greenmedinfo--2020-04-25--Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts.

1,25-Dihydroxyvitamin D ( 3 ) ( 1,25 ( OH ) ( 2 ) D ( 3 ) ) , the biologically active metabolite of Vitamin D ( 3 ) , not only regulates bone and calcium metabolism but also exerts other biological activities , including immunomodulation via the nuclear Vitamin D receptor expressed in antigen-presenting cells and activated T cells .
This regulation is mediated through interference with nuclear transcription factors such as NF-AT and NF-kappaB or by direct interaction with Vitamin D responsive elements in the promoter regions of cytokine genes .
Dendritic cells ( DCs ) are primary @ @ @ @ @ @ @ ( OH ) ( 2 ) D ( 3 ) , as indicated by inhibited DC differentiation and maturation , leading to down-regulated expression of MHC-II , costimulatory molecules and IL-12 .
Moreover , 1,25 ( OH ) ( 2 ) D ( 3 ) enhances IL-10 production and promotes DC apoptosis .
Together , these effects of 1,25 ( OH ) ( 2 ) D ( 3 ) inhibit DC-dependent T cell activation .
Immunomodulation by 1,25 ( OH ) ( 2 ) D ( 3 ) and its analogs in vivo @ @ @ @ @ @ @ autoimmune diseases and transplantation .
Moreover , combining analogs with other immunosuppressants leads to synergism in models of autoimmunity and transplantation .
The availability of 1,25 ( OH ) ( 2 ) D ( 3 ) analogs with immunomodulatory activity at non-hypercalcemic doses may allow exploitation of their immunomodulatory effects in a clinical setting of treatment of autoimmune diseases and prevention of allograft rejection .

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the biologically active metabolite of Vitamin D(3), not only regulates bone and calcium metabolism but also exerts other biological activities, including immunomodulation via the nuclear Vitamin D receptor expressed in antigen-presenting cells and activated T cells. This regulation is mediated through interference with nuclear transcription factors such as NF-AT and NF-kappaB or by direct interaction with Vitamin D responsive elements in the promoter regions of cytokine genes. Dendritic cells (DCs) are primary targets for the immunomodulatory activity of 1,25(OH)(2)D(3), as indicated by inhibited DC differentiation and maturation, leading to down-regulated expression of MHC-II, costimulatory molecules and IL-12. Moreover, 1,25(OH)(2)D(3) enhances IL-10 production and promotes DC apoptosis. Together, these effects of 1,25(OH)(2)D(3) inhibit DC-dependent T cell activation. Immunomodulation by 1,25(OH)(2)D(3) and its analogs in vivo has been demonstrated in different models of autoimmune diseases and transplantation. Moreover, combining analogs with other immunosuppressants leads to synergism in models of autoimmunity and transplantation. The availability of 1,25(OH)(2)D(3) analogs with immunomodulatory activity at non-hypercalcemic doses may allow exploitation of their immunomodulatory effects in a clinical setting of treatment of autoimmune diseases and prevention of allograft rejection.


greenmedinfo--2020-04-25--24R,25-dihydroxyvitamin D3 modulates tumorigenicity in breast cancer in an estrogen receptor-depende

24R,25-dihydroxyvitamin D3 modulates tumorigenicity in breast cancer in an estrogen receptor-dependent manner.

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 @ @ @ @ @ @ @ 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 @ @ @ @ @ @ @

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.


greenmedinfo--2020-04-25--Biologically active 1,25-dihydroxyvitamin D3 protects against experimental sepsis.

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 @ @ @ @ @ @ @ 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 @ @ @ @ @ @ @ 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 .

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.


greenmedinfo--2020-04-25--These results demonstrated that 1,25(OH)2D3 may enhance adriamycin-induced apoptosis.

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 can not 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 @ @ @ @ @ @ @ 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 .
@ @ @ @ @ @ @ 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 .

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.


greenmedinfo--2020-04-25--The change of PD1, PDL1 in experimental autoimmune encephalomyelitis treated by 1,25(OH)2D3

Experimental autoimmune encephalomyelitis ( EAE ) is a common animal model that has the same pathology and pathogenesis as multiple @ @ @ @ @ Dendritic cells ( DCs ) exert an important role in central and peripheral tolerance .
@ @ @ @ @ cell priming and differentiation via playing antigen presentation function but mediate the resolution of advancing @ @ @ @ @ effect .
In this study , we employed 1,25-dihydroxyvitamin D3 ( 1,25 ( OH ) @ @ @ @ @ dendritic cells ( VD3-DCs ) revealing their therapeutic effect through an increase in the development @ @ @ @ @ pathway programmed death 1 ( PD1 ) /programmed death ligand 1 ( PDL1 ) .

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).


greenmedinfo--2020-04-25--1α, 25 Dihydroxyvitamin D (1,25(OH)2D) inhibits the T cell suppressive function of myeloid derived s

1α, 25 Dihydroxyvitamin D (1,25(OH)2D) inhibits the T cell suppressive function of myeloid derived suppressor cells (MDSC).

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 @ @ @ @ @ @ @ 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 @ @ @ @ @ @ @ ( 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 @ @ @ @ @ @ @ 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 .

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.


greenmedinfo--2020-04-25--1,25-Dihydroxyvitamin D protects against age-related osteoporosis by a novel VDR-Ezh2-p16 signal axi

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

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 @ @ @ @ @ @ @ 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 @ @ @ @ @ @ @ .
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 @ @ @ @ @ @ @ .

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.


greenmedinfo--2020-04-25--1,25-Dihydroxyvitamin D insufficiency accelerates age-related bone loss by increasing oxidative stre

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

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 @ @ @ @ @ @ @ 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 ; @ @ @ @ @ @ @ 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 .

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.


greenmedinfo--2020-04-25--Vitamin C supports conversion of human γδ T cells into FOXP3-expressing regulatory cells by epigenet

Vitamin C supports conversion of human γδ T cells into FOXP3-expressing regulatory cells by epigenetic regulation

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 @ @ @ @ @ @ @ 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 @ @ @ @ @

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.


greenmedinfo--2020-04-25--NAC has a therapeutic effect on hepatotoxicity in children being treated with chemotherapeutic agent

NAC has a therapeutic effect on hepatotoxicity in children being treated with chemotherapeutic agents.

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 @ @ @ @ @ @ @ 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 CONCLUSIONS : This study shows @ @ @ @ @ @ @ hepatotoxicity in children being treated with chemotherapeutic agents due to underlying malign diseases .
The early reduction in the results of liver function tests is important for the continuation of chemotherapy .

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 < 0.001). In the non-NAC group, the ALT values on day 7 were lower than the ALT values on day 1. A comparison of the ALT and GGT values in the NAC and non-NAC groups found that the values in the NAC group decreased earlier than in the non-NAC group.
CONCLUSIONS: This study shows that NAC has a therapeutic effect on hepatotoxicity in children being treated with chemotherapeutic agents due to underlying malign diseases. The early reduction in the results of liver function tests is important for the continuation of chemotherapy.


greenmedinfo--2020-04-25--Safranal alleviates dextran sulfate sodium-induced colitis and suppresses macrophage-mediated inflam

Safranal alleviates dextran sulfate sodium-induced colitis and suppresses macrophage-mediated inflammation.

( 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 @ @ @ @ @ @ @ 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 @ @ @ @ @ @ @ 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 @ @ @ @ @ @ @ 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 .

(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.


greenmedinfo--2020-04-25--Saffron could be considered as an alternative to synthetic antidepressants in the treatment of mild

BACKGROUND : Herbal remedies are becoming increasingly popular for the treatment of depression .
Recently , accumulating evidences reveal a positive effect of saffron ( Crocus sativus L. ) in relieving depressive symptoms .
The objective of this meta-analysis was to assess the safety and efficacy of saffron in treating mild to moderate depression by synthesizing all available data .
MATERIALS AND METHODS : Relevant studies were retrieved from electronic databases and cross-checking of reference lists .
Eligible trials were carefully reviewed , and necessary data were extracted .
The Hamilton Rating Scale for Depression or Beck Depression Inventory scores @ @ @ @ @ @ @ and adverse effects were compared between saffron and placebo or saffron and antidepressants to assess the efficacy of saffron for depression .
RESULTS : Twelve studies were included in the meta-analysis .
Overall results showed that saffron possessed better efficacy in the improvement of depressive symptoms when compared with placebo , whereas saffron was as effective as synthetic antidepressants .
No significant difference was detected in the incidence of adverse effects between saffron and placebo or between saffron and antidepressants .
CONCLUSIONS : Saffron could be considered as an alternative to synthetic antidepressants @ @ @ @ @ @ @ depression .
However , multicenter trials with larger sample size , longer treatment duration , and different ethnic groups are required to verify our results .

BACKGROUND: Herbal remedies are becoming increasingly popular for the treatment of depression. Recently, accumulating evidences reveal a positive effect of saffron (Crocus sativus L.) in relieving depressive symptoms. The objective of this meta-analysis was to assess the safety and efficacy of saffron in treating mild to moderate depression by synthesizing all available data.
MATERIALS AND METHODS: Relevant studies were retrieved from electronic databases and cross-checking of reference lists. Eligible trials were carefully reviewed, and necessary data were extracted. The Hamilton Rating Scale for Depression or Beck Depression Inventory scores, response rate, remission rate, and adverse effects were compared between saffron and placebo or saffron and antidepressants to assess the efficacy of saffron for depression.
RESULTS: Twelve studies were included in the meta-analysis. Overall results showed that saffron possessed better efficacy in the improvement of depressive symptoms when compared with placebo, whereas saffron was as effective as synthetic antidepressants. No significant difference was detected in the incidence of adverse effects between saffron and placebo or between saffron and antidepressants.
CONCLUSIONS: Saffron could be considered as an alternative to synthetic antidepressants in the treatment of mild to moderate depression. However, multicenter trials with larger sample size, longer treatment duration, and different ethnic groups are required to verify our results.


greenmedinfo--2020-04-25--Safranal is thought to be used as an effective combination in controlling metabolic complications ca

Safranal is thought to be used as an effective combination in controlling metabolic complications caused by olanzapine.

Objectives : Olanzapine , an atypical antipsychotic , causes weight gain and metabolic disorders in humans .
Safranal , one of the active components of ( saffron ) , has been shown to have anti-obesity , lipid and blood pressure lowering and anti-diabetes effects .
In this investigation , the effect of safranal on metabolic disorders induced by olanzapine was studied .
Materials and Methods : Fourty-two female Wistar rats were divided into 7 groups of 6 animals .
The two groups were selected as controls , which received olanzapine and safranal solvents , respectively .
The third group treated @ @ @ @ @ @ @ , 5 and 6 treated by olanzapine 5 mg/kg plus safranal ( 2.5 , 5 and 10 mg/kg ) and the last group received safranal 10 mg/kg .
The injections were performed intraperitoneally for 14 days and on the 15day the rats were killed and their serum were collected to measure metabolic factors including glucose , insulin , triglyceride , total cholesterol and HDL cholesterol .
Leptin level in plasma was also measured .
Mean systolic blood pressure was measured using tail cuff method at the end of study .
The rats were @ @ @ @ @ @ @ food consumed was measured daily .
Results : Olanzapine significantly elevated body weight , food intake , fasting blood glucose , TG , leptin , and mean systolic blood pressure ( MSBP ) .
It also significantly decreased HDL cholesterol blood level .
Safranal significantly improved all these complications at three doses .
Conclusion : Based on the results of this study , safranal is thought to be used as an effective combination in controlling metabolic complications caused by olanzapine .

Objectives: Olanzapine, an atypical antipsychotic, causes weight gain and metabolic disorders in humans. Safranal, one of the active components of(saffron), has been shown to have anti-obesity, lipid and blood pressure lowering and anti-diabetes effects. In this investigation, the effect of safranal on metabolic disorders induced by olanzapine was studied.
Materials and Methods: Fourty-two female Wistar rats were divided into 7 groups of 6 animals. The two groups were selected as controls, which received olanzapine and safranal solvents, respectively. The third group treated by olanzapine 5 mg/kg. Groups 4, 5 and 6 treated by olanzapine 5 mg/kg plus safranal (2.5, 5 and 10 mg/kg) and the last group received safranal 10 mg/kg. The injections were performed intraperitoneally for 14 days and on the 15day the rats were killed and their serum were collected to measure metabolic factors including glucose, insulin, triglyceride, total cholesterol and HDL cholesterol. Leptin level in plasma was also measured. Mean systolic blood pressure was measured using tail cuff method at the end of study. The rats were weighed every other day and amount of food consumed was measured daily.
Results: Olanzapine significantly elevated body weight, food intake, fasting blood glucose, TG, leptin, and mean systolic blood pressure (MSBP). It also significantly decreased HDL cholesterol blood level. Safranal significantly improved all these complications at three doses.
Conclusion: Based on the results of this study, safranal is thought to be used as an effective combination in controlling metabolic complications caused by olanzapine.


greenmedinfo--2020-04-25--N-Acetylcysteine and Safranal prevented the brain damage induced by hyperthyroidism.

Hyperthyroidism is associated with impairment in the neurotransmission and severe tissue damage in the brain .
The present study explored the potential deleterious effects of experimentally-induced hyperthyroidism on the neurotransmitters , oxidative homeostasis , apoptosis and DNA fragmentation in cerebral cortex , thalamus & hypothalamus , and hippocampus in rats.The ameliorative effects of N-acetylcysteine ( NAC ; 50 mg/kg , oral ) and safranal ( 50 mg/kg , intraperitoneal ) against hyperthyroidism ( L-T4 500µg/kg , subcutaneous ) were investigated .
All treatments continued daily over three weeks .
Hyperthyroidism was manifested by significant elevations in serum fT3 and fT4 @ @ @ @ @ @ @ level and body weight .
It was also characterized by significant elevations in the levels of dopamine , serotonin , and 5-hydroxyindole acetic acid , and monoamine oxidase activity to varying degrees in the brain regions examined and a significant reduction in norepinephrine in hippocampus only .
Hyperthyroidism resulted in a significant oxidative stress in brain typified by elevations in malondialdehyde and nitric oxide content and reductions in glutathione level and SOD and catalase activities .
This led to elevations in Caspases 9 and 3 and a reduction in Bcl2 resulting in DNA @ @ @ @ @ @ @ brain tissue .
The administration of NAC or safranal with L-T4 preventedthese deleterious effects by reducing the oxidative load and improving the brain antioxidant status.Hyperthyroidism disrupted the neurotransmitters in the brain which aggravated the oxidative stress and resulted in apoptosis .
N-Acetylcysteine and safranal prevented these deleterious effects by enhancing the poor antioxidant milieu of the brain .

Hyperthyroidism is associated with impairment in the neurotransmission and severe tissue damage in the brain. The present study explored the potential deleterious effects of experimentally-induced hyperthyroidism on the neurotransmitters, oxidative homeostasis, apoptosis and DNA fragmentation in cerebral cortex, thalamus&hypothalamus, and hippocampus in rats.The ameliorative effects of N-acetylcysteine (NAC; 50 mg/kg, oral) and safranal (50 mg/kg, intraperitoneal) against hyperthyroidism (L-T4 500µg/kg, subcutaneous) were investigated. All treatments continued daily over three weeks. Hyperthyroidism was manifested by significant elevations in serum fT3 and fT4 levels and a decline in serum TSH level and body weight. It was also characterized by significant elevations in the levels of dopamine, serotonin, and 5-hydroxyindole acetic acid, and monoamine oxidase activity to varying degrees in the brain regions examined and a significant reduction in norepinephrine in hippocampus only. Hyperthyroidism resulted in a significant oxidative stress in brain typified by elevations in malondialdehyde and nitric oxide content and reductions in glutathione level and SOD and catalase activities. This led to elevations in Caspases 9 and 3 and a reduction in Bcl2 resulting in DNA damage and confirmed by the histopathology of brain tissue. The administration of NAC or safranal with L-T4 preventedthese deleterious effects by reducing the oxidative load and improving the brain antioxidant status.Hyperthyroidism disrupted the neurotransmitters in the brain which aggravated the oxidative stress and resulted in apoptosis. N-Acetylcysteine and safranal prevented these deleterious effects by enhancing the poor antioxidant milieu of the brain.


greenmedinfo--2020-04-25--Suppression effect of N-acetylcysteine on bone loss in ovariectomized mice.

Oxidative stress can trigger DNA damage response and activation of cellular senescence .
Accumulating studies have demonstrated that senescent cells @ @ @ @ @ that leads to increased bone resorption and decreased bone formation .
And elimination of senescent @ @ @ @ @ secretion has been shown to prevent bone loss in mice .
N-acetylcysteine ( NAC ) @ @ @ @ @ However , it is unclear whether reversed estrogen deficiency-induced bone loss by antioxidant NAC was @ @ @ @ @ oxidative stress , DNA damage , osteocyte senescence and SASP .
In this study , @ @ @ @ @ E2 or NAC , and were compared with each other .
Our results showed that @ @ @ @ @ , osteocyte senescence and the secretion of senescence-associated inflammatory cytokines were increased in OVX mice @ @ @ @ @ However , these parameters were obviously rescued in OVX mice supplemented with E2 or NAC @ @ @ @ @ suggest that NAC can prevent OVX-induced bone loss by inhibiting oxidative stress , DNA damage @ @ @ @ @ secretion of the senescence-associated secretory phenotype .

Oxidative stress can trigger DNA damage response and activation of cellular senescence. Accumulating studies have demonstrated that senescent cells can produce senescence-associated secretory phenotype that leads to increased bone resorption and decreased bone formation. And elimination of senescent cells or inhibition of SASP secretion has been shown to prevent bone loss in mice. N-acetylcysteine (NAC) is a strong antioxidant. However, it is unclear whether reversed estrogen deficiency-induced bone loss by antioxidant NAC was associated with the inhibition of oxidative stress, DNA damage, osteocyte senescence and SASP. In this study, OVX mice were supplemented with/without E2 or NAC, and were compared with each other. Our results showed that oxidative stress, DNA damage, osteocyte senescence and the secretion of senescence-associated inflammatory cytokines were increased in OVX mice compared with sham-operated mice. However, these parameters were obviously rescued in OVX mice supplemented with E2 or NAC. Data from this study suggest that NAC can prevent OVX-induced bone loss by inhibiting oxidative stress, DNA damage, cell senescence and the secretion of the senescence-associated secretory phenotype.


greenmedinfo--2020-04-25--Tanshinone IIA alleviates hypoxia/reoxygenation induced cardiomyocyte injury via lncRNA AK003290/miR

Tanshinone IIA alleviates hypoxia/reoxygenation induced cardiomyocyte injury via lncRNA AK003290/miR-124-5p signaling.

BACKGROUND : Acute myocardial infarction ( AMI ) is the leading cause of death globally and has thus placed a @ @ @ @ @ Tanshinone IIA ( TSA ) is a major active compound , extracted from Salvia miltiorrhiza @ @ @ @ @ pharmacological activities .
The aim of the present study was to investigate the role of @ @ @ @ @ underlying mechanism of action .
RESULTS : We have shown that TSA decreased the apoptosis @ @ @ @ @ LDH , MDA as well as ROS of cardiomyocytes .
Meantime , it elevated mitochondrial @ @ @ @ @ which was decreased by H/R treatment .
It was also determined that miR-124-5p targets AK003290 @ @ @ @ @ expression of AK003290 and its function can be reversed by knock down of AK003290 as @ @ @ @ @ CONCLUSION : TSA exerts the protective role against H/R induced apoptosis , oxidative and MMP @ @ @ @ @ AK003290 and miR-124-5p signaling .

BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of death globally and has thus placed a heavy burden on healthcare. Tanshinone IIA (TSA) is a major active compound, extracted from Salvia miltiorrhiza Bunge, that possesses various pharmacological activities. The aim of the present study was to investigate the role of TSA in AMI and its underlying mechanism of action.
RESULTS: We have shown that TSA decreased the apoptosis rate, the amount of LDH, MDA as well as ROS of cardiomyocytes. Meantime, it elevated mitochondrial membrane potential (MMP) which was decreased by H/R treatment. It was also determined that miR-124-5p targets AK003290 directly. TSA up-regulated the expression of AK003290 and its function can be reversed by knock down of AK003290 as well as miR-124-5p overexpression.
CONCLUSION: TSA exerts the protective role against H/R induced apoptosis, oxidative and MMP loss of cardiomyocytes via regulating AK003290 and miR-124-5p signaling.


greenmedinfo--2020-04-24--Tanshinone II A enhances pyroptosis and represses cell proliferation of HeLa cells.

Cervical cancer is the fourth most common cancer in women globally .
Lack of effective pharmacotherapies for cervical cancer mainly attributed to an elusive understanding of the mechanism underlying its pathogenesis .
Pyroptosis plays a key role in inflammation and cancer .
Our study identified microRNA ( miR ) 145 ( miR-145 ) /gasdermin D ( GSDMD ) signaling pathway as critical mediators in the effect of tanshinone II A on HeLa cells .
In the present study , we found that treatment of tanshinone II A led to an obvious repression of cell proliferation and an increase in apoptosis @ @ @ @ @ @ @ concentration .
Compared with the controlled group , tanshinone II A enhanced the activity of caspase3 and caspase9 .
Notably , the results demonstrated that tanshinone II A regulated cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway .
Treatment of tanshinone II A significantly up-regulated the expression of GSDMD and miR-145 .
After transfection of si-miR-145 plasmids , the effects of tanshinone II A on HeLa cells were converted , including cell proliferation , apoptosis and pyroptosis .
In addition , the results showed that tanshinone II A treatment altered the @ @ @ @ @ @ @ NF-kB p65 and Lc3-I .
Collectively , our findings demonstrate that tanshinone II A exerts anticancer activity on HeLa cells by regulating miR-145/GSDMD signaling .
The present study is the first time to identify miR-145 as a candidate target in cervical cancer and show an association between miR-145 and pyroptosis , which provides a novel therapy for the treatment of cervical cancer .

Cervical cancer is the fourth most common cancer in women globally. Lack of effective pharmacotherapies for cervical cancer mainly attributed to an elusive understanding of the mechanism underlying its pathogenesis. Pyroptosis plays a key role in inflammation and cancer. Our study identified microRNA (miR) 145 (miR-145)/gasdermin D (GSDMD) signaling pathway as critical mediators in the effect of tanshinone II A on HeLa cells. In the present study, we found that treatment of tanshinone II A led to an obvious repression of cell proliferation and an increase in apoptosis on HeLa cells, especially in high concentration. Compared with the controlled group, tanshinone II A enhanced the activity of caspase3 and caspase9. Notably, the results demonstrated that tanshinone II A regulated cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway. Treatment of tanshinone II A significantly up-regulated the expression of GSDMD and miR-145. After transfection of si-miR-145 plasmids, the effects of tanshinone II A on HeLa cells were converted, including cell proliferation, apoptosis and pyroptosis. In addition, the results showed that tanshinone II A treatment altered the expression level of PI3K, p-Akt, NF-kB p65 and Lc3-I. Collectively, our findings demonstrate that tanshinone II A exerts anticancer activity on HeLa cells by regulating miR-145/GSDMD signaling. The present study is the first time to identify miR-145 as a candidate target in cervical cancer and show an association between miR-145 and pyroptosis, which provides a novel therapy for the treatment of cervical cancer.


greenmedinfo--2020-04-24--Tanshinone IIA reduces secretion of pro‑angiogenic factors and inhibits angiogenesis in human colore

Tanshinone IIA reduces secretion of pro‑angiogenic factors and inhibits angiogenesis in human colorectal cancer.

Tumor angiogenesis is an important factor which precipitates recurrence and metastasis of colorectal cancer ( CRC ) .
Angiogenesis is also a significant feature which accompanies invasion and metastasis of CRC .
Tumor hypoxia activates hypoxia inducible factor ( HIF ) , which promotes angiogenesis in CRC .
HIF significantly promotes cell proliferation and angiogenesis in CRC , facilitating invasion and metastasis .
Tanshinone IIA ( Tan IIA ) has been revealed to effectively inhibit angiogenesis in CRC , although the underlying mechanism remains to be determined .
The aim of the present study was to determine the effects of @ @ @ @ @ @ @ cells , the effects of Tan IIA on the expression of pro‑angiogenic factors in CRC cells , and on human umbilical vein endothelial cell ( HUVEC ) tube formation in normal and hypoxic conditions .
The results of the present study revealed that Tan IIA not only decreased HIF‑1α expression and inhibited the secretion level of vascular endothelial growth factor and basic fibroblast growth factor , but also efficiently decreased proliferation , tube formation and metastasis of HUVECs .
The results highlight the potential of Tan IIA‑mediated targeting of HIF‑1α as a potential @ @ @ @ @ @ @ CRC .

Tumor angiogenesis is an important factor which precipitates recurrence and metastasis of colorectal cancer (CRC). Angiogenesis is also a significant feature which accompanies invasion and metastasis of CRC. Tumor hypoxia activates hypoxia inducible factor (HIF), which promotes angiogenesis in CRC. HIF significantly promotes cell proliferation and angiogenesis in CRC, facilitating invasion and metastasis. Tanshinone IIA (Tan IIA) has been revealed to effectively inhibit angiogenesis in CRC, although the underlying mechanism remains to be determined. The aim of the present study was to determine the effects of HIF‑1α on hypoxia induced angiogenesis in CRC cells, the effects of Tan IIA on the expression of pro‑angiogenic factors in CRC cells, and on human umbilical vein endothelial cell (HUVEC) tube formation in normal and hypoxic conditions. The results of the present study revealed that Tan IIA not only decreased HIF‑1α expression and inhibited the secretion level of vascular endothelial growth factor and basic fibroblast growth factor, but also efficiently decreased proliferation, tube formation and metastasis of HUVECs. The results highlight the potential of Tan IIA‑mediated targeting of HIF‑1α as a potential therapeutic option for treatment of patients with CRC.


greenmedinfo--2020-04-24--Tanshinone IIA protects against acute pancreatitis in mice by inhibiting oxidative stress via the Nr

Tanshinone IIA protects against acute pancreatitis in mice by inhibiting oxidative stress via the Nrf2/ROS pathway.

Background : Danshen ( Bunge ) and its main active component Tanshinone IIA ( TSA ) are clinically used in China .
However , the effects of TSA on acute pancreatitis ( AP ) and its potential mechanism have not been investigated .
In this study , our objective was to investigate the protective effects of TSA against AP via three classic mouse models .
Methods : Mouse models of AP were established by caerulein , sodium taurocholate , and L-arginine , separately .
Pancreatic and pulmonary histopathological characteristics and serum amylase and lipase levels were evaluated , and changes @ @ @ @ @ @ @ of acinar cells were observed .
The reactive oxygen species ( ROS ) inhibitor N-Acetylcysteine ( NAC ) and nuclear factor erythroid 2-related factor 2 ( Nrf2 ) knockout mice were applied to clarify the protective mechanism of the drug .
Results : In the caerulein-induced AP model , TSA administration reduced serum amylase and lipase levels and ameliorated the histopathological manifestations of AP in pancreatic tissue .
Additionally , TSA appreciably decreased ROS release , protected the structures of mitochondria and the endoplasmic reticulum , and increased the protein expression of Nrf2 @ @ @ @ @ @ @ .
In addition , the protective effects of TSA against AP were counteracted by blocking the oxidative stress ( NAC administration and Nrf2 knockout in mice ) .
Furthermore , we found that TSA protects pancreatic tissue from damage and pancreatitis-associated lung injury in two additional mouse models induced by sodium taurocholate and by L-arginine .
Conclusion : Our data confirmed the protective effects of TSA against AP in mice by inhibiting oxidative stress via the Nrf2/ROS pathway .

Background: Danshen (Bunge) and its main active component Tanshinone IIA (TSA) are clinically used in China. However, the effects of TSA on acute pancreatitis (AP) and its potential mechanism have not been investigated. In this study, our objective was to investigate the protective effects of TSA against AP via three classic mouse models.
Methods: Mouse models of AP were established by caerulein, sodium taurocholate, and L-arginine, separately. Pancreatic and pulmonary histopathological characteristics and serum amylase and lipase levels were evaluated, and changes in oxidative stress injury and the ultrastructure of acinar cells were observed. The reactive oxygen species (ROS) inhibitor N-Acetylcysteine (NAC) and nuclear factor erythroid 2-related factor 2 (Nrf2) knockout mice were applied to clarify the protective mechanism of the drug.
Results: In the caerulein-induced AP model, TSA administration reduced serum amylase and lipase levels and ameliorated the histopathological manifestations of AP in pancreatic tissue. Additionally, TSA appreciably decreased ROS release, protected the structures of mitochondria and the endoplasmic reticulum, and increased the protein expression of Nrf2 and heme oxygenase 1 of pancreatic tissue. In addition, the protective effects of TSA against AP were counteracted by blocking the oxidative stress (NAC administration and Nrf2 knockout in mice). Furthermore, we found that TSA protects pancreatic tissue from damage and pancreatitis-associated lung injury in two additional mouse models induced by sodium taurocholate and by L-arginine.
Conclusion: Our data confirmed the protective effects of TSA against AP in mice by inhibiting oxidative stress via the Nrf2/ROS pathway.


greenmedinfo--2020-04-24--Combined antioxidant therapy with N-acetylcysteine reduces headaches and migraines in adult migraine

Combined antioxidant therapy with N-acetylcysteine reduces headaches and migraines in adult migraineurs.

OBJECTIVE : To investigate the preventive effects of a combined antioxidant drug known as NEC ( N-acetylcysteine , Vitamin E and C ) on migraine outcomes .
Migraine is characterised by increased oxidative stress and neurogenic inflammation in the brain ; therefore antioxidants may have a migraine preventive effect .
SUBJECTS : Adults reporting 2-8 migraines per month for at least a year .
Methods After a 1 month baseline period , 35 subjects completed 3 months treatment with NEC ( n = 19 ) or sham ( n = 16 ) capsules .
The primary outcome was the difference @ @ @ @ @ @ @ between baseline and final month of the trial , for NEC and sham groups ; secondary outcomes are listed below .
RESULTS : For NEC there was a significant decrease in mean number of headaches by 3.0 per month ( p = .004 ) compared with 1.4 for sham ( p = .073 ) ; there was no significant difference in these changes between the two groups ( p = .052 ) .
Average monthly headache ( p = .041 ) and migraine frequency ( p = .018 ) were significantly less for @ @ @ @ @ @ @ , there was a significant decrease in average monthly migraine days ( -3.1 ) , moderate/severe headache days ( -3.2 ) , migraine duration , headache pain scores and acute headache medication use .
CONCLUSIONS : This is the first RCT to find that combined antioxidant therapy with NEC reduces headaches and migraines in adult migraineurs .
Given the limitations of this pilot study , an adequately powered RCT is planned to further investigate antioxidant prophylaxis in migraine .

OBJECTIVE: To investigate the preventive effects of a combined antioxidant drug known as NEC (N-acetylcysteine, Vitamin E and C) on migraine outcomes. Migraine is characterised by increased oxidative stress and neurogenic inflammation in the brain; therefore antioxidants may have a migraine preventive effect.
DESIGN: Randomized, double-blind, sham-controlled pilot study.
SETTING: Australian community.
SUBJECTS: Adults reporting 2-8 migraines per month for at least a year. Methods After a 1 month baseline period, 35 subjects completed 3 months treatment with NEC (n = 19) or sham (n = 16) capsules. The primary outcome was the difference in mean number of headaches per month between baseline and final month of the trial, for NEC and sham groups; secondary outcomes are listed below.
RESULTS: For NEC there was a significant decrease in mean number of headaches by 3.0 per month (p = .004) compared with 1.4 for sham (p = .073); there was no significant difference in these changes between the two groups (p = .052). Average monthly headache (p = .041) and migraine frequency (p = .018) were significantly less for NEC versus sham. In NEC subjects, there was a significant decrease in average monthly migraine days (-3.1), moderate/severe headache days (-3.2), migraine duration, headache pain scores and acute headache medication use.
CONCLUSIONS: This is the first RCT to find that combined antioxidant therapy with NEC reduces headaches and migraines in adult migraineurs. Given the limitations of this pilot study, an adequately powered RCT is planned to further investigate antioxidant prophylaxis in migraine.


greenmedinfo--2020-04-24--PHLPP2 is a novel biomarker and epigenetic target for the treatment of vitamin C in pancreatic cance

PHLPP2 is a novel biomarker and epigenetic target for the treatment of vitamin C in pancreatic cancer.

Epigenetic dysregulations are closely associated with the development of pancreatic ductal adenocarcinoma ( PDAC ) , which is one of the most aggressive malignancies and currently has limited treatment options .
Vitamin C ( VC ) , an epigenetic mediator , exerts antitumor effects on several types of cancer .
However , the clinical application of VC is limited , particularly in PDAC .
Thus , to investigate the antitumor effects and explore the potential clinical application of VC in PDAC , the survival of patients from The Cancer Genome Atlas database were analyzed , and proliferation , apoptosis and @ @ @ @ @ @ @ study .
It was first established that high expression levels of the sodium‑dependent VC transporter 2 , a critical VC transporter , predicted a good prognosis in patients with pancreatic adenocarcinoma .
It was further confirmed that VC directly inhibited proliferation , induced apoptosis and suppressed migration of human pancreatic cancer cells .
Global 5‑hydroxymethylcytosine ( 5hmC ) content was significantly upregulated in pancreatic cancer cells following VC treatment , predominantly relying on ten‑eleven translocation 2 .
Furthermore , VC could specifically increase 5hmC levels at the promotor region on PH domain leucine‑rich @ @ @ @ @ @ @ and enhance PHLPP2 expression levels .
When PHLPP2 expression levels were knocked down , VC was able to partially overcome the inhibition of pancreatic cancer cells .
These results illustrated a novel and precise mechanism of action of epigenetic alterations that underly the inhibition of VC in pancreatic cancer , and emphasized that PHLPP2 may be a new biomarker and epigenetic target for the clinical treatment of VC in PDAC .

Epigenetic dysregulations are closely associated with the development of pancreatic ductal adenocarcinoma (PDAC), which is one of the most aggressive malignancies and currently has limited treatment options. Vitamin C (VC), an epigenetic mediator, exerts antitumor effects on several types of cancer. However, the clinical application of VC is limited, particularly in PDAC. Thus, to investigate the antitumor effects and explore the potential clinical application of VC in PDAC, the survival of patients from The Cancer Genome Atlas database were analyzed, and proliferation, apoptosis and migration assays were performed in the present study. It was first established that high expression levels of the sodium‑dependent VC transporter 2, a critical VC transporter, predicted a good prognosis in patients with pancreatic adenocarcinoma. It was further confirmed that VC directly inhibited proliferation, induced apoptosis and suppressed migration of human pancreatic cancer cells. Global 5‑hydroxymethylcytosine (5hmC) content was significantly upregulated in pancreatic cancer cells following VC treatment, predominantly relying on ten‑eleven translocation 2. Furthermore, VC could specifically increase 5hmC levels at the promotor region on PH domain leucine‑rich repeat protein phosphatase 2 (PHLPP2) and enhance PHLPP2 expression levels. When PHLPP2 expression levels were knocked down, VC was able to partially overcome the inhibition of pancreatic cancer cells. These results illustrated a novel and precise mechanism of action of epigenetic alterations that underly the inhibition of VC in pancreatic cancer, and emphasized that PHLPP2 may be a new biomarker and epigenetic target for the clinical treatment of VC in PDAC.


greenmedinfo--2020-04-25--Flawed Assumptions Behind GMO Golden Rice

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greenmedinfo--2020-04-25--'Magic' Trio for Suppressing Growth of Thyroid Nodules


greenmedinfo--2020-04-25--Here's How Much Plastic You're Eating Each Week


greenmedinfo--2020-04-25--1, 25-dihydroxyvitamin D3 downregulates cytotoxic effector response in pulmonary tuberculosis.

1,25-dihydroxyvitaminD [ 1,25 ( OH ) D ] modulates both the innate and adaptive immunity in tuberculosis .
We explored @ @ @ @ @ OH ) Don cytolytic molecules like perforin , granulysin , and granzyme-B in T-cells and @ @ @ @ @ tuberculosis ( Mtb ) infection .
Peripheral blood mononuclear cells ( PBMCs ) from 45 @ @ @ @ @ and 45 pulmonary tuberculosis ( PTB ) patients were cultured with Mtb in the absence @ @ @ @ @ OH ) Dfor 72 h. The percentage of perforin , granulysin , and granzyme-B positive @ @ @ @ @ cytometry .
1,25 ( OH ) Dsignificantly decreased the percentage of cytolytic molecules in total @ @ @ @ @ CD56+ cells in HCs and PTB patients ( p

1,25-dihydroxyvitaminD[1,25(OH)D] modulates both the innate and adaptive immunity in tuberculosis. We explored the effect of 1,25(OH)Don cytolytic molecules like perforin, granulysin, and granzyme-B in T-cells and natural killer cells during M. tuberculosis (Mtb) infection. Peripheral blood mononuclear cells (PBMCs) from 45 healthy controls (HCs) and 45 pulmonary tuberculosis (PTB) patients were cultured with Mtb in the absence or presence of 1,25(OH)Dfor 72 h. The percentage of perforin, granulysin, and granzyme-B positive cells were estimated by flow cytometry. 1,25(OH)Dsignificantly decreased the percentage of cytolytic molecules in total, CD4+, CD8+ and CD56+ cells in HCs and PTB patients (p < 0.05). Moreover, 1,25(OH)Ddownregulates IFN-γ levels while upregulate the anti-inflammatory cytokine IL-10. Correlation revealed that the total percentage of cytolytic molecules were positively correlated with IFN-γ level, whereas negatively correlated with IL-10 level in both the study subjects (p < 0.05). This results suggests that 1,25(OH)Ddownregulate the expression of cytolytic molecues and act as anti-inflammatory in adaptive immune response, which might help to reduce inflammation and tissue damage during the active stage of the disease.


greenmedinfo--2020-04-25--Treatment of asthma patients with vitamin D reduced respiratory infections.

BACKGROUND : Vitamin D is a molecule that modulates the immune response and shows anti-inflammatory effects that are beneficial for the control of chronic diseases such as asthma .
The trial aim was to explore the effect of vitamin D supplementation on the colonization of pathogenic bacteria in the upper respiratory tract of allergic asthmatic patients .
METHODS : This study was conducted in 86 patients between 18 and 50 years of age who were randomly divided into two groups .
Both groups received the treatment recommended by the Global Initiative for Asthma ( GINA ) .
One group also @ @ @ @ @ @ @ D ) , and the other group received a placebo .
At baseline and 6 months , skin prick tests were conducted , pharyngeal bacterial cultures were performed , and cathelicidin LL-37 was measured in sputum .
Serum levels of IgE , eosinophils , IL-5 , IL-9 , IL-10 , IL-13 , and IFNγ were quantified at the beginning and the end of the study .
RESULTS : Serum levels of IL-10 and IFNγ increased significantly in the group of patients with vitamin D supplementation , while IL-5 , IL-9 , and IL-13 @ @ @ @ @ @ @ the trial , IgE and eosinophil levels significantly decreased but allergen sensitivity did not show any changes from baseline .
Respiratory infectionswere drastically reduced , and this decrease was related to the number of patients who had high serum levels of IL-10 and IFNγ and expressed LL-37 in their sputum .
CONCLUSION : Treatment of asthma patients with vitamin D reduced respiratory infections , and this effect was related to the increase of cathelicidin LL-37 .

BACKGROUND: Vitamin D is a molecule that modulates the immune response and shows anti-inflammatory effects that are beneficial for the control of chronic diseases such as asthma. The trial aim was to explore the effect of vitamin D supplementation on the colonization of pathogenic bacteria in the upper respiratory tract of allergic asthmatic patients.
METHODS: This study was conducted in 86 patients between 18 and 50 years of age who were randomly divided into two groups. Both groups received the treatment recommended by the Global Initiative for Asthma (GINA). One group also received calcitriol (1,25-(OH)D), and the other group received a placebo. At baseline and 6 months, skin prick tests were conducted, pharyngeal bacterial cultures were performed, and cathelicidin LL-37 was measured in sputum. Serum levels of IgE, eosinophils, IL-5, IL-9, IL-10, IL-13, and IFNγ were quantified at the beginning and the end of the study.
RESULTS: Serum levels of IL-10 and IFNγ increased significantly in the group of patients with vitamin D supplementation, while IL-5, IL-9, and IL-13 decreased significantly. At the end of the trial, IgE and eosinophil levels significantly decreased but allergen sensitivity did not show any changes from baseline. Respiratory infectionswere drastically reduced, and this decrease was related to the number of patients who had high serum levels of IL-10 and IFNγ and expressed LL-37 in their sputum.
CONCLUSION: Treatment of asthma patients with vitamin D reduced respiratory infections, and this effect was related to the increase of cathelicidin LL-37.


greenmedinfo--2020-04-25--Evolving role of vitamin D in immune-mediated disease and its implications in autoimmune hepatitis.

Vitamin D has immunomodulatory , anti-inflammatory , antioxidant , and anti-fibrotic actions that may impact on the occurrence and outcome of immune-mediated disease .
The goals of this review are to describe the nature of these expanded roles , examine the implications of vitamin D deficiency in autoimmune hepatitis , and identify opportunities for future investigation .
Abstracts were identified in PubMed by multiple search terms .
Full-length articles were selected for review , and secondary andtertiary bibliographies were developed .
Vitamin D receptors are expressed on the principal cell populations involved in the innate and adaptive immune responses .
@ @ @ @ @ @ @ D within the microenvironment .
This active form of vitamin D can inhibit immune cell proliferation , promote an anti-inflammatory cytokine profile , expand regulatory T cells , enhance glucocorticoid actions , increase glutathione production , and inhibit hepatic stellate cells .
Vitamin D deficiency has been commonly present in patients with immune-mediated liver and non-liver diseases , and it has been associated with histological severity , advanced hepatic fibrosis , and non-response to conventional glucocorticoid therapy in autoimmune hepatitis .
Vitamin D analogues with high potency , low calcemic effects , and @ @ @ @ @ @ @ .
In conclusion , vitamin D has properties that could ameliorate immune-mediated disease , and vitamin D deficiency has been a common finding in immune-mediated liver and non-liver diseases , including autoimmune hepatitis .
Loss of vitamin D-dependent homeostatic mechanisms may promote diseaseprogression .
Vitamin D analogues that are independent of hepatic hydroxylation constitute an investigational opportunity to supplement current management of autoimmune hepatitis .

Vitamin D has immunomodulatory, anti-inflammatory, antioxidant, and anti-fibrotic actions that may impact on the occurrence and outcome of immune-mediated disease. The goals of this review are to describe the nature of these expanded roles, examine the implications of vitamin D deficiency in autoimmune hepatitis, and identify opportunities for future investigation. Abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary andtertiary bibliographies were developed. Vitamin D receptors are expressed on the principal cell populations involved in the innate and adaptive immune responses. Macrophages and dendritic cells can produce 1,25-dihydroxyvitamin D within the microenvironment. This active form of vitamin D can inhibit immune cell proliferation, promote an anti-inflammatory cytokine profile, expand regulatory T cells, enhance glucocorticoid actions, increase glutathione production, and inhibit hepatic stellate cells. Vitamin D deficiency has been commonly present in patients with immune-mediated liver and non-liver diseases, and it has been associated with histological severity, advanced hepatic fibrosis, and non-response to conventional glucocorticoid therapy in autoimmune hepatitis. Vitamin D analogues with high potency, low calcemic effects, and independence from hepatic hydroxylation are possible interventions. In conclusion, vitamin D has properties that could ameliorate immune-mediated disease, and vitamin D deficiency has been a common finding in immune-mediated liver and non-liver diseases, including autoimmune hepatitis. Loss of vitamin D-dependent homeostatic mechanisms may promote diseaseprogression. Vitamin D analogues that are independent of hepatic hydroxylation constitute an investigational opportunity to supplement current management of autoimmune hepatitis.


greenmedinfo--2020-04-25--Low serum 25-hydroxyvitamin D is associated with increased bladder cancer risk.

The development of some cancers is associated with vitamin D deficiency .
We suggest that reduced conversion of 25-hydroxyvitamin D ( 25 ( OH ) D ) to 1,25-dihydroxyvitamin D ( 1,25 ( OH ) D ) and the resulting modification of tissue specific immune responses may be key .
Non-muscle-invasive bladder cancer is highly immunoresponsive and stimulation of an inflammatory response by intravesical bacillus Calmette-Guerin ( BCG ) treatment prevents recurrence .
To assess the relationship between serum 25 ( OH ) D and bladder cancer risk we conducted a systematic review .
To test our hypothesis , the @ @ @ @ @ @ @ by human bladder epithelial cell lines ( T24/83 and RT4 ) was examined .
Studies were identified from Medline , Web of Science , Embase and Cochrane library ( limited to English language , humans and 1990-2018 ) .
After removal of duplicates , title and abstract review 6 full papers were appraised .
Low vitamin D levels were associated with bladder cancer risk in 5/6 of the studies .
Both cell lines express the vitamin D receptor , 25-hydroxyvitamin D 1α-hydroxylase ( 1α-OHase ) and 24-hydroxylase ( 24-OHase ) mRNA , which @ @ @ @ @ @ @ D. 24-OHase mRNA was also increased by 25 ( OH ) D indicating 1α-OHase activity .
Both cell types expressed TLR1,2,4 and the TLR partners MyD88 and CD14mRNA .
Cathelicidin mRNA was undetectable in both cell lines but was induced by 1,25 ( OH ) D and 25 ( OH ) D in RT4 cells .
The systematic review demonstrated that bladder cancer risk correlates with serum 25 ( OH ) D levels .
In addition , we have shown that transitional epithelial cells express functional vitamin D signaling and can synthesize sufficient @ @ @ @ @ @ @ a local immune response .
We suggest that in order to maintain optimal immune surveillance within the bladder adequate levels of serum 25 ( OH ) D are required for direct synthesis of 1,25 ( OH ) D by bladder epithelial cells .

The development of some cancers is associated with vitamin D deficiency. We suggest that reduced conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25-dihydroxyvitamin D (1,25(OH)D) and the resulting modification of tissue specific immune responses may be key. Non-muscle-invasive bladder cancer is highly immunoresponsive and stimulation of an inflammatory response by intravesical bacillus Calmette-Guerin (BCG) treatment prevents recurrence. To assess the relationship between serum 25(OH)D and bladder cancer risk we conducted a systematic review. To test our hypothesis, the synthesis of 1,25(OH)D by human bladder epithelial cell lines (T24/83 and RT4) was examined. Studies were identified from Medline, Web of Science, Embase and Cochrane library (limited to English language, humans and 1990-2018). After removal of duplicates, title and abstract review 6 full papers were appraised. Low vitamin D levels were associated with bladder cancer risk in 5/6 of the studies. Both cell lines express the vitamin D receptor, 25-hydroxyvitamin D 1α-hydroxylase (1α-OHase) and 24-hydroxylase (24-OHase) mRNA, which was induced by 1,25(OH)D. 24-OHase mRNA was also increased by 25(OH)D indicating 1α-OHase activity. Both cell types expressed TLR1,2,4 and the TLR partners MyD88 and CD14mRNA. Cathelicidin mRNA was undetectable in both cell lines but was induced by 1,25(OH)D and 25(OH)D in RT4 cells. The systematic review demonstrated that bladder cancer risk correlates with serum 25(OH)D levels. In addition, we have shown that transitional epithelial cells express functional vitamin D signaling and can synthesize sufficient 1,25(OH)D to stimulate a local immune response. We suggest that in order to maintain optimal immune surveillance within the bladder adequate levels of serum 25(OH)D are required for direct synthesis of 1,25(OH)D by bladder epithelial cells.


greenmedinfo--2020-04-25--Consumption of vitamin D supplements might be helpful in decreasing the prevalence of infection, sep

Consumption of vitamin D supplements might be helpful in decreasing the prevalence of infection, sepsis, and mortality caused by it.

Introduction : The effect of vitamin D deficiency in manifestation of sepsis and its role as an important mediator in the immune system has received attention .
The present study was done with the aim of evaluating the correlation between serum levels of vitamin D and outcome of sepsis patients .
Methods : The present cross-sectional study was performed on patients over 18 years of age suspected to sepsis presenting to an emergency department during 1 year using non-probability convenience sampling .
For all eligible patients , blood sample was drawn for measurement of serum level of vitamin D3 and @ @ @ @ @ @ @ such as mortality , renal failure , liver failure and etc .
was assessed .
Results : 168 patients with the mean age of 70.8± 13.3 ( 43.0 - 93.0 ) years were studied ( 56.0 % male ) .
Mean serum level of vitamin D3 in the studied patients was 19.03 ± 13.08 ( 4.0 - 85.0 ) ng/ml .
By considering 20 - 50 ng/ml as the normal range of vitamin D , 61.6 % of the patients had vitamin D deficiency .
Only age ( r=-0.261 , p=0.037 ) and @ @ @ @ @ @ @ a significant correlation with mean vitamin D. Sepsis patients with older age and those who died had a lower level of vitamin D. Area under the ROC curve of serum vitamin D level regarding 1-month mortality of the sepsis patients was 0.701 ( 95 % CI : 0.439 - 0.964 ) .
Conclusion : Based on the results of the present study , the prevalence of vitamin D deficiency in sepsis patients presenting to the ED was estimated as 61.6 % .
A significant and indirect correlation was found between the serum level @ @ @ @ @ @ @ as older age .
It seems that consumption of vitamin D supplements might be helpful in decreasing the prevalence of infection , sepsis , and mortality caused by it , especially in older age .

Introduction: The effect of vitamin D deficiency in manifestation of sepsis and its role as an important mediator in the immune system has received attention. The present study was done with the aim of evaluating the correlation between serum levels of vitamin D and outcome of sepsis patients.
Methods: The present cross-sectional study was performed on patients over 18 years of age suspected to sepsis presenting to an emergency department during 1 year using non-probability convenience sampling. For all eligible patients, blood sample was drawn for measurement of serum level of vitamin D3 and the correlation of this vitamin with outcomes such as mortality, renal failure, liver failure and etc. was assessed.
Results: 168 patients with the mean age of 70.8± 13.3 (43.0 - 93.0) years were studied (56.0% male). Mean serum level of vitamin D3 in the studied patients was 19.03 ± 13.08 (4.0 - 85.0) ng/ml. By considering 20 - 50 ng/ml as the normal range of vitamin D, 61.6% of the patients had vitamin D deficiency. Only age (r=-0.261, p=0.037) and mortality (r=-0.426, p=0.025) showed a significant correlation with mean vitamin D. Sepsis patients with older age and those who died had a lower level of vitamin D. Area under the ROC curve of serum vitamin D level regarding 1-month mortality of the sepsis patients was 0.701 (95%CI: 0.439 - 0.964).
Conclusion: Based on the results of the present study, the prevalence of vitamin D deficiency in sepsis patients presenting to the ED was estimated as 61.6%. A significant and indirect correlation was found between the serum level of vitamin D3 and mortality as well as older age. It seems that consumption of vitamin D supplements might be helpful in decreasing the prevalence of infection, sepsis, and mortality caused by it, especially in older age.


greenmedinfo--2020-04-25--Effects of 1,25-dihydroxyvitamin D3 on experimental periodontitis and AhR/NF-κB/NLRP3 inflammasome p

Effects of 1,25-dihydroxyvitamin D3 on experimental periodontitis and AhR/NF-κB/NLRP3 inflammasome pathway.

: Vitamin D has been known to have important regulatory functions in inflammation and immune response and shows inhibitory effects on experimental periodontitis in animal models .
However , the potential mechanism has yet to be clarified .
Recent studies have highlighted Aryl hydrocarbon receptor ( AhR ) and its downstream signaling as a crucial regulator of immune homeostasis and inflammatory regulation .
OBJECTIVE : This study aimed to clarify the effect of 1,25-dihydroxyvitamin D3 ( VD3 ) on experimental periodontitis and AhR/nuclear factor-κB ( NF-κB ) /NLR pyrin domain-containing 3 ( NLRP3 ) inflammasome pathway in the gingival epithelium @ @ @ @ @ @ @ We induced periodontitis in male C57BL/6 wild-type mice by oral inoculation of Porphyromonas gingivalis ( P. gingivalis ) , and subsequently gave intraperitoneal VD3 injection to the mice every other day for 8 weeks .
Afterwards , we examined the alveolar bone using scanning electron microscopy ( SEM ) and detected the gingival epithelial protein using western blot analysis and immunohistochemical staining .
RESULTS : SEM images demonstrated that alveolar bone loss was reduced in the periodontitis mouse model after VD3 supplementation .
Western blot analyses and immunohistochemical staining of the gingival epithelium @ @ @ @ @ @ @ receptor , AhR and its downstream cytochrome P450 1A1 were enhanced upon VD3 application .
Additionally , VD3 decreased NF-κB p65 phosphorylation , and NLRP3 , apoptosis-associated speck-like protein , caspase-1 , interleukin-1β ( IL-1β ) and IL-6 protein expression .
CONCLUSIONS : These results implicate the alleviation of periodontitis and the alteration of AhR/NF-κB/NLRP3 inflammasome pathway by VD3 in the mouse model .
The attenuation of this periodontal disease may correlate with the regulation of AhR/NF-κB/NLRP3 inflammasome pathway by VD3 .

: Vitamin D has been known to have important regulatory functions in inflammation and immune response and shows inhibitory effects on experimental periodontitis in animal models. However, the potential mechanism has yet to be clarified. Recent studies have highlighted Aryl hydrocarbon receptor (AhR) and its downstream signaling as a crucial regulator of immune homeostasis and inflammatory regulation.
OBJECTIVE: This study aimed to clarify the effect of 1,25-dihydroxyvitamin D3 (VD3) on experimental periodontitis and AhR/nuclear factor-κB (NF-κB)/NLR pyrin domain-containing 3 (NLRP3) inflammasome pathway in the gingival epithelium in a murine model.
METHODOLOGY: We induced periodontitis in male C57BL/6 wild-type mice by oral inoculation of Porphyromonas gingivalis (P. gingivalis), and subsequently gave intraperitoneal VD3 injection to the mice every other day for 8 weeks. Afterwards, we examined the alveolar bone using scanning electron microscopy (SEM) and detected the gingival epithelial protein using western blot analysis and immunohistochemical staining.
RESULTS: SEM images demonstrated that alveolar bone loss was reduced in the periodontitis mouse model after VD3 supplementation. Western blot analyses and immunohistochemical staining of the gingival epithelium showed that the expression of vitamin D receptor, AhR and its downstream cytochrome P450 1A1 were enhanced upon VD3 application. Additionally, VD3 decreased NF-κB p65 phosphorylation, and NLRP3, apoptosis-associated speck-like protein, caspase-1, interleukin-1β (IL-1β) and IL-6 protein expression.
CONCLUSIONS: These results implicate the alleviation of periodontitis and the alteration of AhR/NF-κB/NLRP3 inflammasome pathway by VD3 in the mouse model. The attenuation of this periodontal disease may correlate with the regulation of AhR/NF-κB/NLRP3 inflammasome pathway by VD3.


greenmedinfo--2020-04-25--Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system.

Vitamin D is an important immune system regulator .
The active form of vitamin D , 1,25-dihydroxyvitamin D3 [ 1,25 ( OH ) 2D3 ] , has been shown to inhibit the development of autoimmune diseases , including inflammatory bowel disease ( IBD ) .
Paradoxically , other immune system-mediated diseases ( experimental asthma ) and immunity to infectious organisms were unaffected by 1,25 ( OH ) 2D3 treatment .
There are similar paradoxical effects of vitamin D deficiency on various immune system functions .
Vitamin D and vitamin D receptor ( VDR ) deficiency resulted in accelerated IBD .
@ @ @ @ @ @ @ OH ) 2D3 treatment and was less severe among VDR-deficient mice .
Vitamin D is a selective regulator of the immune system , and the outcome of 1,25 ( OH ) 2D3 treatment , vitamin D deficiency , or VDR deficiency depends on the nature of the immune response ( eg , infectious disease , asthma , or autoimmune disease ) .
An additional factor that determines the effect of vitamin D status on immune function is dietary calcium .
Dietary calcium has independent effects on IBD severity .
Vitamin D-deficient mice on @ @ @ @ @ @ @ , and 1,25 ( OH ) 2D3 treatment of mice on low-calcium diets improved IBD symptoms .
However , the best results for IBD were observed when the calcium concentration was high and 1,25 ( OH ) 2D3 was administered .
Both the type of immune response and the calcium status of the host determine the effects of vitamin D status and 1,25 ( OH ) 2D3 on immunity .

Vitamin D is an important immune system regulator. The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to inhibit the development of autoimmune diseases, including inflammatory bowel disease (IBD). Paradoxically, other immune system-mediated diseases (experimental asthma) and immunity to infectious organisms were unaffected by 1,25(OH)2D3 treatment. There are similar paradoxical effects of vitamin D deficiency on various immune system functions. Vitamin D and vitamin D receptor (VDR) deficiency resulted in accelerated IBD. Experimental asthma was unaffected by 1,25(OH)2D3 treatment and was less severe among VDR-deficient mice. Vitamin D is a selective regulator of the immune system, and the outcome of 1,25(OH)2D3 treatment, vitamin D deficiency, or VDR deficiency depends on the nature of the immune response (eg, infectious disease, asthma, or autoimmune disease). An additional factor that determines the effect of vitamin D status on immune function is dietary calcium. Dietary calcium has independent effects on IBD severity. Vitamin D-deficient mice on low-calcium diets developed the most severe IBD, and 1,25(OH)2D3 treatment of mice on low-calcium diets improved IBD symptoms. However, the best results for IBD were observed when the calcium concentration was high and 1,25(OH)2D3 was administered. Both the type of immune response and the calcium status of the host determine the effects of vitamin D status and 1,25(OH)2D3 on immunity.


greenmedinfo--2020-04-25--L-threonic acid magnesium salt supplementation was found to be effective and well tolerated.

Attention-deficit/hyperactivity disorder ( ADHD ) is estimated to affect up to 5 % of adults worldwide .
Preclinical work demonstrates @ @ @ @ @ ( LTAMS ) administration is associated with neurobiological and neurofunctional effects that could offer clinical @ @ @ @ @ 15 adults with ADHD of moderate severity .
Subjects received up to 12 weeks of @ @ @ @ @ and MMFS202 .
The study was approved by the Institutional Review Board and posted on @ @ @ @ @ % of subjects met our criteria of response attaining a CGI-Improvement score≤2 and AISRS total @ @ @ @ @ improvement was seen in the AISRS , CGI-I , and the shifting subscale of the @ @ @ @ @ and WASI-II performance were favorable and significant in the study population.LTAMS supplementation was found to @ @ @ @ @ .
Nearly half of participants met our definition of ADHD symptom clinical response .
These @ @ @ @ @ further evaluate this compound in larger samples under double-blind conditions .

Attention-deficit/hyperactivity disorder (ADHD) is estimated to affect up to 5% of adults worldwide. Preclinical work demonstrates that L-Threonic Acid Magnesium Salt (LTAMS) administration is associated with neurobiological and neurofunctional effects that could offer clinical benefits in ADHD treatment.Participants were 15 adults with ADHD of moderate severity. Subjects received up to 12 weeks of open-label LTAMS administered as MMFS302 and MMFS202. The study was approved by the Institutional Review Board and posted on ClinicalTrails.Gov (NCT02558790).47% of subjects met our criteria of response attaining a CGI-Improvement score≤2 and AISRS total reduction ≥25%. Significant improvement was seen in the AISRS, CGI-I, and the shifting subscale of the BRIEF. Changes in IQ and WASI-II performance were favorable and significant in the study population.LTAMS supplementation was found to be effective and well tolerated. Nearly half of participants met our definition of ADHD symptom clinical response. These results support the need to further evaluate this compound in larger samples under double-blind conditions.


greenmedinfo--2020-04-25--Magnesium-L-threonate may have therapeutic value for treating pain and comorbid depression or memory

Magnesium-L-threonate may have therapeutic value for treating pain and comorbid depression or memory deficits in bladder pain syndrome/interstitial cystitis.

BACKGROUND : Bladder-related pain symptoms in patients with bladder pain syndrome/interstitial cystitis ( BPS/IC ) are often accompanied by depression and memory deficits .
Magnesium deficiency contributes to neuroinflammation and is associated with pain , depression , and memory deficits .
Neuroinflammation is involved in the mechanical allodynia of cyclophosphamide ( CYP ) -induced cystitis .
Magnesium-L-Threonate ( L-TAMS ) supplementation can attenuate neuroinflammation .
This study aimed to determine whether and how L-TAMS influences mechanical allodynia and accompanying depressive symptoms and memory deficits in CYP-induced cystitis .
METHODS : Injection of CYP ( 50 mg/kg , intraperitoneally , every @ @ @ @ @ @ @ used to establish a rat model of BPS/IC .
L-TAMS was administered in drinking water ( 604 mg·kg·day ) .
Mechanical allodynia in the lower abdomen was assessed with von Frey filaments using the up-down method .
Forced swim test ( FST ) and sucrose preference test ( SPT ) were used to measure depressive-like behaviors .
Novel object recognition test ( NORT ) was used to detect short-term memory function .
Concentrations of Mgin serum and cerebrospinal fluid ( CSF ) were measured by calmagite chronometry .
Western blot and immunofluorescence staining @ @ @ @ @ @ @ factor-κB ( TNF-α/NF-κB ) , interleukin-1β ( IL-1β ) , and N-methyl-D-aspartate receptor type 2B subunit ( NR2B ) of the N-methyl-D-aspartate receptor in the L6-S1 spinal dorsal horn ( SDH ) and hippocampus .
RESULTS : Free Mgwas reduced in the serum and CSF of the CYP-induced cystitis rats on days 8 , 12 , and 20 after the first CYP injection .
Magnesium deficiency in the serum and CSF correlated with the mechanical withdrawal threshold , depressive-like behaviors , and short-term memory deficits ( STMD ) .
Oral application of L-TAMS @ @ @ @ @ @ @ ( n = 14 ) and normalized depressive-like behaviors ( n = 10 ) and STMD ( n = 10 ) .
The upregulation of TNF-α/NF-κB signaling and IL-1β in the L6-S1 SDH or hippocampus was reversed by L-TAMS .
The change in NR2B expression in the SDH and hippocampus in the cystitis model was normalized by L-TAMS .
CONCLUSIONS : Normalization of magnesium deficiency by L-TAMS attenuated mechanical allodynia , depressive-like behaviors , and STMD in the CYP-induced cystitis model via inhibition of TNF-α/NF-κВ signaling and normalization of NR2B expression .
Our @ @ @ @ @ @ @ therapeutic value for treating pain and comorbid depression or memory deficits in BPS/IC patients .

BACKGROUND: Bladder-related pain symptoms in patients with bladder pain syndrome/interstitial cystitis (BPS/IC) are often accompanied by depression and memory deficits. Magnesium deficiency contributes to neuroinflammation and is associated with pain, depression, and memory deficits. Neuroinflammation is involved in the mechanical allodynia of cyclophosphamide (CYP)-induced cystitis. Magnesium-L-Threonate (L-TAMS) supplementation can attenuate neuroinflammation. This study aimed to determine whether and how L-TAMS influences mechanical allodynia and accompanying depressive symptoms and memory deficits in CYP-induced cystitis.
METHODS: Injection of CYP (50 mg/kg, intraperitoneally, every 3 days for 3 doses) was used to establish a rat model of BPS/IC. L-TAMS was administered in drinking water (604 mg·kg·day). Mechanical allodynia in the lower abdomen was assessed with von Frey filaments using the up-down method. Forced swim test (FST) and sucrose preference test (SPT) were used to measure depressive-like behaviors. Novel object recognition test (NORT) was used to detect short-term memory function. Concentrations of Mgin serum and cerebrospinal fluid (CSF) were measured by calmagite chronometry. Western blot and immunofluorescence staining measured the expression of tumor necrosis factor-α/nuclear factor-κB (TNF-α/NF-κB), interleukin-1β (IL-1β), and N-methyl-D-aspartate receptor type 2B subunit (NR2B) of the N-methyl-D-aspartate receptor in the L6-S1 spinal dorsal horn (SDH) and hippocampus.
RESULTS: Free Mgwas reduced in the serum and CSF of the CYP-induced cystitis rats on days 8, 12, and 20 after the first CYP injection. Magnesium deficiency in the serum and CSF correlated with the mechanical withdrawal threshold, depressive-like behaviors, and short-term memory deficits (STMD). Oral application of L-TAMS prevented magnesium deficiency and attenuated mechanical allodynia (n = 14) and normalized depressive-like behaviors (n = 10) and STMD (n = 10). The upregulation of TNF-α/NF-κB signaling and IL-1β in the L6-S1 SDH or hippocampus was reversed by L-TAMS. The change in NR2B expression in the SDH and hippocampus in the cystitis model was normalized by L-TAMS.
CONCLUSIONS: Normalization of magnesium deficiency by L-TAMS attenuated mechanical allodynia, depressive-like behaviors, and STMD in the CYP-induced cystitis model via inhibition of TNF-α/NF-κВ signaling and normalization of NR2B expression. Our study provides evidence that L-TAMS may have therapeutic value for treating pain and comorbid depression or memory deficits in BPS/IC patients.