The comparison of paricalcitol and calcitriol effects on pulse wave velocity, osteocalcin, and fetuin-A in chronic hemodialysis patients.

INTRODUCTION: Vascular calcification is an intervenable factor in the pathophysiology of cardiovascular disease. Treatment-related factors might worsen the arterial stiffness in chronic hemodialysis patients. The aim of the study is to compare the effects of 1-year treatment with paricalcitol or calcitriol on pulse wave velocity (PWV), which is an indicator of arterial stiffness and osteocalcin and fetuin-A levels. METHODS: Seventy-six hemodialysis patients who had similar PWV1 at the beginning were evaluated after a 1-year treatment of paricalcitol or calcitriol. PWV2, serum osteocalcin, and fetuin-A levels were measured at the end of the study. RESULTS: At the end of the study, PWV2 of paricalcitol group was statistically lower than the calcitriol group. Osteocalcin levels were statistically lower and fetuin-A levels were statistically higher in the paricalcitol group than the calcitriol group at the end of the study. The number of patients with PWV2 > 7 m/s and using paricalcitol was 16 (39%) but 25 (41%) patients were using calcitriol; the differences were statistically significant. CONCLUSIONS: The long-term benefits of paricalcitol were superior to the benefits of calcitriol. Paricalcitol has protective effects from vascular calcification in chronic hemodialysis patients.

The therapeutic potential of 1, 25-dihydroxy vitamin D3 on cisplatin-affected neurological functions is associated with the regulation of oxidative stress and inflammatory markers as well as levels of MMP2/9.

Calcitriol as a biologically active form of vitamin D3 has beneficial effects on all body systems. This vitamin has a potent neuroprotective effect via several independent mechanisms against brain insults induced by anticancer drugs. The present study was designed to examine the neuroprotective effects of calcitriol against neurotoxicity induced by cisplatin. Induction of neurotoxicity was done with cisplatin administration (5 mg/kg/week) for 5 successive weeks in male Wistar rats. The neuroprotective influence of calcitriol supplementation (100ng/kg/day for 5 weeks) was assessed through behavioral, electrophysiological, and molecular experiments. Cisplatin administration impaired spatial learning and memory and decreased prefrontal brain-derived neurotrophic factor (BDNF). Peripheral sensory neuropathy was induced through cisplatin administration. Cisplatin also reduced the amplitudes of the compound action potential of sensory nerves in electrophysiological studies. Cisplatin treatment elevated MDA levels and reduced anti-oxidant (SOD and GPx) enzymes. Pro-inflammatory cytokines (IL-1ß and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were augmented through treatment with cisplatin. Learning and memory impairments along with BDNF changes caused by cisplatin were amended with calcitriol supplementation. Reduced sensory nerve conduction velocity in the cisplatin-treated group was improved by calcitriol. Calcitriol partially improved redox imbalance and diminished the pro-inflammatory cytokines and MMP-2/9 levels. Our findings showed that calcitriol supplementation can relieve cisplatin-induced peripheral neurotoxicity. Calcitriol can be regarded as a promising new neuroprotective agent.

Topical Calcipotriol Plus 5-Fluorouracil in the Treatment of Actinic Keratosis, Bowen's Disease, and Squamous Cell Carcinoma: A Systematic Review.

BACKGROUND/OBJECTIVES: Actinic keratoses (AK) are premalignant skin lesions caused by chronic sun exposure, topically managed by 5-fluorouracil (5-FU), diclofenac 3% gel, and imiquimod. Despite their effectiveness, long treatment duration and severe adverse local skin reactions have limited patient concordance. Calcipotriol has recently been used as a combination agent for existing topical AK treatments. A systematic review was performed to determine the clinical efficacy of 5-FU and calcipotriol for the treatment of AK, Bowen's disease, and squamous cell carcinoma (SCC). METHODS: A systematic literature search was conducted on Medline, Embase, and Cochrane Library. Among the 84 records screened, 12 were retrieved for full-text review and 8 were included in the final analysis. RESULTS: Among the 8 studies, there were 214 control patients and 288 patients who received the intervention. The combination 5% 5-FU with calcipotriol resulted in a significant reduction in the number of AKs on the face, scalp, right upper extremity, and left upper extremity for all sites at 8 weeks (P < .0001). No significant difference in SCC incidence was observed at 1 or 2 years, but there was a significant reduction observed at 3 years for SCC on face and scalp. No study assessed the combination for Bowen's disease. CONCLUSIONS: Combination 5% 5-FU with calcipotriol is an effective treatment for Aks; however, future trials may consider longer treatment and follow-up periods for the treatment and prevention of AK, SCC in situ, and SCC.

Revisiting the significance of nano-vitamin D for food fortification and therapeutic application.

OBJECTIVE: Vitamin D (a prohormone) is an important micronutrient required by the body for skeletal homeostasis and a range of non-skeletal actions. Calcitriol, the active form of vitamin D, regulates a variety of cellular and metabolic processes through both genomic and nongenomic pathways. Often prescribed for treating rickets and osteoporosis, vitamin D deficiency can exacerbate various other medical conditions. SIGNIFICANCE, METHODS, AND RESULTS: Despite its multifunctional uses, the sensitivity of vitamin D makes formulating an efficient drug delivery system a challenging task, which is further complicated by its poor aqueous solubility. Enhancing the oral absorption of vitamin D is vital in utilizing its full efficacy. Recent developments in encapsulation and nanotechnology have shown promising results in overcoming these constraints. CONCLUSION: This review thus offers an insight to adequately comprehend the mechanistic pharmacology of vitamin D, its pathophysiological role, and justification of its medical indications, along with the benefits of utilizing nanotechnology for vitamin D delivery.

Targeting Calcitriol Metabolism in Acute Vitamin D Toxicity-A Comprehensive Review and Clinical Insight.

High-dose vitamin D supplementation is common in the general population, but unsupervised high-dose supplementation in vitamin D-replete individuals poses a risk of severe toxicity. Susceptibility to vitamin D toxicity shows a significant inter-individual variability that may in part be explained by genetic predispositions (i.e., CYP24A1 polymorphism). The classic manifestation of vitamin D toxicity is hypercalcemia, which may be refractory to conventional therapy. Its causes include the endogenous overaction of 1α-hydroxylase, monogenic alterations affecting vitamin D metabolizing enzymes and exogenous vitamin D intoxication. In this manuscript, we include a literature review of potential pharmacological interventions targeting calcitriol metabolism to treat vitamin D intoxication and present a case of severe, exogenous vitamin D intoxication responding to systemic corticosteroids after the failure of conventional therapy. Systemic glucocorticoids alleviate acute hypercalcemia by inhibiting enteric calcium absorption and increasing the degradation of vitamin D metabolites but may cause adverse effects. Inhibitors of 1α-hydroxylase (keto/fluconazole) and inducers of CYP3A4 (rifampicin) may be considered steroid-sparing alternatives for the treatment of vitamin D intoxication.

A High Dose of Calcitriol Inhibits Glycolysis and M2 Macrophage Polarization in the Tumor Microenvironment by Repressing mTOR Activation: in vitro and Molecular Docking Studies.

BACKGROUND/AIMS: Macrophages interact with tumor cells within the tumor microenvironment (TME), which plays a crucial role in tumor progression. Cancer cells also can instruct macrophages to facilitate the spread of cancer and the growth of tumors. Thus, modulating macrophages-cancer cells interaction in the TME may be therapeutically beneficial. Although calcitriol (an active form of vitamin D) has anticancer properties, its role in TME is unclear. This study examined the role of calcitriol in the regulation of macrophages and cancer cells in the TME and its influence on the proliferation of breast cancer cells. METHODS: We modeled the TME, in vitro, by collecting conditioned medium from cancer cells (CCM) and macrophages (MCM) and culturing each cell type separately with and without (control) a high-dose (0.5 µM) calcitriol (an active form of vitamin D). An MTT assay was used to examine cell viability. Apoptosis was detected using FITC (fluorescein isothiocyanate) annexin V apoptosis detection kit. Western blotting was used to separate and identify proteins. Quantitative real-time PCR was used to analyze gene expression. Molecular docking studies were performed to evaluate the binding type and interactions of calcitriol to the GLUT1 and mTORC1 ligand-binding sites. RESULTS: Calcitriol treatment suppressed the expression of genes and proteins implicated in glycolysis (GLUT1, HKII, LDHA), promoted cancer cell apoptosis, and reduced viability and Cyclin D1gene expression in MCM-induced breast cancer cells. Additionally, calcitriol treatment suppressed mTOR activation in MCM-induced breast cancer cells. Molecular docking studies further showed efficient binding of calcitriol with GLUT1 and mTORC1. Calcitriol also inhibited CCM-mediated induction of CD206 and increased TNFα gene expression in THP1-derived macrophages. CONCLUSION: The results suggest that calcitriol may impact breast cancer progression by inhibiting glycolysis and M2 macrophage polarization via regulating mTOR activation in the TME and warrants further investigation in vivo.

Effect of active vitamin-D on left ventricular mass index: Results of a randomized controlled trial in type 2 diabetes and chronic kidney disease.

BACKGROUND: Active vitamin-D deficiency is a potential modifiable risk factor for increased ventricular mass. We explored the effects of active vitamin-D (calcitriol) treatment on left ventricular mass in patients with type-2 diabetes (T2D) and chronic kidney disease (CKD). METHODS: We performed a 48-week duration single center randomized double-blind parallel group trial examining the impact of calcitriol, 0.5 mcg once daily, as compared to placebo on a primary endpoint of change from baseline in left ventricular mass index (LVMI) measured by magnetic resonance imaging . Patients with T2D, CKD stage-3 and raised left ventricular mass on stable renin angiotensin aldosterone system blockade, who all had elevated intact parathyroid hormone were eligible. Secondary endpoints included interstitial myocardial fibrosis, assessed with cardiac magnetic resonance imaging. In total, 45 (male 73%) patients with T2D and stage-3 CKD were studied (calcitriol n = 19, placebo n = 26). RESULTS: Following 48-weeks calcitriol treatment, the median difference and the (95% CI) of LVMI between the 2 treatment arms was 1.84 (-1.28, 4.96), similar between the 2 groups studied. Intact parathyroid hormone fell only in the calcitriol group from 142 pg/mL (80-293) to 76 pg/mL (41-204)(median, interquartile range, P= .04). No significant differences were observed in interstitial myocardial fibrosis or other secondary endpoints. CONCLUSIONS: The study did not provide evidence that treatment with calcitriol as compared to placebo might improve LVMI in patients with T2D, mild left ventricular hypertrophy and stable CKD. Our data does not support the routine use of active vitamin-D for LVMI regression and cardiovascular protection in patients with T2D and stage-3 CKD.

Effect of calcitriol treatment on arterial stiffness in people with type 2 diabetes and stage 3 chronic kidney disease.

AIMS: Active vitamin D deficiency is associated with increased aortic-pulse wave velocity (Ao-PWV) in people with type 2 diabetes (T2DM) and chronic kidney disease (CKD). There are no randomised controlled trials investigating the effect of active vitamin D treatment on Ao-PWV in people with T2DM and CKD. METHODS: A 48-week duration single-centre randomised double-blind parallel-group trial examined the impact of oral 1,25 dihydroxyvitamin D (calcitriol 0.25 mcg OD) as compared to placebo on a primary endpoint of Ao-PWV. People with T2DM and stable stage 3 CKD with intact parathyroid hormone (iPTH) level >30 pg/mL were eligible. RESULTS: In total, 127 (70% male) people were randomised (calcitriol n = 64 or placebo n = 63). There was no change in Ao-PWV observed, mean ± standard deviation (SD), in the calcitriol group of 11.79 (±2.5) to 12.08 (3.0) m/s as compared to 10.90 (±2.4) to 11.39 (±2.6) m/s with placebo. The between-treatment group adjusted mean (95% confidence interval [(CI]] change was 0.23 (-0.58 to 1.05) m/s, P = .57. No effect of calcitriol was observed on central arterial pressures, albuminuria, serum calcium or phosphate levels. However, iPTH fell with calcitriol treatment (mean [95% CI] between-group difference of -27.8 (-42.3 to -13.2) pg/mL, P < .001. CONCLUSION: In T2DM and stage 3 CKD, calcitriol as compared to placebo does not improve Ao-PWV or other markers of arterial stiffness. Our study does not provide evidence for the use of active vitamin D for improving arterial stiffness in T2DM with stage 3 CKD.

Vitamin D Ameliorates Podocyte Injury by Enhancing Autophagy Activity in Diabetic Kidney Disease.

INTRODUCTION: Restoration of podocyte autophagy is considered as a feasible strategy for the treatment of diabetic kidney disease (DKD). This study aimed at investigating the protective effect and potential mechanism of vitamin D on podocyte injury of DKD. METHODS: Type 2 diabetic db/db mice received intraperitoneal injections of vitamin D analog paricalcitol 400 ng/kg per day for 16 weeks. Immortalized mouse podocytes were cultured in high glucose (HG) medium with active vitamin D3 calcitriol or autophagy inhibitor 3-methyladenine. Renal function and urine albumin creatinine ratio were assessed at week 24. HE, PAS staining, and electron microscopy were used to evaluate renal histopathology and morphological changes. Immunohistochemistry, immunofluorescence, and Western blot were used to evaluate protein expression of nephrin and podocin in kidney tissue and podocytes. The expression of autophagy-related proteins (LC3, Beclin-1, Vps34) and apoptosis-related proteins (cleaved caspase-3, Bax) was determined by Western blotting. Podocyte apoptosis was further evaluated by using flow cytometer. RESULTS: Albuminuria in a db/db mouse model was markedly attenuated after treatment with paricalcitol. This was accompanied by alleviation of mesangial matrix expansion and podocyte injury. Besides, the impaired autophagy in podocytes under diabetic conditions was also markedly enhanced after paricalcitol or calcitriol treatment, accompanied by restored decreased podocyte slit diaphragm proteins podocin and nephrin. Furthermore, the protective effect of calcitriol against HG-induced podocyte apoptosis could be abated by autophagy inhibitor 3-methyladenine. CONCLUSION: Vitamin D ameliorates podocyte injury of DKD by enhancing podocyte autophagy activity, which may become a potential candidate autophagy activator for the therapeutic interventions for DKD.

A Parathyroid Hormone-Guided Calcium and Calcitriol Supplementation Protocol Reduces Hypocalcemia-Related Readmissions Following Total Thyroidectomy.

OBJECTIVE: To determine the effect of a 4-hour postoperative serum parathyroid hormone (PTH)-guided calcium (Ca) and calcitriol supplementation protocol on the incidence of hypocalcemia and hospital readmissions in patients undergoing total thyroidectomy. METHODS: This was a single-institution, retrospective chart review of patients who underwent total thyroidectomy; 148 and 389 of the patients underwent surgery prior to and after the protocol implementation, respectively. The risk of hypocalcemia was stratified as low (PTH level of >30 pg/mL), medium (15-30 pg/mL), and high (<15 pg/mL), using serum PTH values obtained 4 hours postoperatively. Hypocalcemia was defined as a total serum Ca level of <8 mg/dL. Baseline demographic and operative characteristics and postoperative outcome were recorded for both groups. The Fisher exact test and Wilcoxon rank sum test were used to compare the characteristics of the 2 groups. A multivariate logistic regression model was applied to account for potentially confounding variables. RESULTS: Postoperative hypocalcemia occurred significantly less frequently in the protocol group compared with that in the preprotocol group (10.3% vs 20.9%, P = .002). The reduction in hypocalcemia in the protocol group was observed in both patients with (16.3% vs 25.6%) and without (8.4% vs 19.3%) cervical lymph node dissection. The protocol group had a significantly lower incidence of hospital readmission events than the preprotocol group (1.0% vs 4.7%, P = .013). CONCLUSION: Compared with a historical cohort, a PTH-guided protocol for Ca and calcitriol supplementation significantly reduces the postoperative hypocalcemia and hospital readmission rates in patients undergoing total thyroidectomy.

Calcitriol attenuates vascular remodeling in association with alteration of ppET-1/ETBR/eNOS and ETAR expression in acute and chronic phases of kidney ischemia-reperfusion injury in mice.

Kidney ischemia-reperfusion injury (IRI) causes acute kidney injury with increasing risk of maladaptive repair through endothelin-1 (ET-1)/endothelin type A receptor (ETAR) signaling. Calcitriol shows renoprotection in kidney fibrosis, however, its effects on vasoactive substances expression and vascular remodeling following kidney IRI remain unclear. This research aimed to investigate Calcitriol's effects on preproendothelin-1 (ppET-1), ETAR, endothelial nitric oxide synthase (eNOS) mRNA expression and vascular remodeling in acute and chronic phases of kidney IRI in mice. Twenty-five male Swiss mice were randomly divided into five groups (n = 5): SO (sham-operated), IR3 (3 day kidney IRI), IR12 (12 day kidney IRI), IRD3 (3 day kidney IRI + Calcitriol 0.5 µg/kg body weight (BW)/day), and IRD12 (12 day kidney IRI + Calcitriol 0.5 µg/kg BW/day). Ischemia-reperfusion injury groups underwent bilateral renal pedicles clamping for 30 min, then reperfusion. Kidneys were harvested for Sirius Red staining to observe interstitial fibrosis and vascular remodeling, polymerase chain reaction to quantify ppET-1, endothelin type B receptor (ETBR), eNOS mRNA expression, and Western blotting to quantify ETAR protein expression. Calcitriol treatment in both phases of kidney IRI showed lower serum creatinine and ETAR protein expression, while higher eNOS and ETBR mRNA expression than IRI-only groups. Furthermore, ppET-1 mRNA expression was higher in IRD3 than IR3, but lower in IRD12 than IR12. Calcitriol also prevented vascular remodeling as indicated by lower wall thickness and higher lumen/wall area ratio than IRI-only groups.

Calcitriol supplementation before parathyroidectomy and calcium level after surgery in parathyroid adenoma patients: a randomized controlled trial.

BACKGROUND: Hypocalcemia is the most common complication after parathyroidectomy, contributing to extended hospital stays and higher hospitalization costs. The present study aimed to evaluate whether preoperative Calcitriol could help reduce hypocalcemia rates. METHOD: In this randomized controlled trial, we included 80 patients with primary hyperparathyroidism candidates for parathyroidectomy. The intervention group received Calcitriol 0.25 µg/day 1 week before parathyroidectomy. Baseline laboratory data, parathyroid hormone level (before, during, after 5, and 10 min of operation), calcium level (6, 24, and 48 h after operation), and clinical signs and symptoms were recorded. RESULTS: Of the 80 participants, 40 (mean age: 53.36 ± 12.97) were randomized to the intervention, and 40 (mean age: 52.84 ± 12.32) to the control group. There were no statistically significant differences in age, tumor size, gender, baseline laboratory data, intra-operative PTH, and calcium level 6 and 24 h after the operation. We observed a significantly higher calcium level in the intervention group 48 h post-operation (8.57 ± 0.30 vs. 8.33 ± 0.38). Also, days of hospital stay and symptomatic hypocalcemia rate were significantly lower in the intervention group. CONCLUSION: In patients with primary hyperparathyroidism, preoperative Calcitriol may be of value in preventing post-parathyroidectomy hypocalcemia and subsequent complications.

Steroid responsive idiopathic calcitriol induced hypercalcemia: a case report and review of the literature.

BACKGROUND: Idiopathic Calcitriol Induced Hypercalcemia is a rare cause of a common condition of hypercalcemia. Hypercalcemia is most commonly the result of hyperparathyroidism and together with hypercalcemia of malignancy accounts for over 95% of cases. Idiopathic Calcitriol Induced Hypercalcemia can mimic hypercalcemia secondary to granulomatous diseases like sarcoidosis, but with apparent absences of both imaging and physical exam findings consistent with the disease. We report here a 51-year-old man who presented with recurrent nephrolithiasis, hypercalcemia, and acute kidney injury. CASE PRESENTATION: A 51-year-old man presented with severe back pain and mild hematuria. He had a history of recurrent nephrolithiasis over the course of a 15-year period. On presentation his calcium was elevated at 13.4 mg/dL, creatinine was 3.1 mg/dL (from baseline of 1.2), and his PTH was reduced at 5 pg/mL. CT abdomen and pelvis showed acute nephrolithiasis which was managed medically. Work up for the hypercalcemia included an SPEP which was normal, Vit D,1,25 (OH)2 was elevated at 80.4 pg/mL, CT chest showed no evidence of sarcoidosis. Management with 10 mg prednisone showed marked improvement in the hypercalcemia and he no longer had any symptoms of hypercalcemia. CONCLUSION: Idiopathic Calcitriol Induced Hypercalcemia is a rare cause of hypercalcemia. All reported cases benefit from more intensive long-term immunosuppression. This report helps consolidate the diagnosis of Idiopathic Calcitriol Induced Hypercalcemia and encourages researchers to better investigate its underlying pathogenesis.

Real-World Evidence on the Use of Calcipotriene and Betamethasone Dipropionate Aerosol Foam 0.005%/0.064% in the Treatment of Psoriasis: A Review of Investigator-Initiated Studies Around the Globe.

Topical medications are commonly used to manage mild-to-moderate psoriasis and serve as adjunct therapies used in combination with phototherapy and systemic treatments. Fixed-dose calcipotriene (Cal) 0.005%/betamethasone dipropionate (BD) 0.064% aerosol foam is a safe, efficacious topical therapy approved for the treatment of psoriasis vulgaris in the United States and European Union. Several investigator-initiated studies (IISs) have been conducted to provide real-world evidence related to the safety, effectiveness, and therapeutic indications of Cal/BD foam and are relevant to clinicians' every-day practice. This paper summarizes the findings of the IISs around the globe published to date and presents the real-world data related to the effectiveness and clinical considerations of Cal/BD foam as a treatment for psoriasis. J Drugs Dermatol. 2023;22:9(Suppl 2):s5-14.

Effectiveness and safety of topical calcipotriol in the treatment of flat seborrheic keratosis on the face.

Seborrheic keratosis is the most common slow-growing, benign epithelial tumour, usually appearing on sun-exposed areas. Treatment modalities for seborrheic keratosis may be uncomfortable and/or time-consuming. We present a case series of 12 patients with solitary seborrheic keratosis localized on the face treated with 0.005% calcipotriol ointment. The treatment lasted 3-8 months and resulted in complete regression of the lesions. Remission (follow-up period) lasted from 6 to 10 years. We conclude that topical calcipotriol may be a useful treatment option for seborrheic keratosis.

Calcitriol, an Active Form of Vitamin D3, Mitigates Skin Barrier Dysfunction in Atopic Dermatitis NC/Nga Mice.

Atopic dermatitis and psoriasis are prevalent chronic inflammatory skin diseases that are characterized by dysfunctional skin barriers and substantially impact patients' quality of life. Vitamin D3 regulates immune responses and keratinocyte differentiation and improves psoriasis symptoms; however, its effects on atopic dermatitis remain unclear. Here, we investigated the effects of calcitriol, an active form of vitamin D3, on an NC/Nga mouse model of atopic dermatitis. We observed that the topical application of calcitriol decreased the dermatitis scores and epidermal thickness of NC/Nga mice with atopic dermatitis compared to untreated mice. In addition, both stratum corneum barrier function as assessed by the measurement of transepidermal water loss and tight junction barrier function as evaluated by biotin tracer permeability assay were improved following calcitriol treatment. Moreover, calcitriol treatment reversed the decrease in the expression of skin barrier-related proteins and decreased the expression of inflammatory cytokines such as interleukin (IL)-13 and IL-33 in mice with atopic dermatitis. These findings suggest that the topical application of calcitriol might improve the symptoms of atopic dermatitis by repairing the dysfunctional epidermal and tight junction barriers. Our results suggest that calcitriol might be a viable therapeutic agent for the treatment of atopic dermatitis in addition to psoriasis.

Non-psoriatic uses of calcipotriol: a concise updated review.

Calcipotriol (calcipotriene) is a synthetic vitamin D3 derivative that is a standard treatment option for psoriasis. It is generally well tolerated with minimal side effects. Due to its ability to reduce keratinocyte proliferation and induce keratinocyte differentiation as well as its immunomodulatory effects, calcipotriol has been used to treat a variety of skin disorders such as atopic dermatitis, actinic keratoses, lichen planus, seborrheic keratoses, and vitiligo [1]. We surveyed the literature examining the use of calcipotriol for non-psoriatic dermatologic disease.

SMAD3 interacts with vitamin D receptor and affects vitamin D-mediated oxidative stress to ameliorate cerebral ischaemia-reperfusion injury.

Cerebral ischaemia/reperfusion (I/R) injury is caused by blood flow restoration after an ischaemic insult, and effective treatments targeting I/R injury are still insufficient. Oxidative stress plays a critical role in the pathogenesis of cerebral I/R injury. This study investigated whether vitamin D receptor (VDR) could inhibit oxidative stress caused by cerebral I/R injury and explored the detailed mechanism. VDR was highly expressed in brain tissues of mice with cerebral I/R injury. Pretreatment with the active vitamin D calcitriol and synthetic vitamin D analogue paricalcitol (PC) reduced autophagy and apoptosis, improved neurological deficits and decreased infarct size in mice after cerebral I/R. Calcitriol or PC upregulated VDR expression to prevent cerebral I/R injury by affecting oxidative stress. Silencing of VDR reversed the protective effects of calcitriol or PC on brain tissues in mice with cerebral I/R. The bioinformatics analysis revealed that VDR interacted with SMAD family member 3 (SMAD3). It was validated through the chromatin immunoprecipitation assay that SMAD3 can bind to the VDR promoter and VDR can bind to the SMAD3 promoter. Collectively, these findings provide evidence that reciprocal activation between SMAD3 and VDR transcription factors defines vitamin D-mediated oxidative stress to prevent cerebral I/R injury.

Use of Teriparatide in Hyperphosphatemic Familial Tumor Calcinosis: Evaluating the Interaction Between FGF23 and PTH on the Phosphaturic Effect.

Hyperphosphatemic familial tumor calcinosis (HFTC) is a rare disease characterized by hyperphosphatemia and calcium and phosphorus crystal deposition. It occurs due to the loss of function of FGF23. Herein, we report a case of a 50-year-old woman diagnosed with HFTC (homozygous variant in the GALNT3 gene, c.803_804 C insertion) with a history of ectopic calcifications in the past 30 years. Laboratory tests on admission were as follows: phosphate (P) 7.1 mg/dL (Normal range (NR) 2.5-4.5 mg/dL), FGF23 c-terminal 2050 RU/mL (NR < 150 RU/mL), and intact FGF23 (iFGF23) 18.93 pg/mL (NR 12.0-69.0 pg/mL). Treatment with acetazolamide, sevelamer, and a phosphorus-restricted diet was started, but phosphatemia remained high and calcifications continued to progress. In an attempt to further decrease P, a 36-day cycle of teriparatide (TPTD) 20 mcg twice daily was added, decreasing P from 6.2 to 5.2 mg/dL and increasing the 1.25(OH)2 vitamin D by 34.2%. As urinalysis was not feasible at the end of the 36-day cycle, a second cycle was performed for another 28 days, producing a similar decrease in P (from 6.4 to 5.5 mg/mL) and an evident decrease in the rate of tubular reabsorption of P (from 97.2 to 85.3%), however, accompanied by a worrying increase in calciuria. The use of TPTD 20 mcg twice daily in a patient with genetic resistance to FGF23 (HFTC) was associated with consistent increase in phosphaturia and reduction in phosphatemia, in addition to an increase in calcitriol. The resulting hypercalciuria precludes the therapeutic use of TPTD in HFTC and suggests an important role of FGF23, not only in phosphate homeostasis but also in avoiding any excess of calcitriol.

Calcitriol supplementation accelerates the recovery of patients with tuberculosis who have vitamin D deficiency: a randomized, single-blind, controlled clinical trial.

BACKGROUND: This study aimed to evaluate whether calcitriol supplementation enhances CD4+ T cell count and prognosis in patients with tuberculosis and low 25(OH)D levels. METHODS: This randomized controlled clinical trial enrolled treatment-naïve patients with tuberculosis admitted to Zigong First People's Hospital (June 2016 to April 2017). The patients were grouped as the serum 25(OH)D ≥ 75 nmol/L (Normal-25(OH)D) and 25(OH)D < 75 nmol/L (Low-25(OH)D) groups. The Low-Vit-D group was randomized to the Low-25(OH)D and Low-25(OH)D-Calcitriol groups. All patients were treated with the 2HRZE/4HR regimen. The patients in the Low-25(OH)D-Calcitriol group received calcitriol 0.25 µg bid. The main endpoints were CD4+ T cell count during treatment, time to sputum culture conversion, time to 50% lesion absorption, and a 6-month cure rate. RESULTS: This study included 30 patients in each group. Baseline 25-(OH) D levels and CD4+ T cell counts were higher in the Normal-25(OH)D group than in the Low-25(OH)D and Low-25(OH)D-Calcitriol groups (25(OH)D: 79.3 ± 3.4 vs. 37.8 ± 13.4 vs. 11.9 nmol/L, P < 0.05; 671 ± 287 vs. 200 ± 110 vs. 194 ± 119 cell/µL, P < 0.05). 25-(OH) D levels and CD4+ T cell counts increased in the Low-25(OH)D-Calcitriol group during treatment to reach higher levels than in the Low-25(OH)D group at 1, 4, 8, and 24 weeks (all P < 0.05). Compared with the Low-25(OH)D group, the Low-25(OH)D-Calcitriol group showed shorter time to sputum culture conversion (3.2 ± 1.4 vs. 5.9 ± 2.5 days, P < 0.001) and time to 50% lesion absorption (7.4 ± 1.5 vs. 10.9 ± 4.0 days, P = 0.014) and similar to those in the Normal-25(OH)D group (3.1 ± 1.2 and 7.3 ± 1.5 days, respectively. The cure rate was 86.7% in the Low-25(OH)D group and 96.7% in the two other groups. CONCLUSIONS: Calcitriol supplementation can elevate CD4+ T cell levels, shorten the time to sputum culture conversion, and accelerate lesion absorption in patients with tuberculosis and 25(OH)D deficiency. Trial registration The study is registered at the Chinese Clinical Trial Registry (ChiCTR2000039832).