#dysbiotic index

[falconmio]

New Post has been published on

New Post has been published on http://salutevincente.online/vivere-in-salute/sara-il-futuro-candidato-probiotico-contro-le-malattie-infiammatorie-croniche-dellintestino/

Sarà il Futuro Candidato Probiotico contro le Malattie Infiammatorie Croniche dell'Intestino

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Il candidato probiotico di prossima generazione per la lotta contro le malattie infiammatorie croniche dell’intestino sicuramente sarà il Faecalibacterium prausnitzii.

Ma perchè?

E’uno dei batteri presenti in alta percentuale nel microbiota sano del genere umano e anche se i suoi effetti benefici sulla salute umana cominciano ad essere ampiamente riconosciuti,ancora pochi sono gli studi microbiologici effettuati per isolare altri ceppi di Faecalibacterium prausnitzii al fine di indagare sulla sua biodiversità e sulla sua azione fisiologica in particolare a livello dell’intestino.E’ un batterio anaerobio obbligato.In alcuni ceppi di F.prausnitzii sembrano esserci differenze nella produzione di enzimi,nella resistenza agli antibiotici e anche nella capacità di influenzare il sistema immunitario.E’ altresì capace di produrre acidi grassi a catena corta,denominati SCFA e in modo significativo il Butirrato,uno di questi acidi che interferendo con una citochina antiinfiammatoria presente nelle cellule mononucleate del sangue periferico,porterebbe ad una complessa ma potente azione 

antiinfiammatoria a livello intestinale,preservando quest’organo da patologie anche gravi.Si stima che circa il 5% del Microbiota fecale presente in adulti sani è costituito da Faecalibacterium prausnitzii,in una classifica che nel Microbioma intestinale umano vede predominanti soltanto alcuni ceppi batterici,come Bacteroides,Clostridium,Bifidobacterium e Faecalibacterium,anche se ci sono poi altre specie di batteri,virus,etc.

Relazione tra Faecalibacterium prausnitzii e patologie intestinali

Si è notata una diminuita presenza di questo batterio in pazienti affetti da disturbi intestinali e metabolici,come quelle malattie dell’intestino catalogate con la sigla IBD,IBS (malattie dell’intestino irritabile),nel Cancro del colon retto (CRC),nella Obesità,nella Fibrosi Cistica,nella stessa Malattia Celiaca ed in molti soggetti anziani.Tengo anche a dirti che si è proposto di utilizzare la presenza di questa specie batterica come biomarcatore nella differenziazione della Colite Ulcerosa (UC) e della Malattia di Crohn (CD).Oggi i probiotici in commercio per la maggior parte non contengono i batteri dominanti tra i normali commensali del nostro microbiota intestinale.

Probabilmente ciò è dovuto principalmente al fatto che soltanto nell’ultimo decennio si è cominciato a fare maggiore chiarezza sulle interazioni che si

determinano tra gli stessi commensali del nostro intestino e su come questi microrganismi influenzano il nostro stato di salute.Nonostante ciò il mercato dei Probiotici è in continua crescita e più in Europa che altrove,negli Stati Uniti per esempio.E già oggi il rapporto tra il Faecalibacterium prausnitzii e l’Escherichia coli,chiamato dysbiotic index, viene generalmente usato per valutare il livello di Disbiosi intestinale nei soggetti adulti,visto che questo valore nei bambini non risulta attendibile.

Se vuoi approfondire l’argomento ti consiglio di cliccare sul link che segue:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492426/

P.S. Se l’articolo ti è stato utile mi farebbe piacere che tu lo condividessi,

magari utilizzando i pulsanti Social in basso. In questo modo contribuirai a far conoscere queste informazioni ai tuoi conoscenti.

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[bioadvisers]

Bioadvisers shared on Biotech Advisers

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Content introduction:

A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

In utero priming of highly functional effector T cell responses to human malaria

Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

1. A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, Nicolas Dutzan at NIH in Bethesda, USA and his colleagues demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)–dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Their study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat0797

2. In utero priming of highly functional effector T cell responses to human malaria

Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, Pamela M. Odorizzi at University of California in San Francisco, USA and his colleagues assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria. They found that infants born to mothers with active placental malaria had elevated frequencies of proliferating effector memory fetal CD4+ T cells and higher frequencies of CD4+ and CD8+ T cells that produced inflammatory cytokines. Fetal CD4+ and CD8+ T cells from placental malaria–exposed infants exhibited greater in vitro proliferation to malaria antigens. Malaria-specific CD4+ T cell proliferation correlated with prospective protection from malaria during childhood. These data demonstrate that placental malaria is associated with the generation of proinflammatory malaria-responsive fetal T cells. These findings add to our current understanding of fetal immunity and indicate that a functional and protective pathogen-specific T cell response can be generated in utero.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat6176

3. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, Dionysos Slaga at Genentech Inc in South San Francisco, USA and his colleagues developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat5775

4. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. Ganlan Bian at Fourth Military Medical University in Xi’an, China and his colleagues identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal–regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)–c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Their results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat1470

5. The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, Kexin Shen at University of Pittsburgh School of Medicine in Pittsburgh, USA and his colleagues investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region. Unlike other family members, recombinant Fgr was not activated by SH3-SH2 domain ligands. However, hydrogen-deuterium exchange mass spectrometry data suggested that the regulatory SH3 and SH2 domains packed against the back of the kinase domain in a Src-like manner. Sequence alignment showed that the activation loop of Fgr was distinct from that of all other Src family members, with proline rather than alanine at the +2 position relative to the activation loop tyrosine. Substitution of the activation loop of Fgr with the sequence from Src partially inhibited kinase activity and suppressed colony formation. Last, Fgr expression enhanced the sensitivity of human myeloid progenitor cells to the cytokine GM-CSF. Because its kinase domain is not sensitive to SH3-SH2–mediated control, simple overexpression of Fgr without mutation may contribute to oncogenic transformation in AML and other blood cancers.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat5916

[abbkine]

BioAdvisers said on Biotech Advisers

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Content introduction:

A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

In utero priming of highly functional effector T cell responses to human malaria

Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

1. A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, Nicolas Dutzan at NIH in Bethesda, USA and his colleagues demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)–dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Their study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat0797

2. In utero priming of highly functional effector T cell responses to human malaria

Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, Pamela M. Odorizzi at University of California in San Francisco, USA and his colleagues assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria. They found that infants born to mothers with active placental malaria had elevated frequencies of proliferating effector memory fetal CD4+ T cells and higher frequencies of CD4+ and CD8+ T cells that produced inflammatory cytokines. Fetal CD4+ and CD8+ T cells from placental malaria–exposed infants exhibited greater in vitro proliferation to malaria antigens. Malaria-specific CD4+ T cell proliferation correlated with prospective protection from malaria during childhood. These data demonstrate that placental malaria is associated with the generation of proinflammatory malaria-responsive fetal T cells. These findings add to our current understanding of fetal immunity and indicate that a functional and protective pathogen-specific T cell response can be generated in utero.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat6176

3. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, Dionysos Slaga at Genentech Inc in South San Francisco, USA and his colleagues developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat5775

4. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. Ganlan Bian at Fourth Military Medical University in Xi’an, China and his colleagues identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal–regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)–c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Their results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat1470

5. The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, Kexin Shen at University of Pittsburgh School of Medicine in Pittsburgh, USA and his colleagues investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region. Unlike other family members, recombinant Fgr was not activated by SH3-SH2 domain ligands. However, hydrogen-deuterium exchange mass spectrometry data suggested that the regulatory SH3 and SH2 domains packed against the back of the kinase domain in a Src-like manner. Sequence alignment showed that the activation loop of Fgr was distinct from that of all other Src family members, with proline rather than alanine at the +2 position relative to the activation loop tyrosine. Substitution of the activation loop of Fgr with the sequence from Src partially inhibited kinase activity and suppressed colony formation. Last, Fgr expression enhanced the sensitivity of human myeloid progenitor cells to the cytokine GM-CSF. Because its kinase domain is not sensitive to SH3-SH2–mediated control, simple overexpression of Fgr without mutation may contribute to oncogenic transformation in AML and other blood cancers.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat5916