PMID: 

Steroids. 2019 10 ;150:108447. Epub 2019 Jul 11. PMID: 31302113

Abstract Title: 

24R,25-dihydroxyvitamin Dmodulates tumorigenicity in breast cancer in an estrogen receptor-dependent manner.

Abstract: 

Vitamin D has long been prescribed as a supplement to breast cancer patients. This is partially motivated by data indicating that low serum vitamin D, measured as 25-hydroxyvitamin D3 [25(OH)D], is associated with worsened cancer prognosis and decreased survival rates in cancer patients. However, clinical studies investigating the role of vitamin D supplementation in breast cancer treatment are largely inconclusive. One reason for this may be that many of these studies ignore the complexity of the vitamin D metabolome and the effects of these metabolites at the cellular level. Once ingested, vitamin D is metabolized into 37 different metabolites, including 25(OH)D, which is the metabolite actually measured clinically, as well as 1,25(OH)Dand 24,25(OH)D. Recent work by our lab and others has demonstrated a role for 24R,25(OH)D, in the modulation of breast cancer tumors via an estrogen receptorα-dependent mechanism. This review highlights the importance of considering estrogen receptor status in vitamin d-associated prognostic studies of breast cancer and proposes a potential mechanism for 24R,25(OH)Dsignaling in breast cancer cells.

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PMID: 

Int J Mol Med. 2019 Sep ;44(3):1151-1160. Epub 2019 Jul 5. PMID: 31524226

Abstract Title: 

Biologically active 1,25-dihydroxyvitamin D3 protects against experimental sepsis by negatively regulating the Toll-like receptor 4/myeloid differentiation primary response gene 88/Toll-IL-1 resistance

Abstract: 

The hormonally active form of vitamin D (VD), 1,25‑dihydroxyvitamin D3, has been reported to be a key immunoregulator in the reduction of inflammation. In this study, we investigated the effects of VD in an experimental sepsis cell model, and the underlying mechanisms. The sepsis cell model was first established in monocytes, isolated from newborns and healthy adults, which were stimulation with lipopolysaccharide (LPS). We observed that cell viability was significantly impaired in the monocytes after LPS stimulation, using a Cell Counting Kit‑8 and trypan blue assays. Additionally, ELISA revealed that LPS stimulation significantly elevated the expression of interleukin 6 (IL‑6), IL‑10 and tumor necrosis factor‑α (TNF‑α). The expression levels of Toll‑like receptor (TLR4), myeloid differentiation primary response gene 88 (MyD88), and Toll‑IL‑1 resistance‑domain‑containing adapter‑inducing interferon‑β (TRIF)mRNA were also significantly elevated under LPS stimulation using reverse transcription‑quantitative PCR and western blot analysis. VD treatment could significantly suppress the effects of LPS simulation on monocytes by negatively regulating inflammatory cytokines and TLR4/MyD88/TRIF signaling. Furthermore, a regulatory feedback mechanism was proposed to involve TLR4, MyD88 and TRIF in the sepsis cell model. In conclusion, VD may effectively decrease the release of inflammatory cytokines by inhibiting the TLR4/MyD88/TRIF signaling pathway, could be considered as a potential therapeutic agent for the treatment of sepsis.

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PMID: 

Mol Med Rep. 2019 Sep ;20(3):2641-2648. Epub 2019 Jul 25. PMID: 31524258

Abstract Title: 

1,25‑Dihydroxyvitamin D3 enhances the susceptibility of anaplastic thyroid cancer cells to adriamycin‑induced apoptosis by increasing the generation of reactive oxygen species.

Abstract: 

Anaplastic thyroid cancer (ATC) is a very aggressive malignancy that is resistant to various types of chemotherapy in humans. Most patients with late‑stage ATC cannot undergo surgery and receive chemotherapy drugs. The present study investigated the influence of 1,25‑dihydroxyvitamin D3 (1,25(OH)2D3) pretreatment on adriamycin (ADM) chemotherapy efficacy in the 8305c and 8505c ATC cell lines. The apoptotic effects of ADM on ATC cells pretreated with 1,25(OH)2D3 were evaluated. Cell viability was identified by using the Cell Counting Kit‑8 assay. Apoptosis was assessed by flow cytometry and staining with Hoechst 33342. The expression of the apoptotic protein cleaved caspase‑3 was tested with a colorimetric assay kit and by westernblotting. Reactive oxygen species (ROS) generation was assessed with the antioxidant N‑acetyl‑L‑cysteine (NAC) and the assay H2‑DCFDA. In addition, ROS production could be reversed by NAC treatment. The present study demonstrated that 1,25(OH)2D3 enhanced ADM‑induced apoptosis in 8305c and8505c cell lines. Furthermore, 1,25(OH)2D3 improved the ADM‑induced ROS production and expression of cleaved caspase‑3. NAC treatment inhibited the expression of cleaved caspase‑3 in ATC cells, and reduced apoptosis in cells that were pretreated with 1,25(OH)2D3 and ADM. These results demonstrated that 1,25(OH)2D3 may enhance ADM‑induced apoptosis by increasing ROS generation in ATC cells.

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PMID: 

J Neuroimmunol. 2020 Jan 15 ;338:577079. Epub 2019 Oct 31. PMID: 31731230

Abstract Title: 

The change of PD1, PDL1 in experimental autoimmune encephalomyelitis treated by 1,25(OH)D.

Abstract: 

Experimental autoimmune encephalomyelitis (EAE) is a common animal model that has the same pathology and pathogenesis as multiple sclerosis (MS). Dendritic cells (DCs) exert an important role in central and peripheral tolerance. DCs not only drive T cell priming and differentiation via playing antigen presentation function but mediate the resolution of advancing immune responses with its tolerogenic effect. In this study, we employed 1,25-dihydroxyvitamin D3 (1,25(OH)D) to induce tolerogenic dendritic cells (VD3-DCs) revealing their therapeutic effect through an increase in the development of the negative regulatory signaling pathway programmed death 1 (PD1)/programmed death ligand 1 (PDL1).

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PMID: 

J Steroid Biochem Mol Biol. 2020 Apr ;198:105557. Epub 2019 Nov 26. PMID: 31783150

Abstract Title: 

1α, 25 Dihydroxyvitamin D (1,25(OH)D) inhibits the T cell suppressive function of myeloid derived suppressor cells (MDSC).

Abstract: 

Myeloid derived suppressor cells (MDSC) suppress the ability of cytotoxic T cells to attack and clear tumor cells from the body. The active form of vitamin D, 1,25 dihydroxyvitamin D (1,25(OH)D), regulates myeloid cell biology and previous research showed that in mouse models 1,25(OH)D reduced the tumor level of CD34+ cells, an MDSC precursor, and reduced metastasis. We tested whether MDSC are vitamin D target cells by examining granulocytic- (G-MDSC) and monocytic (M-MDSC) MDSC from tumors, spleen, and bone marrow. Vitamin D receptor (VDR) mRNA levels are low in MDSC from bone marrow and spleen but are 20-fold higher in tumor MDSC. At all sites, M-MDSC have 4-fold higher VDR mRNA expression than G-MDSC. Bone marrow MDSC were induced to differentiate in vitro into tumor MDSC-like cells by treating with IFN-γ, IL-13, and GM-CSF for 48 h. This treatment significantly elevated Arg1 and Nos2 levels, activated the T cell-suppressive function of MDSC, increased VDR expression 50-fold, and made the MDSC responsive to 1,25(OH)D treatment. Importantly, 1,25(OH)D treatment reduced the T cell suppressive capacity of cytokine-induced total MDSC and M-MDSC by≥70 % and tumor-derived M-MDSC by 30-50 %. Consistent with this finding, VDR deletion (KO) increased T cell suppressive function of in vitro M-MDSC by 30 % and of tumor-derived M-MDSC by 50 % and G-MDSC by 400 %. VDR KO did not alter Nos2 mRNA levels but significantly increased Arg1 mRNA levels intumor M-MDSC by 100 %. In contrast, 1,25(OH)D treatment reduced nitric oxide production in both in vitro derived M- and G- MDSC. The major finding of this study is that 1,25(OH)D signaling through the VDR decreases the immunosuppressive capability of MDSC. Collectively, our data suggest that activation of vitamin D signaling could be used to suppress MDSC function and release a constraint on T-cell mediated clearance of tumor cells.

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PMID: 

Aging Cell. 2020 02 ;19(2):e13095. Epub 2019 Dec 26. PMID: 31880094

Abstract Title: 

1,25-Dihydroxyvitamin D protects against age-related osteoporosis by a novel VDR-Ezh2-p16 signal axis.

Abstract: 

To determine whether 1,25-dihydroxyvitamin D (1,25(OH)D) can exert an anti-osteoporosis role through anti-aging mechanisms, we analyzed the bone phenotype of mice with 1,25(OH)D deficiency due to deletion of the enzyme, 25-hydroxyvitamin D 1α-hydroxylase, while on a rescue diet. 1,25(OH)D deficiency accelerated age-related bone loss by activating the p16/p19 senescence signaling pathway, inhibiting osteoblastic bone formation, and stimulating osteoclastic bone resorption, osteocyte senescence, and senescence-associated secretory phenotype (SASP). Supplementation of exogenous 1,25(OH)Dcorrected the osteoporotic phenotype caused by 1,25(OH)D deficiency or natural aging by inhibiting the p16/p19 pathway. The proliferation, osteogenic differentiation, and ectopic bone formation of bone marrow mesenchymal stem cells derived from mice with genetically induced deficiency of the vitamin D receptor (VDR) were significantly reduced by mechanisms including increased oxidative stress, DNA damage, and cellular senescence. We also demonstrated that p16 deletion largely rescued the osteoporotic phenotype caused by 1,25(OH)Ddeficiency, whereas 1,25(OH)Dcould up-regulate the enzyme Ezh2 via VDR-mediated transcription thereby enriching H3K27me3 and repressing p16/p19 transcription. Finally, we demonstrated that treatment with 1,25(OH)Dimproved the osteogenic defects of human BM-MSCs caused by repeated passages by stimulating their proliferation and inhibiting their senescence via the VDR-Ezh2-p16 axis. The results of this study therefore indicate that 1,25(OH)Dplays a role in preventing age-related osteoporosis by up-regulating Ezh2 via VDR-mediated transcription, increasing H3K27me3 and repressing p16 transcription, thus promoting the proliferation and osteogenesis of BM-MSCs and inhibiting their senescence, while also stimulating osteoblastic bone formation, and inhibiting osteocyte senescence, SASP, and osteoclastic bone resorption.

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PMID: 

Am J Transl Res. 2020 ;12(2):507-518. Epub 2020 Feb 15. PMID: 32194899

Abstract Title: 

1,25-Dihydroxyvitamin D insufficiency accelerates age-related bone loss by increasing oxidative stress and cell senescence.

Abstract: 

We investigated the role of insufficiency of the active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)D] in age-related bone loss. We employed mice with heterozygous deletion of, the gene encoding the enzyme that synthesizes 1,25(OH)D, as a model for 1,25(OH)D insufficiency and compared the phenotype of lumber vertebrae from 3-, 9- and 18-month-oldmice and their wild-type littermates. We found that in wild-type mice, bone mineral density, bone volume, andprotein expression levels decreased progressively with age, accompanied by declining osteoblastic bone formation and increasing osteoclastic bone resorption, however these age-related skeletal alterations were more severe inmice which had significantly lower serum 1,25(OH)D levels. We then assessed the effect of 1,25(OH)D haploinsufficiency on oxidative stress and DNA damage, cell senescence and senescence-associated secretory phenotype (SASP) in 9-month-old wild-type andmice. Our results demonstrated that, inmice compared with their wild-type littermates, the parameters of oxidative stress and DNA damage were significantly increased, whereas the expression levels of antioxidant enzymes were significantly down-regulated; the percentage of senescent osteocytes and bone marrow mesenchymal stem cells, and the expression levels of SASP molecules and p16, p19 and p53 proteins were all significantly increased in bone tissues. Taken together, the results of this study indicate that 1,25(OH)D insufficiency accelerates age-related bone loss by increasing oxidative stress and DNA damage, inducing bone cell senescence and SASP, and subsequently inhibiting osteoblastic bone formation while stimulating osteoclastic bone resorption.

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PMID: 

Sci Rep. 2020 Apr 16 ;10(1):6550. Epub 2020 Apr 16. PMID: 32300237

Abstract Title: 

Vitamin C supports conversion of humanγδ T cells into FOXP3-expressing regulatory cells by epigenetic regulation.

Abstract: 

Humanγδ T cells are potent cytotoxic effector cells, produce a variety of cytokines, and can acquire regulatory activity. Induction of FOXP3, the key transcription factor of regulatory T cells (Treg), by TGF-β in human Vγ9 Vδ2 T cells has been previously reported. Vitamin C is an antioxidant andacts as multiplier of DNA hydroxymethylation. Here we have investigated the effect of the more stable phospho-modified Vitamin C (pVC) on TGF-β-induced FOXP3 expression and the resulting regulatory activity of highly purified human Vγ9 Vδ2 T cells. pVC significantly increased the TGF-β-induced FOXP3 expression and stability and also increased the suppressive activity of Vγ9 Vδ2 T cells. Importantly, pVC induced hypomethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 gene. Genome-wide methylation analysis by Reduced Representation Bisulfite Sequencing additionally revealed differentially methylated regions in several important genes upon pVC treatment of γδ T cells. While Vitamin C also enhances effector functions of Vγ9 Vδ2 T cells in the absence of TGF-β, our results demonstrate that pVC potently increases the suppressive activity and FOXP3 expression in TGF-β-treated Vγ9 Vδ2 T cells by epigenetic modification of the FOXP3 gene.

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PMID: 

Ir J Med Sci. 2020 Apr 1. Epub 2020 Apr 1. PMID: 32239424

Abstract Title: 

Therapeutic effect of N-acetylcysteine on chemotherapy-induced liver injury.

Abstract: 

BACKGROUND: N-acetylcysteine (NAC) may be useful in the management of chemotherapy-induced liver injury.AIMS: The present study evaluates the possible therapeutic effects of NAC on chemotherapy-induced hepatotoxicity.METHODS: A total of 102 patients' files who were diagnosed with cancer between 2015 and 2019 were evaluated retrospectively. Two patient groups with and without NAC were selected. NAC was administered in a 3-μg/kg IV dose in a 24-h infusion to 70 patients when any alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) values reached three times the normal levels. The other group consisted of 32 patients who were not treated with NAC. Alanine aminotransferase and GGT values were recorded atpretreatment, and on the 1st, 3rd, 5th, and 7th days in both the NAC and non-NAC groups from files.RESULTS: In the NAC group, ALT and GGT values on day 1, 3, 5, and 7 differed from each other, decreasing from day 1 to day 7. A statistically significant difference was noted between the values in the NAC group (p 

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PMID: 

Front Pharmacol. 2019 ;10:1281. Epub 2019 Nov 1. PMID: 31736758

Abstract Title: 

Safranal Alleviates Dextran Sulfate Sodium-Induced Colitis and Suppresses Macrophage-Mediated Inflammation.

Abstract: 

(saffron) is widely used in China, Iran, and India for dyeing and as a food additive and medicinal plant. Safranal, as one of the main constituents of saffron, is responsible for its aroma and has been reported to have anticancer, antioxidant, and anti-inflammation properties.In this study, we investigated the anti-inflammatory effects of Safranal in RAW264.7 cells, bone marrow-derived macrophages (BMDMs), and dextran sulfate sodium (DSS)-induced colitis mice.Safranal toxicity was determined using an MTT assay. We evaluated the inhibitory effect of nitric oxide (NO) and levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 cells and BMDMs. We assessed the inhibitory effect of pro-inflammatory cytokines, and the mRNA expressions of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), classical inflammatory pathways (MAPK and NF-κB), and the nuclear translocation factors AP-1 and NF-κB p65 were investigated. Theanti-inflammatory effects of Safranal were assessed in a DSS-induced colitis model. DSS3.5% was used to induce colitis in mice with or without Safranal for 7 days; weight and disease activity index (DAI) were recorded daily. At the end of the experiment, the colon, mesenteric lymph nodes (MLNs), and spleen were collected for flow cytometry, ELISA, and Western blot analysis.Safranal suppressed NO production, iNOS, and COX-2 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and BMDMs. Safranal decreased the production and mRNA expression of IL-6 and TNF-α in the RAW264.7 cell line and inhibited the phosphorylation and nuclear translocation of components of the MAPK and NF-κB pathways. Safranal alleviated clinical symptoms in the DSS-induced colitis model, and colon histology showed decreased severity of inflammation, depth of inflammatory involvement, and crypt damage. Immunohistochemical staining and flow cytometry showed reduced macrophage infiltration in colonic tissues and macrophage numbers in MLNs and the spleen. The levels of colonic IL-6 and TNF-α also decreased in Safranal-treated colitis mice. This study elucidates the anti-inflammation activity of Safranal, which may be a candidate for inflammatory bowel syndrome (IBD) therapy.

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