Electrocardiographic, biochemical, and scintigraphic evidence for the cardioprotective effect of paricalcitol and vitamin D3 on doxorubicin-induced acute cardiotoxicity in rats.

AIM: We aimed to investigate the possible cardioprotective effects of paricalcitol (PR), its vitamin D receptor agonist, and vitamin D3 (VIT-D3) on an experimental model of doxorubicin (DX) cardiotoxicity by 99mTc-PYP scintigraphy, electrocardiographic (ECG) and biochemical methods. METHOD: Forty-two male Wistar/Albino rats (250‒300 g; aged 10‒12 weeks) were randomly separated into six groups, namely into control (CN), doxorubicin (DX), paricalcitol (PR), vitamin D3 (VIT-D3), paricalcitol + doxorubicin (PR+DX), and vitamin D3 + doxorubicin (VIT-D3+DX) groups. Cardiotoxicity was induced by three doses of DX (18 mg/kg, i.p.) at 24-hour intervals on days 18, 19 and 20. PR (0.5 ug/ kg, i.p) and VIT-D3 (5,000 IU/kg, i.p) were injected for 20 days before and after the application of DX (18 mg/kg, i.p.). On day 21 of the experiment, biochemical parameters [tumor necrosis factor TNF-alpha (TNF-α); interleukin-6 (IL-6), nitric oxide (NO), and cardiac troponin T (cTnT)], as well as ECG and scintigraphic (99mTc-PYP) features were assessed. RESULTS: Compared to CN, DX significantly raised TNF-α, IL-6, and NO in heart tissue, cTnT in serum, 99mTc-PYP uptake in the myocardium, and ECG parameters, specifically QRS complex duration, QT interval duration, and ST-segment amplitude, while also reducing heart rate (p<0.001). Pretreatment with PR and VIT-D3 mitigated these abnormalities produced by DX in the heart (p<0.001). CONCLUSION: Results show that vitamin D receptor agonist paricalcitol and vitamin D protect against DX-induced cardiotoxicity through anti-inflammatory and antioxidant effects (Fig. 4, Ref. 59). Text in PDF www.elis.sk Keywords: paricalcitol, doxorubicin, vitamin D, ECG, 99mTc-PYP scintigraphy, cardiotoxicity, inflammation.

The rs11568820 Variant in the Promoter Region of Vitamin D Receptor Gene Is Associated with Clinical Remission in Rheumatoid Arthritis Patients Receiving Tumor Necrosis Factor Inhibitors.

The vitamin D receptor (VDR), binding to the active form of the vitamin, promotes the transcription of numerous genes involved in the proliferation of immune cells, cytokine production and lymphocyte activation. It is known that vitamin D deficiency can influence the risk of developing rheumatoid arthritis (RA) or modulate its disease activity. The aim of this study was to investigate a possible association between the rs11568820 (C > T) polymorphism in the promoter region of VDR gene and the response to therapy with anti-TNF drugs in patients with RA. A total of 178 consecutive Italian patients with RA treated with anti-TNF, naïve for biological therapy, were recruited. Disease activity data were evaluated using specific indices such as DAS28, CDAI and SDAI, measured at the start of therapy and subsequently at 22, 52, 104 and 240 weeks. A statistically significant association emerged between the rs11568820 variant allele of VDR gene and failure to remission assessed by CDAI and SDAI at 52 weeks, and by DAS28, CDAI and SDAI at 104 weeks of follow-up. Furthermore, the variant allele of this polymorphism was observed more frequently in patients who did not undergo sustained remission calculated by CDAI and SDAI. The variant T allele of rs11568820 in VDR gene is associated with a reduced remission rate with anti-TNFα drugs. These data suggest the role of VDR genetic variability in the response to therapy and in the achievement of remission.

Correlation of vitamin D receptor genotypes, specific IgE levels and other variables with asthma control in children.

INTRODUCTION: Asthma is a common condition affecting millions of children globally. The main goal of this study is to assess factors related to asthma management, particularly atopy level and the impact of genetic variants of the vitamin D receptor (VDR) gene. METHODS: Asthmatic children were enrolled in an outpatient respiratory clinic. Information on patients' medication adherence, medical and medication factors, and sociodemographic were gathered. Spirometry FEV1% and FVC% measurements, and the asthma control test were used to evaluate the severity of asthma, and genotyping of the VDR gene and radioallergosorbent test (RAST) were conducted. Regression analyses were conducted to evaluate variables associated with asthma control and spirometry measures. RESULTS: A total of 313 participants (67.4% males) were recruited in the current study. The mean age was 9.37 (±3.45) years. The mean score for adherence was 4.26 (±2.52), and only 46% of the participants had controlled asthma. Forward conditional stepwise binary regression showed that low and moderate Inhaled corticosteroids (ICS) dose (OR= 0.42 (95% CI 0.20-0.90), p = 0.026; OR = 0.371 (95% CI 0.2-0.72), p = 0.003, respectively) decreased the odds of being in the controlled asthma group, while higher inhaler score (OR = 2.75 (95% CI 2.17-3.49, p < 0.001)) increased the odds of being in the controlled asthma group. However, results found no association between VDR genotype and asthma control, spirometry values or hospitalization due to asthma. CONCLUSIONS: The results indicated that many of the asthma patients had poorly controlled asthma. Factors that were associated with poor asthma control included poor inhaler technique.

Vitamin D/vitamin D receptor pathway in non-alcoholic fatty liver disease.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, but underlying mechanisms are not fully understood. In recent years, a growing body of evidence has emphasized the therapeutic role of vitamin D in NAFLD, but the specific mechanism remains to be investigated. AREAS COVERED: This review summarized the roles of vitamin D/VDR (vitamin D receptor) pathway in different types of liver cells (such as hepatocytes, hepatic stellate cells, liver macrophages, T lymphocytes, and other hepatic immune cells) in case of NAFLD. Meanwhile, the effects of pathways in the gut-liver axis, adipose tissue-liver axis, and skeletal muscle-liver axis on the development of NAFLD were further reviewed. Relevant literature was searched on PubMed for the writing of this review. EXPERT OPINION: The precise regulation of regional vitamin D/VDR signaling pathway based on cell-specific or tissue-specific function will help clarify the potential mechanism of vitamin D in NAFLD, which may provide new therapeutic targets to improve the safety and efficacy of vitamin D based drugs.

Piscine Vitamin D Receptors Vdra/Vdrb in the Absence of Vitamin D Are Utilized by Grass Carp Reovirus for Promoting Viral Replication.

The vitamin D receptor (VDR) plays a pivotal role in the biological actions of vitamin D (VitD). However, little is known about the functions of VDR in the production of viral inclusion bodies (VIBs). Using a representative strain of grass carp reovirus (GCRV) genotype I, GCRV-873, we show that GCRV-873 recruits grass carp Vdrs for promoting the production of VIBs in the absence of VitD. Inhibition of cholesterol synthesis by lovastatin impairs the production of VIBs and blocks the effects of grass carp Vdrs in promoting the production of VIBs in the absence of VitD. Furthermore, grass carp Vdrs are found to form the Vdra-Vdrb heterodimer, which is vital for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (hmgcr)-dependent cholesterol synthesis and GCRV replication. Intriguingly in the presence of VitD, grass carp Vdra but not Vdrb forms the heterodimer with the retinoid X receptor beta b (Rxrbb), which induces the transcription of those genes involved in the RIG-I-like receptor (RLR) antiviral signaling pathway for inhibiting GCRV infection. Furthermore, the VitD-activated Vdra-Vdrb heterodimer attenuates the transcription of the RLR antiviral signaling pathway induced by VitD. In the presence of VitD, a balance between the Vdra-Rxrbb heterodimers as coactivators and Vdra-Vdrb heterodimers as corepressors in affecting the transcriptional regulation of the RLR antiviral signaling pathway may eventually determine the outcome of GCRV infection. Transfection with VitD can abolish the effect of grass carp Vdrs in promoting GCRV replication in a dose-dependent manner. Taken together, these findings demonstrate that GCRV utilizes host Vdrs to increase hmgcr-dependent cholesterol synthesis for promoting its replication, which can be prevented by VitD treatment. IMPORTANCE Grass carp reovirus (GCRV) is the causative agent of grass carp hemorrhagic disease, which seriously harms freshwater fish. Although many positive or negative regulators of GCRV infection have been identified in teleosts, little is known about the molecular mechanisms by which GCRV utilizes host factors to generate its infectious compartments beneficial for viral replication and infection. Here, we show that in the absence of VitD, the GCRV-873 strain utilizes host vitamin D receptors Vdra/Vdrb to increase hmgcr-dependent cholesterol synthesis for promoting the production of VIBs, which are important functional sites for aquareovirus replication and assembly. The negative regulation of Vdrs during viral infection can be prevented by VitD treatment. Thus, this present work broadens understanding of the pivotal roles of Vdrs in the interaction between the host and GCRV in the absence or presence of VitD, which might provide a rational basis for developing novel anti-GCRV strategies.

A Prospective Study to Evaluate the Possible Role of Cholecalciferol Supplementation on Autoimmunity in Hashimoto's Thyroiditis.

A Prospective Study to Evaluate the Possible Role of Cholecalciferol Supplementation on Autoimmunity in Hashimoto's Thyroiditis Biva Bhakat1 , Jyotirmoy Pal2 , Sukdeb Das3 , Sumit Kr Charaborty4 1,3Nil Ratan Sircar Medical College, Kolkata, 2 RG Kar Medical College and Hospital, 4 North Bengal Medical College, Siliguri Introduction: Hashimoto thyroiditis (HT) is an autoimmune disease that destroys thyroid cells by antibody and call-mediated immune processes. Hashimoto thyroiditis is the commonest cause of goitre in iodine-sufficient regions.[1] The aetiology of Hashimoto disease is very poorly understood. Most patients develop antibodies to a variety of thyroid antigens, the most common of which is anti-thyroid peroxidase (anti-TPO). Many also form antithyroglobulin (anti-Tg) and TSH receptor blocking antibodies (TBII). These antibodies attack the thyroid tissue, eventually leading to inadequate production of thyroid hormone. There is a small subset of the population, around 10-15% with the clinically evident disease, that are serum antibody-negative.[2][3] The mechanisms underlying the assumption that vitamin D is linked with autoimmunity are not clear but probably are associated with its anti-inflammatory and immunomodulatory functions. The dendritic cells are antigen-presenting cells originating from bone marrow and also a primary target for the immunomodulatory activity of vitamin D. 1,25[OH]2D has direct immunomodulatory effects at the level of the T cell vitamin D receptor. Together, these immunomodulatory effects can lead to the protection of target tissues, such as thyroid cells in autoimmune diseases. Considering that in HT, a disorder of T cell-mediated immunity, immunologic attack is triggered when thyrocytes express MHC class II surface HLA-DR antigens, a process induced by the production of Th1 type inflammatory cytokines (especially IFN-γ). Moreover, at another stage, after being activated by T cells, B cells' ongoing proliferation might be inhibited and apoptosis might be induced by 1,25[OH]2D. Thus, 1,25[OH]2D might decrease antibodies that react with thyroid antigens. The exact levels of vitamin D that are sufficient to improve the immune regulatory function and lead to an effective immune response, should be investigated. Several clinical studies have reported a low vitamin D status in AITD or HT, indicating an association between vitamin D deficiency and thyroid autoimmunity. If supplementation of the Vitamin D decreased thyroid antibody titres in Vitamin D deficient subjects, in the future Vitamin D may become a part of AITDs' treatment, especially in those with Vitamin D deficiency. [4] So, our study tries to assess any potential therapeutic role of vitamin D in the management of patients with Hashimoto's thyroiditis. AIMS AND OBJECTIVES: Most studies have shown an association between low vitamin D status and pathogenesis of AITD, especially HT. However, there are only few preliminary interventional studies for HT. whether vitamin D supplementation is beneficial for AITD or HT, should be evaluated. Treatment of HT mainly based on thyroid hormone supplementation, so if a beneficial role of vitamin D supplementation is identified/ confirmed, it will be helpful in the treatment of patients with HT and may be a part of treatment of HT patients. AIMS AND OBJECTIVES: Evaluating the role of vitamin D on an excessive thyroid immune response. MATERIALS AND METHODS: Study area: N.R.S. Medical college and hospital, Kolkata (Department of General Medicine). STUDY PERIOD: 1 year (January,2019 to December,2019 Sample size: 100 patients both male and female. Sample Design: Patients attending outpatient dept in N.R.S medical college. STUDY DESIGN: Prospective, hospital based, single centre study. INCLUSION CRITERIA: Newly diagnosed patients (age >18 years and of both sexes) with HT and vitamin D deficiency. EXCLUSION CRITERIA: Patients suffering from: Other autoimmune diseases. Chronic illnesses like diabetes mellitus, chronic kidney disease, chronic liver disease, malignancy. Pregnancy Study tools: Estimation from serum: TSH. Free thyroxine (FT4) 25 hydroxy vitamin D Anti-thyroid peroxidase (anti-TPO) antibody' Study techniques: This is a prospective study conducted in N.R.S Medical college, Kolkata, India. Total 100 adult patients of both sexes diagnosed with HT and vitamin D deficiency (vit D<30 ng/ml)12, having none of the exclusion criteria and getting treatment on out-patient department basis, who gave informed consent were included in our study. Blood samples drawn for anti TPO antibody and 25hydroxy vitamin D from all the participants. The correlations between serum Vit D and anti TPO antibody were measured and presented by correlation coef ficient (r2). Study participants are randomly assigned into two groups by random permuted block. Cholecalciferol supplement given in the dose of 60,000 IU weekly for 8 weeks in one group (n = 50). Another group (n = 50) were given placebo (empty soft gelatine capsule). At the onset of the study, patients were requested to keep their habitual diet and routine level of physical activity throughout the study period and not to take any medication that might affect their reproductive physiology. Compliance to the consumption of supplement and placebo was examined by empty blister packets. However, 2 patients from cholecalciferol group and 1 patient from control group lost to follow up. After 8 weeks blood anti TPO antibody level measured in both the groups (n = 48 & 49 in 2 group). The change in the mean value of anti TPO antibody measured and statistical significance of the change checked. Results considered significant or non-significant when P> or < 0.05, respectively. TSH, T4 measurement Performed with chemiluminescence using ADVIA Centaur XP Immunoassay System. Work plan: Study was done over 12 months. Data collected and compilation done and then statistical analysis done by standard statistical method. STATISTICAL ANALYSIS: For statistical analysis data were entered into a Microsoft excel spreadsheet and then analyzed by SPSS (version 27.0; SPSS Inc., Chicago, IL, USA) and GraphPad Prism version 5. p-value ≤ 0.05 was considered for statistically significant. The Negative Correlation was found between Serum 25 hydroxy vitamin D (ng/ml) vs Serum TSH (mU/L) which was statistically significant. Distribution of mean serum anti-TPO antibody level (IU/ml) [mean±SD] in both groups before and after intervention Reduction of serum anti-TPO antibody level in cholecalciferol group is 30.5% and reduction of serum anti-TPO antibody level in placebo group is 16.5%. DISCUSSION: This study is carried out with the total no. of 100 outdoor based patients of diagnosed Hashimoto's Thyroiditis (elevated Anti-thyroid peroxidase antibody) and vitamin D deficiency (vit D < 30 ng/mL)12 in Nil Ratan Sircar medical college and hospital within the mentioned study period. The study focussed on evaluating the role of vitamin D on an excessive thyroid immune response i.e. the effect of vitamin D supplementation on thyroid autoimmunity and that low vitamin D levels and the risk of HT are closely associated and the potential application of vitamin D in the treatment of AITD. The result demonstrates a negative Correlation between Serum 25 hydroxy vitamin D (ng/mL) vs anti TPO antibody (IU/ml) which was statistically significant. Pearson Correlation Coefficient (r)= -0.775, p value = 0.0001. Goswami et al. conducted a community-based survey on 642 adults to investigate the relationship between serum vitamin D concentrations and thyroid autoimmunity. Their results highlighted a significant inverse association between 25(OH)D3 and TPO Ab levels [40]. This inverse correlation was substantiated in the following studies.[5-8] As regards thyroid function in the context of HT, Mackawy and co-workers demonstrated a strong negative association between serum vitamin D concentrations and TSH levels, leading to speculate that vitamin D deficiency in HT patients could be associated with a progression towards hypothyroidism (TSH > 5.0 m UI/L) [45]. Our study also demonstrates negative Correlation between Serum 25 hydroxy vitamin D (ng/mL) vs Serum TSH (mU/L) and the result was statistically significant. Pearson Correlation Coefficient (r) = -0.301, p value = 0.003. So, the results indicate that vitamin D deficiency is a risk factor of Hashimoto's thyroiditis. Mean (mean± s.d.) Serum anti TPO antibody (IU/ml) before intervention was 545.06± 230.82 and after cholecalciferol supplementation the mean value decreased to 378.6± 160.49. So, there is a 30.5% reduction in the mean value of anti TPO antibody level. Difference of mean Serum anti TPO antibody (IU/mL) was statistically significant (p < 0.0001). In the placebo group the mean Serum anti TPO antibody (IU/ml) (mean ± s.d.) of patients was 686.97± 290.19 and after 8 weeks of placebo the mean value was 573.1 ± 254.09. So, in the placebo group the reduction is only 16.5%. Difference of mean Serum anti TPO antibody (IU/ml) was statistically significant (p < 0.0001). Therefore, in line with the hypothesis the data contributes clearer understanding that vitamin D supplementation results in a reduction of thyroid autoimmunity. This result also supports the previous research. Simsek et al. prospectively evaluated 82 patients with HT randomized in two groups: the first group treated with cholecalciferol for one month and the second group without vitamin D replacement. Their results showed that TPO Ab and Tg Ab levels were significantly decreased by the vitamin D replacement therapy in the first group [46]. These findings were also confirmed by other prospective studies and randomized controlled trials.[9-11] So, the result of our studyclearly indicates that vitamin D supplementation could exert a positive effect on thyroid function as well as thyroid autoimmunity Limitations: Vitamin D status is not measured at the end of 8 weeks because of economic constraints. So, it is difficult to determine the optimal level of vitamin D needed for improving the evolution of this immunological disorder. Cholecalciferol is used in HT patients in our study, although active form calcitriol might be more beneficial as vitamin D binding protein level may affect the conversion of inactive vitamin D form and thus alters its function on immune cells. HT patients with normal vitamin D level have been excluded from the study, so from our study we cannot comment on beneficial effect of vit D supplementation in HT patient with normal vit D level. As we used empiric dose of levothyroxine in both the groups instead of a fixed dose, we could not analyze the potential role of vitamin D supplementation in reduction of serum TSH in HT There is still a gap in the knowledge regarding the potential of vitamin D supplementation in the treatment of HT patients whether vitamin D supplementation will help in decreasing the replacement dose of levothyroxine or whether it will stop the need of levothyroxine replacement if used in early stages of HT. CONCLUSIONS: The 8 weeks randomized; double-blind, placebo-controlled clinical trial demonstrates a negative correlation between Serum 25 hydroxy vitamin D vs anti TPO antibody level. Treatment with 60,000 IU cholecalciferol weekly for 8 weeks, is associated with significant decrease in antithyroid antibody titers. It also improved serum TSH level compared with the placebo, i.e. supplementary treatment with cholecalciferol seems to have beneficial effects on AITD. However, large multicentre studies are needed to investigate the impact of vitamin D supplementary treatment on meaningful long-term clinical end points in AITD. References Dana L. Mincer; Ishwarlal Jialal. StatPearls [Internet]. Hashimoto Thyroiditis. Treasure Island (FL): StatPearls Publishing; 2020 Jan. Leung AKC, Leung AAC. Evaluation and management of the child with hypothyroidism. World J Pediatr 2019;15(2):124-134. Yuan J, Sun C, Jiang S, et al. The pevalence of thyroid disorders in patients with vitiligo: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2018;. Front Endocrinol (Lausanne). 2018; 9:803. Yoo WS, Chung HK. Recent advances in autoimmune thyroid diseases. Endocrinol Metab (Seoul) 2016;31(3):379-385. Ke W, Sun T, Zhang Y, et al. 25-Hydroxyvitamin D serum level in Hashimoto's thyroiditis, but not Graves' disease is relatively deficient. Endocr J 2017;64(6):581-587. Shin D, Kim KJ, Kim D, et al. Low serum vitamin D is associated with anti-thyroid peroxidase antibody in autoimmune thyroiditis. Yonsei Med J 2014; 55:476-481. ElRawi HA, Ghanem NS, ElSayed, N.M.; et al. Study of vitamin D level and vitamin D receptor polymorphism in hypothyroid egyptian patients. J Thyroid Res 2019. Kim CY, Lee YJ, Choi J, et al. The association between low vitamin d status and autoimmune thyroid disease in korean premenopausal women: the 6th korea national health and nutrition examination survey, 2013-2014. Korean J Fam Med 2019;40:323-328. Chaudhary S, Dutta D, Kumar M, et al. Vitamin D supplementation reduces thyroid peroxidase antibody levels in patients with autoimmune thyroid disease: An open-labelled randomized controlled trial. Indian J Endocrinol Metab 2016;20:391-398. Krysiak R, Szkróbka W, Okopie´n, B. The effect of vitamin D on thyroid autoimmunity in levothyroxine-treated women with Hashimoto's thyroiditis and normal vitamin D Status. Exp. Clin. Endocrinol. Diabetes 2017;125:229-233. Krysiak R, Kowalcze K, Okopie´n B. Selenomethionine potentiates the impact of vitamin D on thyroid autoimmunity in euthyroid women with Hashimoto's thyroiditis and low vitamin D status. 2018;71:367-373. Mazokopakis EE1, Papadomanolaki MG, Tsekouras KC, et al. Is vitamin D related to pathogenesis and treatment of Hashimoto's thyroiditis? Hell J Nucl Med. 2015;18(3):222-7.

XCHT alleviates the pancreatic fibrosis via VDR/NLRP3 signaling pathway in a mouse model of CP.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiao Chai Hu Tang (XCHT) derived from the classic medical book Shang Han Lun (Treatise on Febrile Diseases) in the Eastern Han Dynasty, which has been widely used in China and other Asian countries for the treatment of inflammation and fibrosis of chronic pancreatitis (CP), but the therapeutic mechanism of XCHT in pancreatic fibrosis remains unclear. AIM OF THE STUDY: This study aimed to evaluate the intervention effects and explore pharmacological mechanism of XCHT on inflammation and fibrosis in cerulein-induced CP model. MATERIALS AND METHODS: Fifty male C57BL/6 mice were randomly divided into five main groups, 10 animals in each: Control, CP model (50 µg/kg cerulein), high dose XCHT-treated CP group (60 g/kg XCHT), medium dose XCHT-treated CP group (30 g/kg XCHT) and low dose XCHT-treated CP group (15 g/kg XCHT). Different doses of XCHT were given to mice by gavage twice a day for 2 weeks after the CP model induction. Pancreatic tissues were harvested and the pancreatic inflammation and fibrosis were evaluated by histological score, Sirius red staining, and alpha-smooth muscle actin (α-SMA) immunohistochemical staining. ELISA, IHC and RT-qPCR were performed to detect the expression of Vitamin D3 (VD3) and Vitamin D receptor (VDR) in serum and pancreatic tissues, respectively. The expressions of NLRP3 inflammasome related genes and molecules were assayed by WB, IHC and RT-qPCR. RESULTS: The pathohistological results demonstrated that XCHT markedly inhibited the fibrosis and chronic inflammation of cerulein-induced CP, indicated by reduction of collagen I, collagen III, α-SMA, and NLRP3 expressions. XCHT significantly increased VD3 and VDR expression while reduced the pancreatic NLRP3 expression. Correspondingly, XCHT decreased the levels of NLRP3 downstream targets IL-1ß, TNF-α and IL-6. CONCLUSIONS: These results revealed that XCHT suppressed the pancreatic fibrosis and chronic inflammation in cerulein-induced CP model by enhancing the VD3/VDR expression and inhibiting the secretion of NLRP3-assoicated inflammatory factors.

Investigation of antinociceptive effects of vitamin D and EB1089 in rats.

OBJECTIVES: The aim of this study is to investigate the effect of vitamin D on pain threshold in rats. In addition, to examine, whether EB1089, which is a vitamin D receptor agonist, can contribute to this mechanism by increasing the effects of the receptor. METHODS: In the study, 24 male Wistar Albino rats of 3 months, an average of 240-260 g, were used. The animals were randomly divided into three groups, eight animals in each group. Groups; control, vitamin D (10 µg/kg), and EB1089 (10 µg/kg). Tail flick and hot plate tests were used to evaluate the antinociceptive effect. Measurements were taken at 0 min before drug administration and at 30, 60, and 90 min after drug administration and times were recorded in seconds. Serotonin levels were also analyzed by ELISA method in plasma obtained from intracardiac blood samples taken at the end of the experiment. RESULTS: Vitamin D and EB1089 significantly increased the time to endure pain in the tail flick test compared to the control group (p<0.05). In the hot plate test, EB1089 group significantly extended the pain threshold compared to the control group (p<0.05), while the vitamin D group did not create a significant difference, although it had a higher latency than the control group (p>0.05). There was no significant difference between the groups in terms of serotonin levels (p>0.05). CONCLUSION: As a result of our study, the administration of vitamin D and EB1089 increased the pain threshold in animals and increased pain resistance.

The Impact of Vitamin D Supplementation on the IFNγ-IP10 Axis in Women with Hashimoto's Thyroiditis Treated with Levothyroxine: A Double-blind Randomized Placebo-controlled Trial.

Hashimoto's thyroiditis (HT) results from chemoattraction of inflammatory cells toward the thyroid gland by inducing the production of interferon-gamma (IFNγ)-induced protein 10 (IP10) by T helper (Th) 1 cells. Vitamin D may suppress the IFNγ-IP10 axis, but this new function of vitamin D has not yet been investigated in HT patients. In an intervention and control group, patients received 50000 IU cholecalciferol or placebo every week for three months, respectively. The CD4+ T cells of 40 patients were isolated, and the mRNA expression levels of vitamin D receptor (VDR), peroxisome proliferator-activated receptors (PPAR)-α, and PPAR-γ genes were determined by real-time PCR. ELISA method was used to determine serum levels of vitamin D, tumor necrosis factor-alpha (TNF-α), IFN-γ, and IP10. Vitamin D levels in the intervention group were significantly higher than in the placebo group after supplementation. PPAR-α and PPAR-γ gene expression levels did not differ significantly between the two groups. The serum levels of IP10, IFNγ, and TNF-α decreased significantly in the vitamin D group, as well as in the placebo group.  During this study, vitamin D levels significantly increased in the intervention group and inflammatory factors decreased. Based on the similar results obtained in the placebo group, further studies with larger sample sizes and longer intervention times are recommended.

HuanglianGanjiang Tang alleviates DSS-induced colitis in mice by inhibiting necroptosis through vitamin D receptor.

ETHNOPHARMACOLOGICAL RELEVANCE: HuanglianGanjiang Tang (HGT) is a classic prescription of traditional Chinese medicine (TCM) recorded in Dan Xi Xin Fa, which was used to alleviate manifestations like diarrhea, abdominal pain and hemafecia. In current clinical practices, HGT is adopted for the treatment of ulcerative colitis (UC) and affords good curative effect. However, the underlying mechanism deserves further elucidation. AIM OF THE STUDY: UC is a hard-to-curable and easy-to-recurrent inflammatory disease. This study is to evaluate the potential therapeutics and explore the molecular mechanism of HGT on UC in the mouse model. MATERIALS AND METHODS: The components of HGT extracts were identified by HPLC. The colitis of mice was induced by 3% (w./v.) dextran sulfate sodium (DSS). The HGT decoction was prepared through boiling and centrifuging. The mice were given HGT decoction via oral gavage (0.34 g/ml & 0.68 g/ml; 5 ml/kg b.w.). The protective role of HGT on colitis mice was evaluated by body weight change, colon length, disease activity index (DAI) and histological scores. The expressions of necroptosis-related and vitamin D receptor (VDR)-related proteins were measured by Western blot, RT-qPCR and immunofluorescence. RESULTS: HGT could significantly reduce the loss of body weight and colon length in colitis mice, and alleviated the DAI and histological scores. Mechanically, HGT also promoted the expression of E-cadherin, Occludin, ZO-1 and VDR, and reduced the level of intestinal inflammatory cytokines, such as, IL-6, IL-1ß and TNF-α. Besides, HGT downregulated the protein level of p-RIPK3, p-RIPK1 and p-MLKL while upregulated the protein level of Caspase-8 in colon tissue compared to the model group. CONCLUSION: Our study addressed that HGT can alleviate DSS-induced colitis of mice through inhibiting colonic necroptosis by upregulating the level of VDR.

VDR promotes nucleus pulposus cell mitophagy as a protective mechanism against oxidative stress injury.

Intervertebral disk degeneration (IDD) is a common aging disease. Excessive apoptosis of nucleus pulposus (NP) cells has been widely considered a main contributor to IDD. Emerging science has shown that autophagy plays a protective role against apoptosis under oxidative stress. Vitamin D receptor (VDR) is a steroid hormone receptor that can regulate autophagy. The purpose of this study was to clarify whether VDR alleviates IDD by promoting autophagy. H2O2 stimulation was used to establish oxidative stress conditions. Initially, the expression level of VDR in human degenerative NP tissues was measured by immunohistochemistry. In addition, the CRISPR-dCas9-VPR system and siRNA were utilized to upregulate or downregulate VDR and Parkin expression, respectively. Autophagic and apoptotic markers were determined by Western blotting and RT-qPCR. Transmission electron microscopy was used to monitor the occurrence of autophagy in rat NP cells. VDR expression was downregulated in human degenerative NP tissues and H2O2-stimulated rat NP cells, indicating a negative correlation between VDR expression and IDD. VDR overexpression promoted mitophagy and prevented apoptosis and mitochondrial injury under oxidative stress. Additionally, mitophagy inhibition by 3-MA abolished the protective effect of VDR activation in vitro. Furthermore, VDR activation promoted mitophagy via the PINK1/Parkin pathway in H2O2-treated NP cells. This study demonstrates that VDR activation ameliorates oxidative damage and decreases NP cell apoptosis by promoting PINK1/Parkin-dependent mitophagy, indicating that VDR may serve as a promising therapeutic target in the management of IDD.

1α, 25-Dihydroxyvitamin D3 protects gastric mucosa epithelial cells against Helicobacter pylori-infected apoptosis through a vitamin D receptor-dependent c-Raf/MEK/ERK pathway.

CONTEXT: Due to the resistance of Helicobacter pylori to antibiotics, it is difficult to eradicate this pathogenic bacterium from the host. The role of 1α, 25-dihydroxyvitamin D3 (1,25-D3) in H. pylori-infected gastric mucosa epithelial cells remains unknown. OBJECTIVE: This study investigates the protective property of 1,25-D3 against H. pylori-infected apoptosis in gastric mucosa epithelial cells and its potential molecular mechanisms. MATERIALS AND METHODS: GES-1 cells were infected with H. pylori SS1 strain (MOI: 100) and treated with 1,25-D3 at 100, 200, and 300 nM for 24 h. Mice were orally gavaged with 108 CFUs of H. pylori and 25 µg/kg 1,25-D3 every other day for 1 month. CCK-8, LDH assay, TUNEL assay and western blot were used to determine the effect of 1,25-D3 on H. pylori-induced apoptosis. RESULTS: H. pylori infection decreased cell viability to 59.2%, while 100-300 nM 1,25-D3 increased cell viability to 62.2%, 78.4% and 87.1%, respectively. Compared with positive control (4.53-fold), 1,25-D3 reduced caspase-3 activity to 4.49-, 2.88- and 1.49-fold, reduced caspase-6 activity to 2.36-, 1.88- and 1.50-fold, reduced caspase-9 activity to 4.55-, 2.91- and 2.01-fold. 1,25-D3 alters Bcl-2 family, caspase protein expression and c-Raf/MEK/ERK phosphorylation levels in vivo and in vitro. Suppression of 1,25-D3 in apoptosis was reliant on binding to vitamin D receptor. The pharmacological inhibition of c-Raf/MEK/ERK phosphorylation blocked the anti-apoptotic effect of 1,25-D3. DISCUSSION AND CONCLUSION: 1,25-D3 protected gastric mucosa epithelial cells against H. pylori-infected apoptosis through a VDR-dependent c-Raf/MEK/ERK pathway.

Las piezas del puzle de la "vitamina" D empiezan a encajar: da a los que necesitan / The pieces of the "vitamin" D puzzle begin to fit: give it to those who need it

No disponible

VDR Agonist Prevents Diabetic Endothelial Dysfunction through Inhibition of Prolyl Isomerase-1-Mediated Mitochondrial Oxidative Stress and Inflammation.

BACKGROUND AND AIM: Upregulation of prolyl isomerase-1 (Pin1) protein expression and activity was associated with the pathogenesis of diabetic vasculopathy through induction of endothelial oxidative stress and inflammation. Moreover, VDR agonist protects against high glucose-induced endothelial apoptosis through the inhibition of oxidative stress. We aimed to explore the effects of the VDR agonist on diabetes-associated endothelial dysfunction and the role of Pin1 in this process. METHODS: Streptozocin-induced diabetic mice were randomly treated with vehicle, VDR agonist (10 µg/kg/d, i.g., twice a week), or Pin1 inhibitor, Juglone (1 mg/kg/d, i.p., every other day), for eight weeks. In parallel, human umbilical vein endothelial cells (HUVECs) exposed to high-glucose condition were treated with 1,25-dihydroxyvitamin D3 and Juglone or vehicle for 72 hours. Organ chamber experiments were performed to assess endothelium-dependent relaxation to acetylcholine. Circulatory levels of Pin1, SOD, MDA, IL-1ß, IL-6, and NO in diabetic mice, Pin1 protein expression and activity, subcellular distribution of p66Shc, and NF-κB p65 in high glucose-cultured HUVECs were determined. RESULTS: Both VDR agonist and Juglone significantly improved diabetes-associated endothelial dysfunction and reduced high glucose-induced endothelial apoptosis. Mechanistically, the circulatory levels of SOD and NO were increased compared with those of vehicle-treated diabetic mice. Additionally, Pin1 protein expression and activity, p66Shc mitochondrial translocation, and NF-κB p65 in high glucose-cultured HUVECs were also inhibited by VDR agonist and Juglone. Knockdown of VDR abolished the inhibitory effects of VDR agonist on high glucose-induced upregulation of Pin1 protein expression and activity. CONCLUSIONS: VDR agonist prevents diabetic endothelial dysfunction through inhibition of Pin1-mediated mitochondrial oxidative stress and inflammation.

Perfil antiinflamatorio del paricalcitol en el receptor de trasplante renal / Anti-inflammatory profile of paricalcitol in kidney transplant recipients

Antecedentes y objetivos: El paricalcitol, un activador selectivo del receptor de la vitamina D, se utiliza en el tratamiento del hiperparatiroidismo secundario en el receptor de trasplante renal. Estudios tanto clínicos como experimentales realizados en pacientes renales no trasplantados muestran propiedades antiinflamatorias para esta molécula. En este estudio exploratorio, hemos evaluado el perfil antiinflamatorio del paricalcitol en receptores de trasplante renal. Métodos: Treinta y un pacientes trasplantados con hiperparatiroidismo secundario completaron 3 meses de terapia con paricalcitol oral (1μg/día). Se determinaron las concentraciones séricas y los niveles de expresión génica de citocinas inflamatorias en células mononucleares de sangre periférica al inicio y al final del estudio. Resultados: El paricalcitol provocó una disminución significativa en los niveles de hormona paratiroidea, sin cambios en los de calcio y fósforo. Además, indujo una reducción en las concentraciones séricas de la interleucina (IL)-6 y del factor de necrosis tumoral alfa (TNF-α), con reducciones porcentuales respecto al estado basal de un 29% (p<0,05) y de un 9,5% (p<0,05), respectivamente. Los niveles de expresión génica de la IL-6 y del TNF-α en células mononucleares de sangre periférica experimentaron un descenso de un 14,1% (p<0,001) y de un 34,1% (p<0,001), respectivamente. La proporción entre las citocinas proinflamatorias (TNF-α e IL-6) y la antiinflamatoria IL-10, tanto para los niveles séricos como para los de expresión génica, también disminuyó significativamente. Conclusiones: La administración del paricalcitol a receptores de trasplante renal se asocia con efectos beneficiosos sobre su estado inflamatorio, lo que podría asociarse a un potencial beneficio clínico (AU)

Background and objectives: Paricalcitol, a selective vitamin D receptor activator, is used to treat secondary hyperparathyroidism in kidney transplant patients. Experimental and clinical studies in non-transplant kidney disease patients have found this molecule to have anti-inflammatory properties. In this exploratory study, we evaluated the anti-inflammatory profile of paricalcitol in kidney-transplant recipients. Methods: Thirty one kidney transplant recipients with secondary hyperparathyroidism completed 3 months of treatment with oral paricalcitol (1μg/day). Serum concentrations and gene expression levels of inflammatory cytokines in peripheral blood mononuclear cells were analysed at the beginning and end of the study. Results: Paricalcitol significantly decreased parathyroid hormone levels with no changes in calcium and phosphorous. It also reduced serum concentrations of interleukin (IL)-6 and tumour necrosis factor-alpha (TNF-α) by 29% (P<0.05) and 9.5% (P<0.05) compared to baseline, respectively. Furthermore, gene expression levels of IL-6 and TNF-α in peripheral blood mononuclear cells decreased by 14.1% (P<0.001) and 34.1% (P<0.001), respectively. The ratios between pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory cytokines (IL-10), both regarding serum concentrations and gene expression, also experienced a significant reduction. Conclusions: Paricalcitol administration to kidney transplant recipients has been found to have beneficial effects on inflammation, which may be associated with potential clinical benefits (AU)

[Paricalcitol - a selective vitamin D receptor activator for secondary hyperparathyroidism in patients with chronic kidney disease].

Secondary hyperparathyroidism is a frequently encountered complication of chronic kidney disease (CKD) attributable to altered phosphate/calcium homeostasis, increased synthesis of phosphaturic hormone (FGF-23) and profound active vitamin D deficiency. The disorder is associated with severe bone disease, progressive cardiovascular calcification and increased mortality. Calctriol and its analogs (alphacalcidol) can suppress parathyroid activity, however at the cost of hypercalcemia and hiperphosphatemia, thus aggravating the vascular disease. During the last decade, selective vitamin D receptor activators (VDRA) have been introduced, that reduce parathyroid activity with minimal changes in calcium and phosphate metabolism. Paricalcitol is the only selective VDRA registered in Europe for the management of patients with different stadia of CKD. For today, with its efficacy and safety confirmed in several clinical trials paricalcitol increases the vitamin D therapeutic window in this population. Furthermore, the clinical data on its possible positive effect on survival together with its reduced or even lacking experimental procalcifying effects on vessels, call for extensive research, since selective VDRA may provide additional clinical benefits going beyond mineral-bone disorder.

¿Juega algún papel la vitamina D en las otitis de repetición? / Role of vitamin D in recurrent otitis of children

El papel de la vitamina D en las otitis de repetición en la infancia, o mejor dicho, discernir si juega alguno, es un claro ejemplo de la función que cumple la medicina basada en la evidencia, puesto que trazar la línea entre la mera especulación o hipótesis y lo recientemente demostrado, ya aplicable, aunque con escasas pruebas, convierte nuestra profesión en arte (AU)

The role of vitamin D in recurrent otitis in childhood is a clear example of the evidence based medicine's function. It is the ability to separate hypothesis from recently demonstrated stuff, already applicable, but with poor evidences, which makes of our profession an art (AU)

Effect of VDRA on survival in incident hemodialysis patients: results of the FARO-2 observational study.

BACKGROUND: Mortality rate among patients with stage five chronic kidney disease (CKD) maintained on hemodialysis (HD) is high. Although evidence suggests that use of Vitamin D Receptor Activators (VDRA) in CKD patients increases survival, few studies have examined the effect of VDRA in incident HD patients. The FARO-2 study evaluated the clinical outcome of VDRA therapy on mortality in incident HD patients. METHODS: FARO-2 was a longitudinal epidemiological study performed on 568 incident HD patients followed prospectively from 26 dialysis centers over a 3-year period. Data were collected every 6 months using a questionnaire, obtaining clinical, biochemical and therapeutic parameters. Kaplan-Meier curves and Cox proportional hazard regression models were used to determine cumulative probability of time-to-death and adjusted hazard ratios. RESULTS: 568 patients (68% male) with an average age of 65.5 years were followed up. Mean dialysis duration at study entry was 3 months. VDRA use increased from 46% at 6 months to 54.7% at 36 months of follow-up (p = 0.08). No difference was observed in the presence of comorbid diseases at baseline in patients with and without VDRA therapy. Cumulative probability of survival at 24 months was 74.5% (95% CI: 70.2-78.3). Patients receiving VDRA therapy showed a significant increase in survival at 24 months (80.7%; 95% CI: 75.7-84.8) compared to those without (63.3%; 95% CI: 54.8-70.7, p <0.01). The presence of vascular disease, decreased hemoglobin, increased P and lack of VDRA treatment were significantly associated with an increased risk of mortality. Lack of VDRA treatment still remained significant as a predictor of mortality after adjusting for levels of PTH, P and Ca (HR = 2.16, 95% CI: 1.09-4.30, p = 0.03). CONCLUSIONS: Findings from FARO-2 indicate that in incident HD patients VDRA therapy was associated with increased survival.

Recomendaciones sobre suplementos de vitamina D y calcio para personas adultas en España / Recommendations on Vitamin D and calcium supplements for adults in Spain

Fundamentos: Los suplementos de calcio y vitamina D están involucrados en debates sanitarios actuales, como la seguridad cardiovascular del calcio y la corrección de los niveles vitamínicos. El objetivo de esta revisión es la evaluación de la información existente de los suplementos de calcio y/o vitamina D disponibles y financiados en España, así como la evaluación de las recomendaciones para su utilización. Métodos: Análisis de la oferta comercial e información disponible sobre aspectos farmacológicos de los suplementos medicamentos españoles en 39 fichas técnicas, guías e informes institucionales y profesionales actualizados, con búsqueda complementaria de información y de datos epidemiológicos españoles relacionados en Cochrane Database of Systematic Reviews®, PubMed® (herramienta "Clinical Queries"), base de datos Dialnet y búsqueda manual en revistas españolas directamente relacionadas. Resultados: No existe uniformidad en cuanto a indicación, expresión de contenido, posologías, precauciones y seguridad ni en fichas técnicas ni en los informes técnicos. La búsqueda bibliográfica ha encontrado un mayor volumen de publicaciones recientes para la vitamina D que para el calcio. No se han encontrado pruebas científicas apropiadas para establecer regímenes posológicos indiscutibles ni universales, ni pruebas de biodisponibilidad para colecalciferol con vehiculización acuosa. En España se constata una situación nutricional generalmente adecuada para el calcio pero un estatus mayoritariamente inadecuado para la vitamina D, con varias referencias de insuficiencia y carencia vitamínica en adultos. Los tratamientos correctores inciden fundamentalmente en el uso de suplementos de calcio. Conclusiones: Existe una amplia oferta de suplementos de calcio y vitamina D en España cuyo diseño farmacológico debería replantearse puesto que no responden a las necesidades detectadas ni a las posibilidades de corrección actualmente recomendadas. También se debería mejorar y mantener actualizada su información, con especial interés en la situación sanitaria relacionada con la hipovitaminosis D(AU)

Background: Calcium supplements and vitamin D are involved in current debates of health, as cardiovascular safety of calcium, and correction of vitamin levels. The aim is to review the possibilities of making better use of supplements marketed in Spain, depending on their availability, information and related epidemiology. Methods: Analysis of comercial offer and available information about pharmacological aspects of Spanish medicinal supplements in data-sheets (39), guides and reports current institutional and professional, with additional search of this information and epidemiological data related Spanish in Cochrane Database of Systematic Reviews ®, Pub- Med ® (tool "Clinical Queries"), Dialnet database and hand search of Spanish journals directly related. Results: There is no uniformity in terms of indication, expression of content, dosages, precautions and safety in data sheets or technical reports. The literature search found more recent publications volume for vitamin D than calcium, No evidence was found to establish appropriate dosing regimens indisputable or universal, or cholecalciferol bioavailability tests with aqueous vehiculización. In Spain nutritional situation is found generally suitable for the calcium but a status mostly unsuitable for vitamin D with several references for insufficiency and vitamin deficiency in adults. Corrective treatments primarily affect calcium supplements. Conclusions: There is an ample supply of calcium and vitamin D in Spain, whose drug design should rethink because don’t respond to the needs identified or correction possibilities currently recommended. It should also improve and update their information, with particular interest in health status related to hypovitaminosis D(AU)