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Flavonoids, a Prenatal Prophylaxis via Targeting JAK2/STAT3 Signaling to Oppose IL-6/Mia Associated AutismParker-Athill, Ellisa, Luo, Deyan, Bailey, Antoinette, Giunta, Brian, Tian, Jun, Shytle, R. Douglas, Murphy, Tanya, Legradi, Gabor, Tan, Jun 10 December 2009 (has links)
Maternal immune activation (MIA) can affect fetal brain development and thus behavior of young and adult offspring. Reports have shown that increased Interleukin-6 (IL-6) in the maternal serum plays a key role in altering fetal brain development, and may impair social behaviors in the offspring. Interestingly, these effects could be attenuated by blocking IL-6. The current study investigated the effects of luteolin, a citrus bioflavonoid, and its structural analog, diosmin, on IL-6 induced JAK2/STAT3 (Janus tyrosine kinase-2/signal transducer and activator of transcription-3) phosphorylation and signaling as well as behavioral phenotypes of MIA offspring. Luteolin and diosmin inhibited neuronal JAK2/STAT3 phosphorylation both in vitro and in vivo following IL-6 challenge as well as significantly diminishing behavioral deficits in social interaction. Importantly, our results showed that diosmin (10 mg/kg day) was able to block the STAT3 signal pathway; significantly opposing MIA-induced abnormal behavior and neuropathological abnormalities in MIA/adult offspring. Diosmin's molecular inhibition of JAK2/STAT3 pathway may underlie the attenuation of abnormal social interaction in IL-6/MIA adult offspring.
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Role of STAT3 and SDF-1/CXCL 12 in mitochondrial function in hematopoietic stem and progenitor cellsMessina-Graham, Steven V. 10 August 2016 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Mitochondria are the major ATP producing source within cells. There is increasing data supporting a direct involvement of mitochondria and mitochondrial function in regulating stem cell pluripotency. Mitochondria have also been shown to be important for hematopoietic stem and progenitor cell function. Hematopoietic stem cells have lower numbers of mitochondria (mass), lower mitochondrial membrane potential, and lower ATP levels as compared to other blood cell types. Mitochondria play an important role in hematopoietic stem and progenitor cells, thus we investigated the role of the chemokine, SDF-1/CXCL12, in mitochondrial function in hematopoietic stem and progenitor cells using an SDF-1/CXCL12 transgenic mouse model. We found increased mitochondrial mass is linked to CD34 surface expression in hematopoietic stem and progenitor cells, suggesting that mitochondrial biogenesis is linked to loss of pluripotency. Interestingly these hematopoietic progenitor cells have low mitochondrial membrane potential and these mitochondrial become active prior to leaving the progenitor cell compartment. We also tested the ability of SDF-1/CXL12 to modulate mitochondrial function in vitro by treating the human leukemia cell line, HL-60, and primary mouse lineage- bone marrow cells with SDF-1/CXCL12. We found significantly reduced mitochondrial function at two hours while mitochondrial function was significantly increased at 24 hours. This suggests that SDF1/CXCL12 regulates mitochondrial function in a biphasic manner in a model of hematopoietic progenitors and immature blood cells. This suggests SDF1/CXCL12 may play a role in regulating mitochondrial function in hematopoiesis. We also investigated STAT3 in hematopoietic stem and progenitor cells. Mitochondrial STAT3 plays an essential role in regulating mitochondrial function. By using a knockout (Stat3-/-) mouse model we found that Stat3-/- hematopoietic progenitor cells had reduced colony forming ability, slower cell cycling status, and loss of proliferation in response to multi-cytokine synergy. We also found mitochondrial dysfunction in Stat3-/- hematopoietic stem and progenitor cells. Our results suggest an essential role for mitochondria in HSC function and a novel role for SDF-1/CXCL12 and STAT3 in regulating mitochondrial function in hematopoietic stem and progenitor cells.
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Specificity protein 1 induces the expression of angiomotin in response to IL-6/STAT3 activation to mediate YAP-dependent growth of breast cancer cellsBringman, Lauren R. 16 June 2016 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Chronic inflammation is a major driver of tumor progression in over fifty
percent of breast cancers. Tumors activate inflammatory processes by secreting
factors that recruit and trigger inflammatory cells to release cytokines such as
Interleukin 6 (IL-6). IL-6 stimulates the activity of signal transducers and
activators of transcription 3 (STAT3), a transcription factor that has been
extensively studied for its role in promoting breast cancer. Recently,
downregulated HIPPO signaling was shown to drive the pro-growth effects of IL
6. Reduced HIPPO signaling allows for the nuclear translocation of
transcriptional co-activator yes associated protein (YAP), implicating IL-6 in the
co-activation of several transcription factors such as the TEADs that trigger pro
growth programs. While IL-6/STAT3 stimulation has been shown to increase
YAP activity, the mechanism driving this remains undocumented. The
Angiomotins (Amots) are adapters of the HIPPO pathway that directly bind and
regulate YAP activity. Molecular characterization of Amot transcriptional
regulation unexpectedly revealed a single promoter controlling the expression of
its two major isoforms: Amot 130 and Amot 80. Through immunofluorescent
analysis, this study found that total Amot levels were elevated across multiple
breast tumor subtypes and highest in samples with increased presence of
stromal inflammatory cells. Further, the induction of total Amot expression by IL
6 was found to be essential for YAP dependent growth of breast cancer cells. The activation of Amot transcription by IL-6 was found to be through Specificity
Protein 1 (Sp1), a transcription factor that is activated by STAT3. This work
connects the activation of YAP1 by IL-6/STAT3 through the elevation of Amot
expression by Sp1. Taken together, this explains a new avenue whereby breast
cancer cells acquire enhanced oncogenic properties in response to inflammatory signaling.
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Leptin Receptor Somatic Mutations are Frequent in HCV-Infected Cirrhotic Liver and Associate with Hepatocellular Carcinoma / C型肝炎ウイルス感染による肝硬変組織ではレプチンレセプター遺伝子の体細胞変異が潜在し肝細胞癌と関連するIkeda, Atsuyuki 24 March 2014 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18156号 / 医博第3876号 / 新制||医||1003(附属図書館) / 31014 / 京都大学大学院医学研究科医学専攻 / (主査)教授 野田 亮, 教授 武藤 学, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Inflammation in plexiform neurofibroma development and growth.Fletcher, Jonathan S. January 2018 (has links)
No description available.
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Engineering Approaches to Understanding Hypertrophic Signaling in the Context of Pressure OverloadWinkle, Alexander Joseph January 2021 (has links)
No description available.
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THE DEVELOPMENT AND COMMITMENT OF T HELPER SUBSETSStritesky, Gretta L. 09 March 2011 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / T helper cells play a crucial role in providing protection against a wide variety of pathogens. The differentiation and effector function of T helper cell subsets is dependent on cytokine activation of Signal Transducer and Activator of Transcription (STAT) family members. The development of Th17 cells, which are important for immunity to fungi and extracellular bacteria, relies on STAT3. We show that IL-23 in combination with IL-1β promotes maintenance of the Th17 phenotype following multiple rounds of stimulation. However, IL-23 does not promote commitment of Th17 cells, and when Th17 cells are cultured with IL-12 or IL-4 they switch to a Th1 and Th2 phenotype, respectively. The maintenance of the Th17 phenotype by IL-23 also requires STAT4. STAT4-deficient memory cells cultured with IL-23 have reduced IL-17 production following stimulation with either anti-CD3 or IL-18+IL-23 stimulation compared to wild type memory cells. Furthermore, STAT4-deficient mice have impaired in vivo Th17 development following immunization with ovalbumin. This challenges a one-STAT/one-subset paradigm and suggests that multiple STAT proteins can contribute to a single phenotype. To test this further we examined whether STAT3 is required for the development of Th2 cells, a subset known to depend upon the IL-4-induced activation of STAT6 for immunity to parasites and promoting allergic inflammation. We demonstrate that in the absence of STAT3, the expression of Th2-associated cytokines and transcription factors is dramatically reduced. STAT3 is also required for in vivo development of Th2 cells. Moreover, allergic inflammation is diminished in mice that have T cells lacking expression of STAT3. STAT3 does not affect STAT6 activation, but does impact how STAT6 functions in binding target genes. Thus, multiple STAT proteins can cooperate in promoting the development of specific T helper subsets.
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Sex-dependent Effects of Adipocyte STAT3 Inhibition on the Inflammatory Response during SepsisDavis, Xenia January 2022 (has links)
No description available.
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IL-6 Signals Through pStat3 to Prevent Functional Immune Suppression by Human Regulatory T CellsGoodman, Wendy Ann January 2010 (has links)
No description available.
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Characterization of STAT3 Expression, Signaling and Inhibition in Feline Oral Squamous Cell CarcinomaBrown, Megan 19 May 2015 (has links)
No description available.
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