinsic or acquired treatment resistance in advanced cases. In this review, we will discuss how overexpression of efflux pumps, perturbation of apoptosis-related factors, increased expression of antioxidants, glucose metabolism, metallotheionein expression, increased DNA repair, cancer stem cells, epithelial-mesenchymal transition, non-coding RNA and the tumour microenvironment contribute towards resistance of HNC to chemotherapy and/or radiotherapy. These mechanisms have been investigated for years and been exploited for therapeutic gain in resistant patients, paving the way to the development of new promising drugs. Since in vitro studies on resistance requires a suitable model, we will also summarize published techniques and treatment schedules that have been shown to generate acquired resistance to chemo- and/or radiotherapy that most closely mimics the clinical scenario. [ABSTRACT FROM AUTHOR]

Background: Falls are a major public health concern. Daily vitamin D supplementation is a proposed fall prevention strategy; however, safety concerns have arisen from some clinical trials showing increased fall risk when using higher vitamin D dosing methods. The relationship between vitamin D and falls may be influenced by factors, such as inflammation, which can alter the balance of essential nutrients like vitamin D and retinol, potentially affecting motor function. We use a genetic epidemiological approach to explore the association of inflammation, vitamin D, and fall risk. Methods: We included 307,082 UK Biobank participants and conducted observational and Mendelian randomization (MR) analyses to investigate associations between 25-hydroxyvitamin D [25(OH)D] and fall risk, with analyses including restriction to participants who had fallen and had inflammation as defined by CRP ≥ 5 mg/L. Results: In the observational analysis, CRP was associated with a higher (per 5 mg/L CRP increase OR = 1.06, 95% CI 1.05–1.07) and 25(OH)D with a lower odds of falls. The association between 25(OH)D concentrations and fall risk was non-linear (p < 0.001), reflecting a plateauing of the association at higher concentrations. There was an interaction between 25(OH)D and CRP on their association with the odds of falls (p = 0.009). In participants with CRP ≥ 5 mg/L, the association was U-shaped, and the fall risk was elevated for both 25(OH)D < 25 nmol/L and ≥ 100 nmol/L (p < 0.004). The association between high 25(OH)D and falls was most pronounced for participants with CRP ≥ 20 mg/L (≥ 100 nmol/L vs. 50–74.99 nmol/L: OR = 2.40, 95% CI, 1.50–3.86). Genetically predicted higher 25(OH)D was not associated with fall risk in the overall population, but a suggestive association with fall risk was seen in participants who had fallen and had CRP > 20 mg/L (926 cases; OR = 1.20, 95% CI, 1.00–1.44). Conclusions: Our study suggests that inflammation might modify the vitamin D and fall risk relationship. Both low and high 25(OH)D levels are associated with more falls in individuals with chronic inflammation, with supporting evidence seen in both observational and MR analyses. This may provide insight into the increased fall risk following high-dose vitamin D supplementation in clinical trials, warranting further research. [ABSTRACT FROM AUTHOR]

Two APOBEC DNA cytosine deaminase enzymes, APOBEC3A and APOBEC3B, generate somatic mutations in cancer, thereby driving tumour development and drug resistance. Here, we used single-cell RNA sequencing to study APOBEC3A and APOBEC3B expression in healthy and malignant mucosal epithelia, validating key observations with immunohistochemistry, spatial transcriptomics and functional experiments. Whereas APOBEC3B is expressed in keratinocytes entering mitosis, we show that APOBEC3A expression is confined largely to terminally differentiating cells and requires grainyhead-like transcription factor 3 (GRHL3). Thus, in normal tissue, neither deaminase appears to be expressed at high levels during DNA replication, the cell-cycle stage associated with APOBEC-mediated mutagenesis. In contrast, in squamous cell carcinoma we find that, there is expansion of GRHL3expression and activity to a subset of cells undergoing DNA replication and concomitant extension of APOBEC3A expression to proliferating cells. These findings suggest that APOBEC3A may play a functional role during keratinocyte differentiation, and offer a mechanism for acquisition of APOBEC3A mutagenic activity in tumours. Synopsis: APOBEC3A and APOBEC3B encode DNA editing enzymes with anti-viral roles that generate somatic mutations in cancer. This study provides insight into their expression in healthy and cancerous epithelial tissues, and identifies Grainyhead-like transcription factor (GRHL3) as regulator of the APOBEC3A gene. APOBEC3B is expressed during cell division and is restricted to proliferating cells in healthy human epithelia, while APOBEC3A is induced during keratinocyte differentiation following cell cycle exit. APOBEC3A and APOBEC3B expression patterns observed in healthy squamous epithelia are recapitulated in squamous cell carcinomas. APOBEC3A expression in head and neck squamous cell cancer cell lines and differentiating keratinocytes is dependent upon the epithelial-specific transcription factor, GRHL3. Aberrant GRHL3 activation in dividing cells represents a potential driver of mutagenic APOBEC3A activity in cancer. DNA-editing enzymes APOBEC3A and APOBEC3B function context-dependently in malignant squamous epithelia and healthy keratinocyte differentiation. [ABSTRACT FROM AUTHOR]

Simple Summary: As we age, our immune system becomes less effective, a process called immunosenescence. This weakening of the immune system makes older adults more susceptible to infections, reduces the effectiveness of vaccines, and increases the risk of age-related diseases. Our review examines the complex biological mechanisms behind immunosenescence and explores how lifestyle factors like diet, exercise, and stress management can influence this process. We discuss recent scientific findings that shed light on how aging affects immune cells at the molecular level and how these changes contribute to chronic low-grade inflammation often seen in older adults. Understanding these processes is crucial for developing strategies to maintain a healthy immune system as we age. Our research suggests that adopting certain lifestyle habits and potential medical interventions could help slow down or partially reverse some aspects of immune aging, potentially leading to better health outcomes for older populations. Immunosenescence, the age-related decline in immune function, is a complex biological process with profound implications for health and longevity. This phenomenon, characterized by alterations in both innate and adaptive immunity, increases susceptibility to infections, reduces vaccine efficacy, and contributes to the development of age-related diseases. At the cellular level, immunosenescence manifests as decreased production of naive T and B cells, accumulation of memory and senescent cells, thymic involution, and dysregulated cytokine production. Recent advances in molecular biology have shed light on the underlying mechanisms of immunosenescence, including telomere attrition, epigenetic alterations, mitochondrial dysfunction, and changes in key signaling pathways such as NF-κB and mTOR. These molecular changes lead to functional impairments in various immune cell types, altering their proliferative capacity, differentiation, and effector functions. Emerging research suggests that lifestyle factors may modulate the rate and extent of immunosenescence at both cellular and molecular levels. Physical activity, nutrition, stress management, and sleep patterns have been shown to influence immune cell function, inflammatory markers, and oxidative stress in older adults. This review provides a comprehensive analysis of the molecular and cellular mechanisms underlying immunosenescence and explores how lifestyle interventions may impact these processes. We will examine the current understanding of immunosenescence at the genomic, epigenomic, and proteomic levels, and discuss how various lifestyle factors can potentially mitigate or partially reverse aspects of immune aging. By integrating recent findings from immunology, gerontology, and molecular biology, we aim to elucidate the intricate interplay between lifestyle and immune aging at the molecular level, potentially informing future strategies for maintaining immune competence in aging populations. [ABSTRACT FROM AUTHOR]

From fertilisation to delivery, calcium must be transported into and within the foetoplacental unit for intracellular signalling. This requires very rapid, precisely located Ca2+ transfers. In addition, from around the eighth week of gestation, increasing amounts of calcium must be routed directly from maternal blood to the foetus for bone mineralisation through a flow-through system, which does not impact the intracellular Ca2+ concentration. These different processes are mediated by numerous membrane-sited Ca2+ channels, transporters, and exchangers. Understanding the mechanisms is essential to direct interventions to optimise foetal development and postnatal bone health and to protect the mother and foetus from pre-eclampsia. Ethical issues limit the availability of human foetal tissue for study. Our insight into the processes of placental Ca2+ handling is advancing rapidly, enabled by developing genetic, analytical, and computer technology. Because of their diverse sources, the reports of new findings are scattered. This review aims to pull the data together and to highlight areas of uncertainty. Areas needing clarification include trafficking, membrane expression, and recycling of channels and transporters in the placental microvilli; placental metabolism of vitamin D in gestational diabetes and pre-eclampsia; and the vascular effects of increased endothelial Orai expression by pregnancy-specific beta-1-glycoproteins PSG1 and PSG9. [ABSTRACT FROM AUTHOR]

Objective: Young plasma is rich in rejuvenating factors that are diminished in aged mice, making it a promising treatment for organ regeneration and hormonal secretion support. Enhancing hormonal renewal suggests that this therapy may influence the expression of vitamin D receptor (VDR), which declines with aging. In this study, plasma therapy was applied to aged rats to evaluate its effects on histomorphological parameters and VDR levels in the jejunum. Materials and Methods: Aged female Wistar rats (12-15 months, n=7) were treated with pooled plasma collected from younger rats (6 months, n=28). Post-treatment, villus height, total mucosal thickness, crypt depth, and surface absorption areas were measured in the jejunum of rats in the experimental group (n=7), control group (n=7), and a positive control young group (YPC) (5 weeks, n=7). VDR expression was assessed using immunohistochemistry, and the number of VDR-positive cells was quantified within 0.01 mm2 areas for all groups. Results: Histomorphological evaluation revealed no statistically significant differences between the experimental group and the YPC group in villus height, total mucosal thickness, and surface absorption area parameters. However, the experimental group exhibited the highest crypt depth compared to the YPC group. Both the YPC and experimental groups demonstrated increases in all parameters, including histological and VDR evaluations, compared to the control group. Conclusion: The plasma treatment supported parameters that facilitate digestion and increased VDR expression, which decreases with aging, thereby exerting a beneficial influence. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR), a significant microvascular complication of diabetes mellitus (DM), remains a major cause of vision loss worldwide. Vitamin D, recognized for its role in bone health, has also been implicated in various non-skeletal conditions, including DR. This systematic review analyzed data from 20 studies involving 22,408 participants to explore the relationship between vitamin D levels and DR. Studies were included based on strict eligibility criteria, ensuring they could distinctly classify participants into DR and non-DR groups and provide quantitative measurements of vitamin D levels. Of these, nine studies were included in the meta-analysis. The pooled analysis revealed a significant association between lower vitamin D levels and increased odds of DR, with a combined odds ratio (OR) of 1.15 (95% CI: 1.10–1.20) under the fixed-effects model and 1.17 (95% CI: 1.08–1.27) under the random-effects model. Mean serum vitamin D levels were lower in individuals with DR (18.11 ± 5.35 ng/mL) compared to those without DR (19.71 ± 7.44 ng/mL), with a progressive decline observed across DR severity stages. Subgroup analyses showed significantly lower levels of vitamin D in proliferative DR compared to non-proliferative stages. Heterogeneity (I2 = 89%) was noted, most probably due to geographic differences, varying methodologies for vitamin D measurement, and DR classification approaches. Secondary analyses indicated that vitamin D deficiency prevalence ranged from 27% to 95% in DR populations, highlighting its potential role in disease progression. This review highlights the need for longitudinal studies to better understand the causal relationship. The findings also call attention to a critical gap in the literature regarding the therapeutic role of vitamin D supplementation in preventing and managing DR. Addressing vitamin D deficiency as a modifiable risk factor in DM care may offer new avenues for reducing the burden of DR. [ABSTRACT FROM AUTHOR]

A panel of four microRNAs (miRNAs) was investigated in normal and neoplastic canine mammary gland samples using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The relationship between these miRNAs and histopathological features, including benign and malignant lesions, as well as different histopathological types (simple carcinoma, complex carcinoma, and other subtypes), was explored. MiR-29b was identified as a potential biomarker of malignancy, as its levels were elevated in malignant samples compared to benign samples. Furthermore, let-7b, miR-29b, and miR-125b, together, appear to have the potential to discriminate among the three histological types. MicroRNAs (miRNAs) are short non-coding RNA molecules involved in post-transcriptional control. They are closely related to cancer-associated processes, making them promising candidates for diagnostic and prognostic biomarkers, as well as targets for cancer therapy. This study investigated the expression levels of let-7b, miR-29b, miR-125b, and miR-146 in normal and neoplastic canine mammary gland samples by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Furthermore, the miRNA profile of the tumors was compared to adjacent mammary glands and to normal control mammary tissues. MiR-29b and miR-125b were downregulated in both benign and malignant lesions compared to the control, while let-7b was significantly downregulated only in malignant lesions. Additionally, miR-29b was upregulated in the malignant group compared to the benign group. Regarding histological type analysis, miR-125b was downregulated in simple carcinomas compared to complex carcinomas, whereas let-7b and miR-29b were upregulated in complex and simple carcinomas compared to the other subtypes, respectively. MiR-29b has been shown to be able to differentiate malignant from benign, while miR-125b can discriminate simple carcinomas from complex carcinomas. In addition, let-7b, miR-29b, and miR-125b, together, can discriminate simple and complex histological types from other histological types. In conclusion, the present study demonstrated that the expression of these miRNA changes during the tumorigeneses process, representing an epigenetic mechanism to sustain canine mammary tumor development, and identified these miRNAs as promising diagnostic biomarkers. [ABSTRACT FROM AUTHOR]

Vitamin D receptor (VDR) polymorphisms are linked with the incidence and severity of several autoimmune diseases. The current work aimed at evaluating if VDR rs1544410 (BsmI), rs7975232 (ApaI) and rs2228570 (FokI) gene polymorphisms could be predictors of response to steroid treatment in patients with immune thrombocytopenia (ITP). The study involved 75 steroid treatment responders and 75 resistant ITP patients. All participants were subjected to VDR BsmI, ApaI and FokI gene polymorphisms analysis through genotyping by RT-PCR. Carrying the FokI F allele was significantly associated with low vitamin D level and increased risk of developing steroid resistance. Interestingly, the tri-allelic haplotypes BAF and BaF were significantly only present in steroid resistant ITP patients. Thus, the present study suggests that VDR FokI F allele may contribute to ITP pathogenesis and resistance to steroid treatment. Knowing the genetic background of patients helps to individualize treatment to obtain a better outcome., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The triglyceride-glucose index (TyG) and the triglyceride to high-density lipoprotein ratio (TG/HDL-c) are novel indicators for assessing insulin resistance (IR) in epidemiological studies. This study aimed to evaluate the association between 25-hydroxy-vitamin D [25(OH)D] levels and these two indicators in the adult population of the United States. 14,380 participants aged 20 years and older were included from the National Health and Nutrition Examination Survey (NHANES). Multivariable linear regression models were used to analyze the association between 25(OH)D and TyG, as well as TG/HDL-c. Smooth fitting curves were employed to identify potential non-linear relationships between 25(OH)D, TyG, and TG/HDL-c. The findings revealed a negative association between 25(OH)D and TyG, with the effect being more pronounced in males and individuals with diabetes (p < 0.01). Similarly, 25(OH)D was negatively associated with TG/HDL-c, with a stronger impact observed in males compared to females. The study population was divided into four quartiles based on 25(OH)D concentration, and TyG and TG/HDL-c levels in Q3 and Q4 were lower than those in Q1. Furthermore, a non-linear relationship was observed between 25(OH)D and TyG, with an inflection point at 19.352 ng/mL. A non-linear relationship was also found between TG/HDL-c and 25(OH)D, with an inflection point at 37.211 ng/mL. 25(OH)D is an independent factor significantly associated with TyG and TG/HDL-c indexes. This negative association may be related to the role of 25(OH)D in insulin resistance., (© 2025 AOCS.)

Diet and nutritional metabolites exhibit wide-ranging effects on health and disease partly by altering tissue composition and function. With rapidly rising rates of obesity, there is particular interest in how obesogenic diets influence tissue homeostasis and risk of tumorigenesis; epidemiologically, these diets have a positive correlation with various cancers, including colorectal cancer. The gastrointestinal tract is a highly specialized, continuously renewing tissue with a fundamental role in nutrient uptake and is, in turn, influenced by diet composition and host metabolic state. Intestinal stem cells are found at the base of the intestinal crypt and can generate all mature lineages that comprise the intestinal epithelium and are uniquely influenced by host diet, metabolic by-products and energy dynamics. Similarly, tumour growth and metabolism can also be shaped by nutrient availability and host diet. In this Review, we discuss how different diets and metabolic changes influence intestinal stem cells in homeostatic and pathological conditions, as well as tumorigenesis. We also discuss how dietary changes and composition affect the intestinal epithelium and its surrounding microenvironment., Competing Interests: Competing interests: O.H.Y. is a scientific advisory board member or adviser to AVA Lifesciences, Nestle Health and Jumble Therapeutics. J.E.S.S. declares no competing interests., (© 2024. Springer Nature Limited.)