The optimal pharmacokinetics (PK) of orally administered nanoparticles (NPs) varies depending on their application (e.g., drug delivery, adsorbent, and adjuvant). Therefore, engineering NPs to achieve optimal PK is essential for the development of drug designs. Some studies have demonstrated that individual NP factors change the intestinal absorption of NPs; however, no technology has been established to control the biodistribution of orally administered NPs. In this study, a database about the influence of NP characteristics on biodistribution after oral administration was provided. A library of N-isopropylacrylamide polymer NPs with various characteristics that could influence the biodistribution after oral administration, such as size, flexibility, hydrophobicity, surface charges, and surface chemistries, were prepared. NPs with various sizes were synthesized by tuning the surfactant concentration only during synthesis, whereas NPs with different flexibility, hydrophobicity, surface charge, and surface chemistry were synthesized by feeding the corresponding functional monomer. The total amount of NPs accumulated in the organs decreased with increasing NP size, rigidity, hydrophobicity, electric potential (whether positive or negative), and polyethylene glycol modification. The results indicated that the absorption of orally administered NPs can be controlled by optimizing the characteristics of NP such as size, flexibility, hydrophobicity, surface charge, and surface chemistry. The results of this study will provide useful information to design NP formulations.

Selenium (Se) is an essential micronutrient for animals. Various chemical forms of Se exist in nature, each with distinct physiological, nutritional, and toxicological properties. In this study, we aimed to determine whether dimethyldiselenide (DMDSe, a monomethylated Se (MMSe) compound) and dimethylselenide (DMSe, a dimethylated Se compound), known gut bacterial metabolites, could serve as Se sources in rats. DMDSe could be utilized for selenoprotein biosynthesis and was metabolized into urinary selenometabolites. By contrast, DMSe was not utilized for selenoprotein biosynthesis but was further methylated to trimethylselenonium ion (TMSe), one of the urinary Se metabolites. Our findings indicate that dimethylated Se is not readily available as an Se source in rats, unlike MMSe. Selenoprotein biosynthesis requires selenide, an unmethylated form of Se, in the metabolic pathway. Our observations support the hypothesis that demethylation occurs on MMSe as a reversible methylation step but not on dimethylated Se. This suggests that the second methylation step is crucial for inactivating Se and plays a significant role in metabolism to maintain Se homeostasis in animals. Gut microbiota, which can synthesize both DMDSe and DMSe, may contribute to host Se metabolism through methylation processes.

Mineralocorticoid receptor (MR) blockers reduce cardiovascular complications as MRs play a crucial role in cardiovascular regulation. Diabetic cardiovascular complications are caused by vascular endothelial dysfunction. This study used a type 2 diabetic mouse model (DM) to investigate whether esaxerenone (ESAX), an MR blocker, ameliorates vascular endothelial dysfunction. ESAX (3 mg/kg/d) was administered via diet to KK-Ay mice or C57BL/6J mice, a nondiabetic control (Control), for 8 weeks, and metabolic parameters and blood pressure were measured. Vascular responses of the aortic segments were analyzed with acetylcholine, sodium nitroprusside, UK14304, or phenylephrine (PE). The other aortas were used for Western blot analysis. DM mice exhibited higher plasma glucose, insulin, metabolic parameters, and blood pressure levels than those of the Control mice. Parameters that did not include blood pressure were unaltered by DM or ESAX-administered DM (DM + ESAX). However, DM impaired UK14304-induced endothelial-dependent relaxation and nitric oxide production and elevated PE-induced contraction. ESAX administration ameliorated endothelial dysfunction and improved the protein kinase B (Akt) phosphorylation under α₂-agonist UK14304 stimulation in the aorta from DM mice compared with that of the Control mice. However, ESAX did not recover the increased G protein-coupled receptor kinase 2 (GRK2) expression and activity in the DM aorta. Furthermore, the DM-induced phosphorylation of serum and glucocorticoid-regulated kinase 1 (SGK1) was inhibited by ESAX. Overall, ESAX attenuates the development of DM-induced endothelial dysfunction by reducing SGK1 activity and enhancing Akt activity without affecting the GRK2 pathway. These results suggest that the vascular protective effects of ESAX could be employed for diabetic vascular complications.

Elastic fibers, which contribute to the flexibility of tissues such as the skin, alveoli, and arteries, have a long half-life and are not regenerated once formed during the fetal stage. Consequently, the degradation of elastic fibers due to aging or inflammation can significantly impact tissue function. In the dermis, degeneration of elastic fibers is characterized by degradation in photoaging, driven by UV radiation, and structural abnormalities of elastic fibers in intrinsic aging. However, the mechanisms driving the abnormalities associated with intrinsic aging remain incomplete. This study aimed to identify the factors involved in the elastic fiber abnormalities associated with intrinsic aging of the dermis. Through a comprehensive analysis of gene expression, this study focused on microfibril-associated protein 5 (MFAP5) as a candidate gene responsible for the elastic fiber abnormalities associated with intrinsic aging. Immunofluorescence staining revealed that aged fibroblasts highly expressed MFAP5 and strongly localized it to aggregated elastic fibers. Furthermore, the elimination of MFAP5 expression suppressed elastic fiber aggregation. The exogenous addition of MFAP5 induced thickening and disorganization of elastic fibers, effects that were not observed with the overexpression of MFAP5 in young fibroblasts, which merely express MFAP5. Moreover, MFAP5 inhibited the interaction between latent transforming growth factor β binding protein 4 and fibulin-5, which are crucial for elastic fiber formation. These results suggest that excess MFAP5 expression associated with aging causes abnormalities in elastic fibers. Understanding the role of MFAP5 in elastic fiber abnormalities highlights its potential as a therapeutic target for mitigating intrinsic dermal aging and improving skin elasticity.

One of the side effects of calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporin A (CsA), is intestinal mucosal damage leading to ulceration and bleeding. However, it remains to be elucidated whether these side effects are direct effects of calcineurin inhibitors on intestinal epithelial cells (IECs). To determine whether IECs are directly damaged by calcineurin inhibitors, we analyzed the effects of calcineurin inhibitors on the intestinal barrier in Caco-2 cells, a human intestinal cell line. Treatment of Caco-2 with calcineurin inhibitors such as FK506, CsA, and deltamethrin inhibited expression of zonula occludens-1, a tight junction protein, and increased permeability of Lucifer Yellow. These effects were observed in confluent cells, but not clear in subconfluent cells. Our findings suggest that calcineurin inhibitors can directly damage IECs.

Recently, the epidemic types of methicillin-resistant Staphylococcus aureus (MRSA) in hospital and community settings in Japan have changed significantly. Before 2010, approximately 80% of the MRSA strains isolated from hospitals were typical healthcare-associated MRSA (HA-MRSA) with staphylococcal cassette chromosome (SCC) mec type II. However, USA400-like community-associated MRSA (CA-MRSA) with SCCmec type IV (defined as USA400/J) has become dominant in hospitals since 2014. By contrast, skin infections caused by the highly virulent CA-MRSA USA300 clone have increased. The USA300 clone is associated with intractable skin infections and necrotizing pneumonia because it carries a cytolytic pore-forming toxin, Panton–Valentine leukocidin (PVL), and an arginine catabolic mobile element that promotes skin colonization. In the past decade, the USA300 clone has shown limited prevalence and has not been considered a serious problem in Japan. However, the USA300 clone has recently spread in community and hospital settings. This review discusses the evolution and current status of the molecular epidemiological features of HA-MRSA and CA-MRSA strains in Japan.

Antimicrobial resistance (AMR) is a serious global concern. AMR pathogens are found in hospitals and communities. Haemophilus influenzae is a common pathogen associated with community-acquired infections. H. influenzae infections are usually treated with β-lactams, macrolides, and quinolones. However, the drug-resistant strains have emerged. The resistance mechanisms of H. influenzae are complex but are roughly characterized by the acquisition of a mutation in antimicrobial-targeting genes and exogenous resistant genes. Generally, the former cannot be transferred horizontally to a susceptible strain. However, several studies have demonstrated that, in the case of H. influenzae, both the former and the latter can be transferred horizontally. In this review, we provide an overview of the bacterial features and antimicrobial resistance of H. influenzae. We also summarize the unique and ingenious antimicrobial resistance mechanisms used by this pathogen based on the findings of recent studies. These are expected to facilitate the understanding of AMR pathogens in the community and develop strategies to combat infections.

In this study, we investigated (1) the functional role of large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels in the regulation of guinea pig vas deferens smooth muscle (VDSM) contractions and (2) the potential contractile effects of 33 physiologically active substances and related chemicals that have not been previously reported to contract VDSM. Iberiotoxin (an inhibitor of BK_Ca channels, 10^–7 M) was the most potent enhancer of both noradrenaline (10^–5 M)- and ATP (10^–6 M)-induced contractions among the 6 types of K⁺ channel inhibitors. In addition, BK_Ca channel mRNA expression was the highest among the 32 types of K⁺ channel mRNAs. Iberiotoxin also enhanced the contractions induced by acetylcholine (10^–6 M), histamine (5 × 10^–5 M), bradykinin (10^–6 M), neurokinin A (10^–6 M), neurokinin B (10^–6 M), and substance P (10^–6 M). In the 33 tested physiologically active substances and related chemicals (15 peptides, 5 amino acids and their derivatives, 11 prostanoid- and isoprostane-related drugs, 1 endocannabinoid, and 1 phospholipid), we found that 3 bombesin-like peptides, neuromedin B (NMB) (10^–6 M), gastrin-releasing peptide (GRP, 10^–8 M), and NMC (10^–6 M), contracted VDSM in the absence of iberiotoxin, and these contractions were strongly enhanced in the presence of iberiotoxin. Among the 3 bombesin receptor subtypes, the mRNA expression level of Grpr (BB₂ receptor) was the highest. These findings suggest that (1) BK_Ca channels are the most powerful negative regulator of VDSM contractility and (2) NMB, GRP, and NMC are physiologically active substances that contract VDSM.

Vitiligo vulgaris is an acquired disorder that is thought to arise from the suppression of melanin synthesis by melanocytes in the basal epidermal layer. To develop therapeutic agents for vitiligo vulgaris, it is critical to identify compounds that promote melanization. In this study, we established a digital image-based method to quantify melanization that does not require biochemical procedures. B16F10 cells were seeded in a white-bottom 96-well microplate. After treatment with or without α-melanocyte-stimulating hormone, followed by fixation of the cells, digital images of the microplates were captured, and the total signal intensity of each well on the image was measured. The extent of melanization in the cells in each well was defined after the subtraction of the signal from the corresponding blank well. This method was found to quantify melanization more sensitively than the conventional technique that measures the absorbance of cell lysates at UV-A wavelengths. We obtained statistical parameters showing that this method was applicable to a high-throughput screening assay; thus, this method appears to be useful for screening and identifying molecules that suppress or promote melanization, the latter of which may be developed as therapeutic agents for vitiligo vulgaris.

Gestational diabetes mellitus (GDM) is a glucose metabolism abnormality that first emerges during pregnancy and may negatively affect the behavioral and neurodevelopmental outcomes of offspring. Quetiapine (QUE) has been shown to promote differentiation of oligodendrocyte precursor cells (OPCs) and protect oligodendrocytes and myelination. To explore the effects of QUE on improving the expression of conditioned place preference (CPP) and myelination in the infralimbic cortex (IL) of the medial prefrontal cortex in alcohol-exposed GDM offspring mice, we evaluated CPP expression in 5-week-old alcohol-exposed GDM offspring and treated them with QUE and the extracellular-regulated protein kinase (ERK) inhibitor U0126. Immunohistochemical staining compared the numbers of mature oligodendrocytes, OPCs, and myelin expression levels. Immunofluorescence staining was employed to examine OPC differentiation and the activation of the ERK1/2 signaling pathway. In GDM offspring, CPP expression increased considerably following alcohol exposure, whereas early treatment with QUE or U0126 significantly decreased CPP expression. Meanwhile, alcohol exposure resulted in substantial activation of the ERK1/2 signaling pathway within OPCs in the IL region, as well as a substantial reduction in OPC differentiation, mature oligodendrocyte count, and myelin expression. QUE or U0126 inhibited the activation of the ERK1/2 signaling pathway within OPCs in the IL region of alcohol-exposed GDM offspring and markedly restored OPC differentiation, mature oligodendrocyte numbers, and myelin expression. Collectively, QUE enhanced the differentiation of OPCs in the IL region of GDM offspring after alcohol exposure by regulating the overactivation of the ERK1/2 signaling pathway, thus partially reversing myelination loss and ultimately improving CPP expression.

In Japan, S-1 is used as adjuvant chemotherapy for pancreatic cancer. Neutropenia during S-1 chemotherapy is reported to be an independent predictor of prolonged survival in patients with advanced gastric cancer. However, this is unclear in pancreatic cancer. This study aimed to examine the effect of severe neutropenia caused by S-1 adjuvant chemotherapy on pancreatic cancer prognosis: overall survival (OS) and recurrence-free survival (RFS), and the potential effect of the duration from surgery to S-1 administration on OS and RFS. This single-center, retrospective, observational study included patients who newly received S-1 adjuvant chemotherapy after curative resection of pancreatic cancer at the Japanese Red Cross Kyoto Daini Hospital between January 1, 2016, and September 30, 2020. Of the 43 patients, 9 had grade 3 or higher neutropenia (G3 group) and had a significantly longer median OS than the other 34 (non-G3 group) did. The median RFS of the G3 group was longer than that of the non-G3 group. The median time from surgery to S-1 administration was significantly shorter in the G3 group than in the non-G3 group. Cox proportional hazards regression analysis revealed that duration from surgery to S-1 administration <51 d (hazard ratio: 0.375, 95% confidence interval: 0.154–0.914, p = 0.031) and occurrence of grade 3 neutropenia (hazard ratio: 0.198, 95% confidence interval: 0.046–0.860, p = 0.031) were significantly associated with prolonged OS. In conclusion, initiating S-1 adjuvant chemotherapy early after surgery and the occurrence of grade 3 neutropenia may improve pancreatic cancer prognosis.

Metallothionein (MT) is a small-molecule protein that functions in essential trace element homeostasis. Among MT isoforms, MT3 is involved in neuronal activity, and its expression is reported to be decreased in patients with neurodegenerative conditions such as Alzheimer’s disease; however, only a few effective drugs have been reported to induce MT3 expression. In this study, we evaluated existing drugs for the induction of MT3 expression in the neuronal cell line of ReNcell CX cells. Using recombinant proteins of MT isoforms with the 3× Flag tag, we performed Western blotting (WB) with the primary antibodies against MT3 or Flag tag, and this method of WB for MT3 was confirmed specifically to detect the MT3 protein. We treated ReNcell CX cells with several HIF-PH inhibitors and evaluated MT3 expression via real-time RT-PCR. We found that FG4592 significantly enhanced MT3 expression at both RNA and protein levels. FG4592 treatment increased the amount of hypoxia-inducible factor 1 alpha (HIF1α) binding to the MT3 promoter. These findings indicate that FG4592 induces MT3 expression via increased HIF1α. In conclusion, we found FG4592 to be an endogenous MT3 inducer in the cells of the nervous system in this study. The findings of this study are expected to lead to the development of new MT3-inducing drugs for neurodegenerative diseases based on FG4592.

Fluorescence imaging analysis was performed in cardiomyocytes from the sinus node, the orthotopic pacemaker, and the pulmonary vein, a potential ectopic pacemaker that may cause atrial fibrillation, focusing on the role of the Na⁺/Ca²⁺ exchanger (NCX). Isolated cardiomyocytes from the guinea pig pulmonary vein and sinus node showing automaticity were loaded with fluorescence probes for analysis. Inhibition of NCX by SEA0400 decreased the Ca²⁺ transient frequency in the pulmonary vein cardiomyocytes but not in the sinus node. The basal intracellular Ca²⁺ concentration, as well as the number of Ca²⁺ sparks in the subsarcolemmal region, was higher in the pulmonary vein cardiomyocytes than in the sinus node. By contrast, the intracellular Na⁺ concentration was not different between the pulmonary vein and sinus node cardiomyocytes. The equilibrium potential for NCX (E_NCX) was estimated to be less negative in the pulmonary vein cardiomyocytes than in the sinus node. In conclusion, the forward mode NCX is involved in spontaneous activity in the pulmonary vein cardiomyocytes but not in the sinus node; this is probably because the Ca²⁺ supply and the driving force for the forward mode NCX are both larger in the pulmonary vein cardiomyocytes than in the sinus node.

Carboxylesterase (CES) plays an important role in the metabolism of ester-containing drugs such as prodrugs and is highly expressed in the human intestine and liver. The ideal prodrug is barely hydrolyzed by human intestinal CES (CES2A1) but is extensively converted to an active drug by human hepatic CES (CES1A). It is, therefore, important to evaluate CES2A1-mediated hydrolysis during intestinal absorption. Unfortunately, Caco-2 cells, the most common enterocyte model for drug permeability, are not suitable for permeability studies of prodrugs due to their high and extremely low expression of CES1A and CES2A1, respectively. Previously, we have prepared CES2/Caco-2^CES1KD cells with reduced human CES1A and highly expressed CES2A1. In the present study, the metabolic and transport properties of CES2/Caco-2^CES1KD cells were characterized. The expression of transporters and metabolizing enzymes other than CESs was similar in CES2/Caco-2^CES1KD and Caco-2 cells. However, the expression of CES2A1 in CES2/Caco-2^CES1KD was about 7–10 fold higher than that of CES1A in Caco-2 cells and comparable to levels found in the human intestine. Hydrolysis during transport across cell monolayers was analyzed using ethyl and butyl esters of p-aminobenzoic acid (PABA). Ethyl PABA, a better substrate for CES1A than CES2A1, was similarly hydrolyzed in Caco-2 and CES2/Caco-2^CES1KD cell monolayers due to the high expression of CES2A1 in CES2/Caco-2^CES1KD cells. Butyl PABA, a good substrate for CES2A1, was substantially hydrolyzed in CES2/Caco-2^CES1KD cell monolayers, in contrast to negligible hydrolysis in Caco-2 cell monolayers. N-Acetylation of PABA derived from PABA esters showed similar activity in Caco-2 and CES2/Caco-2^CES1KD cell monolayers.

The non-canonical phosphorylation of the receptor tyrosine kinase ephrin type-A receptor 2 (EphA2) at Ser-897 plays crucial roles in tumor progression in a tyrosine kinase-independent manner. This phosphorylation is catalyzed by p90 ribosomal S6 kinase (RSK), a kinase downstream of extracellular signal-regulated kinase (ERK). We recently reported that stress-responsive kinase mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), instead of ERK, regulates RSK under cellular stress conditions; however, the function of MK2 in ERK-activated cells is still unknown. We herein clarified that MK2 regulates the RSK-EphA2 axis in ERK-activated echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) lung cancer cells. In addition, an MK2 inhibitor blocked enhancements in cell motility induced by the constitutively activated RSK-EphA2 axis. The present results reveal the importance of MK2 in the ERK-activated non-canonical activation of EphA2.

Enhanced inflammatory and immune responses have been observed in patients with major depressive disorder, pointing to anti-inflammatory substances as potential seeds for developing novel antidepressants. Omega-3 polyunsaturated fatty acid metabolites, such as resolvin D and E series, maresins, and protectins (collectively known as specialized pro-resolving mediators) demonstrate anti-inflammatory effects. This study examined the antidepressant-like effects of maresin-1 (MaR1) on lipopolysaccharide (LPS)-induced depression-like behaviors in mice. Using the tail suspension test (TST) and the forced swim test (FST), we assessed depression-like behaviors 26 and 28 h after intraperitoneal injection of LPS (0.8 mg/kg), respectively. An open field test (OFT) was also conducted to evaluate locomotor activity 24 h after LPS injection. Intracerebroventricular (i.c.v.) injection of MaR1 (10 ng/mouse) immediately after the LPS challenge mitigated the increased immobility time in the TST and FST, without affecting locomotor activity in the OFT, indicating the preventive effects of MaR1 on LPS-induced depression-like behaviors. Furthermore, i.c.v. injection of MaR1 23 h after the LPS challenge reduced the immobility time in both tests, underscoring its therapeutic potential. These findings suggest that MaR1 could be a promising seed for developing novel antidepressants.

A 3-dimensional (3D) cell culture is now being actively pursued to accomplish the in vivo-like cellular morphology and biological functions in cell culture. We recently obtained nano-fibrillated bacterial cellulose (NFBC). In this study, we developed a novel NFBC-based 3D cell-culture system, the OnGel method, and the Suspension method. HepG2 human liver cancer cells were cultured via these methods and formed spherical formulations in the optimized condition, 1.0% (w/v) of NFBC in the OnGel method, and 0.06–0.10% (w/v) of NFBC in the Suspension method. Non-cancerous cells such as human-induced pluripotent stem (iPS) cells and human mesenchymal stem cells (MSCs) also formed spherical formulations. It is noteworthy that both the size and cell viability of spheroids prepared via these methods were comparable to those cultured using commercially available 3D cell-culture systems. Both OnGel and Suspension methods are less complicated than the existing 3D cell-culture systems, which is an invaluable advantage for the preparation of cancer spheroids. The NFBC-based 3D cell-culture systems introduced here show great promise as a tool to prepare cultures for cell-derived spheroids for the progress of both in vitro and in vivo studies of the biological functioning of cells.

Pharmacological activation of G protein-coupled receptor 119 (GPR119) produces pleiotropic beneficial effects, including the promotion of insulin secretion from pancreatic β-cells, enhancement of glucagon-like peptide (GLP)-1 secretion from intestinal L cells, glucose-dependent insulin secretion, and food intake and body weight gain suppression. Thus, GPR119 has attracted attention as a promising new target for type 2 diabetes mellitus (T2DM) treatment. Here, we identified a new small GPR119 agonist, NCP-322. This compound showed potent enhancing effects on insulin and GLP-1 secretion, which played a role in pancreatic β-cells and intestinal L cells. In the oral glucose tolerance test, NCP-322 administration reduced glycemic excursions that were only exhibited during hyperglycemia. Furthermore, NCP-322 administration did not induce hypoglycemia, the main side effect of antidiabetic drugs. These results suggest the promising therapeutic potential of NCP-322 for T2DM treatment.

Oxidative stress and neuroinflammation accompanied by microglial activation are increased in Alzheimer’s disease (AD) and contribute to the pathogenesis of AD. Nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a master transcription factor that acts as an endogenous defense mechanism against oxidative stress and inflammation and is a potential target for preventing AD. Psoraleae Semen (PS) reportedly has antioxidant and anti-inflammatory effects. This study aimed to examine the effects of PS extract (PSE) on Nrf2 activation and prevention of cognitive dysfunction in App^NL-P-F AD model mice. The effects of PSE on antioxidant response element (ARE) activity and cytoprotection in PC12 cells and on microglial activation in BV-2 cells were evaluated. PSE showed high ARE activity and prevented 6-hydroxydopamine-induced cytotoxicity in PC12 cells. Moreover, PSE suppressed lipopolysaccharide-induced nitric oxide production in BV-2 cells. Oral administration of PSE prevented cognitive dysfunction in App^NL-P-F mice without affecting motor function. Our results support that PSE can contribute to the development of new preventive and therapeutic agents for AD focusing on Nrf2 activation.

Vitamin D plays a crucial role in immune system function. Several studies have indicated that genetic variations in the vitamin D receptor (VDR) and vitamin D binding protein (VDBP, encoded by GC gene) increase the risk of developing asthma. However, the effect of these variations on the prognosis and clinical outcomes of asthma remains unclear. This study, involving 152 adult patients with asthma, aimed to assess the influence of VDR and GC polymorphisms on asthma severity and its exacerbation. Gene polymorphisms previously associated with asthma risk were analyzed, and VDR mRNA expression levels were evaluated in peripheral blood mononuclear cells. The AA genotype of the VDR rs2228570 polymorphism was associated with an elevated risk of severe asthma compared to the AG/GG genotype (odds ratio, 3.20; 95% confidence interval [CI], 1.24–8.28). Furthermore, patients with the rs2228570 AA genotype showed an elevated risk of exacerbation during the 1-year follow-up period (hazard ratio, 4.01; 95% CI, 1.75–9.15). VDR mRNA expression was significantly reduced in patients with the AA genotype. Furthermore, the mRNA expression levels of GLCCI1, HDAC2, NR3C1, and NFE2L2, which are associated with steroid response, were reduced in patients with the AA genotype. Our findings indicate that patients with the AA genotype of VDR rs2228570 are more likely to experience severe asthma and exacerbations. This polymorphism has the potential to reduce vitamin D efficacy by altering VDR function and expression, potentially resulting in increased inflammation and reduced steroid responsiveness in patients with asthma.