greenmedinfo--2020-10-10--Apigetrin from Scutellaria baicalensis Georgi inhibits neuroinflammation in BV-2 microglia.

Apigetrin is a flavonoid isolated from various herbal medicines such as Scutellaria baicalensis Georgi , Matricaria chamomilla , Stachys tibetica Vatke , and Teucrium gnaphalodes .
In the present study , we investigated the inhibitory effects of apigetrin on neuroinflammation using the BV-2 microglia cell line .
Our data revealed that apigetrin significantly reduced secretion and mRNA expression of inflammatory cytokines , tumor necrosis factor-alpha ( TNF-α ) and interleukin-6 ( IL-6 ) , in lipopolysaccharide ( LPS ) -stimulated BV-2 mouse microglia .
Apigetrin also significantly decreased LPS-mediated production of prostaglandin E ( PGE ) level and nitric oxide @ @ @ @ @ @ @ expression of cyclooxygenase 2 ( COX-2 ) and inducible nitric oxide synthase ( iNOS ) in BV-2 cells .
In addition , apigetrin suppressed nuclear expression of nuclear factor kappa B ( NF-κB ) in LPS-stimulated BV-2 cells .
Furthermore , apigetrin significantly impaired reactive oxygen species ( ROS ) generation and enhanced expression of antioxidant enzymes , hempxygenase 1 ( HO-1 ) and nuclear factor-like 2 ( Nrf2 ) , in BV-2 cells .
Apigetrin also increased 2,2'-azinobis- ( 3-ethylbenzothiazoline-6-sulfonic acid ) ( ABTS ) radical scavenging activity , indicating antioxidative activity @ @ @ @ @ @ @ that apigetrin inhibited hydrogen peroxide ( HO ) -induced cell death in HT22 hippocampal cells .
Overall , our findings indicate that apigetrin has inhibitory effects on neuroinflammation as well as antioxidation and neuroprotection , suggesting the potential prophylactic activity for neurodegenerative diseases through the inter-regulation of neuroinflammation , oxidative stress , and neuronal injury .

Apigetrin is a flavonoid isolated from various herbal medicines such as Scutellaria baicalensis Georgi, Matricaria chamomilla, Stachys tibetica Vatke, and Teucrium gnaphalodes. In the present study, we investigated the inhibitory effects of apigetrin on neuroinflammation using the BV-2 microglia cell line. Our data revealed that apigetrin significantly reduced secretion and mRNA expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), in lipopolysaccharide (LPS)-stimulated BV-2 mouse microglia. Apigetrin also significantly decreased LPS-mediated production of prostaglandin E(PGE) level and nitric oxide (NO) production as well as expression of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) in BV-2 cells. In addition, apigetrin suppressed nuclear expression of nuclear factor kappa B (NF-κB) in LPS-stimulated BV-2 cells. Furthermore, apigetrin significantly impaired reactive oxygen species (ROS) generation and enhanced expression of antioxidant enzymes, hempxygenase 1 (HO-1) and nuclear factor-like 2 (Nrf2), in BV-2 cells. Apigetrin also increased 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity, indicating antioxidative activity of apigetrin. Moreover, we found that apigetrin inhibited hydrogen peroxide (HO)-induced cell death in HT22 hippocampal cells. Overall, our findings indicate that apigetrin has inhibitory effects on neuroinflammation as well as antioxidation and neuroprotection, suggesting the potential prophylactic activity for neurodegenerative diseases through the inter-regulation of neuroinflammation, oxidative stress, and neuronal injury.


greenmedinfo--2020-10-10--Apigetrin inhibits gastric cancer progression through inducing apoptosis and regulating ROS-modulate

Apigetrin inhibits gastric cancer progression through inducing apoptosis and regulating ROS-modulated STAT3/JAK2 pathway.

Apigetrin ( APG ) , as a flavonoid , has many cellular bioactivities , including regulation of oxidative stress , and induction of apoptosis .
However , the means by which APG suppresses human gastric cancer are still little to be understood .
In the present study , the anti-cancer effects of APG on human gastric cancer cells were investigated .
The results indicated that APG could suppress the proliferation and induce apoptosis in gastric cancer cells .
Its role in apoptosis induction was through reducing Bcl-2 , and enhancing Bax , Caspase-9/-3 and poly ADP-ribose polymerase ( PARP ) @ @ @ @ @ @ @ resulted in the generation of intracellular reactive oxygen species ( ROS ) in cells .
Meanwhile , APG suppressed constitutive and interleukin-6 ( IL-6 ) -stimulated signal transducer and activator of transcription 3 ( STAT3 ) , Janus kinase 2 gene ( JAK2 ) and Src activation .
However , ROS scavenger , N-acety-l-cysteine ( NAC ) , diminished apoptosis induced by APG .
And APG-triggered de-phosphorylation of STAT3/JAK2 was rescued by NAC pre-treatment .
In vivo , APG administration significantly inhibited the gastric cancer cell xenograft tumorigenesis through inducing apoptosis and inhibiting @ @ @ @ @ @ @ findings above illustrated that APG might be used as a promising candidate against human gastric cancer progression .

Apigetrin (APG), as a flavonoid, has many cellular bioactivities, including regulation of oxidative stress, and induction of apoptosis. However, the means by which APG suppresses human gastric cancer are still little to be understood. In the present study, the anti-cancer effects of APG on human gastric cancer cells were investigated. The results indicated that APG could suppress the proliferation and induce apoptosis in gastric cancer cells. Its role in apoptosis induction was through reducing Bcl-2, and enhancing Bax, Caspase-9/-3 and poly ADP-ribose polymerase (PARP) cleavage. In addition, APG incubation resulted in the generation of intracellular reactive oxygen species (ROS) in cells. Meanwhile, APG suppressed constitutive and interleukin-6 (IL-6)-stimulated signal transducer and activator of transcription 3 (STAT3), Janus kinase 2 gene (JAK2) and Src activation. However, ROS scavenger, N-acety-l-cysteine (NAC), diminished apoptosis induced by APG. And APG-triggered de-phosphorylation of STAT3/JAK2 was rescued by NAC pre-treatment. In vivo, APG administration significantly inhibited the gastric cancer cell xenograft tumorigenesis through inducing apoptosis and inhibiting STAT3/JAK2 pathways. Taken together, the findings above illustrated that APG might be used as a promising candidate against human gastric cancer progression.


greenmedinfo--2020-10-10--Apigetrin treatment attenuates LPS-induced acute otitis media though suppressing inflammation and ox

Apigetrin treatment attenuates LPS-induced acute otitis media though suppressing inflammation and oxidative stress.

The natural course of otitis media in children is acute and self-limiting .
Nevertheless , about 10-20 % children could experience recurrent or persistent otitis media .
Thus , finding effective candidate to prevent acute otitis media is urgently required .
In our study , mouse acute otitis media model was constructed by lipopolysaccharide ( LPS ) injection into the middle ear of mice via the tympanic membrane .
Apigetrin ( APT ) is a flavonoid isolated from various herbal medicines , possessing anti-inflammatory and anti-oxidative bioactivities .
However , if APT could attenuate acute otitis media in LPS-induced animal @ @ @ @ @ @ @ .
Hematoxylin and eosin ( H & E ) staining suggested that APT treatment reduced LPS-induced higher mucosa thickness .
LPS-triggered inflammatory response was also inhibited by APT , as evidenced by the down-regulated neutrophils and macrophages .
Additionally , the reduced inflammatory factors , including interleukin-1β ( IL-lβ ) , tumor necrosis factor α ( TNF-α ) , IL-6 and vascular endothelial growth factor ( VEGF ) were observed in APT-treated mice with acute otitis media .
The process was associated with the inhibition of toll-like receptor 4 ( TLR4 ) /nuclear @ @ @ @ @ @ @ , which was proved by theblockage of TLR4 , MyD88 , p-IKKα , p-IκBα , and p-NF-κB using western blot analysis .
Moreover , the production of reactive oxygen species ( ROS ) caused by LPS was also reduced by APT through promoting anti-oxidants , involving superoxide dismutase ( SOD ) activity , heme oxygenase-1 ( HO-1 ) , NADP ( H ) quinone oxidoreductase 1 ( NQO-1 ) and nuclear factor erythroid 2-related factor 2 ( Nrf2 ) expressions .
In contrast , high levels of MDA and kelch-like ECH-associated protein 1 @ @ @ @ @ @ @ were down-regulated by APT , which might be associated with the inactivation of NF-κB .
In vitro , APT exhibited anti-inflammatory and anti-oxidant effects with little cytotoxicity in LPS-stimulated cells .
Together , the data above indicated that APT could ameliorate acute otitis media through inhibiting inflammation and oxidative stress .

The natural course of otitis media in children is acute and self-limiting. Nevertheless, about 10-20% children could experience recurrent or persistent otitis media. Thus, finding effective candidate to prevent acute otitis media is urgently required. In our study, mouse acute otitis media model was constructed by lipopolysaccharide (LPS) injection into the middle ear of mice via the tympanic membrane. Apigetrin (APT) is a flavonoid isolated from various herbal medicines, possessing anti-inflammatory and anti-oxidative bioactivities. However, if APT could attenuate acute otitis media in LPS-induced animal models, little is to be known. Hematoxylin and eosin (H&E) staining suggested that APT treatment reduced LPS-induced higher mucosa thickness. LPS-triggered inflammatory response was also inhibited by APT, as evidenced by the down-regulated neutrophils and macrophages. Additionally, the reduced inflammatory factors, including interleukin-1β (IL-lβ), tumor necrosis factor α (TNF-α), IL-6 and vascular endothelial growth factor (VEGF) were observed in APT-treated mice with acute otitis media. The process was associated with the inhibition of toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway, which was proved by theblockage of TLR4, MyD88, p-IKKα, p-IκBα, and p-NF-κB using western blot analysis. Moreover, the production of reactive oxygen species (ROS) caused by LPS was also reduced by APT through promoting anti-oxidants, involving superoxide dismutase (SOD) activity, heme oxygenase-1 (HO-1), NADP(H) quinone oxidoreductase 1 (NQO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) expressions. In contrast, high levels of MDA and kelch-like ECH-associated protein 1 (Keap 1) in LPS-treated mice were down-regulated by APT, which might be associated with the inactivation of NF-κB. In vitro, APT exhibited anti-inflammatory and anti-oxidant effects with little cytotoxicity in LPS-stimulated cells. Together, the data above indicated that APT could ameliorate acute otitis media through inhibiting inflammation and oxidative stress.


greenmedinfo--2020-10-10--Apigetrin induces extrinsic apoptosis, autophagy and G2/M phase cell cycle arrest in AGS human gastr

Apigetrin induces extrinsic apoptosis, autophagy and G2/M phase cell cycle arrest in AGS human gastric cancer cells.

Apigetrin is a flavonoid glycoside phytonutrient derived from fruits and vegetables that is well known for a variety of biological activities such as antioxidant and anti-inflammatory activities .
In the current study , we determined the effect of apigetrin on AGS gastric cancer cell .
Apigetrin reduced cancer cell proliferation and induced G2/M phase cell cycle arrest by regulating cyclin B1 , cdc25c and cdk1 protein expression in AGS cell .
Apigetrin treatment caused apoptotic cell death in AGS cells , characterized by the accumulation of apoptosis portion , cleavage of caspase-3 and poly ADP-ribose polymerase ( PARP ) .
@ @ @ @ @ @ @ apoptosis pathway proteins and mRNA .
However , intrinsic apoptosis pathway related proteins were not altered .
In addition , AGS cells treated with apigetrin increased autophagic cell death , featured by the formation of autophagic vacuole and acidic vesicular organelles .
Autophagy marker proteins , such as LC3B-II and beclin-1 , were increased , and p62 , an autophagy flux marker protein , was also increased by endoplasmic reticulum stress .
Also , the phosphorylation of PI3K/AKT/mTOR pathway proteins and its downstream targets in apigetrin-treated AGS cells was identified to be decreased @ @ @ @ @ @ @ that apigetrin-treated AGS cells induced G2/M phase cell cycle arrest , extrinsic apoptosis and autophagic cell death through PI3K/AKT/mTOR pathway , which can lead to the inhibition of gastric cancer development .
Thus , our findings strongly indicate that apigetrin is a basic natural derived compound that could be used as a nutrient source with potential anticancer activities against gastric cancer .

Apigetrin is a flavonoid glycoside phytonutrient derived from fruits and vegetables that is well known for a variety of biological activities such as antioxidant and anti-inflammatory activities. In the current study, we determined the effect of apigetrin on AGS gastric cancer cell. Apigetrin reduced cancer cell proliferation and induced G2/M phase cell cycle arrest by regulating cyclin B1, cdc25c and cdk1 protein expression in AGS cell. Apigetrin treatment caused apoptotic cell death in AGS cells, characterized by the accumulation of apoptosis portion, cleavage of caspase-3 and poly ADP-ribose polymerase (PARP). Apigetrin-treated cells increased the expression of extrinsic apoptosis pathway proteins and mRNA. However, intrinsic apoptosis pathway related proteins were not altered. In addition, AGS cells treated with apigetrin increased autophagic cell death, featured by the formation of autophagic vacuole and acidic vesicular organelles. Autophagy marker proteins, such as LC3B-II and beclin-1, were increased, and p62, an autophagy flux marker protein, was also increased by endoplasmic reticulum stress. Also, the phosphorylation of PI3K/AKT/mTOR pathway proteins and its downstream targets in apigetrin-treated AGS cells was identified to be decreased. Taken together, these data suggest that apigetrin-treated AGS cells induced G2/M phase cell cycle arrest, extrinsic apoptosis and autophagic cell death through PI3K/AKT/mTOR pathway, which can lead to the inhibition of gastric cancer development. Thus, our findings strongly indicate that apigetrin is a basic natural derived compound that could be used as a nutrient source with potential anticancer activities against gastric cancer.


greenmedinfo--2020-10-10--Apigetrin ameliorates streptozotocin-induced pancreatic β-cell damages via attenuating endoplasmic r

Apigetrin ameliorates streptozotocin-induced pancreatic β-cell damages via attenuating endoplasmic reticulum stress.

The pathogenesis of diabetes is associated with dysfunction of pancreaticβ-cells .
To ameliorate the β-cell dysfunction , it has propelled great interest to search pharmacological agents from natural plants .
This study explored the protective effect of apigetrin , a flavonoid present in natural plants , against streptozotocin ( STZ ) -induced cell damages in RINm5F cells andthe potential mechanisms .
Apigetrin was found to inhibit the elevation of intracellular reactive oxygen species levels , restore the impairment of antioxidant enzymes , and recover the disruption of redox homeostasis in the STZ-treated pancreatic β-cells .
Moreover , treatment of apigetrin @ @ @ @ @ @ @ analysis of apoptotic sub-Gpopulation and the protein expressions of cleaved poly ( ADP-ribose ) polymerase and caspase-3 .
Furthermore , apigetrin attenuated STZ-induced endoplasmic reticulum ( ER ) stress , indicated by the reduction of ER stress biomarkers , including overloading of mitochondrial calcium , increase in glucose-regulated protein 78 , phosphorylation of protein kinase RNA-like ER kinase and its downstream eukaryotic initiation factor 2α , cleavage of activating transcription factor 6 and caspase-12 , up-regulation of CCAAT/enhancer binding protein homologous protein , and induction of spliced X-box binding protein 1 .
Additionally @ @ @ @ @ @ @ classic ER stress inhibitor , augmented these beneficial effects of apigetrin .
In conclusion , these results demonstrated that apigetrin could improve the STZ-induced pancreatic β-cell damages via mitigation of oxidative stress and ER stress and supported the application of apigetrin to developing the novel therapeutics of diabetes .

The pathogenesis of diabetes is associated with dysfunction of pancreaticβ-cells. To ameliorate the β-cell dysfunction, it has propelled great interest to search pharmacological agents from natural plants. This study explored the protective effect of apigetrin, a flavonoid present in natural plants, against streptozotocin (STZ)-induced cell damages in RINm5F cells andthe potential mechanisms. Apigetrin was found to inhibit the elevation of intracellular reactive oxygen species levels, restore the impairment of antioxidant enzymes, and recover the disruption of redox homeostasis in the STZ-treated pancreatic β-cells. Moreover, treatment of apigetrin significantly suppressed the STZ-induced apoptosis in the analysis of apoptotic sub-Gpopulation and the protein expressions of cleaved poly(ADP-ribose) polymerase and caspase-3. Furthermore, apigetrin attenuated STZ-induced endoplasmic reticulum (ER) stress, indicated by the reduction of ER stress biomarkers, including overloading of mitochondrial calcium, increase in glucose-regulated protein 78, phosphorylation of protein kinase RNA-like ER kinase and its downstream eukaryotic initiation factor 2α, cleavage of activating transcription factor 6 and caspase-12, up-regulation of CCAAT/enhancer binding protein homologous protein, and induction of spliced X-box binding protein 1. Additionally, pretreatment with 4-phenylbutyric acid, a classic ER stress inhibitor, augmented these beneficial effects of apigetrin. In conclusion, these results demonstrated that apigetrin could improve the STZ-induced pancreatic β-cell damages via mitigation of oxidative stress and ER stress and supported the application of apigetrin to developing the novel therapeutics of diabetes.


greenmedinfo--2020-10-10--Sudachitin suppresses lipopolysaccharide-induced inflammatory responses in mouse macrophage-like RAW

Sudachitin suppresses lipopolysaccharide-induced inflammatory responses in mouse macrophage-like RAW264 cells.

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greenmedinfo--2020-10-10--The polymethoxy flavonoid sudachitin suppresses inflammatory bone destruction.

Inflammatory bone diseases , including rheumatoid arthritis , periodontitis and peri-implantitis , are associated not only with the production of inflammatory cytokines but also with local oxidative status , which is defined by intracellular reactive oxygen species ( ROS ) .
Osteoclast differentiation has been reported to be related to increased intracellular ROS levels in osteoclast lineage cells .
Sudachitin , which is a polymethoxyflavone derived from Citrus sudachi , possesses antioxidant properties and regulates various functions in mammalian cells .
However , the effects of sudachitin on inflammatory bone destruction and osteoclastogenesis remain unknown .
In calvaria inflamed by @ @ @ @ @ @ @ , inflammation-induced bone destruction and the accompanying elevated expression of osteoclastogenesis-related genes were reduced by the co-administration of sudachitin and LPS .
Moreover , sudachitin inhibited osteoclast formation in cultures of isolated osteoblasts and osteoclast precursors .
However , sudachitin rather increased the expression of receptor activator of NF-κB ligand ( RANKL ) , which is an important molecule triggering osteoclast differentiation , and the mRNA ratio of RANKL/osteoprotegerin that is a decoy receptor for RANKL , in the isolated osteoblasts , suggesting the presence of additional target cells .
When osteoclast formation @ @ @ @ @ @ @ bone marrow cells in the presence of soluble RANKL and macrophage colony-stimulating factor , sudachitin inhibited osteoclastogenesis without influencing cell viability .
Consistently , the expression of osteoclast differentiation-related molecules including c-fos , NFATc1 , cathepsin K and osteoclast fusion proteins such as DC-STAMP and Atp6v0d2 was reduced by sudachitin .
In addition , sudachitin decreased activation of MAPKs such as Erk and JNK and the ROS production evoked by RANKL in osteoclast lineage cells .
Our findings suggest that sudachitin is a useful agent forthe treatment of anti-inflammatory bone destruction .

Inflammatory bone diseases, including rheumatoid arthritis, periodontitis and peri-implantitis, are associated not only with the production of inflammatory cytokines but also with local oxidative status, which is defined by intracellular reactive oxygen species (ROS). Osteoclast differentiation has been reported to be related to increased intracellular ROS levels in osteoclast lineage cells. Sudachitin, which is a polymethoxyflavone derived from Citrus sudachi, possesses antioxidant properties and regulates various functions in mammalian cells. However, the effects of sudachitin on inflammatory bone destruction and osteoclastogenesis remain unknown. In calvaria inflamed by a local lipopolysaccharide (LPS) injection, inflammation-induced bone destruction and the accompanying elevated expression of osteoclastogenesis-related genes were reduced by the co-administration of sudachitin and LPS. Moreover, sudachitin inhibited osteoclast formation in cultures of isolated osteoblasts and osteoclast precursors. However, sudachitin rather increased the expression of receptor activator of NF-κB ligand (RANKL), which is an important molecule triggering osteoclast differentiation, and the mRNA ratio of RANKL/osteoprotegerin that is a decoy receptor for RANKL, in the isolated osteoblasts, suggesting the presence of additional target cells. When osteoclast formation was induced from osteoclast precursors derived from bone marrow cells in the presence of soluble RANKL and macrophage colony-stimulating factor, sudachitin inhibited osteoclastogenesis without influencing cell viability. Consistently, the expression of osteoclast differentiation-related molecules including c-fos, NFATc1,cathepsin K and osteoclast fusion proteins such as DC-STAMP and Atp6v0d2 was reduced by sudachitin. In addition, sudachitin decreased activation of MAPKs such as Erk and JNK and the ROS production evoked by RANKL in osteoclast lineage cells. Our findings suggest that sudachitin is a useful agent forthe treatment of anti-inflammatory bone destruction.


greenmedinfo--2020-10-10--Sudachitin, polymethoxyflavone from Citrus sudachi, enhances antigen-specific cellular and humoral i

Sudachitin, polymethoxyflavone from Citrus sudachi, enhances antigen-specific cellular and humoral immune responses in BALB/c mice.

Scdachitin is a polymethoxyflavone ( 5,7,4'-trihydroxy-6,8,3-trimethoxyflavone ) that is found in the peel of .
We examined the effect of @ @ @ @ @ ovalbumin-immunized BALB/c mice .
Treatment with sudachitin increased ovalbumin-specific IL-4 and IL-10 productions .
In @ @ @ @ @ sudachitin showed higher levels of ovalbumin-specific IgE , IgG1 and IgG l production than did @ @ @ @ @ response to the thymus-independent antigen 2,4,6-trinitrophenyl Ficoll was not different in the control and sudachitin @ @ @ @ @ does not directly stimulate antibody production .
Anstudy showed that treatment of sudachitin enhanced the @ @ @ @ @ bone marrow-derived dendritic cells .
Furthermore , CD11ccells that had been treated with sudachitin showed @ @ @ @ @ .
The results indicate that sudachitin regulates immune function bothand .

Scdachitin is a polymethoxyflavone (5,7,4'-trihydroxy-6,8,3-trimethoxyflavone) that is found in the peel of. We examined the effect of sudachitin on immune response in ovalbumin-immunized BALB/c mice. Treatment with sudachitin increased ovalbumin-specific IL-4 and IL-10 productions. In addition, mice that received sudachitin showed higher levels of ovalbumin-specific IgE, IgG1 and IgG l production than did control mice. The antibody response to the thymus-independent antigen 2,4,6-trinitrophenyl Ficoll was not different in the control and sudachitin groups, suggesting that sudachitin does not directly stimulate antibody production. Anstudy showed that treatment of sudachitin enhanced the ability of antigen presentation in bone marrow-derived dendritic cells. Furthermore, CD11ccells that had been treated with sudachitin showed increased expression of co-stimulatory molecules. The results indicate that sudachitin regulates immune function bothand.


greenmedinfo--2020-10-10--Sudachitin inhibits Matrix metalloproteinase-1 and -3 production in tumor necrosis factor-α-stimulat

Sudachitin inhibits Matrix metalloproteinase-1 and -3 production in tumor necrosis factor-α-stimulated human oeriodontal ligament cells.

Sudachitin , a polymethoxylated flavonoid found in the skin of Citrus sudachi , is a biologically active substance .
The @ @ @ @ @ to examine whether sudachitin could be used to inhibit the expression of matrix metalloproteinase ( @ @ @ @ @ , which are involved in the destruction of periodontal tissues in periodontal lesions , in @ @ @ @ @ ) -α-stimulated human periodontal ligament cells ( HPDLC ) .
Sudachitin suppressed TNF-α-induced MMP-1 and @ @ @ @ @ On the other hand , it enhanced tissue inhibitor of metalloproteinase ( TIMP ) -1 @ @ @ @ @ Akt phosphorylation in the TNF-α-stimulated HPDLC was decreased bysudachitin treatment .
Moreover , an Akt @ @ @ @ @ production and increased TIMP-1 production .
These findings indicate that sudachitin reduces MMP-1 and MMP-3 @ @ @ @ @ inhibiting the Akt pathway .

Sudachitin, a polymethoxylated flavonoid found in the skin of Citrus sudachi, is a biologically active substance. The aim of this study was to examine whether sudachitin could be used to inhibit the expression of matrix metalloproteinase (MMP)-1 and MMP-3, which are involved in the destruction of periodontal tissues in periodontal lesions, in tumor necrosis factor (TNF)-α-stimulated human periodontal ligament cells (HPDLC). Sudachitin suppressed TNF-α-induced MMP-1 and MMP-3 production in HPDLC. On the other hand, it enhanced tissue inhibitor of metalloproteinase (TIMP)-1 expression. The level of Akt phosphorylation in the TNF-α-stimulated HPDLC was decreased bysudachitin treatment. Moreover, an Akt inhibitor reduced MMP-1 and MMP-3 production and increased TIMP-1 production. These findings indicate that sudachitin reduces MMP-1 and MMP-3 production in TNF-α-stimulated HPDLC by inhibiting the Akt pathway.


greenmedinfo--2020-10-10--Sudachitin induces apoptosis via the regulation of MAPK pathways in human keratinocyte HaCaT cells.

Although we recently reported that sudachitin ( 5,7,4'-trihydroxy-6,8,3'-trimethoxyflavone ) , a polymethoxyflavone isolated from the peel of Citrus sudachi , @ @ @ @ @ keratinocyte HaCaT cells , the mechanism underlying its action remains unclear .
In this study @ @ @ @ @ underlying sudachitin-induced apoptosis in HaCaT cells .
Sudachitin activated p38MAPK and inhibited ERK1/2 , whereas @ @ @ @ @ 5,6,7,8,3',4'-hexamethoxyflavone ) , activated ERK1/2 .
The p38MAPK inhibitor SB203580 significantly attenuated sudachitin-induced heat shock @ @ @ @ @ of p38MAPK , and subsequent apoptosis , indicating that sudachitin induces apoptosis via the p38MAPK @ @ @ @ @ inhibited serum- and EGF-stimulated Raf-1-ERK1/2 activation , and blocked EGF-induced cell migration and proliferation in @ @ @ @ @ suggest that small structural differences in polymethoxyflavones can induce different cellular responses by altering the @ @ @ @ @ that sudachitin may be a potential candidate for developing new drugs for skin diseases such @ @ @

Although we recently reported that sudachitin (5,7,4'-trihydroxy-6,8,3'-trimethoxyflavone), a polymethoxyflavone isolated from the peel of Citrus sudachi, can induce apoptosis in human keratinocyte HaCaT cells, the mechanism underlying its action remains unclear. In this study, we explored the mechanisms underlying sudachitin-induced apoptosis in HaCaT cells. Sudachitin activated p38MAPK and inhibited ERK1/2, whereas another polymethoxyflavone, nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), activated ERK1/2. The p38MAPK inhibitor SB203580 significantly attenuated sudachitin-induced heat shock protein 27 phosphorylation, downstream of p38MAPK, and subsequent apoptosis, indicating that sudachitin induces apoptosis via the p38MAPK pathway. Additionally, sudachitin inhibited serum- and EGF-stimulated Raf-1-ERK1/2 activation, and blocked EGF-induced cell migration and proliferation in HaCaT cells. These results suggest that small structural differences in polymethoxyflavones can induce different cellular responses by altering the regulation of MAPK activities and that sudachitin may be a potential candidate for developing new drugs for skin diseases such as psoriasis.


greenmedinfo--2020-10-10--O. vulgare extract improved function and structure of testis tissue against finasteride-induced test

O. vulgare extract improved function and structure of testis tissue against finasteride-induced testicular toxicity.

The aim of the current study was to investigate antioxidant , anti-inflammatory and anti-apoptotic effects of Origanum vulgare on finasteride-induced oxidative injury in mouse testis and sperm parameters .
Thirty BALB/c mice were divided into 5 groups : negative control , received 0.5 ml/day distilled water ; positive control , received 25 mg/kg finasteride orally ; and three groups received 100 , 200 and 400 mg/kg/day O. vulgare extract plus 25 mg kg dayfinasteride for 35 days .
At day 36 , serum luteinising hormone , follicle-stimulating hormone and testosterone , inflammatory cytokines ( IL-6 , TNF-α , IL-1β ) @ @ @ @ @ @ @ nitric oxide levels were assessed .
Also , apoptotic changes investigated through genes expression and immunohistochemical staining .
Finasteride in 35 days resulted in significant destructive alterations in the testis architecture , suppressed antioxidant enzymes and increased lipid peroxidation .
The expression of Bcl-2 was down-regulated , whereas p53 and caspase-3 were up-regulated .
Origanum vulgare improvedthe serum level of hormones and restored the antioxidant defence .
200 and 400 mg/kg/day of O. vulgare alleviated the testis structure and sperm parameters , up-regulated the anti-apoptotic gene Bcl-2 and down-regulated the p53 , caspase-3 @ @ @ @ @ @ @ indicate that O. vulgareextract improved function and structure of testis tissue against finasteride-induced testicular toxicity .

The aim of the current study was to investigate antioxidant, anti-inflammatory and anti-apoptotic effects of Origanum vulgare on finasteride-induced oxidative injury in mouse testis and sperm parameters. Thirty BALB/c mice were divided into 5 groups: negative control, received 0.5 ml/day distilled water; positive control, received 25 mg/kg finasteride orally; and three groups received 100, 200 and 400 mg/kg/day O. vulgare extract plus 25 mg kg dayfinasteride for 35 days. At day 36, serum luteinising hormone, follicle-stimulating hormone and testosterone, inflammatory cytokines (IL-6, TNF-α, IL-1β), glutathione peroxidase, superoxide dismutase and nitric oxide levels were assessed. Also, apoptotic changes investigated through genes expression and immunohistochemical staining. Finasteride in 35 days resulted in significant destructive alterations in the testis architecture, suppressed antioxidant enzymes and increased lipid peroxidation. The expression of Bcl-2 was down-regulated, whereas p53 and caspase-3 were up-regulated. Origanum vulgare improvedthe serum level of hormones and restored the antioxidant defence. 200 and 400 mg/kg/day of O. vulgare alleviated the testis structure and sperm parameters, up-regulated the anti-apoptotic gene Bcl-2 and down-regulated the p53, caspase-3 genes in treated groups. The findings indicate that O. vulgareextract improved function and structure of testis tissue against finasteride-induced testicular toxicity.


greenmedinfo--2020-10-10--Didymin induces Fas-mediated apoptotic pathway in human non-small-cell lung cancer cells.

Epidemiological studies provided evidence that the high dietary intake of flavonoids with fruits and vegetables could be associated with lower @ @ @ @ @ Didymin , a dietary flavonoid glycoside from citrus fruits , possesses antioxidant properties .
This @ @ @ @ @ effect of didymin in human non-small-cell lung cancer A549 and H460 cells .
To identity @ @ @ @ @ , we assayed its effect on apoptosis , cell cycle distribution , and levels of @ @ @ @ @ receptor , and Fas ligand .
The results showed that didymin-induced apoptosis of A549 and @ @ @ @ @ p53 and p21/WAF1 .
We suggest that Fas/Fas ligand apoptotic system is the main pathway @ @ @ @ @ and H460 cells .
Importantly , a novel chemotherapeutic agent for the treatment of non-small-cell @ @ @ @ @ supported by animal studies which have shown didymin delay the tumor growth in nude mice @ @ @ @ @ for the first time that the activity of the Fas/Fas ligand apoptotic system may participate @ @ @ @ @ didymin in A549 and H460 cells .

Epidemiological studies provided evidence that the high dietary intake of flavonoids with fruits and vegetables could be associated with lower cancer prevalence in humans. Didymin, a dietary flavonoid glycoside from citrus fruits, possesses antioxidant properties. This study first investigates the anticancer effect of didymin in human non-small-cell lung cancer A549 and H460 cells. To identity the anticancer mechanism of didymin, we assayed its effect on apoptosis, cell cycle distribution, and levels of p53, p21/WAF1, Fas/APO-1 receptor, and Fas ligand. The results showed that didymin-induced apoptosis of A549 and H460 cells without mediation of p53 and p21/WAF1. We suggest that Fas/Fas ligand apoptotic system is the main pathway of didymin-mediated apoptosis of A549 and H460 cells. Importantly, a novel chemotherapeutic agent for the treatment of non-small-cell lung cancer, and is supported by animal studies which have shown didymin delay the tumor growth in nude mice. Our study reports here for the first time that the activity of the Fas/Fas ligand apoptotic system may participate in the antiproliferative activity of didymin in A549 and H460 cells.


greenmedinfo--2020-10-10--Didymin induces apoptosis by inhibiting N-Myc and upregulating RKIP in neuroblastoma.

Neuroblastomas arise from the neural crest cells and represent the most common solid tumors outside the nervous system in children .
The amplification of N-Myc plays a primary role in the pathogenesis of neuroblastomas , whereas acquired mutations of p53 lead to refractory and relapsed cases of neuroblastomas .
In this regard , dietary compounds which can target N-Myc and exert anticancer effects independent of p53 status acquire significance in the management of neuroblastomas .
Hence , we investigated the anticancer properties of the flavonoid didymin in neuroblastomas .
Didymin effectively inhibited proliferation and induced apoptosis irrespective of p53 status @ @ @ @ @ @ @ , pAkt , Akt , vimentin , and upregulated RKIP levels .
Didymin induced G ( 2 ) /M arrest along with decreasing the levels of cyclin D1 , CDK4 , and cyclin B1 .
Importantly , didymin inhibited N-Myc as confirmed at protein , mRNA , and transcriptional level by promoter-reporter assays .
High-performance liquid chromatography analysis of didymin-treated ( 2 mg/kg b.w . )
mice serum revealed effective oral absorption with free didymin concentration of 2.1μmol/L .
Further in vivo mice xenograft studies revealed that didymin-treated ( 2 mg/kg b.w .
@ @ @ @ @ @ @ size compared with controls .
Didymin strongly inhibited the proliferation ( Ki67 ) and angiogenesis ( CD31 ) markers , as well as N-Myc expression , as revealed by thehistopathologic examination of paraffin-embedded section of resected tumors .
Collectively , our in vitro and in vivo studies elucidated the anticancer properties and mechanisms of action of a novel , orally active , and palatable flavonoid didymin , which makes it a potential new approach for neuroblastoma therapy ( NANT ) to target pediatric neuroblastomas .

Neuroblastomas arise from the neural crest cells and represent the most common solid tumors outside the nervous system in children. The amplification of N-Myc plays a primary role in the pathogenesis of neuroblastomas, whereas acquired mutations of p53 lead to refractory and relapsed cases of neuroblastomas. In this regard, dietary compounds which can target N-Myc and exert anticancer effects independent of p53 status acquire significance in the management of neuroblastomas. Hence, we investigated the anticancer properties of the flavonoid didymin in neuroblastomas. Didymin effectively inhibited proliferation and induced apoptosis irrespective of p53 status in neuroblastomas. Didymin downregulated phosphoinositide 3-kinase, pAkt, Akt, vimentin, and upregulated RKIP levels. Didymin induced G(2)/M arrest along with decreasing the levels of cyclin D1, CDK4, and cyclin B1. Importantly, didymin inhibited N-Myc as confirmed at protein, mRNA, and transcriptional level by promoter-reporter assays. High-performance liquid chromatography analysis of didymin-treated (2 mg/kg b.w.) mice serum revealed effective oral absorption with free didymin concentration of 2.1μmol/L. Further in vivo mice xenograft studies revealed that didymin-treated (2 mg/kg b.w.) animals had significant reductions in tumors size compared with controls. Didymin strongly inhibited the proliferation (Ki67) and angiogenesis (CD31) markers, as well as N-Myc expression, as revealed by thehistopathologic examination of paraffin-embedded section of resected tumors. Collectively, our in vitro and in vivo studies elucidated the anticancer properties and mechanisms of action of a novel, orally active, and palatable flavonoid didymin, which makes it a potential new approach for neuroblastoma therapy (NANT) to target pediatric neuroblastomas.


greenmedinfo--2020-10-10--Neuroprotective effect of didymin on hydrogen peroxide-induced injury in the neuronal membrane syste

Neuroprotective effect of didymin on hydrogen peroxide-induced injury in the neuronal membrane system.

In this study , the flavonoid didymin was administered in vitro in neuronal cells after hydrogen peroxide ( H2O2 ) -induced injury ( neurorescue ) in order to investigate the effects of this natural molecule on cell damage in a neuronal membrane system .
The results showed the effects of didymin in neuronal cells by using a polycaprolactone biodegradable membrane system as an in vitro model .
Two major findings are presented in this study : first is the antioxidant property of didymin and , second , for the first time we provide evidence concerning its ability to rescue neuronal @ @ @ @ @ @ @ radical scavenging activities and it protected the neuronal cells against H2O2-induced neurotoxicity .
Didymin increased cell viability , decreased intracellular reactive oxygen species generation , stimulated superoxide dismutase , catalase and glutathione peroxidase activity in neuronal cells which were previously insulted with H2O2 .
In addition , didymin strikingly inhibited H2O2-induced mitochondrial dysfunctions in terms of reduction of mitochondria membrane potential and the activation of cleaved caspase-3 , and also decreased dramatically the H2O2-induced phosphorylation of c-Jun N-terminal kinase .
Therefore , this molecule is capable of inducing recovery from oxidative damage , @ @ @ @ @ @ @ .
Moreover , the mechanism underlying the protective effects of didymin in H2O2-injured neuronal cells might be related to the activation of antioxidant defense enzymes as well as to the inhibition of apoptotic features , such as p-JNK and caspase-3 activation .
These data suggest that didymin may be a potential therapeutic molecule for the treatment of neurodegenerative disorders associated with oxidative stress .

In this study, the flavonoid didymin was administered in vitro in neuronal cells after hydrogen peroxide (H2O2)-induced injury (neurorescue) in order to investigate the effects of this natural molecule on cell damage in a neuronal membrane system. The results showed the effects of didymin in neuronal cells by using a polycaprolactone biodegradable membrane system as an in vitro model. Two major findings are presented in this study: first is the antioxidant property of didymin and, second, for the first time we provide evidence concerning its ability to rescue neuronal cells from oxidative damage. Didymin showed radical scavenging activities and it protected the neuronal cells against H2O2-induced neurotoxicity. Didymin increased cell viability, decreased intracellular reactive oxygen species generation, stimulated superoxide dismutase, catalase and glutathione peroxidase activity in neuronal cells which were previously insulted with H2O2. In addition, didymin strikingly inhibited H2O2-induced mitochondrial dysfunctions in terms of reduction of mitochondria membrane potential and the activation of cleaved caspase-3, and also decreased dramatically the H2O2-induced phosphorylation of c-Jun N-terminal kinase. Therefore, this molecule is capable of inducing recovery from oxidative damage, and promoting and/or restoring normal cellular conditions. Moreover, the mechanism underlying the protective effects of didymin in H2O2-injured neuronal cells might be related to the activation of antioxidant defense enzymes as well as to the inhibition of apoptotic features, such as p-JNK and caspase-3 activation. These data suggest that didymin may be a potential therapeutic molecule for the treatment of neurodegenerative disorders associated with oxidative stress.


greenmedinfo--2020-10-10--Didymin reverses phthalate ester-associated breast cancer aggravation in the breast cancer tumor mic

Didymin reverses phthalate ester-associated breast cancer aggravation in the breast cancer tumor microenvironment.

The present study demonstrated two novel findings .
To the best of our knowledge , it is the first study to demonstrate that regulated upon activation , normal T-cell expressed and secreted ( RANTES ) , produced by breast tumor-associated monocyte-derived dendritic cells ( TADCs ) following breast cancer cell exposure to phthalate esters , may contribute to the progression of cancer via enhancement of cancer cell proliferation , migration and invasion .
Furthermore , the present study revealed that didymin , a dietary flavonoid glycoside present in citrus fruits , was able to reverse phthalate ester-mediated breast cancer aggravation @ @ @ @ @ @ @ benzyl phthalate ( BBP ) , di-n-butyl phthalate ( DBP ) or di-2-ethylhexyl phthalate ( DEHP ) .
Subsequently , the conditioned medium ( CM ) was harvested and cultured with monocyte-derived dendritic cells ( mdDCs ) .
Cultures of MDA-MB-231 cells with the conditioned medium of BBP- , DBP- or DEHP-MDA-MB-231 tumor-associated mdDCs ( BBP- , DBP- or DEHP-MDA-TADC-CM ) demonstrated enhanced proliferation , migration and invasion .
Exposure of the MDA-MB-231 cells to DBP induced the MDA-TADCs to produce the inflammatory cytokine RANTES , which subsequently induced MDA-MB-231 cell proliferation , @ @ @ @ @ @ @ the effects of DBP-MDA-TADC-mediated MDA-MB-231 cell proliferation , migration and invasion .
In addition , didymin was observed to suppress phthalate-mediated breast cancer cell proliferation , migration and invasion .
The present study suggested that didymin was capable of preventing phthalate ester-associated cancer aggravation .

The present study demonstrated two novel findings. To the best of our knowledge, it is the first study to demonstrate that regulated upon activation, normal T-cell expressed and secreted (RANTES), produced by breast tumor-associated monocyte-derived dendritic cells (TADCs) following breast cancer cell exposure to phthalate esters, may contribute to the progression of cancer via enhancement of cancer cell proliferation, migration and invasion. Furthermore, the present study revealed that didymin, a dietary flavonoid glycoside present in citrus fruits, was able to reverse phthalate ester-mediated breast cancer aggravation. MDA-MB-231 cells were treated with butyl benzyl phthalate (BBP), di-n-butyl phthalate (DBP) or di-2-ethylhexyl phthalate (DEHP). Subsequently, the conditioned medium (CM) was harvested and cultured with monocyte-derived dendritic cells (mdDCs). Cultures of MDA-MB-231 cells with the conditioned medium of BBP-, DBP- or DEHP-MDA-MB-231 tumor-associated mdDCs (BBP-, DBP- or DEHP-MDA-TADC-CM) demonstrated enhanced proliferation, migration and invasion. Exposure of the MDA-MB-231 cells to DBP induced the MDA-TADCs to produce the inflammatory cytokine RANTES, which subsequently induced MDA-MB-231 cell proliferation, migration and invasion. Depleting RANTES reversed the effects of DBP-MDA-TADC-mediated MDA-MB-231 cell proliferation, migration and invasion. In addition, didymin was observed to suppress phthalate-mediated breast cancer cell proliferation, migration and invasion. The present study suggested that didymin was capable of preventing phthalate ester-associated cancer aggravation.


greenmedinfo--2020-10-10--Didymin ameliorates hepatic injury through inhibition of MAPK and NF-κB pathways.

A flavone was isolated from Origanum vulgare and identified as didymin ( O. vulgare didymin , OVD ) .
The @ @ @ @ @ OVD on acute liver injury was then assessed in vivo and in vitro .
Our @ @ @ @ @ alleviated CCl-induced liver injury in mice and markedly decreased serum ALT and AST activities .
@ @ @ @ @ activity , lipid peroxidation level , ROS generation , NO production and pro-inflammatory cytokines ( @ @ @ @ @ and IL-1β ) in liver tissues and RAW 264.7 cells , but enhanced the hepatic @ @ @ @ @ study showed that OVD significantly inhibited the NF-κB and MAPK pathways .
Interestingly , OVD @ @ @ @ @ protein ( RKIP ) expression , and the effects of OVD on histological changes , @ @ @ @ @ largely abolished by the RKIP specific inhibitor locostatin .
Our findings indicate that OVD can @ @ @ @ @ which may be ascribed to its radical scavenging action , antioxidant activity , and modulation @ @ @ @ @ pathways .

A flavone was isolated from Origanum vulgare and identified as didymin (O. vulgare didymin, OVD). The protective effect and mechanism of OVD on acute liver injury was then assessed in vivo and in vitro. Our results showed that OVD significantly alleviated CCl-induced liver injury in mice and markedly decreased serum ALT and AST activities. OVD treatment significantly reduced CYP2E1 activity, lipid peroxidation level, ROS generation, NO production and pro-inflammatory cytokines (such as TNF-α, IL-6 and IL-1β) in liver tissues and RAW 264.7 cells, but enhanced the hepatic antioxidative enzymes activities. Further study showed that OVD significantly inhibited the NF-κB and MAPK pathways. Interestingly, OVD notably enhanced Raf kinase inhibitor protein (RKIP) expression, and the effects of OVD on histological changes, oxidative stress and inflammation was largely abolished by the RKIP specific inhibitor locostatin. Our findings indicate that OVD can ameliorate CCl-induced liver injury, which may be ascribed to its radical scavenging action, antioxidant activity, and modulation of MAPK and NF-κB signaling pathways.


greenmedinfo--2020-10-10--Didymin alleviates hepatic fibrosis.

Didymin alleviates hepatic fibrosis.

BACKGROUND : Didymin has been reported to have anti-cancer potential .
However , the effect of didymin on liver fibrosis remains illdefined .
METHODS : Hepatic fibrosis was induced by CCl4 in rats .
The effects of didymin on liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson 's trichrome staining , respectively .
Serum transaminases activities and collagen-related indicators levels were determined by commercially available kits .
Moreover , the effects of didymin on hepatic stellate cell apoptosis and cell cycle were analyzed by flow cytometry .
Mitochondrial membrane potential was detected by using rhodamine-123 dye .
@ @ @ @ @ @ @ ( RKIP ) and the phosphorylation of the ERK/MAPK and PI3K/Akt pathways were assessed by Western blot .
RESULTS : Didymin significantly ameliorated chronic liver injury and collagen deposition .
It strongly inhibited hepatic stellate cells proliferation , induced apoptosis and caused cell cycle arrest in G2/M phase .
Moreover , didymin notably attenuated mitochondrial membrane potential , accompanied by release of cytochrome C. Didymin significantly inhibited the ERK/MAPK and PI3K/Akt pathways .
The effects of didymin on the collagen accumulation in rats and on the biological behaviors of hepatic stellate cells were @ @ @ @ @ @ @ locostatin .
CONCLUSION : Didymin alleviates hepatic fibrosis by inhibiting ERK/MAPK and PI3K/Akt pathways via regulation of RKIP expression .

BACKGROUND: Didymin has been reported to have anti-cancer potential. However, the effect of didymin on liver fibrosis remains illdefined.
METHODS: Hepatic fibrosis was induced by CCl4 in rats. The effects of didymin on liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively. Serum transaminases activities and collagen-related indicators levels were determined by commercially available kits. Moreover, the effects of didymin on hepatic stellate cell apoptosis and cell cycle were analyzed by flow cytometry. Mitochondrial membrane potential was detected by using rhodamine-123 dye. The expression of Raf kinase inhibitor protein (RKIP) and the phosphorylation of the ERK/MAPK and PI3K/Akt pathways were assessed by Western blot.
RESULTS: Didymin significantly ameliorated chronic liver injury and collagen deposition. It strongly inhibited hepatic stellate cells proliferation, induced apoptosis and caused cell cycle arrest in G2/M phase. Moreover, didymin notably attenuated mitochondrial membrane potential, accompanied by release of cytochrome C. Didymin significantly inhibited the ERK/MAPK and PI3K/Akt pathways. The effects of didymin on the collagen accumulation in rats and on the biological behaviors of hepatic stellate cells were largely abolished by the specific RKIP inhibitor locostatin.
CONCLUSION: Didymin alleviates hepatic fibrosis by inhibiting ERK/MAPK and PI3K/Akt pathways via regulation of RKIP expression.


greenmedinfo--2020-10-10--Didymin: an orally active citrus flavonoid for targeting neuroblastoma.

Neuroblastoma , a rapidly growing yet treatment responsive cancer , is the third most common cancer of children and the most common solid tumor in infants .
Unfortunately , neuroblastoma that has lost p53 function often has a highly treatment-resistant phenotype leading to tragic outcomes .
In the context of neuroblastoma , the functions of p53 and MYCN ( which is amplified in ~25 % of neuroblastomas ) are integrally linked because they are mutually transcriptionally regulated , and because they together regulate the catalytic activity of RNA polymerases .
Didymin is a citrus-derived natural compound that kills p53 wild-type @ @ @ @ @ @ @ in culture .
In addition , orally administered didymin causes regression of neuroblastoma xenografts in mouse models , without toxicity to non-malignant cells , neural tissues , or neural stem cells .
RKIP is a Raf-inhibitory protein that regulates MYCN activation , is transcriptionally upregulated by didymin , and appears to play a key role in the anti-neuroblastoma actions of didymin .
In this review , we discuss how didymin overcomes drug-resistance in p53-mutant neuroblastoma through RKIP-mediated inhibition of MYCN and its effects on GRK2 , PKCs , Let-7 micro-RNA , and clathrin-dependent @ @ @ @ @ @ @ In addition , we will discuss studies supporting potential clinical impact and translation of didymin as a low cost , safe , and effective oral agent that could change the current treatment paradigm for refractory neuroblastoma .

Neuroblastoma, a rapidly growing yet treatment responsive cancer, is the third most common cancer of children and the most common solid tumor in infants. Unfortunately, neuroblastoma that has lost p53 function often has a highly treatment-resistant phenotype leading to tragic outcomes. In the context of neuroblastoma, the functions of p53 and MYCN (which is amplified in ~25% of neuroblastomas) are integrally linked because they are mutually transcriptionally regulated, and because they together regulate the catalytic activity of RNA polymerases. Didymin is a citrus-derived natural compound that kills p53 wild-type as well as drug-resistant p53-mutant neuroblastoma cells in culture. In addition, orally administered didymin causes regression of neuroblastoma xenografts in mouse models, without toxicity to non-malignant cells, neural tissues, or neural stem cells. RKIP is a Raf-inhibitory protein that regulates MYCN activation, is transcriptionally upregulated by didymin, and appears to play a key role in the anti-neuroblastoma actions of didymin. In this review, we discuss how didymin overcomes drug-resistance in p53-mutant neuroblastoma through RKIP-mediated inhibition of MYCN and its effects on GRK2, PKCs, Let-7 micro-RNA, and clathrin-dependent endocytosis by Raf-dependent and -independent mechanisms. In addition, we will discuss studies supporting potential clinical impact and translation of didymin as a low cost, safe, and effective oral agent that could change the current treatment paradigm for refractory neuroblastoma.


greenmedinfo--2020-10-10--Didymin by suppressing NF-κB activation prevents VEGF-induced angiogenesis in vitro and in vivo.

Although didymin , a dietary flavonoid glycoside from citrus fruits , known to be a potent antioxidant with anti-cancer activities @ @ @ @ @ is not known .
In this study , we examined the effect of didymin on @ @ @ @ @ in vivo models .
Our results suggest that treatment of human umbilical vein endothelial cell @ @ @ @ @ significantly prevented the VEGF-induced cell proliferation , migration , and invasion .
Further , didymin @ @ @ @ @ tube formation in culture .
Didymin also attenuated the VEGF-induced generation of ROS , activation @ @ @ @ @ of adhesion molecules such as VCAM-1 , ICAM-1 , and E-selectin in HUVECs .
Further @ @ @ @ @ VEGF-induced microvessel sprouting in ex vivo mouse aortic rings .
Most importantly , didymin significantly @ @ @ @ @ cells and formation of blood capillary-like structures in Matrigel plug model of angiogenesis in mice @ @ @ @ @ suggest a novel antiangiogenic efficacy of didymin in addition to its reported anti-cancer properties , @ @ @ @ @ this agent for cancer therapy .

Although didymin, a dietary flavonoid glycoside from citrus fruits, known to be a potent antioxidant with anti-cancer activities, its role in angiogenesis is not known. In this study, we examined the effect of didymin on VEGF-induced angiogenesis in vitro and in vivo models. Our results suggest that treatment of human umbilical vein endothelial cell (HUVECs) with didymin significantly prevented the VEGF-induced cell proliferation, migration, and invasion. Further, didymin significantly prevented the VEGF-induced endothelial tube formation in culture. Didymin also attenuated the VEGF-induced generation of ROS, activation of NF-κB and the expression of adhesion molecules such as VCAM-1, ICAM-1, and E-selectin in HUVECs. Further, didymin also prevented the VEGF-induced microvessel sprouting in ex vivo mouse aortic rings. Most importantly, didymin significantly prevented the invasion of endothelial cells and formation of blood capillary-like structures in Matrigel plug model of angiogenesis in mice. Thus, our results suggest a novel antiangiogenic efficacy of didymin in addition to its reported anti-cancer properties, which warrant further development of this agent for cancer therapy.


greenmedinfo--2020-10-10--Didymin improves UV irradiation resistance in C. elegans.

Didymin , a type of flavono-o-glycoside compound naturally present in citrus fruits , has been reported to be an effective @ @ @ @ @ its effects on stress resistance are unclear .
In this study , we treatedwith didymin @ @ @ @ @ found that didymin reduced the effects of UV stressor on nematodes by decreasing reactive oxygen @ @ @ @ @ dismutase ( SOD ) activity .
Furthermore , we found that specific didymin-treated mutant nematodes @ @ @ @ @ e1370 ) , ( mu86 ) , ( ok525 ) , ( ok393 ) , @ @ @ @ @ susceptible to UV irradiation , whereas ( e1371 ) was resistant to UV irradiation .
@ @ @ @ @ that didymin not only promoted DAF-16 to transfer from cytoplasm to nucleus , but also @ @ @ @ @ expression levels of SOD-3 and HSP-16.2 after UV irradiation .
Our results show that didymin @ @ @ @ @ it may act onto regulate downstream genes through the insulin/IGF-1-like signaling pathway .

Didymin, a type of flavono-o-glycoside compound naturally present in citrus fruits, has been reported to be an effective anticancer agent. However, its effects on stress resistance are unclear. In this study, we treatedwith didymin at several concentrations. We found that didymin reduced the effects of UV stressor on nematodes by decreasing reactive oxygen species levels and increasing superoxide dismutase (SOD) activity. Furthermore, we found that specific didymin-treated mutant nematodes(mu86)&(e1370),(mu86),(ok525),(ok393), and(hx546) were susceptible to UV irradiation, whereas(e1371) was resistant to UV irradiation. In addition, we found that didymin not only promoted DAF-16 to transfer from cytoplasm to nucleus, but also increased both protein and mRNA expression levels of SOD-3 and HSP-16.2 after UV irradiation. Our results show that didymin affects UV irradiation resistance and it may act onto regulate downstream genes through the insulin/IGF-1-like signaling pathway.


greenmedinfo--2020-10-10--Didymin exhibits anti-diabetic complications and promotes glucose uptake.

Didymin is a naturally occurring orally active flavonoid glycoside ( isosakuranetin 7-O-rutinoside ) found in various citrus fruits , which has been previously reported to possess a wide variety of pharmacological activities including anticancer , antioxidant , antinociceptive , neuroprotective , hepatoprotective , inflammatory , and cardiovascular .
However , there have not been any reports concerning its anti-diabetic potential until now .
Therefore , we evaluated the anti-diabetic potential of didymin via inhibition ofα-glucosidase , protein tyrosine phosphatase 1B ( PTP1B ) , rat lens aldose reductase ( RLAR ) , human recombinant AR ( HRAR ) , and @ @ @ @ @ @ @ inhibitory assays .
Didymin strongly inhibited PTP1B , α-glucosidase , HRAR , RLAR , and AGE in the corresponding assays .
Kinetic study revealed that didymin exhibited a mixed type inhibition against α-glucosidase and HRAR , while it competitively inhibited PTP1B and RLAR .
Docking simulations of didymin demonstrated negative binding energies and close proximity to residues in the binding pocket of HRAR , RLAR , PTP1B and α-glucosidase , indicating that didymin have high affinity and tight binding capacity towards the active site of these enzymes .
Furthermore , we also examined @ @ @ @ @ @ @ of didymin in insulin-resistant HepG2 cells which significantly increased glucose uptake and decreased the expression of PTP1B in insulin-resistant HepG2 cells .
In addition , didymin activated insulin receptor substrate ( IRS ) -1 by increasing phosphorylation at tyrosine 895 and enhanced the phosphorylations of phosphoinositide 3-kinase ( PI3K ) , Akt , and glycogen synthasekinase-3 ( GSK-3 ) .
Interestingly , didymin reduced the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase , two key enzymes involved in the gluconeogenesis and leading to a diminished glucose production .
The results of the present @ @ @ @ @ @ @ useful for developingmultiple target-oriented therapeutic modalities for treatment of diabetes , and diabetes-associated complications .

Didymin is a naturally occurring orally active flavonoid glycoside (isosakuranetin 7-O-rutinoside) found in various citrus fruits, which has been previously reported to possess a wide variety of pharmacological activities including anticancer, antioxidant, antinociceptive, neuroprotective, hepatoprotective, inflammatory, and cardiovascular. However, there have not been any reports concerning its anti-diabetic potential until now. Therefore, we evaluated the anti-diabetic potential of didymin via inhibition ofα-glucosidase, protein tyrosine phosphatase 1B (PTP1B), rat lens aldose reductase (RLAR), human recombinant AR (HRAR), and advanced glycation end-product (AGE) formation inhibitory assays. Didymin strongly inhibited PTP1B, α-glucosidase, HRAR, RLAR, and AGE in the corresponding assays. Kinetic study revealed that didymin exhibited a mixed type inhibition against α-glucosidase and HRAR, while it competitively inhibited PTP1B and RLAR. Docking simulations of didymin demonstrated negative binding energies and close proximity to residues in the binding pocket of HRAR, RLAR, PTP1B and α-glucosidase, indicating that didymin have high affinity and tight binding capacity towards the active site of these enzymes. Furthermore, we also examined the molecular mechanisms underlying the anti-diabetic effects of didymin in insulin-resistant HepG2 cells which significantly increased glucose uptake and decreased the expression of PTP1B in insulin-resistant HepG2 cells. In addition, didymin activated insulin receptor substrate (IRS)-1 by increasing phosphorylation at tyrosine 895 and enhanced the phosphorylations of phosphoinositide 3-kinase (PI3K), Akt, and glycogen synthasekinase-3(GSK-3). Interestingly, didymin reduced the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, two key enzymes involved in the gluconeogenesis and leading to a diminished glucose production. The results of the present study clearly demonstrated that didymin will be useful for developingmultiple target-oriented therapeutic modalities for treatment of diabetes, and diabetes-associated complications.


greenmedinfo--2020-10-10--Apoptosis induced by the flavonoid from lemon fruit and its metabolites in HL-60 cells.

The flavonoid from lemon fruit ( Citrus limon BURM .
f. ) and its metabolites , particularly eriodictyol , 3,4-dihydroxyhydrocinnamic @ @ @ @ @ the function of DNA fragmentation in HL-60 cells when analyzed by flow cytometry .
An @ @ @ @ @ condensation were observed in HL-60 cells when treated with these compounds .
The caspase inhibitor @ @ @ @ @ compounds are anticipated to be useful for medical purposes .

The flavonoid from lemon fruit (Citrus limon BURM. f.) and its metabolites, particularly eriodictyol, 3,4-dihydroxyhydrocinnamic acid, and phloroglucinol had the function of DNA fragmentation in HL-60 cells when analyzed by flow cytometry. An apoptotic DNA ladder and chromatin condensation were observed in HL-60 cells when treated with these compounds. The caspase inhibitor prevented DNA fragmentation. These compounds are anticipated to be useful for medical purposes.


greenmedinfo--2020-10-10--Lemon flavonoid, eriocitrin, suppresses exercise-induced oxidative damage in rat liver.

To examine the preventive effect of the lemon flavonoid , eriocitrin ( eriodictyol 7-O-rutinoside ) , on oxidative stress during acute exercise in vivo , levels of N ( epsilon ) - ( hexanoyl ) lysine , HEL ; o , o-dityrosine , DT ; and nitrotyrosine , NT , as oxidative stress markers , were determined by ELISA in livers of trained rats in addition to thiobarbituric acid-reactive substance ( TBARS ) .
Eriocitrin administration prior to exercise significantly suppressed the increases in TBARS caused by lipid peroxidation during acute exercise .
The contents of HEL , DT , @ @ @ @ @ @ @ by exercise without eriocitrin administration .
However , these increases were significantly suppressed by eriocitrin administration before exercise .
Moreover , in this study , to clarify whether eriocitrin influences glutathione metabolite system that is considered to be important for a defense against the damage by oxidative stress , the levels of glutathione in rat liver were determined during exercise .
The level of reduced glutathione after exercise was maintained by administration of eriocitrin .
The increase in the concentration of oxidized glutathione caused by exercise was significantly suppressed by eriocitrin .
This @ @ @ @ @ @ @ important role in the control of the change in glutathione redox status in rat liver during exercise .
These findings showed that eriocitrin was effective in the prevention of oxidative damages caused by acute exercise-induced oxidative stress .

To examine the preventive effect of the lemon flavonoid, eriocitrin (eriodictyol 7-O-rutinoside), on oxidative stress during acute exercise in vivo, levels of N( epsilon )- (hexanoyl)lysine, HEL; o,o-dityrosine, DT; and nitrotyrosine, NT, as oxidative stress markers, were determined by ELISA in livers of trained rats in addition to thiobarbituric acid-reactive substance (TBARS). Eriocitrin administration prior to exercise significantly suppressed the increases in TBARS caused by lipid peroxidation during acute exercise. The contents of HEL, DT, and NT in rat liver increased dramatically by exercise without eriocitrin administration. However, these increases were significantly suppressed by eriocitrin administration before exercise. Moreover, in this study, to clarify whether eriocitrin influences glutathione metabolite system that is considered to be important for a defense against the damage by oxidative stress, the levels of glutathione in rat liver were determined during exercise. The level of reduced glutathione after exercise was maintained by administration of eriocitrin. The increase in the concentration of oxidized glutathione caused by exercise was significantly suppressed by eriocitrin. This result suggested that eriocitrin might play an important role in the control of the change in glutathione redox status in rat liver during exercise. These findings showed that eriocitrin was effective in the prevention of oxidative damages caused by acute exercise-induced oxidative stress.


greenmedinfo--2020-10-10--Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis.

Lemon ( Citrus limon ) contains various bioactive flavonoids , and prevents obesity and obesity-associated metabolic diseases .
We focused @ @ @ @ @ ) , a powerful antioxidative flavonoid in lemon with lipid-lowering effects in a rat model @ @ @ @ @ investigate the mechanism of action of eriocitrin , we conducted feeding experiments on zebrafish with @ @ @ @ @ of eriocitrin ( 32 mg/kg/day for 28 days ) improved dyslipidaemia and decreased lipid droplets @ @ @ @ @ microarray analysis revealed that eriocitrin increased mRNA of mitochondrial biogenesis genes , such as mitochondria @ @ @ @ @ factor 1 , cytochrome c oxidase subunit 4 , and ATP synthase .
In HepG2 @ @ @ @ @ the corresponding orthologues , and reduced lipid accumulation under conditions of lipid loading .
Eriocitrin @ @ @ @ @ content , which resulted in ATP production in HepG2 cells and zebrafish .
In summary @ @ @ @ @ hepatic steatosis with activation of mitochondrial biogenesis .

Lemon (Citrus limon) contains various bioactive flavonoids, and prevents obesity and obesity-associated metabolic diseases. We focused on eriocitrin (eriodictyol 7-rutinoside), a powerful antioxidative flavonoid in lemon with lipid-lowering effects in a rat model of high-fat diet. To investigate the mechanism of action of eriocitrin, we conducted feeding experiments on zebrafish with diet-induced obesity. Oral administration of eriocitrin (32 mg/kg/day for 28 days) improved dyslipidaemia and decreased lipid droplets in the liver. DNA microarray analysis revealed that eriocitrin increased mRNA of mitochondrial biogenesis genes, such as mitochondria transcription factor, nuclear respiratory factor 1, cytochrome c oxidase subunit 4, and ATP synthase. In HepG2 cells, eriocitrin also induced the corresponding orthologues, and reduced lipid accumulation under conditions of lipid loading. Eriocitrin increased mitochondrial size and mtDNA content, which resulted in ATP production in HepG2 cells and zebrafish. In summary, dietary eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis.


greenmedinfo--2020-10-10--Chemopreventive potential of phenolic compounds in oral carcinogenesis.

OBJECTIVE : To evaluate the chemopreventive potential of phenolic compounds - potassium apigenin , cocoa , catechins , eriocitrin and rosmarinic acid in oral carcinogenesis induced in hamsters by means of the topical application of 7,12-dimethylbenz ( a ) anthracene ( DMBA ) .
STUDY DESIGN : An experimental study at the University of Murcia .
METHODS : 50 male Syrian hamsters ( Mesocricetus auratus ) were divided into five groups of ten : Group I ( control group ) : 0.5 % DMBA ; Group II : 0.5 % DMBA+1.1mg/15ml potassium apigenin ; Group III : 05 % DMBA+2.5mg/15ml @ @ @ @ @ @ @ % DMBA+6mg/15ml eriocitrin ; Group V : 0.5 % DMBA+1.3mg/15ml rosmarinic acid .
The flavonoids were administered orally .
All the animals were sacrificed after 12 weeks .
Macroscopic , microscopic and immunohistochemical ( PCNA and p53 ) analyses of the lesions were performed .
RESULTS : All the groups treated with phenolic compounds showed lower incidences of tumour , greater differentiation and lower scores in the tumour invasion front grading system in comparison with the control group .
Potassium apigenin and rosmarinic acid achieved the best results , the former considerably reduced @ @ @ @ @ @ @ significantly reduced the intensity and aggression of the tumours .
Immunoexpression of PCNA and p53 were significantly altered during DMBA-induced oral carcinogenesis .
CONCLUSIONS : Animals treated with phenolic compounds , particularly potassium apigenin and rosmarinic acid , showed a lower incidence of tumours .

OBJECTIVE: To evaluate the chemopreventive potential of phenolic compounds - potassium apigenin, cocoa, catechins, eriocitrin and rosmarinic acid in oral carcinogenesis induced in hamsters by means of the topical application of 7,12-dimethylbenz(a)anthracene(DMBA).
STUDY DESIGN: An experimental study at the University of Murcia.
METHODS: 50 male Syrian hamsters (Mesocricetus auratus) were divided into five groups of ten: Group I (control group): 0.5% DMBA; Group II: 0.5% DMBA+1.1mg/15ml potassium apigenin; Group III: 05% DMBA+2.5mg/15ml cocoa catechins; Group IV: 0.5% DMBA+6mg/15ml eriocitrin; Group V: 0.5% DMBA+1.3mg/15ml rosmarinic acid. The flavonoids were administered orally. All the animals were sacrificed after 12 weeks. Macroscopic, microscopic and immunohistochemical (PCNA and p53) analyses of the lesions were performed.
RESULTS: All the groups treated with phenolic compounds showed lower incidences of tumour, greater differentiation and lower scores in the tumour invasion front grading system in comparison with the control group. Potassium apigenin and rosmarinic acid achieved the best results, the former considerably reduced the carcinoma tumour volumes developed and both significantly reduced the intensity and aggression of the tumours. Immunoexpression of PCNA and p53 were significantly altered during DMBA-induced oral carcinogenesis.
CONCLUSIONS: Animals treated with phenolic compounds, particularly potassium apigenin and rosmarinic acid, showed a lower incidence of tumours.


greenmedinfo--2020-10-10--Citrus flavanones prevent systemic inflammation and ameliorate oxidative stress.

The flavanones hesperidin , eriocitrin and eriodictyol were investigated for their prevention of the oxidative stress and systemic inflammation caused @ @ @ @ @ mice .
The mice received a standard diet ( 9.5 % kcal from fat ) @ @ @ @ @ % kcal from fat ) or high-fat diet supplemented with hesperidin , eriocitrin or eriodictyol @ @ @ @ @ weeks .
Hesperidin , eriocitrin and eriodictyol increased the serum total antioxidant capacity , and @ @ @ @ @ ( IL-6 ) , macrophage chemoattractant protein-1 ( MCP-1 ) , and C-reactive protein ( @ @ @ @ @ , the liver TBARS levels and spleen mass ( g per kg body weight ) @ @ @ @ @ mice than in the unsupplemented mice .
Eriocitrin and eriodictyol reduced TBARS levels in the @ @ @ @ @ and eriodictyol also reduced fat accumulation and liver damage .
The results showed that hesperidin @ @ @ @ @ protective effects against inflammation and oxidative stress caused by high-fat diet in mice , and @ @ @ @ @ associated with the development of cardiovascular diseases in other animals .

The flavanones hesperidin, eriocitrin and eriodictyol were investigated for their prevention of the oxidative stress and systemic inflammation caused by high-fat diet in C57BL/6J mice. The mice received a standard diet (9.5% kcal from fat), high-fat diet (45% kcal from fat) or high-fat diet supplemented with hesperidin, eriocitrin or eriodictyol for a period of four weeks. Hesperidin, eriocitrin and eriodictyol increased the serum total antioxidant capacity, and restrained the elevation of interleukin-6 (IL-6), macrophage chemoattractant protein-1 (MCP-1), and C-reactive protein (hs-CRP). In addition, the liver TBARS levels and spleen mass (g per kg body weight) were lower for the flavanone-treated mice than in the unsupplemented mice. Eriocitrin and eriodictyol reduced TBARS levels in the blood serum, and hesperidin and eriodictyol also reduced fat accumulation and liver damage. The results showed that hesperidin, eriocitrin and eriodictyol had protective effects against inflammation and oxidative stress caused by high-fat diet in mice, and may therefore prevent metabolic alterations associated with the development of cardiovascular diseases in other animals.


greenmedinfo--2020-10-11--Effect of rutin on diabetic auditory neuropathy in an experimental rat model.

Objectives : Diabetic auditory neuropathy is a common complication of diabetes mellitus that has a major impact on patients ' quality of life .
In this study , we assessed the efficacy of rutin in treating diabetic auditory neuropathy in an experimental rat model .
Methods : Forty Sprague-Dawley rats were randomly assigned to the following groups : group 1 , control ; group 2 , diabetic rats ; and groups 3-5 , rats treated with rutin ( at doses of 50 , 100 , and 150 mg/kg , respectively ) .
We used auditory brain stem response , stereology @ @ @ @ @ @ @ of superoxide dismutase ( SOD ) and malondialdehyde ( MDA ) to evaluate the effects of treatment .
Results : Significant improvements in auditory neuropathy were observed in the rutin-treated groups in comparison with the diabetic group ( P < 0.05 ) .
Auditory threshold , wave latency , wave morphology , the volume and number of neurons in the spiral ganglion , and SOD and MDA activity showed improvements following treatment .
Conclusion : Rutin shows promise as a treatment modality for diabetic auditory neuropathy , but more trials are warranted for @ @ @ @

Objectives: Diabetic auditory neuropathy is a common complication of diabetes mellitus that has a major impact on patients' quality of life. In this study, we assessed the efficacy of rutin in treating diabetic auditory neuropathy in an experimental rat model.
Methods: Forty Sprague-Dawley rats were randomly assigned to the following groups: group 1, control; group 2, diabetic rats; and groups 3-5, rats treated with rutin (at doses of 50, 100, and 150 mg/kg, respectively). We used auditory brain stem response, stereology of the spiral ganglion, and measurements of superoxide dismutase (SOD) and malondialdehyde (MDA) to evaluate the effects of treatment.
Results: Significant improvements in auditory neuropathy were observed in the rutin-treated groups in comparison with the diabetic group (P<0.05). Auditory threshold, wave latency, wave morphology, the volume and number of neurons in the spiral ganglion, and SOD and MDA activity showed improvements following treatment.
Conclusion: Rutin shows promise as a treatment modality for diabetic auditory neuropathy, but more trials are warranted for its clinical application.


greenmedinfo--2020-10-11--Rutin has histoprotective ability against cisplatin-induced toxicities.

Cisplatin is an effective anticancer drug used against a variety of cancers .
The full therapeutic potential of cisplatin is often hampered due to concurrent development of various side effects in the hosts .
Rutin , a naturally occurring bioflavonoid shows several pharmacological activities .
It has been earlier reported by us that rutin and cisplatin in combination show better antitumor activity against murine ascites Dalton 's lymphoma .
As cisplatin is given to cancer-bearing hosts only , the present study was undertaken to explore the histoprotective effect of rutin against some toxicities induced by cisplatin in tumor-bearing mice .
@ @ @ @ @ @ @ architecture such as degenerated hepatocytes with nuclear condensation and sinusoidal dilatation in the liver , glomerular deterioration , infiltration of cells , and tubular congestion in the kidney , and vacuolization of Sertoli cells or dense granules in the cytoplasm and damaged seminiferous tubules in the testes .
In the rutin plus cisplatin combination-treated mice , all the abnormal tissue architectural features were decreased .
Further , as compared to cisplatin treatment , combination treatment did not show any significant elevation in the liver functional biomarkers ( serum aspartate aminotransferase , alanine aminotransferase @ @ @ @ @ @ @ biomarkers ( serum urea and creatinine levels ) .
The combination treatment reduced the sperm abnormalities also as compared to the cisplatin alone treatment .
Thehemolysis assay of red blood cells and scanning electron microscopy revealed that combination treatment lessened the cisplatin-induced hemolysis and abnormalities in RBCs .
Thus , the present findings demonstrate that rutin has histoprotective ability against cisplatin-induced toxicities in tumor-bearing mice .

Cisplatin is an effective anticancer drug used against a variety of cancers. The full therapeutic potential of cisplatin is often hampered due to concurrent development of various side effects in the hosts. Rutin, a naturally occurring bioflavonoid shows several pharmacological activities. It has been earlier reported by us that rutin and cisplatin in combination show better antitumor activity against murine ascites Dalton's lymphoma. As cisplatin is given to cancer-bearing hosts only, the present study was undertaken to explore the histoprotective effect of rutin against some toxicities induced by cisplatin in tumor-bearing mice. Cisplatin treatment caused severe damages in tissue architecture such as degenerated hepatocytes with nuclear condensation and sinusoidal dilatation in the liver, glomerular deterioration, infiltration of cells, and tubular congestion in the kidney, and vacuolization of Sertoli cells or dense granules in the cytoplasm and damaged seminiferous tubules in the testes. In the rutin plus cisplatin combination-treated mice, all the abnormal tissue architectural features were decreased. Further, as compared to cisplatin treatment, combination treatment did not show any significant elevation in the liver functional biomarkers (serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) and renal functional biomarkers (serum urea and creatinine levels). The combination treatment reduced the sperm abnormalities also as compared to the cisplatin alone treatment. Thehemolysis assay of red blood cells and scanning electron microscopy revealed that combination treatment lessened the cisplatin-induced hemolysis and abnormalities in RBCs. Thus, the present findings demonstrate that rutin has histoprotective ability against cisplatin-induced toxicities in tumor-bearing mice.


greenmedinfo--2020-10-11--Nutritional supplementation with precursors glycine and N-acetylcysteine improves comorbidities sugg

Nutritional supplementation with precursors glycine and N-acetylcysteine improves comorbidities suggestive of premature aging in patients with HIV.

Patients with HIV ( PWH ) develop geriatric comorbidities , including functional and cognitive decline at a younger age .
However , contributing mechanisms are unclear and interventions are lacking .
We hypothesized that deficiency of the antioxidant protein glutathione ( GSH ) contributes to multiple defects representing premature aging in PWH , and that these defects could be improved by supplementing the GSH precursors glycine and N-acetylcysteine ( GlyNAC ) .We conducted an open label clinical trial where eight PWH and eight matched uninfected-controls were studied at baseline .
PWH were studied again 12-weeks after receiving GlyNAC , and @ @ @ @ @ @ @ not receive supplementation .
Outcome measures included red-blood cell and muscle GSH concentrations , mitochondrial function , mitophagy and autophagy , oxidative stress , inflammation , endothelial function , genomic damage , insulin resistance , glucose production , muscle-protein breakdown rates , body composition , physical function and cognition.PWH had significant defects in measured outcomes , which improved with GlyNAC supplementation .
However , benefits receded after stopping GlyNAC.This open label trial finds that PWH have premature aging based on multiple biological and functional defects , and identifies novel mechanistic explanations for cognitive @ @ @ @ @ @ @ GlyNAC improves comorbidities suggestive of premature aging in PWH including functional and cognitive decline , and warrants additional investigation .

Patients with HIV (PWH) develop geriatric comorbidities, including functional and cognitive decline at a younger age. However, contributing mechanisms are unclear and interventions are lacking. We hypothesized that deficiency of the antioxidant protein glutathione (GSH) contributes to multiple defects representing premature aging in PWH, and that these defects could be improved by supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC).We conducted an open label clinical trial where eight PWH and eight matched uninfected-controls were studied at baseline. PWH were studied again 12-weeks after receiving GlyNAC, and 8-weeks after stopping GlyNAC. Controls did not receive supplementation. Outcome measures included red-blood cell and muscle GSH concentrations, mitochondrial function, mitophagy and autophagy, oxidative stress, inflammation, endothelial function, genomic damage, insulin resistance, glucose production, muscle-protein breakdown rates, body composition, physical function and cognition.PWH had significant defects in measured outcomes, which improved with GlyNAC supplementation. However, benefits receded after stopping GlyNAC.This open label trial finds that PWH have premature aging based on multiple biological and functional defects, and identifies novel mechanistic explanations for cognitive and physical decline. Nutritional supplementation with GlyNAC improves comorbidities suggestive of premature aging in PWH including functional and cognitive decline, and warrants additional investigation.


greenmedinfo--2020-10-11--You Can Heal The World — An Invitation for YOU to Join Us [Sayer Ji's Video Message]

You can heal the world , starting with your beautiful body , your beautiful life .
One by one , @ @ @ @ @ the reality that human connection is the key ; that loving ourselves , honoring our @ @ @ @ @ into alignment with the sacred , is the answer to all that ails us .
@ @ @ @ @ the upcoming Thank You Body Rally event on October 16th , worldwide , which is @ @ @ @ @ Movement -- a movement that will never end .

Visit our Re-post guidelines This article is copyrighted by GreenMedInfo LLC, 2020
You can heal the world, starting with your beautiful body, your beautiful life. One by one, we are waking up to the reality that human connection is the key; that loving ourselves, honoring our bodies, and bringing ourselves into alignment with the sacred, is the answer to all that ails us. Join Sayer and Kelly for the upcoming Thank You Body Rally event on October 16th, worldwide, which is part of the Human Connection Movement -- a movement that will never end.


greenmedinfo--2020-10-11--N-acetylcysteine reverses antiretroviral-mediated microglial activation by attenuating autophagy-lys

N-acetylcysteine reverses antiretroviral-mediated microglial activation by attenuating autophagy-lysosomal dysfunction.

Successful suppression of viral replication by combined antiretroviral therapy ( cART ) in HIV-1 infected individuals is paradoxically also accompanied by an increased prevalence of HIV-associated neurocognitive disorders ( HAND ) in these individuals .
HAND is characterized by a state of chronic oxidative stress and inflammation .
Microglia are extremely sensitive to a plethora of stimuli , including viral proteins and cART .
The current study aimed to assess the effects of cART-mediated oxidative stress on the induction of inflammatory responses in microglia .
In the present study , we chose a combination of three commonly used antiretroviral drugs-tenofovir @ @ @ @ @ @ @ .
We demonstrated that exposure of microglia to the chosen cART cocktail induced generation of reactive oxygen species , subsequently leading to lysosomal dysfunction and dysregulated autophagy , ultimately resulting in the activation of microglia .
Intriguingly , the potent antioxidant , N-acetylcysteine , reversed the damaging effects of cART .
Thesefindings were further corroboratedwherein cART-treated HIV transgenic ( Tg ) rats demonstrated increased microglial activation , exaggerated lysosome impairment , and dysregulated autophagy in the prefrontal cortices compared with HIV Tg rats not exposed to cART .
Similar tofindings , the treatment @ @ @ @ @ @ @ mitigated the deleterious effects of cART .
Taken together , our findings suggest that oxidative stress-mediated lysosomal dysfunction plays a critical role in the pathogenesis of HAND in drug-treated HIV-infected individuals and that antioxidant-mediated mitigation of oxidative stress could thus be considered as an adjunctive therapeutic strategy for ameliorating/dampening some of the neurological complications of HAND .

Successful suppression of viral replication by combined antiretroviral therapy (cART) in HIV-1 infected individuals is paradoxically also accompanied by an increased prevalence of HIV-associated neurocognitive disorders (HAND) in these individuals. HAND is characterized by a state of chronic oxidative stress and inflammation. Microglia are extremely sensitive to a plethora of stimuli, including viral proteins and cART. The current study aimed to assess the effects of cART-mediated oxidative stress on the induction of inflammatory responses in microglia. In the present study, we chose a combination of three commonly used antiretroviral drugs-tenofovir disoproxil fumarate, emtricitabine, and dolutegravir. We demonstrated that exposure of microglia to the chosen cART cocktail induced generation of reactive oxygen species, subsequently leading to lysosomal dysfunction and dysregulated autophagy, ultimately resulting in the activation of microglia. Intriguingly, the potent antioxidant, N-acetylcysteine, reversed the damaging effects of cART. Thesefindings were further corroboratedwherein cART-treated HIV transgenic (Tg) rats demonstrated increased microglial activation, exaggerated lysosome impairment, and dysregulated autophagy in the prefrontal cortices compared with HIV Tg rats not exposed to cART. Similar tofindings, the treatment of HIV Tg rats with N-acetylcysteine also mitigated the deleterious effects of cART. Taken together, our findings suggest that oxidative stress-mediated lysosomal dysfunction plays a critical role in the pathogenesis of HAND in drug-treated HIV-infected individuals and that antioxidant-mediated mitigation of oxidative stress could thus be considered as an adjunctive therapeutic strategy for ameliorating/dampening some of the neurological complications of HAND.


greenmedinfo--2020-10-11--N-acetylcysteine and glycyrrhizin combination: Benefit outcome in a murine model of acetaminophen-in

N-acetylcysteine and glycyrrhizin combination: Benefit outcome in a murine model of acetaminophen-induced liver failure.

BACKGROUND : Acetaminophen overdose is the most frequent cause of drug-induced liver failure in developed countries .
Substantial progress has been made in understanding the mechanism of hepatocellular injury , but N-acetylcysteine remains the only effective treatment despite its short therapeutic window .
Thus , other hepatoprotective drugs are needed for the delayed treatment of acetaminophen-induced hepatotoxicity .
Our interest focused on glycyrrhizin for its role as an inhibitor of high mobility group box 1 ( HMGB1 ) protein , a member of the family of damage-associated molecular pattern , known to play an important pathological role in various diseases @ @ @ @ @ @ @ of the N-acetylcysteine/glycyrrhizin combination compared to N-acetylcysteine alone in the prevention of liver toxicity .
METHODS : Eight-week-old C57BL/6J wild-type female mice were used for all our experiments .
Mice fasted for 15 h were treated with acetaminophen ( 500 mg/kg ) or vehicle ( phosphate-buffered saline ) by intraperitoneal injection and separated into the following groups : Glycyrrhizin ( 200 mg/kg ) ; N-acetylcysteine ( 150 mg/kg ) ; and N-acetylcysteine/glycyrrhizin .
In all groups , mice were sacrificed 12 h following acetaminophen administration .
The assessment of hepatotoxicity was performed by @ @ @ @ @ @ @ aspartate aminotransferase and lactate dehydrogenase .
Hepatotoxicity was also evaluated by histological examination of hematoxylin and eosin-stained tissues sections .
Survival rates were compared between various groups using Kaplan-Meier curves .
RESULTS : Consistent with data published in the literature , we confirmed that intraperitoneal administration of acetaminophen ( 500 mg/kg ) in mice induced severe liver injury as evidenced by increases in alanine aminotransferase , aspartate aminotransferase and lactate dehydrogenase but also by liver necrosis score .
Glycyrrhizin administration was shown to reduce the release of HMGB1 and significantly decreased the severity @ @ @ @ @ @ @ co-administration of glycyrrhizin and N-acetylcysteine was investigated .
Administered concomitantly with acetaminophen , the combination significantly reduced the severity of liver injury .
Delayed administration of the combination of drugs , 2 h or 6 h after acetaminophen , also induced a significant decrease in hepatocyte necrosis compared to mice treated with N-acetylcysteine alone .
In addition , administration of N-acetylcysteine/glycyrrhizin combination was associated with an improved survival rate compared to mice treated with only N-acetylcysteine .
CONCLUSION : We demonstrate that , compared to N-acetylcysteine alone , co-administration of glycyrrhizin decreases the @ @ @ @ @ @ @ a murine model of acetaminophen-induced liver injury .
Our study opens a potential new therapeutic pathway in the prevention of acetaminophen hepatotoxicity .

BACKGROUND: Acetaminophen overdose is the most frequent cause of drug-induced liver failure in developed countries. Substantial progress has been made in understanding the mechanism of hepatocellular injury, but N-acetylcysteine remains the only effective treatment despite its short therapeutic window. Thus, other hepatoprotective drugs are needed for the delayed treatment of acetaminophen-induced hepatotoxicity. Our interest focused on glycyrrhizin for its role as an inhibitor of high mobility group box 1 (HMGB1) protein, a member of the family of damage-associated molecular pattern, known to play an important pathological role in various diseases.
AIM: To investigate the efficacy of the N-acetylcysteine/glycyrrhizin combination compared to N-acetylcysteine alone in the prevention of liver toxicity.
METHODS: Eight-week-old C57BL/6J wild-type female mice were used for all our experiments. Mice fasted for 15 h were treated with acetaminophen (500 mg/kg) or vehicle (phosphate-buffered saline) by intraperitoneal injection and separated into the following groups: Glycyrrhizin (200 mg/kg); N-acetylcysteine (150 mg/kg); and N-acetylcysteine/glycyrrhizin. In all groups, mice were sacrificed 12 h following acetaminophen administration. The assessment of hepatotoxicity was performed by measuring plasma levels of alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase. Hepatotoxicity was also evaluated by histological examination of hematoxylin and eosin-stained tissues sections. Survival rates were compared between various groups using Kaplan-Meier curves.
RESULTS: Consistent with data published in the literature, we confirmed that intraperitoneal administration of acetaminophen (500 mg/kg) in mice induced severe liver injury as evidenced by increases in alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase but also by liver necrosis score. Glycyrrhizin administration was shown to reduce the release of HMGB1 and significantly decreased the severity of liver injury. Thus, the co-administration of glycyrrhizin and N-acetylcysteine was investigated. Administered concomitantly with acetaminophen, the combination significantly reduced the severity of liver injury. Delayed administration of the combination of drugs, 2 h or 6 h after acetaminophen, also induced a significant decrease in hepatocyte necrosis compared to mice treated with N-acetylcysteine alone. In addition, administration of N-acetylcysteine/glycyrrhizin combination was associated with an improved survival rate compared to mice treated with only N-acetylcysteine.
CONCLUSION: We demonstrate that, compared to N-acetylcysteine alone, co-administration of glycyrrhizin decreases the liver necrosis score and improves survival in a murine model of acetaminophen-induced liver injury. Our study opens a potential new therapeutic pathway in the prevention of acetaminophen hepatotoxicity.


greenmedinfo--2020-10-11--Acetylcysteine for the treatment of suspected remdesivir-associated acute liver Failure in COVID-19.

Remdesivir is a direct-acting nucleoside RNA polymerase inhibitor with activity against the novel SARS-CoV-2 virus used in the treatment of @ @ @ @ @ present two cases of suspected remdesivir-associated acute liver failure ( ALF ) in which the @ @ @ @ @ infusion acetylcysteine and withdrawal of remdesivir .
Both patients had significant increases in transaminases between @ @ @ @ @ of remdesivir therapy accompanied by coagulopathy and encephalopathy .
After initiation of continuous infusion acetylcysteine @ @ @ @ @ patients rapidly improved .
Ultimately one patient fully recovered while the other died of suspected @ @ @ @ @ its novel nature and only recent widespread use , there is very little data on @ @ @ @ @ remdesivir .
Additionally , the data for the use of acetylcysteine to manage non-acetaminophen-induced ALF @ @ @ @ @ important to consider the risk of remdesivir-associated ALF when weighing the risk vs. benefits of @ @ @ @ @ have a role in its management .

Remdesivir is a direct-acting nucleoside RNA polymerase inhibitor with activity against the novel SARS-CoV-2 virus used in the treatment of COVID-19 pneumonia. Here we present two cases of suspected remdesivir-associated acute liver failure (ALF) in which the liver failure improved following continuous infusion acetylcysteine and withdrawal of remdesivir. Both patients had significant increases in transaminases between day 3 and day 10 of remdesivir therapy accompanied by coagulopathy and encephalopathy. After initiation of continuous infusion acetylcysteine, the transaminases of both patients rapidly improved. Ultimately one patient fully recovered while the other died of suspected septic shock. Due to its novel nature and only recent widespread use, there is very little data on the risk of ALF from remdesivir. Additionally, the data for the use of acetylcysteine to manage non-acetaminophen-induced ALF is limited. It is important to consider the risk of remdesivir-associated ALF when weighing the risk vs. benefits of use, and acetylcysteine may have a role in its management.