Vitamin D Analogues Research Articles

Review on Updated Management of Prurigo Nodularis (PN)

Background: Prurigo Nodularis (PN) presents as a challenging chronic dermatological condition characterized by intensely pruritic nodules on the skin, leading to significant morbidity. Despite its prevalence and impact on patients' quality of life, treatment options remain limited, necessitating evidence-based approaches to address this complex condition effectively. Objective: This study aims to provide an updated overview of evidence-based management strategies for PN, highlighting recent advancements in treatment modalities. Method: A systematic review of clinical studies on PN treatment was conducted by searching the PubMed and Scopus databases from January 1, 2001, to December 1, 2023. A total of 706 unique studies published in English were identified and screened for inclusion criteria. Only primary clinical studies investigating treatment strategies in PN patients were included, while case reports and series with fewer than five patients were excluded. Relevant publications were further supplemented by searching bibliographies for additional studies meeting the inclusion criteria. Results: The review identified significant advancements in evidence-based management strategies for PN, driven by a growing body of clinical research and therapeutic innovation. Pharmacological interventions targeting pruritus, inflammation, and lesion resolution have shown efficacy, including topical agents such as corticosteroids, emollients, Vitamin D3 analogues, tacrolimus creams, and systemic therapies like antihistamines, gabapentinoids, immunosuppressant and anti-inflammatory agents, JAK inhibitors, retinoids, and sometimes selective serotonin reuptake inhibitors (SSRIs). Additionally, emerging biological agents and non-pharmacological approaches, such as multidisciplinary interventions, have demonstrated promise in improving patient outcomes. Conclusion: Evidence-based management of PN represents a dynamic field with evolving treatment modalities. While challenges persist, including limited efficacy and safety concerns of certain treatments, recent developments in targeted therapies, systemic immunomodulators, and novel pharmacological approaches offer hope for improved patient care. Further research into genetic underpinnings and personalized therapies is warranted to address the heterogeneous nature of PN and enhance treatment efficacy and safety.

A pharmacovigilance study on clinical factors of active vitamin D3 analog-related acute kidney injury using the Japanese Adverse Drug Event Report Database

Acute kidney injury (AKI) due to vitamin D therapy for osteoporosis is encountered in clinical practice, but epidemiological studies are scarce. We aimed to determine the association between AKI and vitamin D therapy and to identify risk factors for AKI using the Japanese Adverse Drug Event Report database. We used reporting odds ratios (RORs) to detect signals and evaluate risk factors using multiple logistic regression analysis. Among 298,891 reports from April 2004 to September 2023, 1071 implicated active vitamin D3 analogs as suspect drugs for adverse events. There was a significant association between AKI and active vitamin D3 analogs (ROR [95% confidence interval {CI}], eldecalcitol: 16.75 [14.23–19.72], P < 0.001; alfacalcidol: 5.29 [4.07–6.87], P < 0.001; calcitriol: 4.46 [1.88–10.59], P < 0.001). The median duration of administration before AKI onset was 15.4 weeks. Multiple logistic regression analysis showed a significant association between AKI and age ≥ 70 years (odds ratio [95% CI], 1.47 [1.04–2.07]; P = 0.028), weight < 50 kg (1.55 [1.12–2.13]; P = 0.007), hypertension (1.90 [1.42–2.54]; P < 0.001), and concomitant use of nonsteroidal anti-inflammatory drugs (1.58 [1.10–2.25], P = 0.012) and magnesium oxide (1.96 [1.38–2.78]; P < 0.001). Our results suggest that active vitamin D3 analogs are associated with AKI development. Physicians prescribing these medications to patients with risk factors should consider the possibility of AKI, especially during the first 6 months.

Molybdenum Nanoparticles Alleviate MC903-Induced Atopic Dermatitis-Like Symptoms in Mice by Modulating the ROS-Mediated NF-κB and Nrf2 /HO-1 Signaling Pathways.

Atopic dermatitis (AD) is a chronic inflammatory skin condition that can affect individuals of all ages. Recent research has shown that oxidative stress plays a crucial role in the development of AD. Therefore, inhibiting oxidative stress may be an effective therapeutic approach for AD. Nano-molybdenum is a promising material for use as an antioxidant. We aimed to evaluate the therapeutic effects and preliminary mechanisms of molybdenum nanoparticles (Mo NPs) by using a murine model of chemically induced AD-like disease. HaCaT cells, a spontaneously immortalized human keratinocyte cell line, were stimulated by tumor necrosis factor-alpha /interferon-gamma after pre-treatment with Mo NPs. Reactive oxygen species levels, production of inflammatory factors, and activation of the nuclear factor kappa-B and the nuclear factor erythroid 2-related factor pathways were then evaluated. Mo NPs was topically applied to treat a murine model of AD-like disease induced by MC903, a vitamin D3 analog. Dermatitis scores, pruritus scores, transepidermal water loss and body weight were evaluated. AD-related inflammatory factors and chemokines were evaluated. Activation of the nuclear factor kappa-B and nuclear factor erythroid 2-related factor / heme oxygenase-1 pathways was assessed. Our data showed that the topical application of Mo NPs dispersion could significantly alleviate AD skin lesions and itching and promote skin barrier repair. Further mechanistic experiments revealed that Mo NPs could inhibit the excessive activation of the nuclear factor kappa-B pathway, promote the expression of nuclear factor erythroid 2-related factor and heme oxygenase-1 proteins, and suppress oxidative stress reactions. Additionally, they inhibited the expression of thymic stromal lymphopoietin, inflammatory factors, and chemokines, thereby alleviating skin inflammation. Mo NPs present a promising alternative treatment option for patients with AD as they could address three pivotal mechanisms in the pathogenesis of AD concurrently.

Effect of a topical traditional Chinese herbal medicine on skin microbiota in mouse model of atopic dermatitis

This study aims to explore the impact of the herbal ointment Chushi Zhiyang Ruangao (CSZYRG) on the skin's microecological environment in a mouse model of atopic dermatitis (AD) and to understand the underlying mechanisms involved. The AD model was established in C57 mice using calpolitol (a hypocalcemic analog of vitamin D3; MC903). Medication-free matrix ointment, CSZYRG, and mometasone furoate cream (positive control group) were applied to the injured areas. The skin lesions of AD model mice were photographed. Skin lesions were applied for the hematoxylin and eosin (H&E) staining to observe any pathological changes. Serum immunoglobulin IgE was detected by enzyme-linked immunosorbent assay (ELISA). The changes in the expression of inflammation-related factors TNF-α, IL-1β, and IL-6 in mice were detected using ELISA and qRT-PCR. Skin microflora samples were taken for 16S rDNA sequencing and analyzed for changes in the skin flora diversity, abundance, and dominant flora in mice. It was concluded that CSZYRG effectively alleviates skin lesions, serum IgE, and levels of TNF-α, IL-1β, and IL-6 in AD model mice. However, CSZYRG did not affect the skin microbial diversity of AD model mice but could exert an effect on the skin microbial community in AD mice and the relative abundance of the dominant microflora. CSZYRG may play a therapeutic role in AD by affecting the skin microbial community and relative abundance of dominant microflora in AD mice.

Review study of Psoriasis in Iraq

Abstracts are written in Indonesian and English. Describe the introduction, the purpose of writting, research methods, result and conclusion. Minimum 150 and maximum 250 words.. Psoriasis is a multisystem inflammatory disease with predominantly skin and joint involvement. Beyond the physical dimensions of disease, psoriasis has an extensive emotional and psychosocial effect on patients, affecting social functioning and interpersonal relationships. As a disease of systemic inflammation, psoriasis is associated with multiple comorbidities, including cardiovascular disease and malignancy. The diagnosis is primarily clinical and a skin biopsy is seldom required. Depending on the severity of disease, appropriate treatment can be initiated. For mild to moderate disease, first-line treatment involves topical therapies including corticosteroids, vitamin D3 analogues, and combination products. These topical treatments are efficacious and can be safely initiated and prescribed by primary care physicians. Patients with more severe and refractory symptoms might require further evaluation by a dermatologist for systemic therapy .Psoriasis is a chronic, noncommunicable, painful, disfiguring and disabling disease for which there is no cure and with great negative impact on patients’ quality of life . It can occur at any age. The etiology of psoriasis remains unclear. Psoriasis can also be provoked by external and internal triggers, including mild trauma, sunburn, infections, systemic drugs and stress . Psoriasis involves the skin and nails, and is associated with a number of comorbidities. Skin lesions are localized or generalized, mostly symmetrical, sharply demarcated, red papules and plaques, and usually covered with white or silver scales. Lesions cause itching, stinging and pain. Individuals with psoriasis are reported to be at increased risk of developing other serious clinical conditions such as cardiovascular and other noncommunicable diseases . Psoriasis causes great physical, emotional and social burden . Disfiguration, disability and marked loss of productivity are common challenges for people with psoriasis. Topical and systemic therapies as well as phototherapy are available.

Meteorin-like protein/METRNL/Interleukin-41 ameliorates atopic dermatitis-like inflammation.

Meteorin-like protein (METRNL)/Interleukin-41 (IL-41) is a novel immune-secreted cytokine/myokine involved in several inflammatory diseases. However, how METRNL exerts its regulatory properties on skin inflammation remains elusive. This study aims to elucidate the functionality and regulatory mechanism of METRNL in atopic dermatitis (AD). METRNL levels were determined in skin and serum samples from patients with AD and subsequently verified in the vitamin D3 analogue MC903-induced AD-like mice model. The cellular target of METRNL activity was identified by multiplex immunostaining, single-cell RNA-seq and RNA-seq. METRNL was significantly upregulated in lesions and serum of patients with dermatitis compared to healthy controls (p <.05). Following repeated MC903 exposure, AD model mice displayed elevated levels of METRNL in both ears and serum. Administration of recombinant murine METRNL protein (rmMETRNL) ameliorated allergic skin inflammation and hallmarks of AD in mice, whereas blocking of METRNL signaling led to the opposite. METRNL enhanced β-Catenin activation, limited the expression of Th2-related molecules that attract the accumulation of Arginase-1 (Arg1)hi macrophages, dendritic cells, and activated mast cells. METRNL can bind to KIT receptor and subsequently alleviate the allergic inflammation of AD by inhibiting the expansion of immune cells, and downregulating inflammatory gene expression by regulating the level of active WNT pathway molecule β-Catenin.

Activity of hydrogel-vitamin D3 /bacterioruberin nanoparticles on imiquimod-induced fibroblasts-keratinocytes spheroids

Topical administration of vitamin D3 (VD3) analogs and corticosteroids is the mainstay treatment for mild localized psoriasis. VD3 however is an unstable class II drug (insoluble and permeable), classically formulated as unattractive viscous and oil-based ointments or creams. In this work, nanostructured archaeolipid carriers (NAC) with a core loaded with VD3 and the C50 dipolar carotenoid from halophilic archaea bacterioruberin (BR): NAC-VD3, were formulated into a carbopol hydrogel: gNAC-VD3. After its rheological characterization, its anti-inflammatory and antioxidant activity was assessed on bi-cellular spheroids, consisting of a core of fibroblasts surrounded by a ring of keratinocytes activated with imiquimod (IMQ) as a psoriasis model. gNAC-VD3 (0.8 mg VD3/135 μg BR/gram gel) conserved the antioxidant activity, showed pseudoplastic non-Newtonian behaviour, stability over time, good occlusion capacity and spreadability, all suitable properties for topical application in patients with psoriasis. gNAC-VD3 did not decrease the viability of spheroids but significantly reduced the release of proinflammatory cytokines (IL-8, IL-6, TNF-α), oxidative stress (ROS), and matrix metalloproteinases from IMQ-induced spheroids to levels similar to the uninduced spheroids. Results suggest that gNAC-VD3 may constitute a potential anti-inflammatory agent for the topical treatment of mild psoriasis and deserves further in vivo exploration.

Hypoparathyroidism: changes in brain structure, cognitive impairment, and reduced quality of life.

Hypoparathyroidism (HypoPT) is a disease with no/or inadequate production/secretion of parathyroid hormone (PTH) from the parathyroid glands. Low levels of PTH result in hypocalcemia, which is often treated with calcium supplementation and active vitamin-D analogs. However, increasing evidence suggests that HypoPT has a profound impact on several organ systems. Quality of life (QOL) is reduced in patients with HypoPT, partly due to symptoms related to the central nervous system-including subjective feelings of confusion, a reduced ability to focus and think clearly (ie, "brain fog"). However, the extent to which these complex symptoms relate to quantifiable changes in patients' cognitive performance as determined by neuropsychological tests remains unclear. The brains of HypoPT patients may reveal tissue calcifications, but the extent to which long-term brain exposure to low PTH levels and/or changing calcium levels affects brain structure is unknown. In a cross-sectional study, we investigated PTH levels, QOL, cognitive impairment, and brain structure in well-treated post-surgical and non-surgical hypoparathyroid patients compared with healthy controls. QOL was quantified by the SF36v2, WHO-5 wellbeing Index, and two disease-specific questionnaires-the HPQ28 and Hypoparathyroidism Symptom Diary. Cognitive functions were tested using comprehensive neuropsychological. Brain structure was quantified by morphological analyses of magnetic resonance imaging images. We found reduced QOL and cognitive functioning in terms of processing speed, executive functions, visual memory, and auditory memory in HypoPT. Furthermore, HypoPT revealed a reduced volume of the hippocampus-and the size of the thalamus in postsurgical patients was associated with the disease duration. Importantly, patients reporting severe brain fog had a smaller hippocampus than those with less brainfog. HypoPT is associated with quantifiable cognitive deficits and changes in brain structure that align with patient symptoms. Our exploratory study warrants further studies of the neurobiological impact of PTH and of the impact of PTH replacements therapy on patients' cognitive functioning.

Cooperative anti-leukemic effects of vitamin D derivatives and plant polyphenols in AML models: the role of the interplay between NRF2, AP-1, and VDR

Treatment of acute myeloid leukemia (AML) has not significantly improved in the past 40 years. The active form of vitamin D, 1.25-dihydroxyvitamin D3 (1,25D3), has strong in-vitro antileukemic effects at toxic concentrations in vivo. Several low-calcemic vitamin D analogs (VDAs) have been synthesized to reduce 1,25D3 toxicity. We have previously shown that plant polyphenolic antioxidants (PAOx) synergistically enhance the effects of 1,25D3 and VDAs at non-toxic doses. These effects were mediated b y the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and activator protein-1 (AP-1) transcription factors. The study aimed to 1) Character-ize the combined effects of novel highly potent vascular disrupting agents with peroxisomal N(1) –acetyl-spermine/spermidine oxidase on differentiation and growth of acute myeloid leukemia cells; 2) Elucidate the role of the interplay between nuclear factor erythroid 2, activator protein-1, and vitamin D receptor (VDR) in the combined antileukemic effects of vascular disrupting agents and peroxisomal N (1)–acetyl-spermine/spermidine oxidase. This article presents the treatment of AML with pharmaceutical plants and vitamin D. Such techniques as culture dilution (HL60, U937) and Western Blotting were used. We determined the in-vitro antileukemic effects of novel plant vitamin D2-based VDAs with removed C-19 (19-nor analogs; PRI-5201 and PRI-5202) or with a side-chain modification at C-24 (24-cis analogs; PRI-1916 and PRI-1917) on HL60, U937, and MOLM-13 human AML cells. The differentiation potency of PRI-5201 and PRI-5202 was 1-2 orders of magnitude higher than that of 1,25D2 or 1,25D3, while the 24-cis modification was almost ineffective. The 19-nor VDA/CA combinations are promising for treating AML. In vivo, testing of these combinations is in progress. We suggest that direct or indirect Nrf2-mediated up regulation of AP-1 and VDR by PAOx increases the sensitivity of AML cells to low doses of 1,25D3 or VDAs.

Resveratrol modulates the Nrf2/NF-κB pathway and inhibits TSLP-mediated atopic march.

Resveratrol has been found to have anti-inflammatory and anti-allergic properties. The effects of resveratrol on thymic stromal lymphopoietin (TSLP)-mediated atopic march remain unclear. To explore the potential role of resveratrol in TSLP-mediated atopic march. The atopic march mouse model was established by topical application of MC903 (a vitamin D3 analog). Following the treatment with resveratrol, airway resistance in mice was discovered by pulmonary function apparatus, and the number of total cells, neutrophils, and eosinophils in bronchoalveolar lavage fluid was counted. The histopathological features of pulmonary and ear skin tissues, inflammation, and cell infiltration were determined by hematoxylin and eosin staining. The messenger RNA (mRNA) levels of TSLP, immunoglobulin E, interleukin (IL)-4, IL-5, and IL-13 were measured by real-time quantitative polymerase chain reaction. The protein expression of nuclear factor kappa B (NF-κB)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling-associated molecules (p-p65, p65, p-I kappa B kinase alpha (IκBα), IκBα, Nrf2, and TSLP) in lung and ear skin tissues were assessed by Western blot analysis. Resveratrol attenuated airway resistance and infiltration of total cells, eosinophils, and neutrophils in both lung and ear skin tissues. Resveratrol ameliorates serum inflammatory markers in allergic mice. Moreover, the phosphorylation levels of NF-κB pathway-related proteins were significantly reduced by administration of resveratrol in allergic lung and ear skin tissues. Similarly, the protein expression of TSLP in both lung and ear skin tissues was reduced by resveratrol, and Nrf2, a protector molecule, was increased with resveratrol treatment. Resveratrol attenuates TSLP-reduced atopic march through ameliorating inflammation and cell infiltration in pulmonary and ear skin tissues by inhibiting the abnormal activation of NF-κB signaling pathway.

Vitamin D3 exacerbates steatosis while calcipotriol inhibits inflammation in non-alcoholic fatty liver disease in Sod1 knockout mice: a comparative study of two forms of vitamin D.

The role of vitamin D (VD) in non-alcoholic fatty liver disease (NAFLD) remains controversial, possibly due to the differential effects of various forms of VD. In our study, Sod1 gene knockout (SKO) mice were utilized as lean NAFLD models, which were administered 15 000 IU VD3 per kg diet, or intraperitoneally injected with the active VD analog calcipotriol for 12 weeks. We found that VD3 exacerbated hepatic steatosis in SKO mice, with an increase in the levels of Cd36, Fatp2, Dgat2, and CEBPA. However, calcipotriol exerted no significant effect on hepatic steatosis. Calcipotriol inhibited the expression of Il-1a, Il-1b, Il-6, Adgre1, and TNF, with a reduction of NFκB phosphorylation in SKO mice. No effect was observed by either VD3 or calcipotriol on hepatocyte injury and hepatic fibrosis. Co-immunofluorescence stains of CD68, a liver macrophage marker, and VDR showed that calcipotriol reduced CD68 positive cells, and increased the colocalization of VDR with CD68. However, VD3 elevated hepatocyte VDR expression, with no substantial effect on the colocalization of VDR with CD68. Finally, we found that VD3 increased the levels of serum 25(OH)D3 and 24,25(OH)2D3, whereas calcipotriol decreased both. Both VD3 and calcipotriol did not disturb serum calcium and phosphate levels. In summary, our study found that VD3 accentuated hepatic steatosis, while calcipotriol diminished inflammation levels in SKO mice, and the difference might stem from their distinct cellular selectivity in activating VDR. This study provides a reference for the application of VD in the treatment of lean NAFLD.

Efficient Stereo-Selective Fluorination on Vitamin D3 Side-Chain Using Electrophilic Fluorination.

Our research regarding side-chain fluorinated vitamin D3 analogues has explored a series of efficient fluorination methods. In this study, a new electrophilic stereo-selective fluorination methodology at C24 and C22 positions of the vitamin D3 side-chain was developed using N-fluorobenzenesulfonimide (NFSI) and CD-ring imides with an Evans chiral auxiliary (26,27,30).

Differential gene regulation by a synthetic vitamin D receptor ligand and active vitamin D in human cells

Vitamin D (VD) exerts a wide variety of biological functions including calcemic activity. VD nutritional status is closely associated with the onset and development of chronic diseases. To develop a VD analog with the desired VD activity but without calcemic activity, we screened synthetic VDR antagonists. We identified 1α,25-dihydroxyvitamin D3-26-23-lactams (DLAM)-2a-d (DLAM-2s) as nuclear vitamin D receptor (VDR) ligands in a competitive VDR binding assay for 1α,25(OH)2 vitamin D3 (1α,25(OH)2D3), and DLAM-2s showed an antagonistic effect on 1α,25(OH)2 D3-induced cell differentiation in HL60 cells. In a luciferase reporter assay in which human VDR was exogenously expressed in cultured COS-1 cells, DLAM-2s acted as transcriptional antagonists. Consistently, DLAM-2s had an antagonistic effect on the 1α,25(OH)2D3-induced expression of a known VD target gene [Cytochrome P450 24A1 (CYP24A1)], and VDR bound DLAM-2s was recruited to an endogenous VD response element in chromatin in human keratinocytes (HaCaT cells) endogenously expressing VDR. In an ATAC-seq assay, the effects of 1α,25(OH)2 D3 and DLAM-2b on chromatin reorganization were undetectable in HaCaT cells, while the effect of an androgen receptor (AR) antagonist (bicalutamide) was confirmed in prostate cancer cells (LNCaP) expressing endogenous AR. However, whole genome analysis using RNA-seq and ATAC (Assay for Transposase Accessible Chromatin)-seq revealed differential gene expression profiles regulated by DLAM-2b versus 1α,25(OH)2D3. The upregulated and downregulated genes only partially overlapped between cells treated with 1α,25(OH)2D3 and those treated with DLAM-2b. Thus, the present findings illustrate a novel VDR ligand with gene regulatory activity differing from that of 1α,25(OH)2D3.

INNOVATIVE APPROACH TO THE TREATMENT OF PSORIASIS USING NANOTECHNOLOGIES

Psoriasis is a chronic immune-mediated genetic disease with systemic and cutaneous manifestations that can significantly impair patients' quality of life. 2-3% of the world population suffers from psoriasis, and this imposes a significant economic burden on patients. Aetiology is mainly related to genes and environmental factors. The pathophysiology of psoriasis is characterized by T cells and dendritic cells, antimicrobial peptides, genetic predisposition, lipoprotein-2, galactosin-3, fractalkine, vaspin, human neutrophil peptides, etc. in the progression of psoriasis. For patients with psoriasis, conventional treatments include corticosteroids, vitamin D3 analogs, calcineurin inhibitors, methotrexate, cyclosporine, acitretin, phototherapy, and biological agents, etc. Today, there are various standard topical therapeutic approaches that can help control the condition for months to years, however, complete recovery from psoriasis with these treatments has not been reported. Therefore, researchers around the world are mainly considering the possibility of using various nanotechnological therapies for complete recovery. New drug delivery carriers, in particular nanocarriers, can overcome certain disadvantages of conventional treatment methods, such as: dose minimization, frequency of administration, and dose-dependent side effects. Nanodermatology is a new multidisciplinary science that is gaining more and more recognition in the treatment of psoriasis. The use of nanotechnology makes it possible to select drugs to achieve dermal targeting, increase efficiency and minimize unwanted effects. Currently, these nanocarriers are becoming increasingly popular as delivery vehicles for psoriasis drugs due to their non-toxicity, natural degradability, excellent biocompatibility and biodegradability, they do not cause harmful inflammatory reactions and are easily excreted from the body. Reports of nanocarrier delivery for the treatment of psoriasis have shown improved efficacy and reduced toxicity compared to standard pharmacotherapy. To better clarify the application of nanotechnology in the treatment of psoriasis, various drugs based on nanocarriers will be summarized. This review provides a concise overview of the pathophysiology, epidemiology, clinical diagnosis, and classical pharmacotherapy of psoriasis. The review also summarizes various nanotechnological treatments for the effective treatment of psoriasis.

Frequency and determinants of serum calcium monitoring during eldecalcitol therapy in patients with osteoporosis.

Eldecalcitol (ELD) is an active vitamin D3 analog (AVD) commonly used to treat osteoporosis in Japan. Although routine monitoring of serum calcium levels during ELD therapy is recommended, little is known about the actual frequency and determinants of monitoring. This was a descriptive cohort study using a Japanese electronic medical records database. We identified osteoporosis patients who initiated treatment with ELD or other AVDs (alfacalcidol and calcitriol) between April 1, 2011 and September 10, 2021. The index date for cohort entry was the first prescription date of ELD or other AVDs. The frequency of serum calcium monitoring was evaluated every 6 months. Determinants of serum calcium monitoring were identified using multivariable logistic regression models. We also calculated the incidence of hypercalcemia and the frequency of serum calcium monitoring within 6 months before hypercalcemia. We identified 12,671 ELD users and 7867 other AVD users. Within 6 months after cohort entry, 45.9% of ELD users and 58.7% of other AVD users underwent serum calcium monitoring. Female sex, no use of systemic corticosteroids, moderate-to-good renal function, treatment in smaller hospitals, and treatment in orthopedic surgery departments were associated with a lower likelihood of receiving serum calcium monitoring during ELD therapy. The incidence of hypercalcemia among ELD users was 6.36 per 100 person-years, with 20.6% of cases not receiving serum calcium monitoring before hypercalcemia. Our findings suggest that serum calcium monitoring is not given adequate attention during ELD therapy in routine clinical practice.

Synthesis of new 26,27-difluoro- and 26,26,27,27-tetrafluoro-25-hydroxyvitamin D3: Effects of terminal fluorine atoms on biological activity and half-life.

As an extension of our research on providing a chemical library of side-chain fluorinated vitamin D3 analogues, we newly designed and synthesized 26,27-difluoro-25-hydroxyvitamin D3 (1) and 26,26,27,27-tetrafluoro-25-hydroxyvitamin D3 (2) using a convergent method applying the Wittig-Horner coupling reaction between CD-ring ketones (13,14) and A-ring phosphine oxide (5).The basic biological activities of analogues, 1, 2, and 26,26,26,27,27,27-hexafluoro-25-hydroxyvitamin D3 [HF-25(OH)D3] were examined. Although the tetrafluorinated new compound 2 exhibited higher binding affinity for vitamin D receptor (VDR) and resistance to CYP24A1-dependent metabolism compared with the difluorinated 1 and its non-fluorinated counterpart 25-hydroxyvitamin D3 [25(OH)D3], HF-25(OH)D3 showed the highest activity among these compounds. Osteocalcin promoter transactivation activity of these fluorinated analogues was tested, and it decreased in the order of HF-25(OH)D3, 2, 1, and 25(OH)D3 in which HF-25(OH)D3 showed 19-times greater activity than the natural 25(OH)D3.

Advances in the Administration of Vitamin D Analogues to Support Bone Health and Treat Chronic Diseases.

Vitamin D (VD) exerts a wide variety of biological actions in addition to its well-known roles in calcium homeostasis. Nutritional VD deficiency induces rachitic abnormalities in growing children and osteomalacia in adults, and it has been proposed to underlie the onset and development of multiple non-communicable chronic diseases. Therefore, the administration of VD or synthetic VD analogues represents a promising therapeutic strategy; indeed, VD and a VD agonist have shown clinical promise in mitigating osteoporosis and symptoms of insufficient calcium intake. However, even though high doses of VD analogues have shown pre-clinical efficacy against several diseases, including cancers, they have not yet had wide-spread clinical success. This difference may be due to limitation of clinical doses in light of the inherent calcemic action of VD. An approach to overcome this problem involves the development of VD analogues with lower calcemic activity, which could be administered in high doses to attenuate the onset and progress of disease. In a similar strategy, selective estrogen receptor modulators have had success as anti-osteoporosis drugs, and they have shown benefit for other estrogen target organs by serving as partial antagonists or agonists of estrogen receptor α. It is thus conceivable to generate synthetic partial antagonists or agonists for the VD receptor (VDR) that would exert beneficial effects on bone and other VD target organs. In this review, we discuss the molecular basis of the development of such synthetic VDR ligands from the viewpoint of roles of VDR in gene regulation.

Vitamin D3 analogue calcipotriol inhibits the profibrotic effects of transforming growth factor- β1 on pancreatic stellate cells

ObjectiveTo evaluate the inhibitory effect of vitamin D3 analogue calcipotriol (Cal) on the fibrosis of pancreatic stellate cells (PSCs) induced by TGF-β1 and the rationality of Cal use in alcoholic chronic pancreatitis (ACP). Material and methodsDouble-labeling immunofluorescence was used for the identification of VDR+PSCs in the pancreas of healthy controls (HC) and ACP patients. Van Gieson staining for examination of collagen fibers. RT-qPCR and Western Blot for determining the mRNAs and proteins of VDR, TGF-β1 and COL1A1 in the pancreas of ACP or in vitro PSCs. ELISA or LC-MS/MS for detection of serum TGF-β1 and COL1A1 or 25(OH)D3. The PSC line (RP-2 cell) was used for the determination of proteomic alterations in Cal plus TGF-β1 versus TGF-β1 and to examine the effect of VDR gene knockdown. ResultsEnhanced expression of VDR was detected in RP-2 cells stimulated with alcohol (ALC) plus Cal versus Cal alone and in PSCs in the pancreas of ACP versus HC. The increased VDR+PSCs were positively correlated with the levels of COL1A1 mRNAs or areas of collagen deposition in the pancreas of ACP. TGF-β1 was overexpressed in the pancreas of ACP and ALC-treated RP-2 cells while 25(OH)D3 level in serum was significantly decreased in ACP versus HC. Through a VDR-dependent mechanism, Cal antagonized 16 profibrotic proteins in TGF-β1-induced RP-2 cells that included 7 extracellular matrix components, 2 cytoskeletal proteins, 2 fibrosis-associated factors (RUNX1 and TRAF2), TIMP-1, CCN1, integrin α11, an adhesion scaffold protein (TGFB1i1) and an enzyme mediating TGF-β1-induced fibrogenesis (ENPP1). ConclusionThis study suggests that Cal administration may be a potential antifibrotic strategy via inhibiting TGF-β1-mediated PSC action during the development of ACP.

Neuropilin 2 in osteoblasts regulates trabecular bone mass in male mice.

Neuropilin 2 (NRP2) mediates the effects of class 3 semaphorins and vascular endothelial growth factor and is implicated in axonal guidance and angiogenesis. Moreover, NRP2 expression is suggested to be involved in the regulation of bone homeostasis. Indeed, osteoblasts and osteoclasts express NRP2 and male and female global Nrp2 knockout mice have a reduced bone mass accompanied by reduced osteoblast and increased osteoclast counts. We first examined the in vitro effect of the calciotropic hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on Nrp2 transcription in osteoblasts. We next generated mice with a conditional deletion of Nrp2 in the osteoblast cell lineage under control of the paired related homeobox 1 promoter and mice with a conditional Nrp2 knockdown in osteoclasts under control of the Lysozyme promoter. Mice were examined under basal conditions or after treatment with either the bone anabolic vitamin D3 analog WY 1048 or with 1,25(OH)2D3. We show that Nrp2 expression is induced by 1,25(OH)2D3 in osteoblasts and is associated with enrichment of the vitamin D receptor in an intronic region of the Nrp2 gene. In male mice, conditional deletion of Nrp2 in osteoblast precursors and mature osteoblasts recapitulated the bone phenotype of global Nrp2 knockout mice, with a reduced cortical cross-sectional tissue area and lower trabecular bone content. However, female mice with reduced osteoblastic Nrp2 expression display a reduced cross-sectional tissue area but have a normal trabecular bone mass. Treatment with the vitamin D3 analog WY 1048 (0.4 μg/kg/d, 14 days, ip) resulted in a similar increase in bone mass in both genotypes and genders. Deleting Nrp2 from the osteoclast lineage did not result in a bone phenotype, even though in vitro osteoclastogenesis of hematopoietic cells derived from mutant mice was significantly increased. Moreover, treatment with a high dose of 1,25(OH)2D3 (0.5 μg/kg/d, 6 days, ip), to induce osteoclast-mediated bone resorption, resulted in a similar reduction in trabecular and cortical bone mass. In conclusion, osteoblastic Nrp2 expression is suggested to regulate bone homeostasis in a sex-specific manner.

Peroxygenase-catalysed selective and scalable synthesis of 25-hydroxy-grundmann's ketone and its derivatives

Peroxygenases are selective catalysts for C-H bond oxyfunctionalization reactions, however, their potential for organic synthesis still needs to be explored. 25-Hydroxy-Grundmann's ketone is a key structural motifs in various biologically active vitamin D3 analogues. In this study, we report the use of unspecific peroxygenase from Agrocybe aegerita as a highly selective catalyst for the C25 hydroxylation of Grundmanns's ketone and its analogues. Under the optimised conditions, excellent conversion (> 99%) and regioselectivity (> 99%) was obtained. The selected hydroxylation processes were performed on an increased lab scale (up to 200 mL) with up to 1 mmol substrate, which led in 85.7% isolated yield.This simple biocatalytic method holds great potential in streamlining the synthetic pathways of vitamin D3 analogues.