greenmedinfo--2020-05-03--1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sit

1,25-Dihydroxyvitamin D suppresses M1 macrophages and promotes M2 differentiation at bone injury sites.

An indispensable role of macrophages in bone repair has been well recognized .
Previous data have demonstrated the copresence of M1 macrophages and mesenchymal stem cells ( MSCs ) during the proinflammatory stage of bone repair .
However , the exact role of M1 macrophages in MSC function and bone repair is unknown .
This study aimed to define the role of M1 macrophages at bone injury sites via the function of 1,25-Dihydroxyvitamin D ( 1,25 [ OH ] 2D ) in suppressing M1 but promoting M2 differentiation .
We showed that 1,25 ( OH ) 2D suppressed M1 macrophage-mediated @ @ @ @ @ @ @ 1,25 ( OH ) 2D inhibited M1 macrophage secretion of osteogenic proteins ( i.e.
, Oncostatin M , TNF-α , and IL-6 ) .
Importantly , the 1,25 ( OH ) 2D-mediated suppression of osteogenic function in M1 macrophages at the proinflammatory stage was associated with 1,25 ( OH ) 2D-mediated reduction of MSC abundance , compromised osteogenic potential of MSCs , and impairment of fracture repair .
Furthermore , outsidethe proinflammatory stage , 1,25 ( OH ) 2D treatment did not suppress fracture repair .
Accordingly , our data support 2 conclusions @ @ @ @ @ @ @ important for the recruitment and osteogenic priming of MSCs and , hence , are necessary for fracture repair , and ( b ) under vitamin D-sufficient conditions , 1,25 ( OH ) 2D treatment is unnecessary and can be detrimental if provided during the proinflammatory stage of fracture healing .

An indispensable role of macrophages in bone repair has been well recognized. Previous data have demonstrated the copresence of M1 macrophages and mesenchymal stem cells (MSCs) during the proinflammatory stage of bone repair. However, the exact role of M1 macrophages in MSC function and bone repair is unknown. This study aimed to define the role of M1 macrophages at bone injury sites via the function of 1,25-Dihydroxyvitamin D (1,25[OH]2D) in suppressing M1 but promoting M2 differentiation. We showed that 1,25(OH)2D suppressed M1 macrophage-mediated enhancement of MSC migration. Additionally, 1,25(OH)2D inhibited M1 macrophage secretion of osteogenic proteins (i.e., Oncostatin M, TNF-α, and IL-6). Importantly, the 1,25(OH)2D-mediated suppression of osteogenic function in M1 macrophages at the proinflammatory stage was associated with 1,25(OH)2D-mediated reduction of MSC abundance, compromised osteogenic potential of MSCs, and impairment of fracture repair. Furthermore, outsidethe proinflammatory stage, 1,25(OH)2D treatment did not suppress fracture repair. Accordingly, our data support 2 conclusions: (a) M1 macrophages are important for the recruitment and osteogenic priming of MSCs and, hence, are necessary for fracture repair, and (b) under vitamin D-sufficient conditions, 1,25(OH)2D treatment is unnecessary and can be detrimental if provided during the proinflammatory stage of fracture healing.


greenmedinfo--2020-05-03--Calcitriol increases nitric oxide production and modulates microbicidal capacity against Mycobacteri

Calcitriol increases nitric oxide production and modulates microbicidal capacity against Mycobacterium bovis in bovine macrophages.

Bovine tuberculosis , a re-emerging infectious disease caused by Mycobacterium bovis , can be transmitted to humans .
Global prevalence of M. bovis in humans is underestimated and represents a serious public health risk in developing countries .
In light of this situation , it is important to note that our understanding of the immunopathogenesis of human tuberculosis can be improved by studying this disease in the bovine model .
Stimulation of the bovine innate immune system with calcitriol ( 1,25 ( OH ) 2D3 ) leads to an increase in bactericidal molecules involved in macrophage antimicrobial activity .
It @ @ @ @ @ @ @ effect on bovine macrophages impacts intracellular bacterial replication .
With these considerations in mind , this study sought to investigate the specific role of calcitriol in tuberculosis control in bovine macrophages , in the hopes of uncovering information applicable to human tuberculosis .
Assuch , infection with M. bovis was shown to induce expression of CYP27B1 and VDR genes in macrophages .
Moreover , addition of 1,25 ( OH ) 2D3 to cultures of macrophages previously infected with mycobacteria and/or activated by LPS triggered cellular expression of nitric oxide synthase ( NOS2 ) @ @ @ @ @ @ @ of nitric oxide ( NO ) production .
By means of a microbicidal assay , addition of 1,25 ( OH ) 2D3 was seen to increase macrophage phagocytosis and to decrease mycobacterial intracellular replication .
Thus , taken together , our results show that calcitriol can help stimulate the innate immune system of bovines by increasing phagocytosis and decreasing intracellular replication of microorganisms , such as M. bovis , in macrophages , through the VDR pathway .

Bovine tuberculosis, a re-emerging infectious disease caused by Mycobacterium bovis, can be transmitted to humans. Global prevalence of M. bovis in humans is underestimated and represents a serious public health risk in developing countries. In light of this situation, it is important to note that our understanding of the immunopathogenesis of human tuberculosis can be improved by studying this disease in the bovine model. Stimulation of the bovine innate immune system with calcitriol (1,25(OH)2D3) leads to an increase in bactericidal molecules involved in macrophage antimicrobial activity. It is unknown, however, if calcitriol´s effect on bovine macrophages impacts intracellular bacterial replication. With these considerations in mind, this study sought to investigate the specific role of calcitriol in tuberculosis control in bovine macrophages, in the hopes of uncovering information applicable to human tuberculosis. Assuch, infection with M. bovis was shown to induce expression of CYP27B1 and VDR genes in macrophages. Moreover, addition of 1,25(OH)2D3 to cultures of macrophages previously infected with mycobacteria and/or activated by LPS triggered cellular expression of nitric oxide synthase (NOS2) and increased nitrite concentrations, both indicators of nitric oxide (NO) production. By means of a microbicidal assay, addition of 1,25(OH)2D3 was seen to increase macrophage phagocytosis and to decrease mycobacterial intracellular replication. Thus, taken together, our results show that calcitriol can help stimulate the innate immune system of bovines by increasing phagocytosis and decreasing intracellular replication of microorganisms, such as M. bovis, in macrophages, through the VDR pathway.


greenmedinfo--2020-05-03--25(OH)D3 and 1.25(OH)2D3 inhibits TNF-α expression in human monocyte derived macrophages.

PURPOSE : We wanted to investigate effects of vitamin D3 ( 25 ( OH ) D3 and 1.25 ( OH ) 2D3 ) on inflammatory cytokine expression in both activated and non-activated Mφ .
MATERIALS AND METHODS : Mononuclear cells , isolated from healthy donor buffy coats were cultured for a 6-day differentiation-period .
Fully differentiated Mφ were pre-treated with either 25 ( OH ) D3 or 1.25 ( OH ) 2D3 for ( 4 , 12 or 24 hours ) +/-LPS challenge for 4 hours .
Gene expression analyses of VDR , Cyp27b1 and pro-inflammatory markers TNF-α , IL-6 @ @ @ @ @ @ @ using RT-quantitative PCR .
TNF-α protein levels from Mφ culture media wereanalysed by ELISA .
RESULTS : Both 25 ( OH ) D3 and 1.25 ( OH ) 2D3 significantly inhibited TNF-α expression in both LPS-stimulated and unstimulated Mφ .
Also , NF-κB , and to a lesser extend IL-6 and MCP-1 were inhibited .
LPS up-regulated Cyp27b1 gene expression which was partly reverted by 1.25 ( OH ) 2D3 .
CONCLUSION : These data show anti-inflammatory effects of vitamin D3 ( 25 ( OH ) D3 and 1.25 ( OH ) 2D3 @ @ @ @ @ @ @ , that means for targeting high dose vitamin D3 to the immune system may have beneficial clinical effect in inflammatory conditions .

PURPOSE: We wanted to investigate effects of vitamin D3 (25(OH)D3 and 1.25(OH)2D3) on inflammatory cytokine expression in both activated and non-activated Mφ.
MATERIALS AND METHODS: Mononuclear cells, isolated from healthy donor buffy coats were cultured for a 6-day differentiation-period. Fully differentiated Mφ were pre-treated with either 25(OH)D3 or 1.25(OH)2D3 for (4, 12 or 24 hours) +/-LPS challenge for 4 hours. Gene expression analyses of VDR, Cyp27b1 and pro-inflammatory markers TNF-α, IL-6, NF-κB, MCP-1, was performed using RT-quantitative PCR. TNF-α protein levels from Mφ culture media wereanalysed by ELISA.
RESULTS: Both 25(OH)D3 and 1.25(OH)2D3 significantly inhibited TNF-α expression in both LPS-stimulated and unstimulated Mφ. Also, NF-κB, and to a lesser extend IL-6 and MCP-1 were inhibited. LPS up-regulated Cyp27b1 gene expression which was partly reverted by 1.25(OH)2D3.
CONCLUSION: These data show anti-inflammatory effects of vitamin D3 (25(OH)D3 and 1.25(OH)2D3) in human macrophages, and support, that means for targeting high dose vitamin D3 to the immune system may have beneficial clinical effect in inflammatory conditions.


greenmedinfo--2020-05-03--The role of vitamin D in inflammatory bowel disease: mechanism to management.

Vitamin D has been linked to human health benefits that extend far beyond its established actions on calcium homeostasis and bone metabolism .
One of the most well studied facets of extra-skeletal vitamin D is its activity as an immuno-modulator , in particular its potent anti-inflammatory effects .
As a consequence , vitamin D deficiency has been associated with inflammatory diseases including inflammatory bowel disease ( IBD ) .
Low serum levels of the major circulating form of vitamin D , 25-hydroxyvitamin D ( 25-OH-D ) are significantly more prevalent in patients with IBD , particularly in the winter and @ @ @ @ @ @ @ D is lower .
Dietary malabsorption of vitamin D may also contribute to low serum 25 ( OH ) D in IBD .
The benefits of supplementation with vitamin D for IBD patients are still unclear , and improved vitamin D status may help to prevent the onset of IBD as well as ameliorating disease severity .
Beneficial effects of vitamin D in IBD are supported by pre-clinical studies , notably with mouse models , where the active form of vitamin D , 1,25-dihydroxyvitamin D ( 1,25- ( OH ) 2D ) has @ @ @ @ @ @ @ , and promote anti-inflammatory , tolerogenic immune responses .
The current narrative review aims to summarise the different strands of data linking vitamin D and IBD , whilst also outlining the possible beneficial effects of vitamin D supplementation in managing IBD in humans .

Vitamin D has been linked to human health benefits that extend far beyond its established actions on calcium homeostasis and bone metabolism. One of the most well studied facets of extra-skeletal vitamin D is its activity as an immuno-modulator, in particular its potent anti-inflammatory effects. As a consequence, vitamin D deficiency has been associated with inflammatory diseases including inflammatory bowel disease (IBD). Low serum levels of the major circulating form of vitamin D, 25-hydroxyvitamin D (25-OH-D) are significantly more prevalent in patients with IBD, particularly in the winter and spring months when UV-induced synthesis of vitamin D is lower. Dietary malabsorption of vitamin D may also contribute to low serum 25(OH)D in IBD. The benefits of supplementation with vitamin D for IBD patients are still unclear, and improved vitamin D status may help to prevent the onset of IBD as well as ameliorating disease severity. Beneficial effects of vitamin D in IBD are supported by pre-clinical studies, notably with mouse models, where the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH)2D) has been shown to regulate gastrointestinal microbiota function, and promote anti-inflammatory, tolerogenic immune responses. The current narrative review aims to summarise the different strands of data linking vitamin D and IBD, whilst also outlining the possible beneficial effects of vitamin D supplementation in managing IBD in humans.


greenmedinfo--2020-05-03--Health implication of vitamin D on the cardiovascular and the renal system.

Vitamin D regulates the calcium and phosphorus balance in the body .
The activated form of vitamin D ( 1α,25-dihydroxyvitamin @ @ @ @ @ D receptor which regulates genes that control cell proliferation , differentiation and apoptosis .
In @ @ @ @ @ vitamin D receptor is present in cardiomyocytes and the arterial wall .
A clear correlation @ @ @ @ @ cardiovascular diseases is established .
Vitamin D deficiency affects the renin-angiotensin system leading to ventricular @ @ @ @ @ .
While clinical trials highlighted the positive effects of vitamin D supplements on cardiovascular disease @ @ @ @ @ confirmed .
This review outlines the association between vitamin D and cardiovascular and renal disease @ @ @ @ @ selective cardiovascular disorders .

Vitamin D regulates the calcium and phosphorus balance in the body. The activated form of vitamin D (1α,25-dihydroxyvitamin D) binds to vitamin D receptor which regulates genes that control cell proliferation, differentiation and apoptosis. In the cardiovascular system, the vitamin D receptor is present in cardiomyocytes and the arterial wall. A clear correlation between vitamin D level and cardiovascular diseases is established. Vitamin D deficiency affects the renin-angiotensin system leading to ventricular hypertrophy and eventually to stroke. While clinical trials highlighted the positive effects of vitamin D supplements on cardiovascular disease these still need to be confirmed. This review outlines the association between vitamin D and cardiovascular and renal disease summarising the experimental data of selective cardiovascular disorders.


greenmedinfo--2020-05-03--An update on vitamin D and disease activity in multiple sclerosis.

Vitamin D and its main active metabolite 1,25-dihydroxyvitamin D serve a crucial role in maintenance of a healthy calcium metabolism , yet have additional roles in immune and central nervous system cell homeostasis .
Serum levels of 25-hydroxyvitamin D are a biomarker of future disease activity in patients with early relapsing-remitting multiple sclerosis ( RRMS ) , and vitamin D supplementation in patients with low circulating 25-dihydroxyvitamin D levels has been anticipated as a potential efficacious treatment strategy .
The results of the first large randomized clinical trials ( RCTs ) , the SOLAR and CHOLINE studies , have now @ @ @ @ @ @ @ 14,000 IU of vitamin D ( cholecalciferol ) per day with placebo for 48 weeks in 232 randomized patients , whereas CHOLINE compared vitamin D100,000 IU every other week with placebo for 96 weeks in 129 randomized patients .
All patients in both studies also used interferon-β-1a .
None of the studies met their primary endpoints , which were no evidence of disease activity ( NEDA-3 ) at 48 weeks in SOLAR and annualized relapse rate at 96 weeks inCHOLINE .
Both studies did , however , suggest modest effects on secondary endpoints @ @ @ @ @ @ @ number of new or enlarging lesions and new T2 lesions in SOLAR , and the annualized relapse rate and number of new T1 lesions , volume of hypointense T1 lesions , and disability progressionin the 90 patients who completed 96 weeks ' follow-up in CHOLINE .
We conclude that none of the RCTs on vitamin supplementation in MS have met their primary clinical endpoint in the intention to treat cohorts .
This contrasts the observation studies , where each 25 nmol/l increase in 25-hydroxyvitaminD levels were associated with 14-34 % reduced relapse risk @ @ @ @ @ @ @ lesions on magnetic resonnance imaging .
This discrepancy may have several explanations , including confounding and reverse causality in the observational studies .
The power calculations of the RCTs have been based on the observational studies , and the RCTs may have been underpowered to detect less prominent yet important effects of vitamin D supplementation .
Although the effect of vitamin D supplementation is uncertain and less pronounced than suggested by observational studies , current evidence still support that people with MS should avoid vitamin D insufficiency , and preferentially aim for vitamin @ @ @ @ @ @ @ higher .

Vitamin D and its main active metabolite 1,25-dihydroxyvitamin D serve a crucial role in maintenance of a healthy calcium metabolism, yet have additional roles in immune and central nervous system cell homeostasis. Serum levels of 25-hydroxyvitamin D are a biomarker of future disease activity in patients with early relapsing-remitting multiple sclerosis (RRMS), and vitamin D supplementation in patients with low circulating 25-dihydroxyvitamin D levels has been anticipated as a potential efficacious treatment strategy. The results of the first large randomized clinical trials (RCTs), the SOLAR and CHOLINE studies, have now been published. The SOLAR study compared 14,000 IU of vitamin D(cholecalciferol) per day with placebo for 48 weeks in 232 randomized patients, whereas CHOLINE compared vitamin D100,000 IU every other week with placebo for 96 weeks in 129 randomized patients. All patients in both studies also used interferon-β-1a. None of the studies met their primary endpoints, which were no evidence of disease activity (NEDA-3) at 48 weeks in SOLAR and annualized relapse rate at 96 weeks inCHOLINE. Both studies did, however, suggest modest effects on secondary endpoints. Thus, vitamin D reduced the number of new or enlarging lesions and new T2 lesions in SOLAR, and the annualized relapse rate and number of new T1 lesions, volume of hypointense T1 lesions, and disability progressionin the 90 patients who completed 96 weeks' follow-up in CHOLINE. We conclude that none of the RCTs on vitamin supplementation in MS have met their primary clinical endpoint in the intention to treat cohorts. This contrasts the observation studies, where each 25 nmol/l increase in 25-hydroxyvitaminD levels were associated with 14-34% reduced relapse risk and 15-50% reduced risk of new lesions on magnetic resonnance imaging. This discrepancy may have several explanations, including confounding and reverse causality in the observational studies. The power calculations of the RCTs have been based on the observational studies, and the RCTs may have been underpowered to detect less prominent yet important effects of vitamin D supplementation. Although the effect of vitamin D supplementation is uncertain and less pronounced than suggested by observational studies, current evidence still support that people with MS should avoid vitamin D insufficiency, and preferentially aim for vitamin D levels around 100 nmol/L or somewhat higher.


greenmedinfo--2020-05-03--These findings suggest that vitamin D supplementation attenuates inflammatory response in adipose ti

These findings suggest that vitamin D supplementation attenuates inflammatory response in adipose tissue.

Vitamin D status has been implicated in obesity and adipose tissue inflammation .
In the present study , we explored the effects of dietary vitamin D supplementation on adipose tissue inflammation and immune cell population , and the effects of in vitro 1,25-dihydroxyvitamin D3 ( 1,25- ( OH ) 2D3 ) treatment on pro-inflammatory cytokine production by stromal vascular cells ( SVCs ) and adipocytes in lean and high-fat diet-induced obese mice .
The results show that epididymal fat Mcp-1 and Rantes mRNA levels , which were higher in obese mice compared with lean mice , were significantly down-regulated by @ @ @ @ @ @ @ had higher numbers of macrophages and natural killer ( NK ) cells within adipose tissue , these remained unaltered by vitamin D supplementation .
In accordance with these in vivo findings , the in vitro 1,25 ( OH ) 2D3 treatment decreased IL-6 , MCP-1 , and IL-1β production by SVCs from obese mice , but not by adipocytes .
In addition , 1,25 ( OH ) 2D3 treatment significantly decreased Tlr2 expression and increased mRNA levels of Iba and Dusp1 in SVCs .
These findings suggest that vitamin D supplementation attenuates inflammatory @ @ @ @ @ @ @ SVCs , possibly through inhibiting NF-κB and MAPK signaling pathways in SVCs but not by the inhibition of macrophage infiltration .

Vitamin D status has been implicated in obesity and adipose tissue inflammation. In the present study, we explored the effects of dietary vitamin D supplementation on adipose tissue inflammation and immune cell population, and the effects of in vitro 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) treatment on pro-inflammatory cytokine production by stromal vascular cells (SVCs) and adipocytes in lean and high-fat diet-induced obese mice. The results show that epididymal fat Mcp-1 and Rantes mRNA levels, which were higher in obese mice compared with lean mice, were significantly down-regulated by vitamin D supplementation. While obese mice had higher numbers of macrophages and natural killer (NK) cells within adipose tissue, these remained unaltered by vitamin D supplementation. In accordance with these in vivo findings, the in vitro 1,25(OH)2D3 treatment decreased IL-6, MCP-1, and IL-1β production by SVCs from obese mice, but not by adipocytes. In addition, 1,25(OH)2D3 treatment significantly decreased Tlr2 expression and increased mRNA levels of Iba and Dusp1 in SVCs. These findings suggest that vitamin D supplementation attenuates inflammatory response in adipose tissue, especially in SVCs, possibly through inhibiting NF-κB and MAPK signaling pathways in SVCs but not by the inhibition of macrophage infiltration.


greenmedinfo--2020-05-03--1,25(OH)2 D3 inhibited Th17 cells differentiation via regulating the NF-κB activity and expression o

1,25(OH)2 D3 inhibited Th17 cells differentiation via regulating the NF-κB activity and expression of IL-17.

OBJECTIVES : The role of vitamin D ( VD ) in innate and adaptive immune responses to tuberculosis is still unclear .
Our research was aimed to uncover the effect of VD on Th17 cells and elucidate potential molecular mechanism .
MATERIALS AND METHODS : VDR-deficient and wild-type mice were used to obtain CD4 T cells .
Th17 cells were induced and activated by Bacillus Calmette Guerin .
Flow cytometry was used to analyse the apoptosis rate and degree of differentiation of Th17 cells in the treatment of 1,25 ( OH ) D. The interaction between P65 and Rorc was @ @ @ @ @ @ @ assay , EMSA-Super-shelf assay and ChIP assay .
Co-IP assay was carried out to test the interaction between VDR and NF-κB family proteins .
qRT-PCR and Western blot were also performed to detect the levels of P65 , RORγt and IL-17 .
RESULTS : The Th17 cells differentiation was suppressed by 1,25 ( OH ) Din vitro .
We confirmed that Rorc was a downstream gene of the transcription factor P65 .
VDR interacts with P105/P50 , P100/P52 and P65 NF-κB family proteins .
1,25 ( OH ) Dinhibited the expression of RORγt/IL-17 @ @ @ @ @ @ @ nucleus .
In vivo experiments , the expression of IL-17 and RANKL was suppressed by 1,25 ( OH ) Dby VD receptor .
Moreover , 1,25 ( OH ) Dsuppressed the inflammatory infiltrates and inhibited the expression of P65 , RORγt and IL-17 in the spleen tissues of model mice .
CONCLUSIONS : Together , 1,25 ( OH ) Dsuppressed the differentiation of Th17 cells via regulating the NF-κB activity .

OBJECTIVES: The role of vitamin D (VD) in innate and adaptive immune responses to tuberculosis is still unclear. Our research was aimed to uncover the effect of VD on Th17 cells and elucidate potential molecular mechanism.
MATERIALS AND METHODS: VDR-deficient and wild-type mice were used to obtain CD4 T cells. Th17 cells were induced and activated by Bacillus Calmette Guerin. Flow cytometry was used to analyse the apoptosis rate and degree of differentiation of Th17 cells in the treatment of 1,25(OH)D. The interaction between P65 and Rorc was determined by immunofluorescence assay, luciferase reporter assay, EMSA-Super-shelf assay and ChIP assay. Co-IP assay was carried out to test the interaction between VDR and NF-κB family proteins. qRT-PCR and Western blot were also performed to detect the levels of P65, RORγt and IL-17.
RESULTS: The Th17 cells differentiation was suppressed by 1,25(OH)Din vitro. We confirmed that Rorc was a downstream gene of the transcription factor P65. VDR interacts with P105/P50, P100/P52 and P65 NF-κB family proteins. 1,25(OH)Dinhibited the expression of RORγt/IL-17 by suppressing p65 transcription factor translocating to nucleus. In vivo experiments, the expression of IL-17 and RANKL was suppressed by 1,25(OH)Dby VD receptor. Moreover, 1,25(OH)Dsuppressed the inflammatory infiltrates and inhibited the expression of P65, RORγt and IL-17 in the spleen tissues of model mice.
CONCLUSIONS: Together, 1,25(OH)Dsuppressed the differentiation of Th17 cells via regulating the NF-κB activity.


greenmedinfo--2020-05-03--Vitamin D as a potential therapy for multiple sclerosis.

Multiple sclerosis ( MS ) is a chronic demyelinating disease of the central nervous system and is caused by an aberrant immune response to myelin sheath .
Disease-modifying medications , which mainly aim to suppress such aberrant immune response , have significantly improved MS treatment .
However , the disease severity continues to worsen .
In contrast , progressively more data suggest that 1,25-dihydroxyvitamin D or 1,25 ( OH ) D , i.e.
, the active vitamin D , suppresses the differentiation of potentially pathogenic T cells associated with MS , enhances the differentiation of regulatory T cells that suppress @ @ @ @ @ @ @ remyelination .
These novel 1,25 ( OH ) D functions have encouraged investigators to develop vitamin D as a potential therapy for MS .
However , because of the hypercalcemia that is associated with high 1,25 ( OH ) D concentrations , supplementation of native vitamin D has been a major focus in clinical trials for the treatment of MS , but such trials have produced mixed data .
In this article , we will review current progress in the supplementation of different vitamin D forms for the treatment of experimental autoimmune encephalomyelitis @ @ @ @ @ @ @ ) as well as MS .
Furthermore , we will review alternative strategies that our laboratory and others are pursuing in an attempt to circumvent the hurdles that are hampering the effective use of vitamin D as a potential therapy for MS .

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and is caused by an aberrant immune response to myelin sheath. Disease-modifying medications, which mainly aim to suppress such aberrant immune response, have significantly improved MS treatment. However, the disease severity continues to worsen. In contrast, progressively more data suggest that 1,25-dihydroxyvitamin D or 1,25(OH)D, i.e., the active vitamin D, suppresses the differentiation of potentially pathogenic T cells associated with MS, enhances the differentiation of regulatory T cells that suppress the pathogenic T cells, and promotes remyelination. These novel 1,25(OH)D functions have encouraged investigators to develop vitamin D as a potential therapy for MS. However, because of the hypercalcemia that is associated with high 1,25(OH)D concentrations, supplementation of native vitamin D has been a major focus in clinical trials for the treatment of MS, but such trials have produced mixed data. In this article, we will review current progress in the supplementation of different vitamin D forms for the treatment of experimental autoimmune encephalomyelitis (i.e., an MS animal model) as well as MS. Furthermore, we will review alternative strategies that our laboratory and others are pursuing in an attempt to circumvent the hurdles that are hampering the effective use of vitamin D as a potential therapy for MS.


greenmedinfo--2020-05-03--Hepatitis A virus structural protein pX interacts with ALIX and promotes the secretion of virions an

Hepatitis A virus structural protein pX interacts with ALIX and promotes the secretion of virions and foreign proteins through exosome-like vesicles.

Hepatitis A virus ( HAV ) , a classic nonenveloped virus , has recently been found to be released mainly in the form of quasi-enveloped HAV ( eHAV ) by hijacking host endosomal sorting complexes required for transport ( ESCRT ) complexes .
Unlike the nonenveloped virion , eHAV contains the viral protein pX on the surface of the HAV capsid as an extension of VP1 .
How HAV capsids acquire the host envelope and whether the pX protein is involved in this process were previously unknown .
Here , we analyse the role of pX in foreign protein secretion @ @ @ @ @ @ @ and the formation of eHAV .
Fusion of pX to eGFP guided eGFP into exosome-like EVs through directing eGFP into multivesicular bodies ( MVBs ) , and apoptosis-linked gene 2-interacting protein X ( ALIX ) release was significantly enhanced .
Coimmunoprecipitation ( co-IP ) demonstrated the interaction between pX and the ALIX V domain .
Removal of the C-terminal half of pX abolished eHAV release and reduced the interaction between the HAV virion and ALIX .
Finally , the C-terminal half of pX alone was sufficient for loading eGFP into EVs by interacting @ @ @ @ @ @ @ C-terminal part of pX is important for eHAV production and may have potential for large protein complex loading into exosome-like EVs for therapeutic purposes .

Hepatitis A virus (HAV), a classic nonenveloped virus, has recently been found to be released mainly in the form of quasi-enveloped HAV (eHAV) by hijacking host endosomal sorting complexes required for transport (ESCRT) complexes. Unlike the nonenveloped virion, eHAV contains the viral protein pX on the surface of the HAV capsid as an extension of VP1. How HAV capsids acquire the host envelope and whether the pX protein is involved in this process were previously unknown. Here, we analyse the role of pX in foreign protein secretion in exosome-like extracellular vesicles (EVs) and the formation of eHAV. Fusion of pX to eGFP guided eGFP into exosome-like EVs through directing eGFP into multivesicular bodies (MVBs), and apoptosis-linked gene 2-interacting protein X (ALIX) release was significantly enhanced. Coimmunoprecipitation (co-IP) demonstrated the interaction between pX and the ALIX V domain. Removal of the C-terminal half of pX abolished eHAV release and reduced the interaction between the HAV virion and ALIX. Finally, the C-terminal half of pX alone was sufficient for loading eGFP into EVs by interacting with ALIX. In conclusion, the C-terminal part of pX is important for eHAV production and may have potential for large protein complex loading into exosome-like EVs for therapeutic purposes.


greenmedinfo--2020-05-03--Serum exosomal transfer of miR-483-3p might be involved in the inflammatory pathogenesis of H5N1 inf

Serum exosomal transfer of miR-483-3p might be involved in the inflammatory pathogenesis of H5N1 influenza virus infection.

Exosomes , the extracellular vesicles that contain functional proteins and RNAs , regulate cell-cell communication .
Recently , our group @ @ @ @ @ microRNAs ( miRNAs ) in bronchoalveolar lavage fluid exosomes were highly increased in influenza virus-infected @ @ @ @ @ those miRNAs , miR-483-3p , was involved in the potentiation of the innate immune responses @ @ @ @ @ mouse type II pneumocytes .
Here , we evaluated exosomal miR-483-3p levels in the serum @ @ @ @ @ found that miR-483-3p levels were significantly increased during infection with a highly pathogenic avian H5N1 @ @ @ @ @ miR-483-3p-enriched exosomes derived from type II pneumocytes potentiated the expression of proinflammatory cytokine genes in @ @ @ @ @ findings suggest that serum exosomal transfer of miR-483-3p might be involved in the inflammatory pathogenesis @ @ @ @ @ .

Exosomes, the extracellular vesicles that contain functional proteins and RNAs, regulate cell-cell communication. Recently, our group reported that levels of various microRNAs (miRNAs) in bronchoalveolar lavage fluid exosomes were highly increased in influenza virus-infected mice and that one of those miRNAs, miR-483-3p, was involved in the potentiation of the innate immune responses to influenza virus infection in mouse type II pneumocytes. Here, we evaluated exosomal miR-483-3p levels in the serum of influenza virus-infected mice and found that miR-483-3p levels were significantly increased during infection with a highly pathogenic avian H5N1 influenza virus. Moreover, miR-483-3p-enriched exosomes derived from type II pneumocytes potentiated the expression of proinflammatory cytokine genes in vascular endothelial cells. Our findings suggest that serum exosomal transfer of miR-483-3p might be involved in the inflammatory pathogenesis of H5N1 influenza virus infection.


greenmedinfo--2020-05-03--Mycobacterium tuberculosis reactivates HIV-1 via exosome-mediated resetting of cellular redox potent

Mycobacterium tuberculosis reactivates HIV-1 via exosome-mediated resetting of cellular redox potential and bioenergetics.

The synergy betweenand human immunodeficiency virus-1 ( HIV-1 ) interferes with therapy and facilitates the pathogenesis of both human pathogens .
Fundamental mechanisms by whichexacerbates HIV-1 infection are not clear .
Here , we show that exosomes secreted by macrophages infected with , including drug-resistant clinical strains , reactivated HIV-1 by inducing oxidative stress .
Mechanistically , -specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates ( OCR ) and modulated the expression of host genes mediating oxidative stress response , inflammation , and HIV-1 transactivation .
Proteomics analyses revealed the enrichment of several host factors ( e.g.
, HIF-1α @ @ @ @ @ @ @ to promote HIV-1 reactivation in-specific exosomes .
Treatment with a known antioxidant-N-acetyl cysteine ( NAC ) -or with inhibitors of host factors-galectins and Hsp90-attenuated HIV-1 reactivation byspecific exosomes .
Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-coinfection , which will enable the design of effective therapeutic strategies.Globally , individuals coinfected with the AIDS virus ( HIV-1 ) and with ( causative agent of tuberculosis [ TB ] ) pose major obstacles in the clinical management of both diseases .
At the heart of this issue is the @ @ @ @ @ @ @ .
On the one hand , mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized .
On the other hand , while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality , basic mechanisms by whichexacerbates HIV-1 replication and infection remain poorly characterized .
The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-synergy .
The quantification of redox and respiratory parameters affected byin stimulating HIV-1 will greatly enhance our @ @ @ @ @ @ @ wider impact on the biomedical research community and creating new translational opportunities .

The synergy betweenand human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by whichexacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically,-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1α, galectins, and Hsp90) known to promote HIV-1 reactivation in-specific exosomes. Treatment with a known antioxidant-N-acetyl cysteine (NAC)-or with inhibitors of host factors-galectins and Hsp90-attenuated HIV-1 reactivation byspecific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-coinfection, which will enable the design of effective therapeutic strategies.Globally, individuals coinfected with the AIDS virus (HIV-1) and with(causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by whichexacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-synergy. The quantification of redox and respiratory parameters affected byin stimulating HIV-1 will greatly enhance our understanding of HIV-coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.


greenmedinfo--2020-05-03--5G - The Global Human Experiment without Consent & Most Censored Topic of Our Time

Join Sayer Ji and Josh Del Sol for the Soon 5G will significantly increase our wireless RF radiation ( radio frequency microwave ) exposure 24/7/365 .
Senior telecom executives admit they have not done any safety testing on 5G , ( nor do they plan to do any ) , but related research does show is cause for alarm .
Thousands of independent studies indicate adverse health impacts from wireless radiation , ranging from cancer and sterility to DNA damage 5G is the next generation of cell phone infrastructure , yet it is categorically different than its predecessors ( 4G/LTE @ @ @ @ @ @ @ .
It is not a simple upgrade .
It is a major increase - and change - in the type of wireless radiation to which we will all be exposed , without consent , whether we use this service or not .
5G builds on existing infrastructure and , in addition , uses extremely high ( millimeter-wave ) frequencies of 24 gigahertz ( GHz ) or more .
These 5G signals do n't travel far , so antennas will be installed approximately every 2-10 homes in residential neighborhoods .
5G will significantly increase @ @ @ @ @ @ @ microwave ) exposure on a 24/7 and 365 days a year basis .
In a February 2019 U.S. Senate hearing , senior telecom executives admitted they have not done any safety testing on 5G , nor do they plan to do any .
Currently , there are over two dozen cities in the U.S. and countless cities abroad that have 5G , yet there is no scientific evidence to support any claim of safety for it .
What related research does show is cause for alarm .
Thousands of independent studies indicate adverse @ @ @ @ @ @ @ range from cancer and sterility to DNA damage .
The government 's human exposure guidelines have n't been updated in more than 20 years , while radiation from cell phones , cordless phones , WiFi and wireless baby monitors has increased exponentially in that time .
The 5G agenda is vast .
It includes 200 billion transmitting objects , according to estimates , that will be part of the Internet of Things ( IoT ) by 2020 , with one trillion transmitting objects a few years later .
5G is meant to usher @ @ @ @ @ @ @ autonomous vehicles , including 5G antennas installed inside cars - behind our heads and irradiating our brains - so we can talk to people in other vehicles and instruct our driverless cars on where to take us .
5G base stations and 5G devices will have multiple antennas in phased arrays that work together to emit focused , steerable , laser-like beams that track each other .
Each 5G phone will function like a mini cell tower , containing dozens of tiny antennas working together to track and aim a narrowly focused beam @ @ @ @ @ @ @ cell antenna .
The FCC has adopted rules that permit those beams to be as much as 20 watts , ten times more powerful than levels allowed on current phones .
More than 10,000 peer-reviewed scientific studies conducted by independent researchers from around the world demonstrate the harmful biological effects of wireless radiation .
Because of their developmental stages , children are much more susceptible .
You can also view the GreenMedInfo.com database of over 150 documented adverse effects of non-native EMF as signaled in the following 1,000 studies : Electromagnetic Fields .
@ @ @ @ @ @ @ of wireless radiation include : The mechanisms of biological harm from wireless radiation were not well understood until Martin Pall , PhD , demonstrated how voltage-gated calcium channels are disrupted , resulting in excessive intracellular calcium ions affecting our cells .
Numerous independent studies on millimeter-wave radiation already show a range of biological effects , indicating that an increase in frequencies may worsen harmful effects .
The Telecommunications Act of 1996 , section 704 , gives the telecom industry free reign and prohibits opposition to wireless infrastructure based on environmental effects , which @ @ @ @ @ @ @ prohibition is being challenged in court right now .
The telecom industry is supposed to be regulated by the Federal Communications Commission ( FCC ) ; however , the Harvard Center for Ethics describes the FCC as a `` captured agency '' that is dominated by the industry it is purported to regulate .
The multi-trillion dollar telecom industry wields massive lobbying power and formidable public influence through pervasive , propagandistic advertising and media presence promoting 5G .
In the Information Age , data drives the economy .
5G is being touted as @ @ @ @ @ @ @ in fact , it amounts to surveillance capitalism , in which intimate details of our lives are tracked , recorded and sold to the highest bidder , irradiating us all the while .
In addition to millions of new base stations on Earth , 5G includes an eventual 20,000+ satellites in low orbit , affecting the ionosphere .
Players include Elon Musk 's SpaceX , OneWeb and Amazon .
At this time , 66 5G satellites have already been launched , with more on the way .
The direct radiation from these satellites @ @ @ @ @ @ @ ionosphere , along with pollution of the global electrical circuit would likely be catastrophic to all life on Earth .
5G threatens to provoke serious , irreversible effects on humans and permanent damage to all of Earth 's ecosystems .
Immediate measures must be taken to protect life in all of its forms .
One solution is SafeG , wired public networks that allow for wireless inside homes and businesses without forcing it on everyone .
You may have heard of 5G , it stands for fifth-generation cellular wireless .
In a February @ @ @ @ @ @ @ industry was forced to admit they have no safety studies on 5G , and do n't plan to do any .
Meanwhile , there are thousands of independent studies concluding that wireless radiation causes biological harm .
Despite this , the wireless industry is in league with government to deploy 5G -- it 's a global , for-profit , human experiment ... without our consent .
Do n't miss The 5G Summit 2020 : Worldwide Call to Action from June 1-7th , 2020 , free and online !

Join Sayer Ji and Josh Del Sol for the The 5G Summit 2020: Worldwide Call to Action from June 1-7th, 2020, free and online!
Soon 5G will significantly increase our wireless RF radiation (radio frequency microwave) exposure 24/7/365. Senior telecom executives admit they have not done any safety testing on 5G, (nor do they plan to do any), but related research does show is cause for alarm. Thousands of independent studies indicate adverse health impacts from wireless radiation, ranging from cancer and sterility to DNA damage
5G is the next generation of cell phone infrastructure, yet it is categorically different than its predecessors (4G/LTE, 3G, 2G, etc.). It is not a simple upgrade. It is a major increase - and change - in the type of wireless radiation to which we will all be exposed, without consent, whether we use this service or not.
5G builds on existing infrastructure and, in addition, uses extremely high (millimeter-wave) frequencies of 24 gigahertz (GHz) or more. These 5G signals don't travel far, so antennas will be installed approximately every 2-10 homes in residential neighborhoods. 5G will significantly increase our wireless RF radiation (radio frequency microwave) exposure on a 24/7 and 365 days a year basis.
No Safety Studies
In a February 2019 U.S. Senate hearing, senior telecom executives admitted they have not done any safety testing on 5G, nor do they plan to do any. Currently, there are over two dozen cities in the U.S. and countless cities abroad that have 5G, yet there is no scientific evidence to support any claim of safety for it.
What related research does show is cause for alarm. Thousands of independent studies indicate adverse health impacts from wireless radiation. These range from cancer and sterility to DNA damage. The government's human exposure guidelines haven't been updated in more than 20 years, while radiation from cell phones, cordless phones, WiFi and wireless baby monitors has increased exponentially in that time.
Planet Earth Blanketed in Radiation
The 5G agenda is vast. It includes 200 billion transmitting objects, according to estimates, that will be part of the Internet of Things (IoT) by 2020, with one trillion transmitting objects a few years later. 5G is meant to usher in more robotics, artificial intelligence and autonomous vehicles, including 5G antennas installed inside cars - behind our heads and irradiating our brains - so we can talk to people in other vehicles and instruct our driverless cars on where to take us.
5G base stations and 5G devices will have multiple antennas in phased arrays that work together to emit focused, steerable, laser-like beams that track each other. Each 5G phone will function like a mini cell tower, containing dozens of tiny antennas working together to track and aim a narrowly focused beam to search and connect with the nearest cell antenna. The FCC has adopted rules that permit those beams to be as much as 20 watts, ten times more powerful than levels allowed on current phones.
More than 10,000 peer-reviewed scientific studies conducted by independent researchers from around the world demonstrate the harmful biological effects of wireless radiation. Because of their developmental stages, children are much more susceptible. You can also view the GreenMedInfo.com database of over 150 documented adverse effects of non-native EMF as signaled in the following 1,000 studies: Electromagnetic Fields. Some of the more well-established adverse effects of wireless radiation include:
Detrimental effects on fetal and newborn development
Detrimental effects on young children
Brain tumors and other cancers
DNA damage and altered gene expression
Neurological effects and cognitive impairment
Impaired sperm function and quality
Learning and memory deficits
Cardiovascular disease
Altered metabolism
And more
The mechanisms of biological harm from wireless radiation were not well understood until Martin Pall, PhD, demonstrated how voltage-gated calcium channels are disrupted, resulting in excessive intracellular calcium ions affecting our cells. Numerous independent studies on millimeter-wave radiation already show a range of biological effects, indicating that an increase in frequencies may worsen harmful effects.
Government Corruption
The Telecommunications Act of 1996, section 704, gives the telecom industry free reign and prohibits opposition to wireless infrastructure based on environmental effects, which includes health effects. Thankfully, this prohibition is being challenged in court right now.
The telecom industry is supposed to be regulated by the Federal Communications Commission (FCC); however, the Harvard Center for Ethics describes the FCC as a "captured agency" that is dominated by the industry it is purported to regulate. The multi-trillion dollar telecom industry wields massive lobbying power and formidable public influence through pervasive, propagandistic advertising and media presence promoting 5G.
In the Information Age, data drives the economy. 5G is being touted as the next industrial revolution, when, in fact, it amounts to surveillance capitalism, in which intimate details of our lives are tracked, recorded and sold to the highest bidder, irradiating us all the while.
Let's Irradiate the Sky, Too
In addition to millions of new base stations on Earth, 5G includes an eventual 20,000+ satellites in low orbit, affecting the ionosphere. Players include Elon Musk's SpaceX, OneWeb and Amazon. At this time, 66 5G satellites have already been launched, with more on the way. The direct radiation from these satellites, combined with their contamination of our ionosphere, along with pollution of the global electrical circuit would likely be catastrophic to all life on Earth.
5G threatens to provoke serious, irreversible effects on humans and permanent damage to all of Earth's ecosystems. Immediate measures must be taken to protect life in all of its forms. One solution is SafeG, wired public networks that allow for wireless inside homes and businesses without forcing it on everyone.
You may have heard of 5G, it stands for fifth-generation cellular wireless. In a February 2019 US Senate hearing, the wireless industry was forced to admit they have no safety studies on 5G, and don't plan to do any. Meanwhile, there are thousands of independent studies concluding that wireless radiation causes biological harm. Despite this, the wireless industry is in league with government to deploy 5G -- it's a global, for-profit, human experiment... without our consent. Don't miss The 5G Summit 2020: Worldwide Call to Action from June 1-7th, 2020, free and online!


greenmedinfo--2020-05-03--Chronic exposure to MP-RF-EMF radiation emitted from mobile phones may induce oxidative stress, infl

Chronic exposure to MP-RF-EMF radiation emitted from mobile phones may induce oxidative stress, inflammatory response, and HPA axis deregulation.

In the present lifestyle , we are continuously exposed to radiofrequency electromagnetic field ( RF-EMF ) radiation generated mainly by mobile phones ( MP ) .
Among other organs , our brain and hippocampus in specific , is the region where effect of any environmental perturbation is most pronounced .
So , this study was aimed to examine changes in major parameters ( oxidative stress , level of pro-inflammatory cytokines ( PICs ) , hypothalamic-pituitary-adrenal ( HPA ) axis hormones , and contextual fear conditioning ) which are linked to hippocampus directly or indirectly , upon exposure to mobile phone @ @ @ @ @ @ @ .
Exposure was performed on young adult male Wistar rats for 16 weeks continuously ( 2 h/day ) with MP-RF-EMF radiation having frequency , power density , and specific absorption rate ( SAR ) of 1966.1 MHz , 4.0 mW/cm , and 0.36 W/kg , respectively .
Another set of animals kept in similar conditions without any radiation exposure serves as control .
Towards the end of exposure period , animals were tested for fear memory and then euthanized to measure hippocampal oxidative stress , level of circulatory PICs , and stress hormones @ @ @ @ @ @ @ oxidative stress ( p

In the present lifestyle, we are continuously exposed to radiofrequency electromagnetic field (RF-EMF) radiation generated mainly by mobile phones (MP). Among other organs, our brain and hippocampus in specific, is the region where effect of any environmental perturbation is most pronounced. So, this study was aimed to examine changes in major parameters (oxidative stress, level of pro-inflammatory cytokines (PICs), hypothalamic-pituitary-adrenal (HPA) axis hormones, and contextual fear conditioning) which are linked to hippocampus directly or indirectly, upon exposure to mobile phone radiofrequency electromagnetic field (MP-RF-EMF) radiation. Exposure was performed on young adult male Wistar rats for 16 weeks continuously (2 h/day) with MP-RF-EMF radiation having frequency, power density, and specific absorption rate (SAR) of 1966.1 MHz, 4.0 mW/cm, and 0.36 W/kg, respectively. Another set of animals kept in similar conditions without any radiation exposure serves as control. Towards the end of exposure period, animals were tested for fear memory and then euthanized to measure hippocampal oxidative stress, level of circulatory PICs, and stress hormones. We observed significant increase in hippocampal oxidative stress (p < 0.05) and elevated level of circulatory PICs viz. IL-1beta (p < 0.01), IL-6 (p < 0.05), and TNF-alpha (p < 0.001) in experimental animals upon exposure to MP-RF-EMF radiation. Adrenal gland weight (p < 0.001) and level of stress hormones viz. adrenocorticotropic hormone (ACTH) (p < 0.01) and corticosterone (CORT) (p < 0.05) were also found to increase significantly in MP-RF-EMF radiation-exposed animals as compared with control. However, alteration in contextual fear memory was not significant enough. In conclusion, current study shows that chronic exposure to MP-RF-EMF radiation emitted from mobile phones mayinduce oxidative stress, inflammatory response, and HPA axis deregulation. However, changes in hippocampal functionality depend on the complex interplay of several opposing factors that got affected upon MP-RF-EMF exposure.


greenmedinfo--2020-05-03--Impacts of electromagnetic radiation from cellphones and Wi-Fi on spermatogenesis.

With the development of Wi-Fi technology and widespread exposure to electromagnetic radiation ( EMR ) , people are increasingly concerned @ @ @ @ @ by radiofrequency electromagnetic fields as from cellphones and Wi-Fi , particularly about the current decline @ @ @ @ @ in male infertility .
Long-term exposure to EMR not only damages male reproductive organs , @ @ @ @ @ , morphology , motility and oocyte-binding ability of sperm , and indirectly increases the risk @ @ @ @ @ EMR is not unavoidable .
Low-intensity short-term or intermittent exposure to EMR has little adverse @ @ @ @ @ sperm .
And many antioxidant and anti-free radical agents , such as vitamin E and @ @ @ @ @ special populations from EMR .
This review presents an overview of the impacts of EMR @ @ @ @ @ sperm , some countermeasures , and prospects of EMR protection .

With the development of Wi-Fi technology and widespread exposure to electromagnetic radiation (EMR), people are increasingly concerned about the health hazards caused by radiofrequency electromagnetic fields as from cellphones and Wi-Fi, particularly about the current decline in sperm concentration and increase in male infertility. Long-term exposure to EMR not only damages male reproductive organs, but also affects the number, morphology, motility and oocyte-binding ability of sperm, and indirectly increases the risk of infertility. However, EMR is not unavoidable. Low-intensity short-term or intermittent exposure to EMR has little adverse effect on reproductive organs and sperm. And many antioxidant and anti-free radical agents, such as vitamin E and melatonin, can protect some special populations from EMR. This review presents an overview of the impacts of EMR from cellphones and Wi-Fi on sperm, some countermeasures, and prospects of EMR protection.


greenmedinfo--2020-05-03--Vitamin D attenuates human gingival fibroblast inflammatory cytokine production following advanced g

Vitamin D attenuates human gingival fibroblast inflammatory cytokine production following advanced glycation end product interaction with receptors for AGE.

BACKGROUND AND OBJECTIVES : Vitamin D [ 1,25 ( OH ) Dor 1,25D3 ] is critical in musculoskeletal health , inflammation , immune response , and glucose metabolism .
Patients with vitamin D deficiency may be at higher risk of diabetes and periodontitis .
Diabetic patients exhibit exacerbated inflammation and more periodontal destruction .
Advanced glycation end products ( AGEs ) , formed during diabetic hyperglycemia , activate inflammatory pathways in periodontitis .
Human gingival fibroblasts ( HGFs ) express receptors for AGEs ( RAGEs ) and can contribute to inflammation .
OBJECTIVES : Determine whether glycated human serum albumin @ @ @ @ @ @ @ IL-8 production , and whether treatment with 1,25D3 attenuates cytokine production following stimulation with G-HSA + IL-1β and/or IL-17 .
MATERIAL AND METHODS : HGFs were incubated±G-HSA or normal human serum albumin ( HSA ) , ±IL-1β and/or IL-17 , ±1,25D3 .
Cytokines were measured by ELISA .
Neutralizing anti-RAGE was used to assess AGE-RAGE interaction .
Endotoxin was measured using the ToxinSensor™ System .
Data were expressed as mean ± standard deviation and analyzed using a one-way analysis of variance ( ANOVA ) and Scheffe 's F procedure for post hoc comparisons @ @ @ @ @ @ @ but not HSA , significantly stimulated IL-6 and IL-8 production .
G-HSA or HSA when combined with IL-1β or IL-1β + IL-17 synergistically stimulated IL-6 and IL-8 .
Neutralizing anti-RAGE inhibited IL-6 and IL-8 produced by cells stimulated with IL-1β + G-HSA but not ( +HSA ) .
Synergism causedby HSA did not appear to be mediated by endotoxin since its levels in G-HSA and HSA were not sufficient to stimulate fibroblasts .
Vitamin D inhibited IL-6 and IL-8 production stimulated by G-HSA or HSA + IL-1β or IL-1β + IL-17 .
CONCLUSIONS @ @ @ @ @ @ @ '' effects of vitamin D are related to its ability to regulate inflammatory cytokine production by HGFs following AGE-RAGE interaction .

BACKGROUND AND OBJECTIVES: Vitamin D [1,25(OH)Dor 1,25D3] is critical in musculoskeletal health, inflammation, immune response, and glucose metabolism. Patients with vitamin D deficiency may be at higher risk of diabetes and periodontitis. Diabetic patients exhibit exacerbated inflammation and more periodontal destruction. Advanced glycation end products (AGEs), formed during diabetic hyperglycemia, activate inflammatory pathways in periodontitis. Human gingival fibroblasts (HGFs) express receptors for AGEs (RAGEs) and can contribute to inflammation.
OBJECTIVES: Determine whether glycated human serum albumin (G-HSA) augments HGF IL-6 and IL-8 production, and whether treatment with 1,25D3 attenuates cytokine production following stimulation with G-HSA + IL-1β and/or IL-17.
MATERIAL AND METHODS: HGFs were incubated±G-HSA or normal human serum albumin (HSA), ±IL-1β and/or IL-17, ±1,25D3. Cytokines were measured by ELISA. Neutralizing anti-RAGE was used to assess AGE-RAGE interaction. Endotoxin was measured using the ToxinSensor™ System. Data were expressed as mean ± standard deviation and analyzed using a one-way analysis of variance (ANOVA) and Scheffe's F procedure for post hoc comparisons.
RESULTS: G-HSA or IL-1β, but not HSA, significantly stimulated IL-6 and IL-8 production. G-HSA or HSA when combined with IL-1β or IL-1β + IL-17 synergistically stimulated IL-6 and IL-8. Neutralizing anti-RAGE inhibited IL-6 and IL-8 produced by cells stimulated with IL-1β + G-HSA but not (+HSA). Synergism causedby HSA did not appear to be mediated by endotoxin since its levels in G-HSA and HSA were not sufficient to stimulate fibroblasts. Vitamin D inhibited IL-6 and IL-8 production stimulated by G-HSA or HSA + IL-1β or IL-1β + IL-17.
CONCLUSIONS: Results suggest that the"perioprotective"effects of vitamin D are related to its ability to regulate inflammatory cytokine production by HGFs following AGE-RAGE interaction.


greenmedinfo--2020-05-04--Host microRNAs and exosomes that modulate influenza virus infection.

MicroRNAs ( miRNAs ) are small non-coding RNAs that post-transcriptionally regulate over half of human protein-coding genes and play a @ @ @ @ @ , proliferation , metabolism , and homeostasis .
Exosomes are rounded or cup-like extracellular vesicles @ @ @ @ @ , miRNAs , and lipids for release and exchange messages between cells involved in various @ @ @ @ @ is a substantial public health challenge .
The expression of host miRNAs is altered in @ @ @ @ @ virus .
These dysregulated miRNAs directly or indirectly target viral genes to regulate viral replication @ @ @ @ @ immune responses and cell apoptosis during viral infection .
Exosomes released by infected cells are @ @ @ @ @ antigens and key molecules that activate and modulate immune function .
Dysregulation of miRNAs and @ @ @ @ @ with pathogenicity and immune regulation during influenza infection .
This review provides a comprehensive summary @ @ @ @ @ host miRNAs and exosomes that are involved in the modulation of influenza virus infection and @ @ @ @ @ preventative or therapeutic strategies against influenza virus .

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate over half of human protein-coding genes and play a vital role in cellular development, proliferation, metabolism, and homeostasis. Exosomes are rounded or cup-like extracellular vesicles that carry proteins, mRNAs, miRNAs, and lipids for release and exchange messages between cells involved in various cellular processes. Influenza virus is a substantial public health challenge. The expression of host miRNAs is altered in response to stimulation by influenza virus. These dysregulated miRNAs directly or indirectly target viral genes to regulate viral replication and stimulate or suppress innate immune responses and cell apoptosis during viral infection. Exosomes released by infected cells are associated with the transfer of antigens and key molecules that activate and modulate immune function. Dysregulation of miRNAs and secretion of exosomes are associated with pathogenicity and immune regulation during influenza infection. This review provides a comprehensive summary of the information available regarding host miRNAs and exosomes that are involved in the modulation of influenza virus infection and will facilitate the development of preventative or therapeutic strategies against influenza virus.


greenmedinfo--2020-05-04--Human immunodeficiency virus-associated exosomes promote Kaposi's sarcoma-associated herpesvirus inf

Human immunodeficiency virus-associated exosomes promote Kaposi's sarcoma-associated herpesvirus infection.

Kaposi 's sarcoma-associated herpesvirus ( KSHV ) is the causal agent for Kaposi 's sarcoma ( KS ) , the most common malignancy in people living with human immunodeficiency virus ( HIV ) /AIDS .
The oral cavity is a major route for KSHV infection and transmission .
However , how KSHV breaches the oral epithelial barrier for spreading to the body is not clear .
Here , we show that exosomes purified from either the saliva of HIV-positive individuals or the culture supernatants of HIV-1-infected T-cell lines promote KSHV infectivity in immortalized and primary human oral epithelial cells .
@ @ @ @ @ @ @ element ( TAR ) , Tat , and Nef RNAs but do not express Tat and Nef proteins .
The TAR RNA in HIV-associated exosomes contributes to enhancing KSHV infectivity through the epidermal growth factor receptor ( EGFR ) .
An inhibitory aptamer against TAR RNA reduces KSHV infection facilitated by the synthetic TAR RNA in oral epithelial cells .
Cetuximab , a monoclonal neutralizing antibody against EGFR , blocks HIV-associated exosome-enhanced KSHV infection .
Our findings reveal that saliva containing HIV-associated exosomes is a risk factor for the enhancement of KSHV infection @ @ @ @ @ @ @ as a novel strategy for preventing KSHV infection and transmission in the oral cavity.Kaposi 's sarcoma-associated herpesvirus ( KSHV ) is the causal agent for Kaposi 's sarcoma ( KS ) , the most common malignancy in HIV/AIDS patients .
Oral transmission through saliva is considered the most common route for spreading the virus among HIV/AIDS patients .
However , the role of HIV-specific components in the cotransfection of KSHV is unclear .
We demonstrate that exosomes purified from the saliva of HIV-positive patients and secreted by HIV-infected T-cell lines promote KSHV infectivity @ @ @ @ @ @ @ .
HIV-associated exosomes promote KSHV infection , which depends on HIV-activation response element ( TAR ) RNA and EGFR of oral epithelial cells , which can be targeted for reducing KSHV infection .
These results reveal that HIV-associated exosomes are a risk factor for KSHV infection in the HIV-infected population .

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi's sarcoma (KS), the most common malignancy in people living with human immunodeficiency virus (HIV)/AIDS. The oral cavity is a major route for KSHV infection and transmission. However, how KSHV breaches the oral epithelial barrier for spreading to the body is not clear. Here, we show that exosomes purified from either the saliva of HIV-positive individuals or the culture supernatants of HIV-1-infected T-cell lines promote KSHV infectivity in immortalized and primary human oral epithelial cells. HIV-associated saliva exosomes contain the HIV-activation response element (TAR), Tat, and Nef RNAs but do not express Tat and Nef proteins. The TAR RNA in HIV-associated exosomes contributes to enhancing KSHV infectivity through the epidermal growth factor receptor (EGFR). An inhibitory aptamer against TAR RNA reduces KSHV infection facilitated by the synthetic TAR RNA in oral epithelial cells. Cetuximab, a monoclonal neutralizing antibody against EGFR, blocks HIV-associated exosome-enhanced KSHV infection. Our findings reveal that saliva containing HIV-associated exosomes is a risk factor for the enhancement of KSHV infection and that the inhibition of EGFR serves as a novel strategy for preventing KSHV infection and transmission in the oral cavity.Kaposi's sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi's sarcoma (KS), the most common malignancy in HIV/AIDS patients. Oral transmission through saliva is considered the most common route for spreading the virus among HIV/AIDS patients. However, the role of HIV-specific components in the cotransfection of KSHV is unclear. We demonstrate that exosomes purified from the saliva of HIV-positive patients and secreted by HIV-infected T-cell lines promote KSHV infectivity in immortalized and primary oral epithelial cells. HIV-associated exosomes promote KSHV infection, which depends on HIV-activation response element (TAR) RNA and EGFR of oral epithelial cells, which can be targeted for reducing KSHV infection. These results reveal that HIV-associated exosomes are a risk factor for KSHV infection in the HIV-infected population.


greenmedinfo--2020-05-04--Astragaloside IV attenuates IL-1β secretion by enhancing autophagy in H1N1 infection.

Excessive secretion of inflammatory factors ( cytokine storm ) plays a significant role in H1N1-induced acute pneumonia , and autophagy @ @ @ @ @ to regulate inflammation .
Astragaloside IV ( AS-IV ) , originating from the astragalus root @ @ @ @ @ , such as anti-inflammation .
However , the influences of AS-IV on H1N1-induced autophagy and @ @ @ @ @ It has been reported that H1N1 infection leads to the accumulation of autophagosomes but obstructs @ @ @ @ @ whereas the present study showed that AS-IV enhanced autophagy activation in H1N1 infection .
Furthermore @ @ @ @ @ promoted H1N1-triggered formation of autophagosomes and autolysosomes .
Additionally , it was noted that AS-IV @ @ @ @ @ , mRNA level of interleukin-1 beta ( IL-1β ) and pro-IL-1β protein level , but @ @ @ @ @ , and chloroquine ( CQ , as an inhibitor of autophagy ) increased secretion of @ @ @ @ @ In conclusion , AS-IV stimulates the formation of autophagosomes and the fusion of autophagosomes and @ @ @ @ @ may lead to decreased IL-1β secretion .

Excessive secretion of inflammatory factors (cytokine storm) plays a significant role in H1N1-induced acute pneumonia, and autophagy acts as a cell-intrinsic mechanism to regulate inflammation. Astragaloside IV (AS-IV), originating from the astragalus root, possesses multiple pharmacological activities, such as anti-inflammation. However, the influences of AS-IV on H1N1-induced autophagy and inflammation have remained elusive. It has been reported that H1N1 infection leads to the accumulation of autophagosomes but obstructs autophagosomes incorporating into lysosomes, whereas the present study showed that AS-IV enhanced autophagy activation in H1N1 infection. Furthermore, we found that AS-IV promoted H1N1-triggered formation of autophagosomes and autolysosomes. Additionally, it was noted that AS-IV did not affect viral replication, mRNA level of interleukin-1 beta (IL-1β) and pro-IL-1β protein level, but significantly decreased secretion of IL-1β, and chloroquine (CQ, as an inhibitor of autophagy) increased secretion of IL-1β in H1N1 infection. In conclusion, AS-IV stimulates the formation of autophagosomes and the fusion of autophagosomes and lysosomes in H1N1 infection and may lead to decreased IL-1β secretion.


greenmedinfo--2020-05-04--Astragaloside IV effectively suppressed HCC cell proliferation, invasion and anti-apoptosis in vitro

BACKGROUND/AIM : Hepatocellular carcinoma ( HCC ) is a primary malignancy of the liver and the third leading cause of cancer death worldwide .
Although multiple chemotherapies options are available for HCC , chemo-induced toxicity is inevitable during clinical treatment .
Therefore , identifying possible adjuvant agents with both liver-protective and antitumor effects is critical .
Herbal medicines have chemopreventive and anti-HCC effect , such as Juzen taiho-to and Sho-saiko-to .
Astragaloside IV is a compound extracted from the Chinese medical herb Astragalus membranaceus ( Fisch . )
Bge .
with liver protection potential .
However , whether astragaloside IV @ @ @ @ @ @ @ underlying mechanism is remaining unknown .
MATERIALS AND METHODS : Viability analysis , cell-cycle analysis , apoptosis analysis , western blotting analysis and invasion trans-well assay were performed to identify tumor-inhibitory potential of astragaloside IV on HCC cells ( SK-Hep1 and Hep3B cells ) .
RESULTS : We found that astragaloside IV may induce cytotoxicity and extrinsic/intrinsic apoptosis effect , but also trigger Garrest in HCC cells .
The expression of anti-apoptotic proteins of HCC were all reduced by astragaloside IV .
Additionally , astragaloside IV also suppressed HCC cell invasion ability .

BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and the third leading cause of cancer death worldwide. Although multiple chemotherapies options are available for HCC, chemo-induced toxicity is inevitable during clinical treatment. Therefore, identifying possible adjuvant agents with both liver-protective and antitumor effects is critical. Herbal medicines have chemopreventive and anti-HCC effect, such as Juzen taiho-to and Sho-saiko-to. Astragaloside IV is a compound extracted from the Chinese medical herb Astragalus membranaceus (Fisch.) Bge. with liver protection potential. However, whether astragaloside IV may also possess tumor-inhibitory capability and its underlying mechanism is remaining unknown.
MATERIALS AND METHODS: Viability analysis, cell-cycle analysis, apoptosis analysis, western blotting analysis and invasion trans-well assay were performed to identify tumor-inhibitory potential of astragaloside IV on HCC cells (SK-Hep1 and Hep3B cells).
RESULTS: We found that astragaloside IV may induce cytotoxicity and extrinsic/intrinsic apoptosis effect, but also trigger Garrest in HCC cells. The expression of anti-apoptotic proteins of HCC were all reduced by astragaloside IV. Additionally, astragaloside IV also suppressed HCC cell invasion ability.
CONCLUSION: Astragaloside IV effectively suppressed HCC cell proliferation, invasion and anti-apoptosis in vitro.


greenmedinfo--2020-05-04--Astragaloside IV may be a potential candidate agent for treating glioma andother central nervous sys

Astragaloside IV may be a potential candidate agent for treating glioma andother central nervous system tumors.

Astragaloside IV ( AS # IV ) has previously demonstrated antitumoractivity .
We investigated the effect and mechanisms of AS @ @ @ @ @ epithelial-mesenchymal transition ( EMT ) , viainterference with the Wnt/β-catenin signaling pathway in gliomaU251 cells @ @ @ @ @ cells by transforming growthfactor ( TGF ) # β1 activated EMT , including switching E @ @ @ @ @ the expression of Wnt/β-catenin signalingpathway components such as vimentin , β-catenin , and cyclin-D1.AS-IV inhibited @ @ @ @ @ and migration of TGF-β1-induced glioma U251 cells .
AS-IV also interfered with the TGF # @ @ @ @ @ glioma U251 cells.These findings indicate that AS # IV prohibits TGF # β1-induced EMTby disrupting @ @ @ @ @ U251 cells .
AS # IV may thus be a potential candidate agent for treating @ @ @ @ @ tumors .

Astragaloside IV (AS#IV) has previously demonstrated antitumoractivity. We investigated the effect and mechanisms of AS#IV in relation to epithelial-mesenchymal transition (EMT), viainterference with the Wnt/β-catenin signaling pathway in gliomaU251 cells. Induction of glioma U251 cells by transforming growthfactor (TGF)#β1 activated EMT, including switching E#cadherin toN-cadherin and altering the expression of Wnt/β-catenin signalingpathway components such as vimentin, β-catenin, and cyclin-D1.AS-IV inhibited the viability, invasion, and migration of TGF-β1-induced glioma U251 cells. AS-IV also interfered with the TGF#β1-induced Wnt/β-catenin signaling pathway in glioma U251 cells.These findings indicate that AS#IV prohibits TGF#β1-induced EMTby disrupting the Wnt/β-catenin pathway in glioma U251 cells. AS#IV may thus be a potential candidate agent for treating glioma andother central nervous system tumors.


greenmedinfo--2020-05-04--Astragaloside -IV prevents dopaminergic neurodegeneration in Parkinson's disease.

BACKGROUND : Senescent astrocytes have been implicated in the aging brain and neurodegenerative disorders , including Parkinson 's disease ( PD ) .
Astragaloside IV ( AS-IV ) is an antioxidant derivative from a traditional Chinese herbal medicine Astragalus membraneaceus Bunge and exerts anti-inflammatory and longevity effects and neuroprotective activities .
However , its effect on astrocyte senescence in PD remains to be defined .
METHODS : Long culture-induced replicative senescence model and lipopolysaccharide/1-methyl-4-phenylpyridinium ( LPS/MPP ) -induced premature senescence model and a mouse model of PD were used to investigate the effect of AS-IV on astrocyte senescence in vivo @ @ @ @ @ @ @ , subcellular fractionation , flow cytometric analyses , and immunohistochemistry were subsequently conducted to determine the effects of AS-IV on senescence markers .
RESULTS : We found that AS-IV inhibited the astrocyte replicative senescence and LPS/MPP-induced premature senescence , evidenced by decreased senescence-associatedβ-galactosidase activity and expression of senescence marker p16 , and increased nuclear level of lamin B1 , and reduced pro-inflammatory senescence-associated secretory phenotype .
More importantly , we showed that AS-IV protected against the loss of dopamine neurons and behavioral deficits in the mouse model of PD , which companied by @ @ @ @ @ @ @ nigra compacta .
Mechanistically , AS-IV promoted mitophagy , which reduced damaged mitochondria accumulation and mitochondrial reactive oxygen species generation and then contributed to the suppression of astrocyte senescence .
The inhibition of autophagy abolished the suppressive effects of AS-IV on astrocyte senescence .
CONCLUSIONS : Our findings reveal that AS-IV prevents dopaminergic neurodegeneration in PD via inhibition of astrocyte senescence through promoting mitophagy and suggest that AS-IV is a promising therapeutic strategy for the treatment of age-associated neurodegenerative diseases such as PD .

BACKGROUND: Senescent astrocytes have been implicated in the aging brain and neurodegenerative disorders, including Parkinson's disease (PD). Astragaloside IV (AS-IV) is an antioxidant derivative from a traditional Chinese herbal medicine Astragalus membraneaceus Bunge and exerts anti-inflammatory and longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.
METHODS: Long culture-induced replicative senescence model and lipopolysaccharide/1-methyl-4-phenylpyridinium (LPS/MPP)-induced premature senescence model and a mouse model of PD were used to investigate the effect of AS-IV on astrocyte senescence in vivo and in vitro. Immunocytochemistry, qPCR, subcellular fractionation, flow cytometric analyses, and immunohistochemistry were subsequently conducted to determine the effects of AS-IV on senescence markers.
RESULTS: We found that AS-IV inhibited the astrocyte replicative senescence and LPS/MPP-induced premature senescence, evidenced by decreased senescence-associatedβ-galactosidase activity and expression of senescence marker p16, and increased nuclear level of lamin B1, and reduced pro-inflammatory senescence-associated secretory phenotype. More importantly, we showed that AS-IV protected against the loss of dopamine neurons and behavioral deficits in the mouse model of PD, which companied by reduced accumulation of senescent astrocytes in substantia nigra compacta. Mechanistically, AS-IV promoted mitophagy, which reduced damaged mitochondria accumulation and mitochondrial reactive oxygen species generation and then contributed to the suppression of astrocyte senescence. The inhibition of autophagy abolished the suppressive effects of AS-IV on astrocyte senescence.
CONCLUSIONS: Our findings reveal that AS-IV prevents dopaminergic neurodegeneration in PD via inhibition of astrocyte senescence through promoting mitophagy and suggest that AS-IV is a promising therapeutic strategy for the treatment of age-associated neurodegenerative diseases such as PD.


greenmedinfo--2020-05-04--Astragaloside IV enhances cisplatin chemosensitivity in hepatocellular carcinoma by suppressing MRP2

Astragaloside IV enhances cisplatin chemosensitivity in hepatocellular carcinoma by suppressing MRP2.

Decreased chemosensitivity among tumor cells is often an obstacle in cisplatin ( Cis ) chemotherapy .
Overexpression of multidrug resistance-associated protein 2 ( MRP2 ) is a key mechanism underlying decreased Cis chemosensitivity and resistance .
Astragaloside IV ( AS IV ) is an important component derived from the well-known traditional Chinese herb Astragalus membranaceus .
The aim of this study was to explore the role of AS IV in enhancing the antitumor effect of Cis by suppressing MRP2 expression in HepG2 cells and H22 tumor-bearing mice .
After co-treatment of HepG2 cells with Cis and AS IV , we @ @ @ @ @ @ @ apoptosis .
Tumor growth and apoptosis assessment were performed to assess chemosensitivity in H22 tumor-bearing mice .
We used western blotting , immunofluorescence assays , and immunohistochemistry assays to detect MRP2 expression in HepG2 cells , H22 tumor tissues and mouse kidney tissues .
AS IV enhanced Cis chemosensitivity by increasing tumor cell apoptosis and slowing tumor growth in vitro and in vivo .
MRP2 overexpression in tumor cells was induced by Cis , which contributes to decreased chemosensitivity and Cis resistance .
Co-administration of AS IV suppressed MRP2 expression in tumor tissues @ @ @ @ @ @ @ for enhancing Cis chemosensitivity in hepatocellular carcinoma .
Moreover , AS IV alleviated Cis-induced kidney injury in mice without changing MRP2 expression .
In total , AS IV enhanced the antitumor effect of Cis against hepatocellular carcinoma by suppressing MRP2 expression in tumor cells .
The results provide a new insight into the combined use of a chemotherapy drug and natural ingredients to treat cancer .

Decreased chemosensitivity among tumor cells is often an obstacle in cisplatin (Cis) chemotherapy. Overexpression of multidrug resistance-associated protein 2 (MRP2) is a key mechanism underlying decreased Cis chemosensitivity and resistance. Astragaloside IV (AS IV) is an important component derived from the well-known traditional Chinese herb Astragalus membranaceus. The aim of this study was to explore the role of AS IV in enhancing the antitumor effect of Cis by suppressing MRP2 expression in HepG2 cells and H22 tumor-bearing mice. After co-treatment of HepG2 cells with Cis and AS IV, we assessed the effects on cell proliferation and apoptosis. Tumor growth and apoptosis assessment were performed to assess chemosensitivity in H22 tumor-bearing mice. We used western blotting, immunofluorescence assays, and immunohistochemistry assays to detect MRP2 expression in HepG2 cells, H22 tumor tissues and mouse kidney tissues. AS IV enhanced Cis chemosensitivity by increasing tumor cell apoptosis and slowing tumor growth in vitro and in vivo. MRP2 overexpression in tumor cells was induced by Cis, which contributes to decreased chemosensitivity and Cis resistance. Co-administration of AS IV suppressed MRP2 expression in tumor tissues, which might be an important mechanism for enhancing Cis chemosensitivity in hepatocellular carcinoma. Moreover, AS IV alleviated Cis-induced kidney injury in mice without changing MRP2 expression. In total, AS IV enhanced the antitumor effect of Cis against hepatocellular carcinoma by suppressing MRP2 expression in tumor cells. The results provide a new insight into the combined use of a chemotherapy drug and natural ingredients to treat cancer.


greenmedinfo--2020-05-04--Astragaloside IV attenuates chronic intermittent hypoxia-induced myocardial injury by modulating Ca2

Astragaloside IV attenuates chronic intermittent hypoxia-induced myocardial injury by modulating Ca2+ homeostasis.

Obstructive sleep apnea syndrome ( OSAS ) is an important consequence of chronic intermittent hypoxia ( CIH ) .
Astragaloside IV ( AS-IV ) exerts multiple protective effects in diverse diseases .
However , whether AS-IV can attenuate CIH-induced myocardial injury is unclear .
In this study , rats exposed to CIH were established and treated with AS-IV for 4 weeks .
In vitro , H9C2 cardiomyocytes subjected to CIH exposure were treated with AS-IV for 48 hours .
Then the cardiac function , morphology , fibrosis , apoptosis and Cahomeostasis were determined to assess cardiac damage .
Results showed @ @ @ @ @ @ @ lesions in CIH rats .
The increased TUNEL-positive cells and activated apoptotic proteins in CIH rats were reduced by AS-IV .
We also noticed that AS-IV reversed the accumulation of Caand altered expressions of Cahandling proteins ( decreases of SERCA2a and RYR2 , and increases of p-CaMKII and NCX1 ) under CIH exposure .
Furthermore , CIH-induced reduction of SERCA2a activity was increased by AS-IV in rats .
Similar results were also observed in H9C2 cells .
Altogether , these findings indicate that AS-IV modulates Cahomeostasis to inhibit apoptosis , protecting against CIH-induced @ @ @ @ @ @ @ be a potential agent for cardiac damage of OSAS patients .
SIGNIFICANCE OF THE STUDY : Chronic intermittent hypoxia ( CIH ) is a great contributor of OSAS , which is closely associated with cardiovascular diseases .
It is necessary for developing a promising drug to attenuate CIH-induced myocardial injury .
This work suggests that AS-IV can attenuate myocardial apoptosis and calcium disruption , thus protecting against CIH-induced myocardial injury .
It may represent a novel therapeutic for cardiac damage of OSAS .

Obstructive sleep apnea syndrome (OSAS) is an important consequence of chronic intermittent hypoxia (CIH). Astragaloside IV (AS-IV) exerts multiple protective effects in diverse diseases. However, whether AS-IV can attenuate CIH-induced myocardial injury is unclear. In this study, rats exposed to CIH were established and treated with AS-IV for 4 weeks. In vitro, H9C2 cardiomyocytes subjected to CIH exposure were treated with AS-IV for 48 hours. Then the cardiac function, morphology, fibrosis, apoptosis and Cahomeostasis were determined to assess cardiac damage. Results showed that AS-IV attenuated cardiac dysfunction and histological lesions in CIH rats. The increased TUNEL-positive cells and activated apoptotic proteins in CIH rats were reduced by AS-IV. We also noticed that AS-IV reversed the accumulation of Caand altered expressions of Cahandling proteins (decreases of SERCA2a and RYR2, and increases of p-CaMKII and NCX1) under CIH exposure. Furthermore, CIH-induced reduction of SERCA2a activity was increased by AS-IV in rats. Similar results were also observed in H9C2 cells. Altogether, these findings indicate that AS-IV modulates Cahomeostasis to inhibit apoptosis, protecting against CIH-induced myocardial injury eventually, suggesting it may be a potential agent for cardiac damage of OSAS patients. SIGNIFICANCE OF THE STUDY: Chronic intermittent hypoxia (CIH) is a great contributor of OSAS, which is closely associated with cardiovascular diseases. It is necessary for developing a promising drug to attenuate CIH-induced myocardial injury. This work suggests that AS-IV can attenuate myocardial apoptosis and calcium disruption, thus protecting against CIH-induced myocardial injury. It may represent a novel therapeutic for cardiac damage of OSAS.


greenmedinfo--2020-05-04--Astragaloside IV stimulates hippocampal neurogenesis after stroke.

Background : Stroke remains a leading cause of adult disability and the demand for stroke rehabilitation services is growing , and Astragaloside IV ( As IV ) , a primary bioactive compound of Radix Astragali : Bunge ( Fabaceae ) , may be a promising stroke therapy .
Methods : To access the effect of As IV on adult mice after ischemic stroke , a photochemical ischemia model was established on C57BL/6 mice , which were intravenously administered As IV for three consecutive days later .
And then the cognitive benefits and hippocampal neurogenesis were evaluated by Morris Water Maze @ @ @ @ @ @ @ , and immunohistochemical stainingand .
Furthermore , to find out the underlying mechanism , interleukin-17 ( IL-17 ) knockout ( KO ) mice were used , through RNA sequence ( RNA-seq ) analysis and immunohistochemistry .
Then the mechanism of neurogenesis promoted by As IV was observed by western blot bothand .
Specifically , As IV , recombinant mouse IL-17A and IL-17F , and Wingless/integrated ( Wnt ) -expressing virus was administered respectively in neural stem cells ( NSCs ) , and then their diameters and protein expression of Nestin , IL-17 , @ @ @ @ @ @ @ measured .
Results : Administering As IV resulted in significant amelioration of stroke-induced cognitive deficits .
And more hippocampal neurons with normal morphology , significant increments in the length of the apical dendrites , and the density of their spines were observed in As IV-treated mice .
Furthermore , the immunohistochemistry staining of DCX/BrdU and Sox2/Nestin showed As IV could promote hippocampal neurogenesis and NSC proliferation after ischemic stroke , as well as .
For the mechanism underlying , IL-17 expression was downregulated significantly by As IV treatment and knocking out IL-17 was @ @ @ @ @ @ @ according to the analysis of RNA-seq .
Consistent to As IV treatment , knocking out IL-17 showed some promotion on hippocampal neurogenesis and proliferation of NSCs , with activating Wnt pathway after stoke .
Finally , , NSCs ' diameters and protein expression of Nestin , IL-17 , and Wnt pathway were regulated by either administering As IV or inhibiting IL-17 .
Conclusion : As IV stimulates hippocampal neurogenesis after stroke , thus potentially facilitates brain to remodel and repair by downregulating IL-17 expressionWnt pathway .

Background: Stroke remains a leading cause of adult disability and the demand for stroke rehabilitation services is growing, and Astragaloside IV (As IV), a primary bioactive compound of Radix Astragali :Bunge (Fabaceae), may be a promising stroke therapy.
Methods: To access the effect of As IV on adult mice after ischemic stroke, a photochemical ischemia model was established on C57BL/6 mice, which were intravenously administered As IV for three consecutive days later. And then the cognitive benefits and hippocampal neurogenesis were evaluated by Morris Water Maze (MWM) test, Golgi staining, and immunohistochemical stainingand. Furthermore, to find out the underlying mechanism, interleukin-17 (IL-17) knockout (KO) mice were used, through RNA sequence (RNA-seq) analysis and immunohistochemistry. Then the mechanism of neurogenesis promoted by As IV was observed by western blot bothand. Specifically, As IV, recombinant mouse IL-17A and IL-17F, and Wingless/integrated (Wnt)-expressing virus was administered respectively in neural stem cells (NSCs), and then their diameters and protein expression of Nestin, IL-17, and Wnt pathway relevant protein, were measured.
Results: Administering As IV resulted in significant amelioration of stroke-induced cognitive deficits. And more hippocampal neurons with normal morphology, significant increments in the length of the apical dendrites, and the density of their spines were observed in As IV-treated mice. Furthermore, the immunohistochemistry staining of DCX/BrdU and Sox2/Nestin showed As IV could promote hippocampal neurogenesis and NSC proliferation after ischemic stroke, as well as. For the mechanism underlying, IL-17 expression was downregulated significantly by As IV treatment and knocking out IL-17 was associated with nervous regeneration and synapse repair according to the analysis of RNA-seq. Consistent to As IV treatment, knocking out IL-17 showed some promotion on hippocampal neurogenesis and proliferation of NSCs, with activating Wnt pathway after stoke. Finally,, NSCs' diameters and protein expression of Nestin, IL-17, and Wnt pathway were regulated by either administering As IV or inhibiting IL-17.
Conclusion: As IV stimulates hippocampal neurogenesis after stroke, thus potentially facilitates brain to remodel and repair by downregulating IL-17 expressionWnt pathway.


greenmedinfo--2020-05-04--Astragaloside IV acts through multi-scale mechanisms to effectively reduce diabetic nephropathy.

Diabetic nephropathy ( DN ) , a common complication of diabetes mellitus , is the main cause of end-stage nephropathy , and thus developing novel strategies for reversing DN remains urgent .
Astragaloside IV ( AS-IV ) , a glycoside extracted from the Astragalus membranaceus ( Fisch . )
Bunge , is a widely used Traditional Chinese Medicine ( TCM ) in China and presents diverse pharmacological properties including the protective effect on DN .
However , the rudimentary mechanism of AS-IV in remedying DN remains indeterminate .
Currently , we systematically explore the pharmacological mechanism of action of AS-IV @ @ @ @ @ @ @ was evaluated by ADME assessment , and 26 targets were screened out through target prediction .
Then , we decipher the protein-protein interaction ( PPI ) , Gene Ontology ( GO ) enrichment analysis , disease and pathway network analysis to obtain the specific molecular biological process and pharmacological activity of AS-IV in the treatment of DN .
Meanwhile , both in vivo and in vitro experiments confirmed that AS-IV has anti-oxidative stress , anti-inflammatory , anti-epithelial-mesenchymal transition ( EMT ) effects , and can inhibit the Wnt/β-catenin signaling pathway , ultimately ameliorating @ @ @ @ @ @ @ .
Additionally , we also applied molecular docking and molecular dynamics simulation to predict the specific binding sites and binding capacity of AS-IV and related targets .
Overall , the comprehensive systempharmacology method and experiment validations provide an accurate explanation for the molecular mechanism of AS-IV in the treatment of DN .
Moreover , it is expected to provide a brand new strategy for exploring the effective components of TCM .

Diabetic nephropathy (DN), a common complication of diabetes mellitus, is the main cause of end-stage nephropathy, and thus developing novel strategies for reversing DN remains urgent. Astragaloside IV (AS-IV), a glycoside extracted from the Astragalus membranaceus (Fisch.) Bunge, is a widely used Traditional Chinese Medicine (TCM) in China and presents diverse pharmacological properties including the protective effect on DN. However, the rudimentary mechanism of AS-IV in remedying DN remains indeterminate. Currently, we systematically explore the pharmacological mechanism of action of AS-IV for treating DN. Firstly, AS-IV was evaluated by ADME assessment, and 26 targets were screened out through target prediction. Then, we decipher the protein-protein interaction (PPI), Gene Ontology (GO) enrichment analysis, disease and pathway network analysis to obtain the specific molecular biological process and pharmacological activity of AS-IV in the treatment of DN. Meanwhile, both in vivo and in vitro experiments confirmed that AS-IV has anti-oxidative stress, anti-inflammatory, anti-epithelial-mesenchymal transition (EMT) effects, and can inhibit the Wnt/β-catenin signaling pathway, ultimately ameliorating the renal injury caused by high glucose. Additionally, we also applied molecular docking and molecular dynamics simulation to predict the specific binding sites and binding capacity of AS-IV and related targets. Overall, the comprehensive systempharmacology method and experiment validations provide an accurate explanation for the molecular mechanism of AS-IV in the treatment of DN. Moreover, it is expected to provide a brand new strategy for exploring the effective components of TCM.


greenmedinfo--2020-05-04--Structural elucidation and immune-enhancing effects of novel polysaccharide from Grifola frondosa.

Beta-glucan ( -glucan ) is a macromolecule structure where glucose unit has bonded through-glycosidic bond at 1 and 3 positions .
It is well known as a natural immunomodulator without exhibiting any side effects via enhancing immunity .
Mushroom contains a large amount of-glucan and it has anticancerous and antioxidant efficacy .
Structure and physical properties of-glucan are highly influenced by the types of mushroom .
In particular , has-1 , 3 and-1 , 6 bonds in their structure .
It has been noted that-glucan content also depends upon the size of mushroom particles .
The exact content of-glucan and @ @ @ @ @ @ @ ofhave yet to be fully elucidated .
Herein , -glucan contents were analyzed according to the particle size of leaf mushroom followed by cell activation and immunoactivity analysis .
The highest-glucan content was observed at a particle size of 20-30m ( 27.65± 0.30 w/w ) .
All samples showed ~ 103 % cell activation compared to the control and greater cell activity was observed at higher concentration .
The significant increase in cytokines secretion was observed in the presence of 20-30m particle size ofcompared to the control .
This study suggested that 20-30m @ @ @ @ @ @ @ be used as a health supplement and food additive to act as an immune booster , hypotensive agent , and hypoglycemic agent .

Beta-glucan (-glucan) is a macromolecule structure where glucose unit has bonded through-glycosidic bond at 1 and 3 positions. It is well known as a natural immunomodulator without exhibiting any side effects via enhancing immunity. Mushroom contains a large amount of-glucan and it has anticancerous and antioxidant efficacy. Structure and physical properties of-glucan are highly influenced by the types of mushroom. In particular,has-1, 3 and-1, 6 bonds in their structure. It has been noted that-glucan content also depends upon the size of mushroom particles. The exact content of-glucan and their immunological activity by a particle size ofhave yet to be fully elucidated. Herein,-glucan contents were analyzed according to the particle size of leaf mushroom followed by cell activation and immunoactivity analysis. The highest-glucan content was observed at a particle size of 20-30m (27.65± 0.30 w/w). All samples showed ~ 103% cell activation compared to the control and greater cell activity was observed at higher concentration. The significant increase in cytokines secretion was observed in the presence of 20-30m particle size ofcompared to the control. This study suggested that 20-30m size is the suitable size ofthat can be used as a health supplement and food additive to act as an immune booster, hypotensive agent, and hypoglycemic agent.


greenmedinfo--2020-05-04--Grifola frondosa extract and ergosterol reduce allergic reactions in an allergy mouse model by suppr

Grifola frondosa extract and ergosterol reduce allergic reactions in an allergy mouse model by suppressing the degranulation of mast cells.

The increasing number of patients suffering from allergic diseases is a global health problem.is an edible mushroom consumed as a @ @ @ @ @ and has recently been reported to have anti-allergic effects .
We previously reported thatextract ( @ @ @ @ @ components , ergosterol and its derivatives , inhibited the antigen-induced activation of RBL-2H3 cells .
@ @ @ @ @ GFE and ergosterol also had an inhibitory effect on the degranulation of bone marrow-derived mast @ @ @ @ @ alleviated anaphylactic cutaneous responses in mice .
Using an air pouch-type allergic inflammation mouse model @ @ @ @ @ administration of GFE and ergosterol suppressed the degranulation of mast cells .
Our findings suggest @ @ @ @ @ its active component , reduces type I allergic reactions by suppressing mast cell degranulation in @ @ @ @ @ a novel functional food that prevents allergic diseases .

The increasing number of patients suffering from allergic diseases is a global health problem.is an edible mushroom consumed as a health food in Asia, and has recently been reported to have anti-allergic effects. We previously reported thatextract (GFE) and its active components, ergosterol and its derivatives, inhibited the antigen-induced activation of RBL-2H3 cells. Here, we demonstrated that GFE and ergosterol also had an inhibitory effect on the degranulation of bone marrow-derived mast cells (BMMCs) and alleviated anaphylactic cutaneous responses in mice. Using an air pouch-type allergic inflammation mouse model, we confirmed that oral administration of GFE and ergosterol suppressed the degranulation of mast cells. Our findings suggest that, including ergosterol as its active component, reduces type I allergic reactions by suppressing mast cell degranulation in mice, and might be a novel functional food that prevents allergic diseases.