Stress is associated with various health issues. Research has highlighted the relationship between chronic stress and male reproductive health. One of the primary mechanisms underlying stress-induced male reproductive dysfunction is impaired steroidogenesis. In the present study, we validated a chronic unpredictable stress (CUS) model and investigated testicular dysfunction in CUS rats. The CUS paradigm involved exposing rats to a variety of stressors daily for 8 weeks. Vitamin D (10 µg/kg/twice a week, p.o) was administered to CUS rats starting 2 weeks after the onset of stress exposure and continued until the end of study. The stress in rats was confirmed by the occurrence of anxiety and depressive-like behaviours through elevated plus-maze test & novelty-suppressed feeding test and rise in serum corticosterone levels. Testicular dysfunction in CUS rats was assessed via serum gonadotropins, testosterone, cytokines, oxidative stress, and testis-epididymis-sperm morphology. The reduction in steroidogenesis was confirmed via immunohistochemical analysis of 17β-hydroxysteroid dehydrogenase-3 (17β-HSD3), steroidogenic acute regulatory gene (StAR) and vitamin D receptor (VDR) expression. Further, we studied the role of vitamin D in alleviating stress-induced testicular damage and the potential mechanisms underlying steroidogenic alterations in CUS rats. Notably, vitamin D treatment prevented CUS-induced decline in testicular 17β-HSD3, StAR and VDR expression. Moreover, vitamin D ameliorated the CUS-induced reduction in serum testosterone levels. Histological assessment revealed that vitamin D prevented CUS-induced damage in sperm, testis and epididymis morphology. In conclusion, our findings suggest that CUS exposure induces testicular dysfunction, which can be prevented by vitamin D, potentially through the regulation of steroidogenic pathways.

Although biologically known for its central role in calcium homeostasis, Vitamin D3 (VD3), owing to its scattered receptors across bodily tissues and the presence of its metabolizing enzymes, has recently garnered scientific attention. This review examined the literature to document the role and specific mechanisms of action of VD3, its receptors, and metabolizing enzymes in male reproduction. Using the keywords Vitamin D3, vitamin D receptors, vitamin D metabolic enzymes, and male reproductive system to search PUBMED and other academic archives, it was observed that VD3, through its interaction with the VDR and with the backing of the activities of its metabolizing enzymes, modulates the male reproductive functions, acting as an antioxidant and anti-inflammatory in reproductive organs to prevent oxidative damages that may result from exposure to environmental toxicants and the increased oxygen utilization by mitochondria owing to high level of unsaturated fatty acids in the testis, thus preventing male infertility. ESSENTIAL POINTS: Search Strategy: PUBMED, GOOGLE SCHOLAR, MEDLINE, SCOPUS database This review narrated the impact of VD3 on male reproduction: exploring its Receptor-Mediated and Enzymatic Regulation of Fertility, Erectile Function, Testicular Health, and Sperm Quality. Articles used were obtained from PubMed, MEDLINE, and Scopus databases with the Subject title terms "Vitamin D3" OR "Cholecalciferol" OR "1, 25-Dihydroxyvitamin D3" AND "Male fertility" OR "Erectile function" OR "Testicular health" OR "Sperm quality", "Vitamin D3" OR "VD3" AND "Vitamin D receptor" OR "VDR" AND "Male reproductive health" OR "Fertility". "1, 25-Dihydroxyvitamin D3" OR "1-alpha-hydroxylase" AND "Testicular function" OR "Sperm motility" OR "Sperm morphology". "Vitamin D3" OR "VD3" AND "CYP27B1" OR "CYP24A1" AND "Male reproductive biology" OR "Fertility". Articles published in English language were used.

This systematic review and meta-analysis aimed to investigate the influence of single nucleotide polymorphisms (SNPs) related to vitamin D receptor genes (VDR) on caries experience.

The search included five databases, focusing exclusively on human studies. Meta-analyses were conducted for each SNP and polling data from various SNPs within the gene. A Funnel Plot and Egger's test were performed.

Fourteen studies were included in the systematic review and thirteen in the meta-analysis. Seven SNPs related to VDR were assessed, and most (57.1 %) were in exon regions. A total of 4944 participants were included. No individual SNP was found to be significantly associated with caries in any of the evaluated models (allelic, genotypic heterozygous, or homozygous) (p > 0.05). No difference was observed even when stratifying via subgroup analysis according to population (p > 0.05). In the gene-level analysis adjusted by linkage disequilibrium, the overall model showed an OR of 0.93 (95 %CI: 0.69-1.23) for the allelic analysis, 1.15 (95 %CI: 0.84-1.57) for the homozygous genotypic model, and 1.18 (95 %CI: 0.95-1.48) for the heterozygous genotypic model. When stratified by subgroups, the East Asian population was associated with an increased OR of 1.42 (95 %CI: 1.01-2.01) in the heterozygous genotypic model. Egger's test showed no significant publication bias for all models (p > 0.05).

The present findings showed that the SNPs in VDR are influenced by ethnic background and may play an important role in dental caries experience according to different ethnic groups. (CRD42020134424).

Ulcerative Colitis (UC) is a chronic inflammatory condition resulting from an abnormal immune response to gut microbiota, leading to cytokine dysregulation, including elevated interleukin-23 (IL-23) levels. Emerging evidence suggests that vitamin D (VD) plays a crucial role in immune modulation. However, its correlation with IL-23 in UC is not well addressed. This study aims to elucidate the relationship between serum VD and IL-23 levels in UC patients. We included forty-four UC patients and forty-four healthy controls. VD insufficiency was more common in UC patients (n = 14) compared to controls (n = 5). Significant increases in IL-23 levels were observed from remission (46.6 ± 4.3 pg/mL) to severe stages (218.5 ± 62.41 pg/mL), while VD levels did not show a similar trend. IL-23 levels also rose significantly with disease extent, from proctitis to pancolitis. A significant negative correlation was found between VD and IL-23 levels (r = -0.3175; P = 0.035). IL-23 and pulse rate were significant predictors of UC in our cohort. Our findings highlight VD insufficiency to be prevalent in UC patients, with VD levels negatively correlating with IL-23 levels, which increase with disease severity and extent. Further, understanding the interplay between VD and IL-23 will help design therapeutic interventions to modulate immune response and disease progression.

Diabetic retinopathy (DR), one of the most common microvascular complications of diabetes mellitus (DM), remains to be a major driver of vision loss worldwide. Vitamin D has been reported to be involved in DR pathogenesis, but results have been inconsistent. We aimed to explore the relationship between blood 25-hydroxyvitamin D, 25(OH)D, level and the risk of DR in patients with type 2 diabetes (T2DM).

A total of 535 adults with T2DM from our department were included. Demographic information, biochemical data, 25(OH)D, and sex hormones were collected. Fundus photography was performed to determine the presence of DR. Participants were grouped into the DR group and the non-DR (NDR) group according to the fundus examinations and four groups based on serum 25(OH)D levels as follows: normal, insufficient, deficient, and severely deficient. Multivariate logistic regression analysis was used to evaluate the association between 25(OH)D and risk of DR.

Males but not females with DR had significantly decreased levels of 25(OH)D (16.4 ± 5.6 ng/ml vs. 21.0 ± 5.0 ng/ml, P = 0.001) and increased proportion of severe 25(OH)D deficiency (14.8% vs. 6.7%, P = 0.022) compared to those without DR. Likewise, there was a gradually increasing percentage of DR with the reduction of 25(OH)D levels only in males (35.7%, 44.4%, 53.2%, 70.3%, P = 0.022). Intriguingly, total testosterone (TT) levels decreased markedly in males with DR (12.9 ± 5.2 nmol/L vs. 14.2 ± 5.5 nmol/L, P = 0.035) compared to their counterparts and correlated positively with 25(OH)D (β = 0.161, P = 0.007), which did not occur in females. After multivariate adjustment, we observed a significant inverse association between serum 25(OH)D and the occurrence of DR in males, showing that the adjusted ORs (AORs) and 95% confidence interval for DR were 0.233 (0.070-0.779) in the normal group, 0.280 (0.103-0.756) in the insufficient group, and 0.477 (0.196-1.164) in the deficiency group with the severely deficient group as a reference (P-trend = 0.003). However, such a significant association was not observed in females (P-trend = 0.137).

We concluded a gender-specific relationship between serum 25(OH)D and the incidence of DR in T2DM, supported by a significant inverse association between serum 25(OH)D and DR only in males, which could be mediated by a marked reduction in TT levels.

Single-nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) contribute to inadequate metabolic profiles in individuals with type 2 diabetes mellitus (T2DM).

We sought to elucidate the relationship among SNPs in the VDR and markers for glycemic control, lipid profile, and inflammation in individuals with T2DM.

We performed a systematic search in the MEDLINE (via PubMed), EMBASE, and SCOPUS databases in July 2021 and updated the search in October 2023.

6 observational studies were selected from the databases, and 1 study was included after checking the reference list. Two authors independently completed the selection and data extraction of studies and population characteristics, the prevalence of SNPs in the VDR, genotyping methods, and laboratory findings, and performed summary statistics of the results.

The meta-analyses were performed on 5 studies including 1198 adults with T2DM. The duration of the diabetes diagnosis ranged from 5.0 to 14.7 years. A random-effects model was used to pool the results using a 2-tailed (P < .05). Effect sizes were reported as standardized mean differences (SMDs) and 95% confidence intervals (CIs). Four SNPs in the VDR were identified (Fokl, BsmI, Taql, and Apal) by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Fokl SNP was identified in 5 studies and associated with a higher percentage of glycated hemoglobin (HbA1c%) (SMD,  0.41 [95% CI, 0.15-0.67]). The Bsml in 4 studies was associated with higher triacylglycerol (SMD, 0.21 [95% CI, 0.03-0.38]). The Taql SNP was identified in 2 studies and did not show any associations, and the Apal SNP was identified in only 1 study and was not analysed in the meta-analysis.

Although the studies identified 4 SNPs in the VDR, the results of the meta-analysis allowed us to infer only the association of the SNPs Fokl and Bsml with increased %HbA1c and triacylglycerol levels, respectively, in individuals with T2DM.

PROSPERO registration number CRD42021268152.

Hashimoto's thyroiditis (HT) is an autoimmune disease influenced by genetic factors and environmental triggers that affect immune system function. Data suggest that vitamin D may also play a role in the etiopathogenesis of HT.

This retrospective study included patients admitted to the Endocrinology and Metabolic Diseases Outpatient Clinic. Data from individuals aged 18 years and older were analyzed, including serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-TG), and vitamin D. HT was diagnosed based on the presence of anti-TPO and/or anti-TG antibodies, while individuals with negative results for both were classified as non-HT. Thyroid function was categorized as euthyroid if TSH levels were between 0.55 mU/L and 4.78 mU/L and fT4 levels were between 0.89 ng/dL and 1.76 ng/dL; hypothyroid status was defined as TSH > 4.78 mU/L. Vitamin D levels were classified as deficient (<50 nmol/L), insufficient (50-74.9 nmol/L), or sufficient (≥75 nmol/L).

Of the total participants, 25,018 did not have HT, while 27,800 were diagnosed with HT. Vitamin D level was significantly higher in the HT group than the non-HT group (41.43 nmol/L and 39.44 nmol/L, p < 0.001). Vitamin D deficiency was present in 65.5% of the non-HT group and 62.1% of the HT group (p < 0.001). Subgroup analyses based on thyroid function showed that vitamin D levels were highest in the euthyroid HT group and similar in the euthyroid non-HT, hypothyroid non-HT, and hypothyroid HT groups (p < 0.001).

In conclusion, while vitamin D levels were higher in the HT group compared to the non-HT group, no clinically significant association between vitamin D levels and HT or autoantibody positivity was observed. Vitamin D deficiency was more prevalent in the hypothyroid group compared to the euthyroid group. This study suggests that although vitamin D deficiency may not be directly involved in the pathogenesis of HT, it may still play a role in modulating immune activity or influencing the disease phenotype..

This research focused on the association of vitamin D receptor (VDR) and vitamin D binding protein (VDBP) gene polymorphisms with sepsis susceptibility and prognosis.

110 septic patients were selected as the sepsis group, and another 100 patients with common infections who did not develop sepsis as the control group. 28 days death of patients in the sepsis group were counted. Within 24 h of admission, patients were scored by Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) and Sequential Organ Failure Assessment (SOFA). Serum lactate (Lac), C-reactive protein (CRP), procalcitoninogen (PCT) and vitamin D levels were evaluated. All patient DNAs were extracted. The polymorphisms of VDR and VDBP genes and vitamin D genes Fok Ⅰ (rs2228570) and VDBP rs4588 locus were tested and compared in both groups; and the receiver operating characteristic (ROC) curves were plotted to calculate the area under the area under the curve (AUC) and assess the diagnostic value of each indicator for sepsis. Patients in the sepsis group were categorized into a death group and a survival group, the above indicators were compared in the two groups and the factors affecting the prognosis of sepsis patients were analyzed.

Compared to the control group, the sepsis group exhibited higher APACHE II scores, SOFA scores, serum Lac, CRP, PCT levels, VDR Fok Ⅰ (rs2228570) locus f allele and VDBP rs4588 locus A allele frequencies, and lower vitamin D levels (P < 0.05). The ROC curve analysis showed that the AUC for the diagnosis of sepsis using the AA genotype at the VDBP gene rs4588 locus was 0.579 (95% CI: 0.501-0.656) (sensitivity: 52.70%; specificity: 63.00%, P < 0.05). APACHE II and SOFA scores and serum levels of Lac, CRP, and PCT in the death group were raised and vitamin D levels were diminished than those in the survival group (P < 0.05). Raised APACHE II and SOFA scores were independent risk factors affecting sepsis prognosis.

The f allele at the VDR Fok Ⅰ (rs2228570) locus and the A allele at the VDBP rs4588 locus significantly raise the risk of sepsis in patients.

Since the beginning of COVID-19 pandemic, there has been a noticeable increase in the consumption of vitamin D. Evidence accentuates the generation of a pro-tolerogenic T helper 2 cell state with vitamin D, suppressing T helper 1 inflammatory response. T helper 2 cell polarization is characteristic of atopy. However, although the literature on vitamin D and atopy has yielded controversial results, multiple studies have described an inverse relationship between vitamin D levels and the severity of atopy, as well as an improvement of the pathology with vitamin D supplementation. A different approach is offered in the analysis of the immunological mechanisms by which vitamin D acts in the human body, supporting its use as a promoter of homeostasis. In this sense, vitamin D promotes a balanced state through the action of regulatory T cells, controlling cytokines, both pro- and anti-inflammatory, and by reducing B cell prolif eration and differentiation, thus preventing the possible development of atopy.

The causal relationships between hallux valgus (HV), sedentary behavior and calcium homeostasis remain unclear. This study aimed to explore these associations using Mendelian randomization (MR) analysis. Leisure screen time (LST) was used as an indicator of sedentary behavior, while seven traits and three diseases were selected to represent calcium homeostasis. Two-sample MR was performed to assess the causal effect of sedentary behavior and calcium homeostasis on HV. Two-step MR was conducted to quantify the mediating roles of calcium homeostasis-related traits in the association between sedentary behavior and HV. Our results showed that longer LST was strongly associated with higher risk of HV (odds ratio (OR) = 1.1902, 95 %CI = 1.0129-1.3986, p = 0.0343). By contrast, serum calcium (S-Ca) levels were negatively associated with HV risk (OR = 0.7530, 95 %CI = 0.5675-0.9992, p = 0.0494). Mediation analyses found that S-Ca played an important mediating role in the effect of LST on HV (proportion mediated = 10.4 %). Our results extend the understanding of the pathogenesis of HV, and highlight the importance of preoperative metabolic optimization and postoperative behavioral and calcium supplementation strategies to enhance surgical outcomes and mitigate recurrence.

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.

Proper regulation of intestinal permeability is essential for maintaining the integrity of the intestinal mucosal barrier. An abnormal increase in permeability can significantly contribute to the onset and progression of various diseases, including autoimmune disorders, metabolic conditions, allergies, and inflammatory bowel diseases. The potential connection between intestinal permeability and maternal health during pregnancy is increasingly recognized, yet a comprehensive review remains lacking. Pregnancy triggers a series of physiological structural adaptations and significant hormonal fluctuations that collectively contribute to an increase in intestinal permeability. Although an increase in intestinal permeability is typically a normal physiological response during pregnancy, an abnormal rise is associated with immune dysregulation, metabolic disorders, and various pregnancy-related complications, such as recurrent pregnancy loss, gestational diabetes mellitus, overweight and obesity during pregnancy, intrahepatic cholestasis of pregnancy, and preeclampsia. This paper discusses the components of the intestinal mucosal barrier, the concept of intestinal permeability and its measurement methods, and the mechanisms and physiological significance of increased intestinal permeability during pregnancy. It thoroughly explores the association between abnormal intestinal permeability during pregnancy and maternal diseases, aiming to provide evidence for the pathophysiology of disease development in pregnant women. Additionally, the paper examines intervention methods, such as gut microbiota modulation and nutritional interventions, to regulate intestinal permeability during pregnancy, improve immune and metabolic states, and offer feasible strategies for the prevention and adjuvant treatment of clinical pregnancy complications.

Background/Objectives: Patients suffering from rare diseases are particularly vulnerable to vitamin D deficiency. The role of vitamin D status in rare disease management remains insufficiently investigated and employed in routine clinical practice. Methods: This review analyses current data on vitamin D status in selected rare diseases of organs involved in vitamin D metabolism: skin (epidermolysis bullosa, morphea), liver (autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis), kidney (Alport syndrome, Fabry disease), and cystic fibrosis as a model of a systemic rare disease. Additionally, this review critically examines potential drug-vitamin D interactions in the context of rare disease patient polypharmacy. Results: Evidence suggests that vitamin D deficiency is prevalent in rare disease patient populations, often at once exacerbating and being simultaneously exacerbated by the underlying condition. Vitamin D deficiency correlates with worse clinical outcomes and lower quality of life across the examined diseases. Immunoregulatory properties of vitamin D appear relevant for rare diseases with autoimmune components. Conclusions: An urgent need for developing disease-specific clinical practice guidelines, implementing routine vitamin D monitoring in rare disease patient care, and introducing tailored supplementation under the principles of precision medicine is emphasized.

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.

Current approaches to vitamin D supplementation are generally limited to its oral intake. In this experimental study, the effects of applying vitamin D-fortified sunscreen creams to the skin on the absorption, and therefore levels of serum vitamin D metabolites were investigated. Forty 8-week-old male Wistar Albino rats were used in the study. Eight rats (Group B) were sacrificed to determine the baseline values of biochemical parameters. The remaining 32 rats were randomly divided into 4 equal groups as follows: Group S, only the back skin of the rats were shaved; Group SD, only vitamin D3 diluted with sunflower oil was applied to the shaved area; Group SC, only sunscreen cream was applied to the shaved area; and Group SDC, sunscreen cream fortified with vitamin D3 was applied to the shaved area. Serum 25(OH)D3 and 24,25(OH)2D3 levels were determined at the end of 8 weeks. Mean (± SD) serum 25(OH)D3 levels of groups B, S, SD, SC, and SDC were determined as 17.7 ± 5.7, 13.5 ± 3.1, 54.1 ± 13.0, 19.6 ± 2.7, 67.2 ± 16.5 ng/mL, respectively. There were statistically significant differences in serum 25(OH)D3 values between groups S and SD (p < 0.001) and between groups SC and SDC (p = 0.002). A positive correlation was found between serum 25(OH)D3 and 24,25(OH)2D3 parameters (r = 0.772; p < 0.001). With this study, it was concluded that vitamin D-fortified sunscreen cream increases serum vitamin D levels by exerting transdermal activity. Further studies are required to confirm this observations.

Vitamin D deficiency is linked to worse outcomes in patients with chronic liver diseases (CLD). However, data in patients with autoimmune hepatitis (AIH) remain limited.

We aimed to assess the impact of vitamin D deficiency on the outcomes of individuals with AIH.

This retrospective cohort study used the TriNetX research network to identify patients with AIH. Patients were matched using propensity score matching and stratified to sufficient vitamin D levels (e.g., 25 (OH) D3 ≥ 30 ng/mL), vitamin D insufficiency (25 (OH) D3: 20-29.9 ng/mL) and vitamin D deficiency (e.g., 25 (OH) D3 < 20 ng/mL). The primary outcome was the all-cause mortality among adult patients with AIH. Secondary outcomes included decompensated liver cirrhosis, acute hepatic failure, liver transplantation (LT), all-cause hospitalizations and all-cause critical care admissions.

A total of 1288 AIH patients with vitamin D deficiency were identified and propensity matched with 1288 patients with normal vitamin D levels. Patients with vitamin D deficiency had significantly increased odds for all-cause mortality compared to those with normal levels (adjusted odds ratio (aOR) = 3.2, 95%CI: 2.3-4.48). Patients with vitamin D deficiency were at increased odds of all-cause hospitalizations (aOR = 2.37, 95%CI: 1.97-2.84), critical care unit admissions (aOR = 2.8, 95%CI: 2.21-3.71), decompensated liver cirrhosis (aOR = 2.74, 95%CI: 2.13-3.54), acute hepatic failure (aOR = 3.11, 95%CI: 2.09-4.62) and LT (aOR = 3.47, 95%CI: 1.71-7.04), as compared to those with normal vitamin D levels.

This cohort study showed significantly increased odds for all-cause mortality in AIH patients with vitamin D deficiency. Vitamin D deficiency in patients with AIH was associated with increased likelihood of hospitalisation, decompensated liver cirrhosis, acute liver failure and LT.

To understand the status of vitamin D deficiency in girls with growth and developmental variations, as well as the impact of COVID-19 on their vitamin D levels, and to provide reference for the prevention and treatment of vitamin D deficiency in children.

A retrospective analysis was conducted on 1,345 instances of girls with growth and developmental variations who visited our pediatric endocrinology department and completed vitamin D detection. A total of 279 girls with complete data were included in this study. Among them, 246 girls were classified into four groups based on different growth and developmental variations: early puberty group, menarche group, obesity group, short stature group, and 33 healthy girls served as the control group. Besides, the girls were divided into pre-epidemic and post-epidemic groups by the occurrence of the COVID-19 epidemic. Vitamin D were measured in all girls. The 25(OH)D <20 ng/ml was used as the standard for vitamin D deficiency.

The levels of vitamin D in the early puberty group, menarche group, obesity group, short stature group, and control group were as follows: 20.23 ± 5.90 ng/ml, 17.85 ± 5.69 ng/ml, 21.31 ± 8.99 ng/ml, 27.90 ± 12.27 ng/ml, and 29.42 ± 12.65 ng/ml, respectively. The levels of vitamin D in the early puberty group, menarche group, and obesity group were significantly lower than those in the control group (P < 0.05). The individual vitamin D deficiency rates in the aforementioned groups were 52.07%, 73.91%, 59.46%, 30.95%, and 30.30%, respectively. The vitamin D levels in the pre-epidemic and post-epidemic groups were 20.48 ± 6.22 ng/ml and 22.50 ± 9.74 ng/ml, respectively (P > 0.05).

Girls with early puberty, menarche, and obesity have a certain deficiency of vitamin D levels, and appropriate vitamin D treatment should be provided clinically. Girls with short stature and healthy girls also have certain levels of vitamin D deficiency, and awareness of prevention should be strengthened.

Cardiac remodeling is a compensatory adaptive response to chronic heart failure (HF) altering the structure, function, and metabolism of the heart. Many nutritional and metabolic diseases can aggravate the pathophysiological development of cardiac remodeling. Vitamin D deficiency leads to cardiac remodeling by activating the renin-angiotensin-aldosterone system (RAAS), resulting in enhanced inflammation and directly promoting cardiac fibrosis and extracellular matrix deposition. Hyperparathyroidism upregulates protein kinase A or protein kinase C, enhances intracellular calcium influx, promotes oxidative stress, activates RAAS, and increases aldosterone levels, thereby aggravating cardiac remodeling. Besides, fibroblast growth factor 23 (FGF23) plays a direct role in the heart, resulting in ventricular hypertrophy and myocardial fibrosis. Vitamin D deficiency leads to hyperparathyroidism, which in turn increases the level of FGF23. Elevated levels of FGF23 further inhibit vitamin D synthesis. Evidence exists that vitamin D deficiency, hyperparathyroidism, and marked elevations in FGF23 concentration form a vicious cycle and are believed to contribute directly to cardiac remodeling. Therefore, the purpose of this article is to introduce the specific effects of the above substances on the heart and to explain the significance of understanding the vitamin D-parathyroid hormone-FGF23 axis in improving or even reversing cardiac remodeling, thus contributing to the treatment of patients with HF.

As BAG family members, Bcl-2 associated athanogene family protein 1 (BAG1) and 2 (BAG2) are implicated in multiple cellular processes, including apoptosis, autophagy, protein folding and homeostasis. Although structurally similar, they considerably differ in many ways. Unlike BAG2, BAG1 has four isoforms (BAG1L, BAG1M, BAG1S and BAG1 p29) displaying different expression features and functional patterns. BAG1 and BAG2 play different cellular functions by interacting with different molecules to participate in the regulation of various diseases, including cancer/tumor and neurodegenerative diseases. Commonly, BAG1 acts as a protective factor to predict a good prognosis of patients with some types of cancer or a risk factor in some other cancers, while BAG2 is regarded as a risk factor to promote cancer/tumor progression. In neurodegenerative diseases, BAG2 commonly acts as a neuroprotective factor. In this review, we summarized the differences in molacular structure and biological function between BAG1 and BAG2, as well as the influences of them on pathogenesis of diseases, and explore the prospects for their clinical therapy application by specifying the activators and inhibitors of BAG1 and BAG2, which might provide a better understanding of the underlying pathogenesis and developing the targeted therapy strategies for diseases.

Central precocious puberty (CPP) is an endocrine disease in children, characterized by rapid genital development and secondary sexual characteristics before the age of eight in girls and nine in boys. The premature activation of the hypothalamic-pituitary-gonadal axis (HPGA) limits the height of patients in adulthood and is associated with a higher risk of breast cancer. How to prevent and improve the prognosis of CPP is an important problem. Vitamin D receptor (VDR) is widely expressed in the reproductive system, participates in the synthesis and function of regulatory sex hormones, and affects the development and function of gonads. In addition, gut microbiota plays an important role in human health by mainly regulating metabolites, energy homeostasis, and hormone regulation. This review aims to clarify the effect of vitamin D deficiency on the occurrence and development of CPP and explore the role of gut microbiota in it. Although evidence on the interaction between vitamin D deficiency, gut microbiota, and sexual development remains limited, vitamin D supplementation and gut microbiota interventions offer a promising, non-invasive strategy for managing CPP.

Background: The condition of vitamin D (25OHD) deficiency represents an important public health problem. In Europe, hypovitaminosis is common not only in the elderly population but also between 50 and 70 years, both in males and females. Data regarding vitamin D intake in the Italian population are very limited. In a recent paper, reporting data collected by a specific Frequency Food Questionnaire (FFQ), we observed in a small group of healthy subjects that the dietary consumption of vitamin D, both in females and males, was far below the average. Methods: With the aim of expanding our preliminary data, we conducted a survey on a large cohort of subjects from different areas of Northern, Central, and Southern Italy. The FFQ contained 11 different questions regarding the amount and type of intake of foods containing ergocalciferol and cholecalciferol. It was submitted to 870 subjects, 627 females and 243 males, with an age range from 40 to 80 years; 31.6% of the studied population was apparently in good health, while 68.4% were affected by different pathologies. Results: The present data confirm previous observations: the global quantity of vitamin D intake in 14 days was 70.8 μg (±1.8 SE, ±54.4 SD) in females and 87.5 μg (±1.9 SE, ±57.1 SD) in males; the mean daily intake of vitamin D in females and males was 5.05 μg (±0.5 SE, ±3.8 SD) and 6.25 μg (±0.21 SE, ±4.1 SD), respectively. In healthy subjects, a gradual decrease was observed in the overall intake of vitamin D in both females and males according to an increase in age bracket, ranging from 74.5 μg and 103.8 μg in the 40-50 age group to 54.5 μg and 87.8 μg in the 71-80 age group, respectively. Conclusions: In conclusion, the present data, collected in a large Italian cohort, underscore that the daily intake of vitamin D is far below the recommended daily average, thereby contributing to the development of potential hypovitaminosis.

Numerous observational studies have demonstrated a significant inverse association between vitamin D status and the risk of major chronic disease, including type 2 diabetes (T2D), cardiovascular disease (CVD), and cancer. However, findings from Mendelian randomization (MR) studies and randomized controlled trials (RCTs) suggest minimal or no benefit of increased vitamin D levels. We provide an overview of recent literature linking vitamin D to major chronic diseases. Because emerging evidence indicates a potential threshold effect of vitamin D, future well-designed studies focused on diverse populations with vitamin D deficiency or insufficiency are warranted for a more comprehensive understanding of the effect of maintaining sufficient vitamin D status on the prevention of major chronic diseases.

Vitamin D status, the vitamin D receptor (VDR), and the ability to produce active vitamin D [1,25(OH)2D, regulated by Cyp27b1] regulate fetal and adult hematopoiesis. Transgenic reporter mice that express the tdTomato RFP as an indication of Vdr expression were used to identify immune cells that express the Vdr. Vdr/tdTomato+ hematopoietic progenitors were identified as early as embryonic day (E)15.5, establishing that these cells have expressed the Vdr and are vitamin D targets. Maternal vitamin D deficiency [D-; serum 25(OH)D < 20 ng/ml] or Vdr knockout or Cyp27b1 knockout resulted in embryos with fewer fetal progenitors. Vdr/tdTomato+ expression was found to increase with age in CD8+ T cells and innate lymphoid cells (ILCs)1 and ILC3, suggesting that initial Vdr expression in these cells is dependent on environmental factors immediately postbirth. In adult tissues, the frequencies of mature T cells and ILCs as well as Vdr/tdTomato expression were reduced by D-. Maternal D- resulted in fewer progenitors that expressed Vdr/tdTomato+ at E15.5 and fewer Vdr/tdTomato+ immune cells in the adult spleen than offspring from D+ mice. We challenged D- mice with H1N1 influenza infection and found that D- mice were more susceptible than D+ mice. Treating D- mice with vitamin D restored Vdr/tdTomato+ expression in splenic T cells and partially restored resistance to H1N1 infection, which shows that developmental D- results in lingering effects on Vdr expression in the adult immune system that compromise the immune response to H1N1 infection. Vitamin D and the Vdr regulate hematopoiesis in both fetal and postnatal phases of immune cell development that impact the immune response to a viral infection.

Background/Objectives: Type II diabetes mellitus (T2DM) is recognized as a condition of mild chronic inflammation, marked by increased levels of acute-phase proteins and various inflammatory indicators. These inflammatory substances, along with inflammation of adipose tissue and the secretion of adipocytokines, can contribute to insulin resistance and β cell dysfunction. By influencing both innate and adaptive immunity, vitamin D can inhibit the production of inflammatory cytokines and help mitigate the low-grade chronic inflammation associated with T2DM. Several strategies have been proposed to increase vitamin D levels effectively and safely, but the recent and strong ones have common tactics. Short-term high doses increase the level acutely, and long-term lower doses maintain sufficient levels. Methods: The aim of our work was to determine and verify the effectiveness of high doses of vitamin D to safely increase its level in patients with type 2 diabetes mellitus, as well as the effect of these doses on selected metabolic parameters. Data from 20 studies (vitamin D group n = 612, and control group n = 592) regarding the influence of vitamin D supplementation with doses above 4000 IU on serum 25(OH)D, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), blood pressure, serum calcium, and parathormone were pooled. Results: Vitamin D supplementation significantly improved serum 25(OH)D levels, with an average increase after intervention versus baseline at 177.09%. Our studies suggest that vitamin D supplementation may benefit various parameters in T2DM patients, including glycemic control, blood pressure, and PTH levels. Conclusions: Vitamin D supplementation may have beneficial effects on various parameters in type 2 diabetes patients, including glycemic control, blood pressure, and parathormone levels. However, the results are only sometimes consistent across all studies. Further examination is needed.

Vitamin D (vitD) deficiency is frequently observed in patients with pulmonary arterial hypertension (PAH) and, in these patients, low levels of vitD correlate with worse prognosis. The aim of this study was to examine the expression and the antiproliferative role of vitD receptor (VDR) and its signalling pathway in the human pulmonary vasculature. VDR presence and expression was analyzed in lungs, pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) from controls and PAH-patients. VDR expression and VDR-target genes were examined in PASMC treated with calcitriol. The antiproliferative effect of 48 h-calcitriol was studied in PASMC by MTT and BrdU assays. VDR is expressed in PASMC. It is downregulated in lungs and in PASMC, but not in PAEC, from PAH-patients compared to non-hypertensive controls. Calcitriol strongly upregulated VDR expression in PASMC and the VDR target genes KCNK3 (encoding TASK1), BIRC5 (encoding survivin) and BMP4. Calcitriol produced an antiproliferative effect which was diminished by silencing or by pharmacological inhibition of survivin or BMPR2, but not of TASK1. In conclusion, the expression of VDR is low in PAH-patients and can be rescued by calcitriol. VDR exerts an antiproliferative effect in PASMC by modulating survivin and the BMP signalling pathway.

Vitamin D3's role in mineral homeostasis through its endocrine function, associated with the main circulating metabolite 25-hydroxyvitamin D3, is well characterized. However, the increasing recognition of vitamin D3's paracrine and autocrine functions-such as cell growth, immune function, and hormone regulation-necessitates examining vitamin D3 levels across different tissues post-supplementation. Hence, this review explores the biodistribution of vitamin D3 in blood and key tissues following oral supplementation in humans and animal models, highlighting the biologically active metabolite, 1,25-dihydroxyvitamin D3, and the primary clearance metabolite, 24,25-dihydroxyvitamin D3. While our findings indicate significant progress in understanding how circulating metabolite levels respond to supplementation, comprehensive insight into their tissue concentrations remains limited. The gap is particularly significant during pregnancy, a period of drastically increased vitamin D3 needs and metabolic alterations, where data remains sparse. Within the examined dosage ranges, both human and animal studies indicate that vitamin D3 and its metabolites are retained in tissues selectively. Notably, vitamin D3 concentrations in tissues show greater variability in response to administered doses. In contrast, its metabolites maintain a more consistent concentration range, albeit different among tissues, reflecting their tighter regulatory mechanisms following supplementation. These observations suggest that serum 25-hydroxyvitamin D3 levels may not adequately reflect vitamin D3 and its metabolite concentrations in different tissues. Therefore, future research should aim to generate robust human data on the tissue distribution of vitamin D3 and its principal metabolites post-supplementation. Relating this data to clinically appropriate exposure metrics will enhance our understanding of vitamin D3's cellular effects and guide refinement of clinical trial methodologies.

Acne is an inflammatory condition of the pilosebaceous unit. Previous studies have established a link between acne and vitamin D deficiency and the potential effectiveness of vitamin D supplementation in treatment. However, the efficacy of vitamin D as an adjuvant treatment for acne remains unknown.

To evaluate the efficacy of weekly vitamin D2 oral administration as an adjunctive treatment to standard topical care for acne.

This study was a randomized, double-blind, placebo-controlled trial including subjects with mild-to-moderate acne. Topical 2.5% benzoyl peroxide was applied twice daily for 12 weeks to all subjects. Subjects were randomly allocated to receive either oral vitamin D2 40,000 IU weekly or placebo weekly during the treatment period. No additional treatment was administered during the 4-week follow-up period.

A total of 44 subjects were included in this study. All of them had inadequate 25(OH)D levels. Both regimens showed significant improvement in acne during the treatment period. Weekly vitamin D2 supplementation significantly prevented the relapse of inflammatory acne lesions (P = .048) at the follow-up visit. No adverse effects or biochemical changes were observed.

There were no subjects of severe acne vulgaris.

Adjunctive weekly vitamin D2 supplementation to standard topical benzoyl peroxide could reduce relapses of inflammatory lesions in mild-to-moderate acne.

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches.

Colorectal Cancer (CRC) has been molecularly classified into several subtypes according to tumor, stromal, and immune components. Here, we investigated whether the preventive effect of vitamin D on CRC varies with subtypes defined by Vitamin D receptor (VDR) expression in tumors and their surrounding stroma, along with the association of somatic mutations in CRC.

In a population-based prospective study of 22,743 Japanese participants, VDR expression levels in tumors and their surrounding stroma were defined in 507 cases of newly diagnosed CRC using immunohistochemistry. Hazard ratios of CRC and its subtypes according to dietary vitamin D intake were estimated using multivariable Cox proportional hazards models.

Dietary vitamin D intake was not associated with CRC or its subtypes defined by VDR expression in tumors. However, an inverse association was observed for CRC with high VDR expression in the stroma (the highest tertile vs the lowest tertile: 0.46 [0.23-0.94], Ptrend = 0.03), but not for CRC with low VDR expression in the stroma (Pheterogeneity = 0.02). Furthermore, CRC with high VDR expression in the stroma had more somatic TP53 and BRAF mutations and fewer APC mutations than those with low VDR expression in the stroma.

This study provides the first evidence that the preventive effect of vitamin D on CRC depends on VDR expression in the stroma rather than in the tumors. CRC with high VDR expression in the stroma is likely to develop through a part of the serrated polyp pathway, which tends to occur with BRAF but not with APC mutations.

Rheumatoid arthritis (RA) exhibits a robust association with cardiovascular disease. Our study aims to elucidate the correlation between RA prevalence and Life's Essential 8 (LE8), a recently updated measure of cardiovascular health (CVH).

We conducted a population-based cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2007 to 2018. Utilizing multivariable logistic and restricted cubic spline models, we explored the relationship between LE8 and RA. Our analysis included 17,263 participants. We found that higher LE8 scores were closely associated with reduced odds of RA (odds ratio for each 10-point increase, 0.91 (95% CI, 0.75-0.87)). Furthermore, we observed a nonlinear association between LE8 and RA after adjusting for potential confounders. Specifically, higher scores for sleep health, nicotine exposure, body mass index, and blood pressure within the LE8 components were significantly correlated with a lower risk of RA. Additionally, the inverse relationship between LE8 scores and RA was notably stronger among young and female individuals.

Our findings suggest a negative correlation between LE8 and RA prevalence, indicating that adherence to the lifestyle defined by LE8 may confer protective effects against RA.

In December 2019, Corona Virus Disease 2019 (COVID-19) was first identified and designated as a pandemic in March 2020 due to rapid spread of the virus globally. At the beginning of the pandemic, only a few treatment options, mainly focused on supportive care and repurposing medications, were available. Due to its effects on immune system, vitamin D was a topic of interest during the pandemic, and researchers investigated its potential impact on COVID-19 outcomes. However, the results of studies about the impact of vitamin D on the disease are inconclusive. In the present narrative review, different roles of vitamin D regarding the COVID-19 have been discussed to show that vitamin D supplementation should be recommended carefully.

Obesity aggravates ferroptosis, and vitamin D (VD) may inhibit ferroptosis. We hypothesized that weight reduction and/or calcitriol administration have benefits against the sepsis-induced liver redox imbalance and ferroptosis in obese mice. Mice were fed a high-fat diet for 11 weeks, then half of the mice continued to consume the diet, while the other half were transferred to a low-energy diet for 5 weeks. After feeding the respective diets for 16 weeks, sepsis was induced by cecal ligation and puncture (CLP). Septic mice were divided into four experimental groups: OS group, obese mice injected with saline; OD group, obese mice with calcitriol; WS group, weight-reduction mice with saline; and WD group, weight-reduction mice with calcitriol. Mice in the respective groups were euthanized at 12 or 24 h after CLP. Results showed that the OS group had the highest inflammatory mediators and lipid peroxide levels in the liver. Calcitriol treatment reduced iron content, enhanced the reduced glutathione/oxidized glutathione ratio, upregulated nuclear factor erythroid 2-related factor 2, ferroptosis-suppressing protein 1, and solute carrier family 7 member 11 expression levels. Also, mitochondrion-associated nicotinamide adenine dinucleotide phosphate oxidase 1, peroxisome proliferator-activated receptor-γ coactivator 1, hypoxia-inducible factor-1α, and heme oxidase-1 expression levels increased in the late phase of sepsis. These results were not noted in the WS group. These findings suggest that calcitriol treatment elicits a more-balanced glutathione redox status, alleviates liver ferroptosis, and enhances mitochondrial biogenesis-associated gene expressions. Weight reduction alone had minimal influences on liver ferroptosis and mitochondrial biogenesis in obese mice with sepsis.

Despite their significant impact, comprehensive screenings and detailed analyses of per- and polyfluoroalkyl substance (PFAS) binding strengths at the orthosteric and allosteric sites of NRs are currently lacking. This study addresses this gap by focusing on the binding interaction analysis of both common and uncommon PFAS with the nuclear receptors (NRs) vitamin D receptor (VDR), peroxisome proliferator-activated receptor gamma (PPARγ), pregnane X receptor (PXR), and estrogen receptor alpha (ERα). Advanced docking simulations were used to screen 9507 PFAS chemicals at the orthosteric and allosteric sites of PPARγ, PXR, VDR, and ERα. All receptors exhibited strong binding interactions at the orthosteric and allosteric site with a significant number of PFAS. We verified the accuracy of the docking protocol through multiple docking controls and validations. A mixture modeling analysis indicates that PFAS can bind in various combinations with themselves and endogenous ligands simultaneously, to disrupt the endocrine system and cause carcinogenic responses. These findings reveal that PFAS can interfere with nuclear receptor activity by displacing endogenous or native ligands by binding to the orthosteric and allosteric sites. The purpose of this study is to explore the mechanisms through which PFAS exert their endocrine-disrupting effects, potentially leading to more targeted therapeutic strategies. Importantly, this study is the first to explore the binding of PFAS at allosteric sites and to model PFAS mixtures at nuclear receptors. Given the high concentration and persistence of PFAS in humans, this study further emphasizes the urgent need for further research into the carcinogenic mechanisms of PFAS and the development of therapeutic strategies that target nuclear receptors.

A total hip arthroplasty (THA) can improve quality of life, but loosening of the hip prosthesis is a complex problem in which vitamin D may also play a role. The Vitamin D Receptor (VDR) is involved in the response of cells to the action of vitamin D, and its genetic variability raises the question of whether individual differences could influence the risk of prosthesis loosening. The aim of this study was to investigate the relationship between VDR single nucleotide polymorphisms (SNPs) (ApaI, BsmI, FokI and TaqI) and the serum VDR and 25(OH)D levels in three groups of patients: (1) arthroscopy patients after THA without loosening of the prosthesis (CA-Control Arthroplasty), (2) patients after THA with loosened hip prostheses (L-Loosening) and (3) the control group (C-Control). Our results suggest that the genotypes tt of TaqI, BB of BsmI, and FF of FokI may influence the VDR effect in patients with loosened protheses. Our results showed that the ACAC haplotype (AtBF) was over two times more frequent in the L group than in CA + C: OR =2.35 [95% CI 1.44-3.83; p = 0.001]. There was no significant correlation between the VDR and serum 25(OH)D levels, but there were differences between studied groups.

Vitamin D possesses a crucial role in preserving bone health, modulating the immune system responses, and supporting various physiological functions throughout the body. Chronic atrophic autoimmune gastritis (CAAG) constitutes an autoimmune condition marked by inflammation and damage to the stomach cells, often resulting in a decreased ability to absorb certain nutrients, including vitamin B12 and iron. Although, vitamin D is not directly affected by this condition, the sufficiency of this micronutrient seems to have important implications for overall health and management of the disease. The aim of the current review was to assess the incidence and related features of vitamin D deficiency in patients with CAAG and to elucidate the complex regulatory role of this nutrient, in an effort to improve patient outcomes. Vitamin D greatly contributes to the regulation of the immune system. In patients with CAAG, the immune system attacks the stomach lining; thus, the maintenance of a healthy and balanced immune response is important. In autoimmune conditions such as CAAG, where inflammation plays a decisive role in disease progression, vitamin D could potentially exert a role in managing and controlling the associated symptoms. Adequate vitamin D levels may help in regulating the immune response and reducing inflammation. In addition, patients with CAAG are at risk of nutrient deficiencies, including vitamin B12 and iron, which can lead to anemia and bone health issues. As vitamin D is critical for calcium absorption and bone health, assurance of sufficient levels of this micronutrient can be beneficial in preventing or mitigating bone-related complications. In conclusion, regular monitoring of vitamin D levels, among other nutrients, and appropriate supplementation, when necessary, can help improve overall health and well-being in these patients.

Several single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) have been observed in association with susceptibility to various pathologies, including autism, major depression, age-related changes in cognitive functioning, and Parkinson's and Alzheimer's diseases. This study aimed to establish the association between Fok1/Apa1 polymorphic variants and anxious/depressive symptoms in nonclinical adolescents from central Italy, with the goal of identifying the risk of developing both symptoms. We found no significant difference in genotype distribution or dominant/recessive models of Fok1/Apa1 VDR polymorphic variants between subjects with anxious/depressive symptoms and controls. HN9.10e cell lines carrying the AA genotype for Fok1 and the CC genotype for Apa1 responded better to treatment with vitamin D3 than cell lines carrying the AG genotype for Fok1 and CA genotype for Apa1. Cell lines carrying the GG genotype for Fok1 and the AA genotype for Apa1 did not respond at all, suggesting avenues for future studies in both the general population and individuals with mental and/or neuropsychiatric disorders. These studies suggest that the level of response to vitamin D3 administered to prevent and/or treat mental or neurological disorders could depend on the polymorphic variants of the vitamin D receptor.

Vitamin D deficiencies are linked to multiple human diseases. Optimizing its synthesis, physicochemical properties, and delivery systems while minimizing side effects is of clinical relevance and is of great medical and industrial interest. Biotechnological techniques may render new modified forms of vitamin D that may exhibit improved absorption, stability, or targeted physiological effects. Novel modified vitamin D derivatives hold promise for developing future therapeutic approaches and addressing specific health concerns related to vitamin D deficiency or impaired metabolism, such as avoiding hypercalcemic effects. Identifying and engineering key enzymes and biosynthetic pathways involved, as well as developing efficient cultures, are therefore of outmost importance and subject of intense research. Moreover, we elaborate on the critical role that microbial bioconversions might play in the a la carte design, synthesis, and production of novel, more efficient, and safer forms of vitamin D and its analogs. In summary, the novelty of this work resides in the detailed description of the physiological, medical, biochemical, and epidemiological aspects of vitamin D supplementation and the steps towards the enhanced and simplified industrial production of this family of bioactives relying on microbial enzymes. KEY POINTS: • Liver or kidney pathologies may hamper vitamin D biosynthesis • Actinomycetes are able to carry out 1α- or 25-hydroxylation on vitamin D precursors.

Fertility in dairy cattle has declined as an unintended consequence of single-trait selection for high milk yield. The unfavorable genetic correlation between milk yield and fertility is now well documented; however, the underlying physiological mechanisms are still uncertain. To understand the relationship between these traits, we developed a method that clusters variants with similar patterns of effects and, after the integration of gene expression data, identifies the genes through which they are likely to act. Biological processes that are enriched in the genes of each cluster were then identified. We identified several clusters with unique patterns of effects. One of the clusters included variants associated with increased milk yield and decreased fertility, where the "archetypal" variant (i.e., the one with the largest effect) was associated with the GC gene, whereas others were associated with TRIM32, LRRK2, and U6-associated snRNA. These genes have been linked to transcription and alternative splicing, suggesting that these processes are likely contributors to the unfavorable relationship between the 2 traits. Another cluster, with archetypal variant near DGAT1 and including variants associated with CDH2, BTRC, SFRP2, ZFHX3, and SLITRK5, appeared to affect milk yield but have little effect on fertility. These genes have been linked to insulin, adipose tissue, and energy metabolism. A third cluster with archetypal variant near ZNF613 and including variants associated with ROBO1, EFNA5, PALLD, GPC6, and PTPRT were associated with fertility but not milk yield. These genes have been linked to GnRH neuronal migration, embryonic development, or ovarian function. The use of archetypal clustering to group variants with similar patterns of effects may assist in identifying the biological processes underlying correlated traits. The method is hypothesis generating and requires experimental confirmation. However, we have uncovered several novel mechanisms potentially affecting milk production and fertility such as GnRH neuronal migration. We anticipate our method to be a starting point for experimental research into novel pathways, which have been previously unexplored within the context of dairy production.

Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.

Vitamin D receptors are expressed in many organs and tissues, which suggests that vitamin D (VD) affects physiological functions beyond its role in maintaining bone health. Deficiency or inadequacy of 25(OH)VD is widespread globally. Population studies demonstrate that a positive association exists between a high incidence of VD deficiency and a high incidence of chronic diseases, including dementia, diabetes, and heart disease. However, many subjects have difficulty achieving the required circulating levels of 25(OH)VD even after high-dose VD supplementation, and randomized controlled clinical trials have reported limited therapeutic success post-VD supplementation. Thus, there is a discordance between the benefits of VD supplementation and the prevention of chronic diseases in those with VD deficiency. Why this dissociation exists is currently under debate and is of significant public interest. This review discusses the downregulation of VD-metabolizing genes needed to convert consumed VD into 25(OH)VD to enable its metabolic action exhibited by subjects with metabolic syndrome, obesity, and other chronic diseases. Research findings indicate a positive correlation between the levels of 25(OH)VD and glutathione (GSH) in both healthy and diabetic individuals. Cell culture and animal experiments reveal a novel mechanism through which the status of GSH can positively impact the expression of VD metabolism genes. This review highlights that for better success, VD deficiency needs to be corrected at multiple levels: (i) VD supplements and/or VD-rich foods need to be consumed to provide adequate VD, and (ii) the body needs to be able to upregulate VD-metabolizing genes to convert VD into 25(OH)VD and then to 1,25(OH)2VD to enhance its metabolic action. This review outlines the association between 25(OH)VD deficiency/inadequacy and decreased GSH levels, highlighting the positive impact of combined VD+LC supplementation on upregulating GSH, VD-metabolizing genes, and VDR. These effects have the potential to enhance 25(OH)VD levels and its therapeutic efficacy.