Vitamin D and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Novel Mechanistic Insights.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition characterized by abnormal fat accumulation in the liver, often associated with metabolic disorders. Emerging evidence suggests a potential link between vitamin D deficiency and the development and progression of MASLD. The current review provides a concise overview of recent studies uncovering novel mechanistic insights into the interplay between vitamin D and MASLD. Several epidemiological studies have highlighted a significant association between low vitamin D levels and an increased risk of MASLD. Vitamin D, traditionally known for its role in bone health, has now been recognized as a key player in various physiological processes, including immune regulation and inflammation. Experimental studies using animal models have demonstrated that vitamin D deficiency exacerbates liver steatosis and inflammation, suggesting a potential protective role against MASLD. Mechanistically, vitamin D appears to modulate MASLD through multiple pathways. Firstly, the vitamin D receptor (VDR) is abundantly expressed in liver cells, indicating a direct regulatory role in hepatic function. Activation of the VDR has been shown to suppress hepatic lipid accumulation and inflammation, providing a mechanistic basis for the observed protective effects. Additionally, vitamin D influences insulin sensitivity, a critical factor in MASLD pathogenesis. Improved insulin sensitivity may mitigate the excessive accumulation of fat in the liver, thus attenuating MASLD progression. In parallel, vitamin D exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines implicated in MASLD pathophysiology. Experimental evidence suggests that the immunomodulatory effects of vitamin D extend to the liver, reducing inflammation and oxidative stress, key drivers of MASLD, and the likelihood of hepatocyte injury and fibrosis. Understanding the complex interplay between vitamin D and MASLD provides a basis for exploring targeted therapeutic strategies and preventive interventions. As vitamin D deficiency is a modifiable risk factor, addressing this nutritional concern may prove beneficial in mitigating the burden of MASLD and associated metabolic disorders.

Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1.

Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (Litonjua and Weiss, 2007). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D-mediated immunoregulation. Here, we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases. We demonstrate increased vitamin D receptor (Vdr) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long-term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the Ikzf3-encoded protein Aiolos to suppress IL-2 signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders.

Maternal Vitamin D Deficiency Impairs the Development of ß Cells in Offspring Rats in a Sex-Dependent Manner.

Recent studies have shown that maternal vitamin D deficiency (VDD) causes long-term metabolic changes in offspring. However, little is known about the impact of maternal VDD on offspring endocrine pancreas development and insulin secretion in the adult life of male and female animals. Female rats (Wistar Hannover) were fed either control (1000 IU Vitamin D3/kg), VDD (0 IU Vitamin D3/kg), or a Ca2+-enriched VDD diet (0 IU Vitamin D3/kg + Ca2+ and P/kg) for 6 weeks and during gestation and lactation. At weaning, VDD status was confirmed based on low serum calcidiol levels in dams and pups. Next, male and female offspring were randomly separated and fed a standard diet for up to 90 days. At this age, serum calcidiol levels were restored to normal levels in all groups, but serum insulin levels were decreased in VDD males without affecting glucagon levels, glycemia, or glucose tolerance. Islets isolated from VDD males showed lower insulin secretion in response to different glucose concentrations, but this effect was not observed in VDD females. Furthermore, VDD males, but not females, showed a smaller total pancreatic islet area and lower ß cell mass, an effect that was accompanied by reduced gene expression of Ins1, Ins2, Pdx1, and SLC2A2. The decrease in Pdx1 expression was not related to the methylation profile of the promoter region of this gene. Most of these effects were observed in the male VDD+Ca2+ group, indicating that the effects were not due to alterations in Ca2+ metabolism. These data show that maternal VDD selectively impairs the morphology and function of ß cells in adult male offspring rats and that female offspring are fully protected from these deleterious effects.

Association of Vitamin D with Severity and Outcome of COVID-19: Clinical and Experimental Evidence.

INTRODUCTION: The role of vitamin in COVID-19 remains controversial. We investigated the association between endogenous vitamin D and the severity of COVID-19 as well as the mechanisms of action of vitamin D supplementation. METHODS: 25(OH)D3 in serum was associated with disease severity and outcome in 190 COVID-19 patients. In a COVID-19 animal model using intravenous injection of plasma from patients with COVID-19 acute respiratory distress syndrome into C57/BL6 mice, mice were treated with 0.25 µg human 1,25(OH)D3 or vehicle. Mice were sacrificed on day 4. Cytokines and myeloperoxidase (MPO) in tissues were measured. Changes in gene expression after vitamin D supplementation were measured. RESULTS: Vitamin D deficiency and insufficiency were associated with increased severity and unfavorable outcome after 28 days. Vitamin D levels were negatively associated with biomarkers of COVID-19 severity. Vitamin D supplementation after challenge of mice with COVID-19 plasma led to reduced levels of TNFα, IL-6, IFNγ, and MPO in the lung, as well as down-regulation of pro-inflammatory pathways. CONCLUSION: Normal levels of endogenous vitamin D are associated with reduced severity and risk of unfavorable outcome in COVID-19, possibly through attenuation of tissue-specific hyperinflammation.

Maternal Vitamin D Deficiency in Mice Sex-Dependently Affects Hepatic Lipid Accumulation in Offspring.

SCOPE: Vitamin D deficiency (VDD) is becoming a global issue and low 25-hydroxyvitamin D (25(OH)D) plasma levels have been linked to hepatic steatosis in adulthood. Nevertheless, the impact of maternal VDD on lipid metabolism and hepatic steatosis remains poorly documented, especially under obesogenic condition. The goal of this study is to assess the effects of maternal VDD on hepatic lipid accumulation in adult offspring fed a normal or obesogenic diet. METHODS AND RESULTS: Several approaches are implemented including histology and lipidomics on the liver in both males and females. No major impact of high-fat (HF) or VDD is observed at histological level in both males and females. Nevertheless, in males born from VDD mice and fed an HF diet, an increase of total lipids and modulation of the relative lipid species distribution characterized by a decrease of triglycerides and increase of phospholipids is observed. In female no major lipid profile is noticed. CONCLUSION: Maternal VDD combined with a HF diet in male may predispose to hepatic hypertrophia, with a specific lipid profile. Such observations reinforce our knowledge of the impact of maternal VDD on hepatic programming in the offspring.

The Effect of Vitamin D on Metabolic Bone Disease and Chronic Diseases.

The history of vitamin D begins more than 100 years ago, with the initial documentation of rickets in industrialized cities of England [...].

Compromised NHE8 Expression Is Responsible for Vitamin D-Deficiency Induced Intestinal Barrier Dysfunction.

Objectives: Vitamin D (VitD) and Vitamin D receptor (VDR) are suggested to play protective roles in the intestinal barrier in ulcerative colitis (UC). However, the underlying mechanisms remain elusive. Evidence demonstrates that Na+/H+ exchanger isoform 8 (NHE8, SLC9A8) is essential in maintaining intestinal homeostasis, regarded as a promising target for UC therapy. Thus, this study aims to investigate the effects of VitD/VDR on NHE8 in intestinal protection. Methods: VitD-deficient mice, VDR-/- mice and NHE8-/- mice were employed in this study. Colitis mice were established by supplementing DSS-containing water. Caco-2 cells and 3D-enteroids were used for in vitro studies. VDR siRNA (siVDR), VDR over-expression plasmid (pVDR), TNF-α and NF-κb p65 inhibitor QNZ were used for mechanical studies. The expression of interested proteins was detected by multiple techniques. Results: In colitis mice, paricalcitol upregulated NHE8 expression was accompanied by restoring colonic mucosal injury. In VitD-deficient and VDR-/- colitis mice, NHE8 expression was compromised with more serious mucosal damage. Noteworthily, paricalcitol could not prevent intestinal barrier dysfunction and histological destruction in NHE8-/- mice. In Caco-2 cells and enteroids, siVDR downregulated NHE8 expression, further promoted TNF-α-induced NHE8 downregulation and stimulated TNF-α-induced NF-κb p65 phosphorylation. Conversely, QNZ blocked TNF-α-induced NHE8 downregulation in the absence or presence of siVDR. Conclusions: Our study indicates depressed NHE8 expression is responsible for VitD-deficient-induced colitis aggravation. These findings provide novel insights into the molecular mechanisms of VitD/VDR in intestine protection in UC.

Vitamin D status & bone health in patients with liver cirrhosis.

Background & objectives: Vitamin D plays an important role in bone metabolism, and liver is the intermediary site of vitamin D metabolism. The purpose of this study was to study the prevalence of vitamin D deficiency and bone health in patients with cirrhosis. Methods: Prospectively, serum 25-hydroxy vitamin D [25(OH)D] level were assessed in cirrhotics by chemiluminescence method. Endocrine Society Clinical practice guideline was used to define deficiency and insufficiency of vitamin D. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry and the World Health Organization criteria was used to define osteoporosis and osteopenia. The lowest T score at the left hip neck or lumbar spine was taken as osteoporosis or osteopenia. The Child-Turcotte-Pugh score was used to assess the severity of cirrhosis. Results: Cirrhotics (n=350, male: 278, compensated: 210) were included. Mean serum 25(OH)D level was 8.75 ng/ml. The prevalence of vitamin D deficiency (VDD) and low-BMD (osteopenia and osteoporosis) was 89.4 and 86 per cent, respectively. VDD, insufficiency and osteoporosis was found in 86.7, 11.9 and 33.8 per cent, respectively, in patients with compensated cirrhosis; and 93.6, 3.6 and 40 per cent, respectively, in patients with decompensated cirrhosis. Body mass index of >25 kg/m2 was protective for bone health. Interpretation & conclusions: VDD and low-BMD is prevalent in Indian patients with cirrhosis and should be looked for in patients with cirrhosis for its prevention.

The Role of Vitamin D and Its Molecular Bases in Insulin Resistance, Diabetes, Metabolic Syndrome, and Cardiovascular Disease: State of the Art.

In the last decade, an increasing awareness was directed to the role of Vitamin D in non-skeletal and preventive roles for chronic diseases. Vitamin D is an essential hormone in regulating calcium/phosphorous balance and in the pathogenesis of inflammation, insulin resistance, and obesity. The main forms of vitamin D, Cholecalciferol (Vitamin D3) and Ergocalciferol (Vitamin D2) are converted into the active form (1,25-dihydroxyvitamin D) thanks to two hydroxylations in the liver, kidney, pancreas, and immune cells. Some anti-inflammatory cytokines are produced at higher levels by vitamin D, while some pro-inflammatory cytokines are released at lower levels. Toll-Like Receptor (TLR) expression is increased, and a pro-inflammatory state is also linked to low levels of vitamin D. Regardless of how it affects inflammation, various pathways suggest that vitamin D directly improves insulin sensitivity and secretion. The level of vitamin D in the body may change the ratio of pro- to anti-inflammatory cytokines, which would impact insulin action, lipid metabolism, and the development and function of adipose tissue. Many studies have demonstrated an inverse relationship between vitamin D concentrations and pro-inflammatory markers, insulin resistance, glucose intolerance, metabolic syndrome, obesity, and cardiovascular disease. It is interesting to note that several long-term studies also revealed an inverse correlation between vitamin D levels and the occurrence of diabetes mellitus. Vitamin D supplementation in people has controversial effects. While some studies demonstrated improvements in insulin sensitivity, glucose, and lipid metabolism, others revealed no significant effect on glycemic homeostasis and inflammation. This review aims to provide insight into the molecular basis of the relationship between vitamin D, insulin resistance, metabolic syndrome, type 1 and 2 diabetes, gestational diabetes, and cardiovascular diseases.

Correlation of CYP2R1 gene promoter methylation with circulating vitamin D levels among healthy adults.

Background & objectives: Despite being a tropical country, vitamin D deficiency is highly prevalent in India with studies indicating 40-99 per cent prevalence. Apart from calcium and phosphate metabolism, vitamin D is involved in cell cycle regulation, cardiovascular, hepatoprotection. The metabolism of vitamin D is regulated by vitamin D tool genes (CYP2R1/CYP27B1/CYP24A1/VDR). The promoter regions of some of these genes have CpG islands, making them prone to methylation induced gene silencing, which may cause a reduction in circulating vitamin D levels. Epigenetic basis of vitamin D deficiency is yet to be studied in India, and hence, this pilot study was aimed to analyze whether methylation levels of CYP2R1 gene were correlated with the levels of 25(OH)D in healthy, adult individuals in Indian population. Methods: In this cross-sectional study, healthy adults of 18-45 yr of age with no history of malabsorption, thyroidectomy, chronic illness or therapeutic vitamin D supplementation were recruited. DNA methylation analysis was carried out by methylation specific quantitative PCR. Serum calcium, phosphate and vitamin D levels were also quantified. Statistical analysis was done by R 4.0.5 software. Results: A total of 61 apparently healthy adults were analyzed. The serum vitamin D levels did not correlate with CYP2R1 methylation levels in our study population. Significant positive correlation was observed between age and serum vitamin D levels. Significant association of gender was found with CYP2R1 methylation levels. Interpretation & conclusions: This study found no significant correlation between levels of CYP2R1 methylation and circulating 25(OH)D deficiency. Further studies on the Indian population having a larger sample size including entire vitamin D tool genes, among different ethnic groups may be conducted to elucidate molecular etiology of circulating 25(OH)D deficiency. The high prevalence of normal serum calcium and phosphate levels among vitamin D deficient subjects in this study coupled with the strikingly high prevalence of the deficiency at the national level, may suggest the need to revise the cut-off criteria for vitamin D deficiency in the Indian population.

Pregnancy, Breastfeeding, and Vitamin D.

Exclusive breastfeeding is considered the ideal food in the first six months of life; however, paradoxically, vitamin D content in human breast milk is clearly low and insufficient to obtain the recommended intake of 400 IU daily. This article summarizes the extraordinary metabolism of vitamin D during pregnancy and its content in human breast milk. The prevalence of hypovitaminosis D in pregnant women and/or nursing mothers and its potential maternal-fetal consequences are analyzed. The current guidelines for vitamin D supplementation in pregnant women, nursing mothers, and infants to prevent hypovitaminosis D in breastfed infants are detailed. Low vitamin D content in human breast milk is probably related to active changes in human lifestyle habits (reduced sunlight exposure).

Influence of Vitamin D Deficiency on the Expression of Genes and Proteins in Patients With Medium Rotator Cuff Tears.

BACKGROUND: Whether vitamin D deficiency is related to rotator cuff muscle and tendon physiology is controversial. PURPOSE: To assess the relationship between vitamin D deficiency and various gene expression patterns in patients with rotator cuff tears. STUDY DESIGN: Controlled laboratory study. METHODS: During arthroscopic surgery, samples from the supraspinatus muscle, deltoid muscle, and supraspinatus tendon were acquired from 12 patients with vitamin D deficiency (serum 25-hydroxyvitamin D concentration <20 ng/dL) and 12 patients with sufficient vitamin D levels (control group, serum 25-hydroxyvitamin D concentration ≥30 ng/dL) who were matched for age, sex, and tear size. Alterations in the expression of genes and proteins associated with myogenesis, muscle atrophy, adipogenesis, inflammation, and apoptosis, as well as in vitamin D receptor expression, were assessed using quantitative reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry and were compared between the 2 groups. RESULTS: Vitamin D receptor gene expression in the deltoid muscle was significantly lower in the vitamin D deficiency group than in the control group (P = .043). Additionally, in the deltoid muscle, myoDgene expression levels were lower and atrogin levels were higher in the vitamin D deficiency group than in the control group (P = .034 and P = .011, respectively). However, in the supraspinatus muscle, no differences were observed between groups in the expression of myogenesis- or atrophy-related genes (all P > .05). The expression of inflammation-related genes (interleukin (IL)-1ß and IL-6) was significantly higher in the vitamin D deficiency group, in both the deltoid and supraspinatus muscles (all P < .05). The supraspinatus tendon tissue did not show any significant differences in any gene expression evaluated (all P > .05). A correlation between gene and protein expression was observed for atrogin and IL-1ß in the deltoid muscle (P = .019 and P = .037, respectively) and for IL-6 in the supraspinatus muscle (P = .044). CONCLUSION: Vitamin D deficiency was not associated with the expression of myogenesis-related or muscle atrophy-related genes in the supraspinatus muscle of patients with rotator cuff tears, unlike in the deltoid muscle; rather, vitamin D deficiency was associated with increased proinflammatory cytokine expression. CLINICAL RELEVANCE: In patients with rotator cuff tears, vitamin D deficiency was observed to be associated with increased levels of proinflammatory cytokines in the rotator cuff muscles, without significant changes in gene expression related to myogenesis or muscle atrophy.

Association of flame retardants, polybrominated diethyl ethers (PBDEs), with vitamin D in female subjects.

INTRODUCTION: A class of flame retardants, polybrominated diethyl ethers (PBDEs), are known endocrine disrupters and may induce the hepatic enzymes CYP24 and CYP3A that promote 25-hydroxylation of vitamin D3. Therefore, this study examined the association of PBDEs with vitamin D3 (25(OH)D3) and the active 1,25-dihydrovitamin D3 (1,25(OH)2D3) in a cohort of non-obese women. METHODS: 58 female participants (age:31.9 ± 4.6 years; body mass index (BMI):25.7 ± 3.7 kg/m2) had seven indicator PBDEs [PBDE28; PBDE47; PBDE99; PBDE100; PBDE153; PBDE154; PBDE183] measured using high resolution gas chromatography, with Æ©PBDE level calculated. 25(OH)D3 and 1,25(OH)2D3 levels were determined by isotope-dilution liquid chromatography tandem mass spectrometry. Plasma level of calcium/calmodulin-dependent protein kinase type 1 (CaMK1) was measured by Somascan proteomics. RESULTS: In this cohort, vitamin D3 (25(OH)D3) and 1,25(OH)2D3 levels were 22.9 ± 11.2 ng/mL and 0.05 ± 0.02 ng/mL, respectively. Of those, 28 had vitamin D deficiency [25(OH)D3 level <20 ng/mL (<50 nmol/L)]. For the whole group, individual PBDEs (PBDE28; PBDE47; PBDE99; PBDE100; PBDE153; PBDE154; PBDE183) and Æ©PBDEs did not correlate with 25(OH)D3 or its active metabolite 1,25(OH)2D3 nor with BMI. For the subset who were 25(OH)D3 sufficient, negative correlations were found for 1,25(OH)2D3 with PBDE153 (ρ = -0.77; p = 0.02) and PBDE100 (ρ = -0.72; p = 0.005). In the subset of women who were 25(OH)D3 deficient, positive correlations were found for 1,25(OH)2D3 with PBDE153 (ρ = 0.68; p = 0.02) and Æ©PBDEs (ρ = 0.57; p = 0.03). Using sufficient and deficient subset categories, no correlations were seen with 25(OH)D3 nor any of the PBDEs, and PBDEs did not correlate to renal function (estimated glomerular filtration rate, eGFR). 1,25(OH)2D3 was negatively associated with CaMK1 (r = -0.36; p = 0.03) as was PBDE153 (r = -0.31; p = 0.02). CONCLUSION: PBDEs were not associated with 25(OH)D3, but PBDE100 and 153 correlated with its active 1,25(OH)2D3 metabolite and PBDE153 correlated to the calcium modulator CaMKI, suggesting that PBDE effects could either be mediated through vitamin D status or that functional inactivation or inhibition of 1,25(OH)2D3 may contribute to the impact of vitamin D deficiency.

SIRT1 and antioxidants in infertile females: Exploration of the role of vitamin D.

BACKGROUND: Deficiency of silent information regulator 1 (SIRT1) can trigger inflammation, mitochondrial malfunctioning, and apoptosis through the hypothalamic-pituitary-ovarian axis, producing poor quality oocytes, leading to infertility. Normal vitamin D (VD) levels promote SIRT1 activity required for optimal fertility, and low levels of either may result in fertility problems owing to cell-membrane de-stabilization, increased autophagy, DNA damage leading to increased reactive oxygen species and mitochondrial dysfunction. Therefore, in this study, we want to estimate the levels of VD, SIRT1 and antioxidants (MnSOD; manganese superoxide dismutase, GR; glutathione reductase, visfatin) and oxidants (adrenaline & cortisol) in individuals living with infertility and explore the association of VD with SIRT1 expression (levels), antioxidants, and oxidants contributing to infertility in women. The significance of this study is that it highlights the importance of maintaining optimal levels of VD for reproductive health in females. METHODS: This cross-sectional study included 342 (135 infertile and 207 fertile) female subjects. Serum levels of MnSOD, SIRT1, visfatin, GR, VD, adrenaline, and cortisol were analyzed by ELISA and were compared in fertile and infertile samples using the Mann Whitney U test. RESULTS: There were significantly high levels of VD, SIRT1, GR, MnSOD and visfatin in fertile female participants. However, mean adrenaline and cortisol levels were higher in infertile samples with a significant negative correlation with VD. A significant negative correlation of VD with MnSOD, SIRT1, visfatin and GR was observed (p <0.01). In VD subset groups, MnSOD levels were significantly high in VD sufficient groups however, adrenaline and cortisol levels were significantly high in groups suffering from VD deficiency. CONCLUSIONS: Deficiency of VD is associated with a decrease in SIRT1 and other antioxidants, which may deter natural reproductive functions leading to infertility. Further studies are required to determine the cause-effect relationship of VD deficiency on conception and interpretation of the involved mechanism.

Vitamin D deficiency in early life regulates gut microbiome composition and leads to impaired glucose tolerance in adult and offspring rats.

Vitamin D has been found to be involved in glucose metabolism in recent years. Its deficiency is very common, especially in children. Whether vitamin D deficiency in early life affects adult diabetes risk is unknown. In this study, a rat model of early life vitamin D deficiency (F1 Early-VDD) was established by depriving it of vitamin D from the 0 to the 8th week. Further, some rats were switched to normal feeding conditions and sacrificed at the 18th week. Other rats were mated randomly to generate offspring rats (F2 Early-VDD), and F2 rats were fed under normal conditions and sacrificed at the 8th week. Serum 25(OH)D3 level decreased in F1 Early-VDD at the 8th week and returned to normal at the 18th week. Serum 25(OH)D3 level in F2 Early-VDD at the 8th week was also lower than that in control rats. Impaired glucose tolerance was observed in F1 Early-VDD at the 8th week and 18th week and also in F2 Early-VDD at the 8th week. The gut microbiota composition in F1 Early-VDD at the 8th week significantly changed. Among the top ten genera with a rich difference, Desulfovibrio, Roseburia, Ruminiclostridium, Lachnoclostridium, A2, GCA-900066575, Peptococcus, Lachnospiraceae_FCS020_ group, and Bilophila increased owing to vitamin D deficiency, whereas Blautia decreased. There were 108 significantly changed metabolites in F1 Early-VDD at the 8th week, of which 63 were enriched in known metabolic pathways. Correlations between gut microbiota and metabolites were analyzed. Blautia was positively related to 2-picolinic acid, whereas Bilophila was negatively related to indoleacetic acid. Moreover, some of the changes in microbiota, metabolites, and enriched metabolic pathways still existed in F1 Early-VDD rats at the 18th week and F2 Early-VDD rats at the 8th week. In conclusion, vitamin D deficiency in early life leads to impaired glucose tolerance in adult and offspring rats. This effect may be partly achieved by regulating gut microbiota and their co-metabolites.

Bone turnover profile and muscular status in major orthopaedic surgery: a case series.

BACKGROUND Sarcopenia refers to a chronic loss of skeletal muscle mass, often associated with hypovitaminosis D and advanced age, which involves a greater risk of falls and fractures. The association of sarcopenia and osteoporosis defines osteo-sarcopenia. In this work, the authors analyzed the osteometabolic profile and the loco-regional muscular state of patients undergoing major orthopedic surgery, in order to define the incidence of district osteosarcopenic states, linked to a condition of disuse.   METHODS   19 patients (10M-9F), between 15 and 85 years old, underwent major orthopedic surgery (15 resection prosthesis and custom made, 2 resection and reconstruction with transplant) were evaluated, of which 9 on an oncological basis. In all patients, the phospho-calcium metabolism was assessed by blood tests and intraoperative muscle biopsy was performed at the intervention site and contralaterally; in 3 cases a densitometric comparative study of the affected/contralateral limb was performed.   RESULTS   Results shows 5 patients with hypovitaminosis D; 7 pcs with hypocalcemia; 5 with PTH rise; 4pcs with ALP increase. In 100% of cases, the biopsy revealed sarcopenic patterns exclusively on the affected limb. 2 out of 3 DEXAs (66%) showed loco-regional osteoporosis compared to the contralateral.   CONCLUSIONS   The fact that in our sample sarcopenia is unilateral affecting only the pathological limb, that it is frequently associated with osteoporosis which is also unilateral and that for the most part it is not associated with vitamin D deficiency, suggests that it is an independent condition, with etiopathogenetic mechanisms different from osteosarcopenia itself. In major orthopedic surgery, bone integration and muscle status are both essential for achieving and lasting positive results. Considering the high incidence of district osteosarcopenia, an integrated surgical, pharmacological, and rehabilitative approach is desirable for the optimization of results, as well as more studies for the definition of the etiopathogenesis of this pathological condition.

Prenatal vitamin D supplementation mitigates inflammation-related alveolar remodeling in neonatal mice.

The development of chronic lung disease in the neonate, also known as bronchopulmonary dysplasia (BPD), is the most common long-term complication in prematurely born infants. In BPD, the disease-characteristic inflammatory response culminates in nonreversible remodeling of the developing gas exchange area, provoked by the impact of postnatal treatments such as mechanical ventilation (MV) and oxygen treatment. To evaluate the potential of prenatal treatment regimens to modulate this inflammatory response and thereby impact the vulnerability of the lung toward postnatal injury, we designed a multilayered preclinical mouse model. After administration of either prenatal vitamin D-enriched (VitD+; 1,500 IU/g food) or -deprived (VitD-; <10 IU/kg) food during gestation in C57B6 mice (the onset of mating until birth), neonatal mice were exposed to hyperoxia (FiO2 = 0.4) with or without MV for 8 h at days 5-7 of life, whereas controls spontaneously breathed room air. Prenatal vitamin D supplementation resulted in a decreased number of monocytes/macrophages in the neonatal lung undergoing postnatal injury together with reduced TGF-ß pathway activation. In consequence, neonatal mice that received a VitD+ diet during gestation demonstrated less extracellular matrix (ECM) remodeling upon lung injury, reflected by the reduction of pulmonary α-smooth muscle actin-positive fibroblasts, decreased collagen and elastin deposition, and lower amounts of interstitial tissue in the lung periphery. In conclusion, our findings support strategies that attempt to prevent vitamin D insufficiency during pregnancy as they could impact lung health in the offspring by mitigating inflammatory changes in neonatal lung injury and ameliorating subsequent remodeling of the developing gas exchange area.NEW & NOTEWORTHY Vitamin D-enriched diet during gestation resulted in reduced lung inflammation and matrix remodeling in neonatal mice exposed to clinically relevant, postnatal injury. The results underscore the need to monitor the subclinical effects of vitamin D insufficiency that impact health in the offspring when other risk factors come into play.

The Role of Maternal Vitamin D Deficiency in Offspring Obesity: A Narrative Review.

Currently, vitamin D (VD) deficiency during pregnancy is widespread globally, causing unfavorable pregnancy outcomes for both mothers and infants for a longer time than expected, based on the Developmental Origins of Health and Disease (DOHaD) theory. As VD plays a key role in maintaining normal glucose and lipid metabolism, maternal VD deficiency may lead to obesity and other obesity-related diseases among offspring later in life. This review mainly focuses on the effect of maternal VD deficiency on offspring lipid metabolism, reviewing previous clinical and animal studies to determine the effects of maternal VD deficit on offspring obesity and potential mechanisms involved in the progression of offspring obesity. Emerging clinical evidence shows that a low VD level may lead to abnormal growth (either growth restriction or largeness for gestational age) and lipid and glucose metabolism disorders in offspring. Here, we also outline the link between maternal VD deficiency and life-long offspring effects, including the disorder of adipogenesis, the secretion of adipocytokines (including leptin, resistin, and adiponectin), activated systemic inflammation, increased oxidative reactions in adipose tissue, insulin resistance, and abnormal intestinal gut microbiota. Thus, there is an urgent need to take active steps to address maternal VD deficiency to relieve the global burden of obesity.

Aerobic Exercise Ameliorates Myocardial Fibrosis via Affecting Vitamin D Receptor and Transforming Growth Factor-ß1 Signaling in Vitamin D-Deficient Mice.

Myocardial fibrosis is a pathological phenomenon associated with cardiovascular disease (CVD) that plays a crucial role in the development of heart diseases. Vitamin D deficiency can promote the development of CVD and exercise plays a role in the treatment of CVD. This study aimed to explore the effects of 12-week aerobic exercise training on myocardial fibrosis in vitamin D-deficient mice. A vitamin D-deficient mouse model was induced by a vitamin D-deficient (0 IU Vitamin D3/kg) diet. Twenty-four C57BL/6J male mice were randomly divided into three groups: a control sedentary group (CONS, n = 8), a vitamin D-deficient sedentary group (VDDS, n = 8), and a vitamin D-deficient exercise group (VDDE, n = 8) which was aerobically trained for 12 weeks. The results showed that the serum 25-hydroxyvitamin D [25(OH)D] levels of the VDDS group were <50 nmol/L, which was significantly lower than that of the CONS group. Compared with the CONS group, the VDDS group showed cardiac dysfunction and significant fibrosis, together with lower vitamin D receptor (VDR) mRNA and protein expression levels, higher mRNA expression levels of profibrotic and inflammatory factors, and higher transforming growth factor-ß1 (TGF-ß1) and phospho-Smad2/3 (P-Smad2/3) protein expression levels. Serum 25(OH)D levels in the VDDE group were significantly higher than those in the VDDS group. Compared with the VDDS group, the VDDE group showed improved cardiac function and alleviated myocardial fibrosis. Meanwhile, the VDDE group had significantly higher VDR mRNA and protein expression levels; lower mRNA expression levels of profibrotic and inflammatory factors; and lower TGF-ß1 and P-Smad2/3 protein expression levels. In conclusion, aerobic exercise training remains a promising intervention for treating myocardial fibrosis in vitamin D deficiency.

Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry.

High-altitude hypoxia challenges reproduction; particularly in non-native populations. Although high-altitude residence is associated with vitamin D deficiency, the homeostasis and metabolism of vitamin D in natives and migrants remain unknown. We report that high altitude (3600 m residence) negatively impacted vitamin D levels, with the high-altitude Andeans having the lowest 25-OH-D levels and the high-altitude Europeans having the lowest 1α,25-(OH)2-D levels. There was a significant interaction of genetic ancestry with altitude in the ratio of 1α,25-(OH)2-D to 25-OH-D; with the ratio being significantly lower in Europeans compared to Andeans living at high altitude. Placental gene expression accounted for as much as 50% of circulating vitamin D levels, with CYP2R1 (25-hydroxylase), CYP27B1 (1α-hydroxylase), CYP24A1 (24-hydroxylase), and LRP2 (megalin) as the major determinants of vitamin D levels. High-altitude residents had a greater correlation between circulating vitamin D levels and placental gene expression than low-altitude residents. Placental 7-dehydrocholesterol reductase and vitamin D receptor were upregulated at high altitude in both genetic-ancestry groups, while megalin and 24-hydroxylase were upregulated only in Europeans. Given that vitamin D deficiency and decreased 1α,25-(OH)2-D to 25-OH-D ratios are associated with pregnancy complications, our data support a role for high-altitude-induced vitamin D dysregulation impacting reproductive outcomes, particularly in migrants.