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Article ; Online: Identifying Function Determining Residues in Neuroimmune Semaphorin 4A.

Chapoval, Svetlana P / Lee, Mariah / Lemmer, Aaron / Ajayi, Oluwaseyi / Qi, Xiulan / Neuwald, Andrew F / Keegan, Achsah D

International journal of molecular sciences

2022 Volume 23, Issue 6

Abstract: Semaphorin 4A (Sema4A) exerts a stabilizing effect on human Treg cells in PBMC and CD4+ T cell cultures by engaging Plexin B1. Sema4A deficient mice display enhanced allergic airway inflammation accompanied by fewer Treg cells, while Sema4D deficient ... ...

Abstract	Semaphorin 4A (Sema4A) exerts a stabilizing effect on human Treg cells in PBMC and CD4+ T cell cultures by engaging Plexin B1. Sema4A deficient mice display enhanced allergic airway inflammation accompanied by fewer Treg cells, while Sema4D deficient mice displayed reduced inflammation and increased Treg cell numbers even though both Sema4 subfamily members engage Plexin B1. The main objectives of this study were: 1. To compare the in vitro effects of Sema4A and Sema4D proteins on human Treg cells; and 2. To identify function-determining residues in Sema4A critical for binding to Plexin B1 based on Sema4D homology modeling. We report here that Sema4A and Sema4D display opposite effects on human Treg cells in in vitro PBMC cultures; Sema4D inhibited the CD4+CD25+Foxp3+ cell numbers and CD25/Foxp3 expression. Sema4A and Sema4D competitively bind to Plexin B1 in vitro and hence may be doing so in vivo as well. Bayesian Partitioning with Pattern Selection (BPPS) partitioned 4505 Sema domains from diverse organisms into subgroups based on distinguishing sequence patterns that are likely responsible for functional differences. BPPS groups Sema3 and Sema4 into one family and further separates Sema4A and Sema4D into distinct subfamilies. Residues distinctive of the Sema3,4 family and of Sema4A (and by homology of Sema4D) tend to cluster around the Plexin B1 binding site. This suggests that the residues both common to and distinctive of Sema4A and Sema4D may mediate binding to Plexin B1, with subfamily residues mediating functional specificity. We mutated the Sema4A-specific residues M198 and F223 to alanine; notably, F223 in Sema4A corresponds to alanine in Sema4D. Mutant proteins were assayed for Plexin B1-binding and Treg stimulation activities. The F223A mutant was unable to stimulate Treg stability in in vitro PBMC cultures despite binding Plexin B1 with an affinity similar to the WT protein. This research is a first step in generating potent mutant Sema4A molecules with stimulatory function for Treg cells with a view to designing immunotherapeutics for asthma.
MeSH term(s)	Alanine ; Animals ; Bayes Theorem ; Forkhead Transcription Factors/genetics ; Humans ; Inflammation ; Leukocytes, Mononuclear/metabolism ; Mice ; Nerve Tissue Proteins/metabolism ; Semaphorins/metabolism
Chemical Substances	Forkhead Transcription Factors ; Nerve Tissue Proteins ; SEMA4A protein, human ; Semaphorins ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2022-03-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23063024
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Article ; Online: Mice Expressing Cosegregating Single Nucleotide Polymorphisms (D298G and N397I) in TLR4 Have Enhanced Responses to House Dust Mite Allergen.

Fink, Marc Y / Qi, Xiulan / Shirey, Kari Ann / Fanaroff, Rachel / Chapoval, Svetlana / Viscardi, Rose M / Vogel, Stefanie N / Keegan, Achsah D

Journal of immunology (Baltimore, Md. : 1950)

2022 Volume 208, Issue 9, Page(s) 2085–2097

Abstract: Asthma is a common and ubiquitous chronic respiratory disease that is associated with airway inflammation and hyperreactivity resulting in airway obstruction. It is now accepted that asthma is controlled by a combination of host genetics and environment ... ...

Abstract	Asthma is a common and ubiquitous chronic respiratory disease that is associated with airway inflammation and hyperreactivity resulting in airway obstruction. It is now accepted that asthma is controlled by a combination of host genetics and environment in a rather complex fashion; however, the link between sensing of the environment and development and exacerbation of allergic lung inflammation is unclear. Human populations expressing cosegregating D299G and T399I polymorphisms in the
MeSH term(s)	Allergens ; Animals ; Antigens, Dermatophagoides/immunology ; Asthma/genetics ; Asthma/pathology ; Inflammation ; Lipopolysaccharides ; Mice ; Polymorphism, Single Nucleotide ; Pulmonary Eosinophilia ; Pyroglyphidae ; Toll-Like Receptor 4/genetics
Chemical Substances	Allergens ; Antigens, Dermatophagoides ; Lipopolysaccharides ; Tlr4 protein, mouse ; Toll-Like Receptor 4
Language	English
Publishing date	2022-04-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2100926
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Article ; Online: Semaphorin 4A Stabilizes Human Regulatory T Cell Phenotype via Plexin B1.

Chapoval, Svetlana P / Hritzo, Molly / Qi, Xiulan / Tamagnone, Luca / Golding, Amit / Keegan, Achsah D

ImmunoHorizons

2019 Volume 3, Issue 2, Page(s) 71–87

Abstract: We previously reported that neuroimmune semaphorin (Sema) 4A regulates the severity of experimental allergic asthma and increases regulatory T (Treg) cell numbers in vivo; however, the mechanisms of Sema4A action remain unknown. It was also reported that ...

Abstract	We previously reported that neuroimmune semaphorin (Sema) 4A regulates the severity of experimental allergic asthma and increases regulatory T (Treg) cell numbers in vivo; however, the mechanisms of Sema4A action remain unknown. It was also reported that Sema4A controls murine Treg cell function and survival acting through neuropilin 1 (NRP-1) receptor. To clarify Sema4A action on human T cells, we employed T cell lines (HuT78 and HuT102), human PBMCs, and CD4
MeSH term(s)	Antibodies ; Asthma/immunology ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Forkhead Transcription Factors/metabolism ; Humans ; Interleukin-2/metabolism ; Interleukin-2 Receptor alpha Subunit/metabolism ; Nerve Tissue Proteins/immunology ; Nerve Tissue Proteins/metabolism ; Neuropilin-1/metabolism ; Phenotype ; Receptors, Cell Surface/immunology ; Receptors, Cell Surface/metabolism ; Semaphorins/metabolism ; Semaphorins/pharmacology ; T-Lymphocytes, Regulatory/cytology ; T-Lymphocytes, Regulatory/metabolism ; Transforming Growth Factor beta/metabolism
Chemical Substances	Antibodies ; FOXP3 protein, human ; Forkhead Transcription Factors ; IL2RA protein, human ; Interleukin-2 ; Interleukin-2 Receptor alpha Subunit ; Nerve Tissue Proteins ; PLXNB1 protein, human ; Receptors, Cell Surface ; SEMA4A protein, human ; Semaphorins ; Transforming Growth Factor beta ; Neuropilin-1 (144713-63-3)
Language	English
Publishing date	2019-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2573-7732
ISSN (online)	2573-7732
DOI	10.4049/immunohorizons.1800026
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Article ; Online: Oxaliplatin disrupts pathological features of glioma cells and associated macrophages independent of apoptosis induction.

Roberts, Nathan B / Alqazzaz, Aymen / Hwang, Jacqueline R / Qi, Xiulan / Keegan, Achsah D / Kim, Anthony J / Winkles, Jeffrey A / Woodworth, Graeme F

Journal of neuro-oncology

2018 Volume 140, Issue 3, Page(s) 497–507

Abstract: Introduction: Emerging evidence suggests that effective treatment of glioblastoma (GBM), the most common and deadly form of adult primary brain cancer, will likely require concurrent treatment of multiple aspects of tumor pathobiology to overcome tumor ... ...

Abstract	Introduction: Emerging evidence suggests that effective treatment of glioblastoma (GBM), the most common and deadly form of adult primary brain cancer, will likely require concurrent treatment of multiple aspects of tumor pathobiology to overcome tumor heterogeneity and the complex tumor-supporting microenvironment. Recent studies in non-central nervous system (CNS) tumor cells have demonstrated that oxaliplatin (OXA) can induce multi-faceted anti-tumor effects, in particular at drug concentrations below those required to induce apoptosis. These findings motivated re-investigation of OXA for the treatment of GBM. Methods: The effects of OXA on murine KR158 and GL261 glioma cells including cell growth, cell death, inhibition of signal transducer and activator of transcription (STAT) activity, O-6-methylguanine-DNA methyltransferase (MGMT) expression, and immunogenic cell death (ICD) initiation, were evaluated by cytotoxicity assays, Western blot analysis, STAT3-luciferase reporter assays, qRT-PCR assays, and flow cytometry. Chemical inhibitors of endoplasmic reticulum (ER) stress were used to investigate the contribution of this cell damage response to the observed OXA effects. The effect of OXA on bone marrow-derived macrophages (BMDM) exposed to glioma conditioned media (GCM) was also analyzed by Western blot analysis. Results: We identified the OXA concentration threshold for induction of apoptosis and from this determined the drug dose and treatment period for sub-cytotoxic treatments of glioma cells. Under these experimental conditions, OXA reduced STAT3 activity, reduced MGMT levels and increased temozolomide sensitivity. In addition, there was evidence of immunogenic cell death (elevated EIF2α phosphorylation and calreticulin exposure) following prolonged OXA treatment. Notably, inhibition of ER stress reversed the OXA-mediated inhibition of STAT3 activity and MGMT expression in the tumor cells. In BMDMs exposed to GCM, OXA also reduced levels of phosphorylated STAT3 and decreased expression of Arginase 1, an enzyme known to contribute to pro-tumor functions in the tumor-immune environment. Conclusions: OXA can induce notable multi-faceted biological effects in glioma cells and BMDMs at relatively low drug concentrations. These findings may have significant therapeutic relevance against GBM and warrant further investigation.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Cell Line, Tumor ; Endoplasmic Reticulum Stress ; Glioma/drug therapy ; Glioma/metabolism ; Humans ; Macrophages/drug effects ; Macrophages/metabolism ; Mice ; Oxaliplatin/pharmacology ; STAT3 Transcription Factor/metabolism ; Temozolomide
Chemical Substances	Antineoplastic Agents ; STAT3 Transcription Factor ; Oxaliplatin (04ZR38536J) ; Temozolomide (YF1K15M17Y)
Language	English
Publishing date	2018-08-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	604875-4
ISSN	1573-7373 ; 0167-594X
ISSN (online)	1573-7373
ISSN	0167-594X
DOI	10.1007/s11060-018-2979-1
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Article ; Online: Absence of the common gamma chain (γ(c)), a critical component of the Type I IL-4 receptor, increases the severity of allergic lung inflammation.

Dasgupta, Preeta / Qi, Xiulan / Smith, Elizabeth P / Keegan, Achsah D

PloS one

2013 Volume 8, Issue 8, Page(s) e71344

Abstract: The T(H)2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation and drive the alternative activation of macrophages (AAM). Although both cytokines share receptor subunits, IL-4 and IL-13 have differential roles in asthma ... ...

Abstract	The T(H)2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation and drive the alternative activation of macrophages (AAM). Although both cytokines share receptor subunits, IL-4 and IL-13 have differential roles in asthma pathogenesis: IL-4 regulates T(H)2 cell differentiation, while IL-13 regulates airway hyperreactivity and mucus production. Aside from controlling T(H)2 differentiation, the unique contribution of IL-4 signaling via the Type I receptor in airway inflammation remains unclear. Therefore, we analyzed responses in mice deficient in gamma c (γ(c)) to elucidate the role of the Type I IL-4 receptor. OVA primed CD4⁺ OT-II T cells were adoptively transferred into RAG2⁻/⁻ and γ(c)⁻/⁻ mice and allergic lung disease was induced. Both γ(c)⁻/⁻ and γcxRAG2⁻/⁻ mice developed increased pulmonary inflammation and eosinophilia upon OVA challenge, compared to RAG2⁻/⁻ mice. Characteristic AAM proteins FIZZ1 and YM1 were expressed in lung epithelial cells in both mouse strains, but greater numbers of FIZZ1+ or YM1+ airways were present in γ(c)⁻/⁻ mice. Absence of γc in macrophages, however, resulted in reduced YM1 expression. We observed higher T(H)2 cytokine levels in the BAL and an altered DC phenotype in the γ(c)⁻/⁻ recipient mice suggesting the potential for dysregulated T cell and dendritic cell (DC) activation in the γ(c)-deficient environment. These results demonstrate that in absence of the Type I IL-4R, the Type II R can mediate allergic responses in the presence of T(H)2 effectors. However, the Type I R regulates AAM protein expression in macrophages.
MeSH term(s)	Animals ; Cells, Cultured ; DNA-Binding Proteins/genetics ; Dendritic Cells/physiology ; Gene Deletion ; Hypersensitivity/complications ; Hypersensitivity/genetics ; Hypersensitivity/immunology ; Interleukin Receptor Common gamma Subunit/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Pneumonia/complications ; Pneumonia/genetics ; Pneumonia/immunology ; Receptors, Interleukin-4/genetics ; Severity of Illness Index ; Th2 Cells/physiology
Chemical Substances	DNA-Binding Proteins ; Interleukin Receptor Common gamma Subunit ; Rag2 protein, mouse ; Receptors, Interleukin-4
Language	English
Publishing date	2013-08-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0071344
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Article ; Online: The extracellular and transmembrane domains of the γC and interleukin (IL)-13 receptor α1 chains, not their cytoplasmic domains, dictate the nature of signaling responses to IL-4 and IL-13.

Heller, Nicola M / Qi, Xiulan / Gesbert, Franck / Keegan, Achsah D

The Journal of biological chemistry

2012 Volume 287, Issue 38, Page(s) 31948–31961

Abstract: Previously, we demonstrated that the γC subunit of type I IL-4 receptor was required for robust tyrosine phosphorylation of the downstream adapter protein, IRS-2, correlating with the expression of genes (ArgI, Retnla, and Chi3l3) characteristic of ... ...

Abstract	Previously, we demonstrated that the γC subunit of type I IL-4 receptor was required for robust tyrosine phosphorylation of the downstream adapter protein, IRS-2, correlating with the expression of genes (ArgI, Retnla, and Chi3l3) characteristic of alternatively activated macrophages. We located an I4R-like motif (IRS-2 docking sequence) in the γC cytoplasmic domain but not in the IL-13Rα1. Thus, we predicted that the γC tail directed enhanced IRS-2 phosphorylation. To test this, IL-4 signaling responses were examined in a mutant of the key I4R motif tyrosine residue (Y325F) and different γC truncation mutants (γ285, γ308, γ318, γ323, and γFULL LENGTH (FL)) co-expressed in L-cells or CHO cells with wild-type (WT) IL-4Rα. Surprisingly, IRS-1 phosphorylation was not diminished in Y325F L-cell mutants suggesting Tyr-325 was not required for the robust insulin receptor substrate response. IRS-2, STAT6, and JAK3 phosphorylation was observed in CHO cells expressing γ323 and γFL but not in γ318 and γ285 mutants. In addition, when CHO cells expressed γ318, γ323, or γFL with IL-2Rβ, IL-2 induced phospho-STAT5 only in the γ323 and γFL clones. Our data suggest that a smaller (5 amino acid) interval than previously determined is necessary for JAK3 activation/γC-mediated signaling in response to IL-4 and IL-2. Chimeric receptor chains of the γC tail fused to the IL-13Rα1 extracellular and transmembrane domain did not elicit robust IRS-2 phosphorylation in response to IL-13 suggesting that the extracellular/transmembrane domains of the IL-4/IL-13 receptor, not the cytoplasmic domains, control signaling efficiency. Understanding this pathway fully will lead to rational drug design for allergic disease.
MeSH term(s)	Animals ; CHO Cells ; Cell Line ; Cricetinae ; Cricetulus ; Cytokines/metabolism ; Cytoplasm/metabolism ; Flow Cytometry ; Interleukin Receptor Common gamma Subunit/chemistry ; Interleukin-13/chemistry ; Interleukin-13 Receptor alpha1 Subunit/chemistry ; Interleukin-4/chemistry ; Mice ; Models, Biological ; Mutation ; Phosphorylation ; Protein Structure, Tertiary ; Receptors, IgE/metabolism ; Receptors, Interleukin-4/metabolism ; STAT6 Transcription Factor/metabolism ; Signal Transduction
Chemical Substances	Cytokines ; Interleukin Receptor Common gamma Subunit ; Interleukin-13 ; Interleukin-13 Receptor alpha1 Subunit ; Receptors, IgE ; Receptors, Interleukin-4 ; STAT6 Transcription Factor ; Interleukin-4 (207137-56-2)
Language	English
Publishing date	2012-07-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.348896
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Article ; Online: The adaptor protein insulin receptor substrate 2 inhibits alternative macrophage activation and allergic lung inflammation.

Dasgupta, Preeta / Dorsey, Nicolas J / Li, Jiaqi / Qi, Xiulan / Smith, Elizabeth P / Yamaji-Kegan, Kazuyo / Keegan, Achsah D

Science signaling

2016 Volume 9, Issue 433, Page(s) ra63

Abstract: Insulin receptor substrate 2 (IRS2) is an adaptor protein that becomes tyrosine-phosphorylated in response to the cytokines interleukin-4 (IL-4) and IL-13, which results in activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway. IL-4 and IL-13 ... ...

Abstract	Insulin receptor substrate 2 (IRS2) is an adaptor protein that becomes tyrosine-phosphorylated in response to the cytokines interleukin-4 (IL-4) and IL-13, which results in activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway. IL-4 and IL-13 contribute to allergic lung inflammation. To examine the role of IRS2 in allergic disease, we evaluated the responses of IRS2-deficient (IRS2(-/-)) mice. Unexpectedly, loss of IRS2 resulted in a substantial increase in the expression of a subset of genes associated with the generation of alternatively activated macrophages (AAMs) in response to IL-4 or IL-13 in vitro. AAMs secrete factors that enhance allergic responses and promote airway remodeling. Moreover, compared to IRS2(+/+) mice, IRS2(+/-) and IRS2(-/-) mice developed enhanced pulmonary inflammation, accumulated eosinophils and AAMs, and exhibited airway and vascular remodeling upon allergen stimulation, responses that partially depended on macrophage-intrinsic IRS2 signaling. Both in unstimulated and IL-4-stimulated macrophages, lack of IRS2 enhanced phosphorylation of Akt and ribosomal S6 protein. Thus, we identified a critical inhibitory loop downstream of IRS2, demonstrating an unanticipated and previously unrecognized role for IRS2 in suppressing allergic lung inflammation and remodeling.
Language	English
Publishing date	2016-06-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aad6724
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Article ; Online: NF-κB signaling participates in both RANKL- and IL-4-induced macrophage fusion: receptor cross-talk leads to alterations in NF-κB pathways.

Yu, Minjun / Qi, Xiulan / Moreno, Jose L / Farber, Donna L / Keegan, Achsah D

Journal of immunology (Baltimore, Md. : 1950)

2011 Volume 187, Issue 4, Page(s) 1797–1806

Abstract: NF-κB activation is essential for receptor activator for NF-κB ligand (RANKL)-induced osteoclast formation. IL-4 is known to inhibit the RANKL-induced osteoclast differentiation while at the same time promoting macrophage fusion to form multinucleated ... ...

Abstract	NF-κB activation is essential for receptor activator for NF-κB ligand (RANKL)-induced osteoclast formation. IL-4 is known to inhibit the RANKL-induced osteoclast differentiation while at the same time promoting macrophage fusion to form multinucleated giant cells (MNG). Several groups have proposed that IL-4 inhibition of osteoclastogenesis is mediated by suppressing the RANKL-induced activation of NF-κB. However, we found that IL-4 did not block proximal, canonical NF-κB signaling. Instead, we found that IL-4 inhibited alternative NF-κB signaling and induced p105/50 expression. Interestingly, in nfκb1(-/-) bone marrow-derived macrophages (BMM), the formation of both multinucleated osteoclast and MNG induced by RANKL or IL-4, respectively, was impaired. This suggests that NF-κB signaling also plays an important role in IL-4-induced macrophage fusion. Indeed, we found that the RANKL-induced and IL-4-induced macrophage fusion were both inhibited by the NF-κB inhibitors IκB kinase 2 inhibitor and NF-κB essential modulator inhibitory peptide. Furthermore, overexpression of p50, p65, p52, and RelB individually in nfκb1(-/-) or nfκb1(+/+) BMM enhanced both giant osteoclast and MNG formation. Interestingly, knockdown of nfκb2 in wild-type BMM dramatically enhanced both osteoclast and MNG formation. In addition, both RANKL- and IL-4-induced macrophage fusion were impaired in NF-κB-inducing kinase(-/-) BMM. These results suggest IL-4 influences NF-κB pathways by increasing p105/p50 and suppressing RANKL-induced p52 translocation and that NF-κB pathways participate in both RANKL- and IL-4-induced giant cell formation.
MeSH term(s)	Animals ; Bone Marrow Cells/immunology ; Cell Fusion ; Cells, Cultured ; Giant Cells/immunology ; Interleukin-4/genetics ; Interleukin-4/immunology ; Mice ; Mice, Knockout ; NF-kappa B/genetics ; NF-kappa B/immunology ; Osteoclasts/immunology ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/immunology ; RANK Ligand/genetics ; RANK Ligand/immunology ; NF-kappaB-Inducing Kinase
Chemical Substances	NF-kappa B ; RANK Ligand ; Tnfsf11 protein, mouse ; Interleukin-4 (207137-56-2) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2011-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1002628
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Article: Microbial transformation of dextromethorphan by Cunninghamella blakesleeana AS 3.153.

Lin, Lihong / Huang, Haihua / Zhang, Peng / Qi, Xiulan / Zhong, Dafang

Chemical & pharmaceutical bulletin

2007 Volume 55, Issue 4, Page(s) 658–661

Abstract: The capability of Cunninghamella blakesleeana AS 3.153 to transform CYP2D6 probe drug dextromethorphan was investigated. Metabolites produced by strain AS 3.153 were detected by liquid chromatography-tandem mass spectrometry (LC-MS(n)) and the metabolite ...

Abstract	The capability of Cunninghamella blakesleeana AS 3.153 to transform CYP2D6 probe drug dextromethorphan was investigated. Metabolites produced by strain AS 3.153 were detected by liquid chromatography-tandem mass spectrometry (LC-MS(n)) and the metabolite dextrorphan was identified by reference to confirm its structure. The yield of dextrorphan produced by C. blakesleeana AS 3.153 was over 90%. Quinidine, a CYP2D6 selective inhibitor, was applied to investigate its effect on biotransformation. The concentration of quinidine was 4-folds higher than that of dextromethorphan and the yield of dextrorphan was reduced by 84%, which proved there was drug metabolism enzyme similar to CYP2D6 in C. blakesleeana AS 3.153. It is concluded that C. blakesleeana AS 3.153 can be used as the suitable model strain in vitro to mimic human CYP2D6 metabolism.
MeSH term(s)	Analgesics, Opioid/metabolism ; Biotransformation ; Chromatography, Liquid ; Cunninghamella/metabolism ; Dextromethorphan/metabolism ; Quinidine/pharmacology ; Spectrometry, Mass, Electrospray Ionization
Chemical Substances	Analgesics, Opioid ; Dextromethorphan (7355X3ROTS) ; Quinidine (ITX08688JL)
Language	English
Publishing date	2007-01-25
Publishing country	Japan
Document type	Journal Article
ZDB-ID	213307-6
ISSN	1347-5223 ; 0009-2363
ISSN (online)	1347-5223
ISSN	0009-2363
DOI	10.1248/cpb.55.658
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Article ; Online: IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway.

Carey, Gregory B / Semenova, Elena / Qi, Xiulan / Keegan, Achsah D

Cell research

2007 Volume 17, Issue 11, Page(s) 942–955

Abstract: Interleukin-4 (IL-4) promotes lymphocyte survival and protects primary lymphomas from apoptosis. Previous studies reported differential requirements for the signal transducer and activator of transcription 6 (STAT6) and IRS2/phosphatidylinositol 3 kinase ...

Abstract	Interleukin-4 (IL-4) promotes lymphocyte survival and protects primary lymphomas from apoptosis. Previous studies reported differential requirements for the signal transducer and activator of transcription 6 (STAT6) and IRS2/phosphatidylinositol 3 kinase (PI-3K) signaling pathways in mediating the IL-4-induced protection from Fas-mediated apoptosis. In this study, we characterized IL-4-activated signals that suppress anti-IgM-mediated apoptosis and growth arrest of CH31, a model B-cell lymphoma line. In CH31, anti-IgM treatment leads to the loss of mitochondrial membrane potential, phospho-Akt, phospho-CDK2, and c-myc protein. These losses are followed by massive induction of p27(Kip1) protein expression, cell cycle arrest, and apoptosis. Strikingly, IL-4 treatment prevented or reversed these changes. Furthermore, IL-4 suppressed the activation of caspases 9 and 3, and, in contrast to previous reports, induced the phosphorylation (deactivation) of BAD. IL-4 treatment also induced expression of BclxL, a STAT6-dependent gene. Pharmacologic inhibitors and dominant inhibitory forms of PI-3K and Akt abrogated the anti-apoptotic function of IL-4. These results suggest that the IL-4 receptor activates several signaling pathways, with the Akt pathway playing a major role in suppression of the apoptotic program activated by anti-IgM.
MeSH term(s)	Animals ; Antibodies/pharmacology ; Apoptosis/drug effects ; B-Lymphocytes/enzymology ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyclin-Dependent Kinase Inhibitor p27 ; Enzyme Inhibitors/pharmacokinetics ; Enzyme Inhibitors/pharmacology ; Humans ; Immunoglobulin M/metabolism ; Interleukin-4/pharmacology ; Intracellular Signaling Peptides and Proteins/metabolism ; Lymphoma, B-Cell/enzymology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-myc ; Receptors, Interleukin-4/agonists ; Receptors, Interleukin-4/metabolism ; STAT6 Transcription Factor/metabolism ; Signal Transduction/drug effects ; bcl-Associated Death Protein/metabolism ; bcl-X Protein/metabolism
Chemical Substances	Antibodies ; BAD protein, human ; BCL2L1 protein, human ; CDKN1B protein, human ; Enzyme Inhibitors ; IL4 protein, human ; Immunoglobulin M ; Intracellular Signaling Peptides and Proteins ; MYC protein, human ; Proto-Oncogene Proteins c-myc ; Receptors, Interleukin-4 ; STAT6 Transcription Factor ; STAT6 protein, human ; bcl-Associated Death Protein ; bcl-X Protein ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; Interleukin-4 (207137-56-2) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Caspase 3 (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-)
Language	English
Publishing date	2007-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1319303-x
ISSN	1748-7838 ; 1001-0602
ISSN (online)	1748-7838
ISSN	1001-0602
DOI	10.1038/sj.cr.2007.90
Database	MEDical Literature Analysis and Retrieval System OnLINE

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