Xiaonan Han

Jianghan University

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Lee A. Denson

Cincinnati Children's Hospital Medical Center

Richard Moriggl

University of Salzburg

Shila Gilbert

Cincinnati Children's Hospital Medical Center

Mitchell P. Fink

University of Pittsburgh

Ingrid Jurickova

Cincinnati Children's Hospital Medical Center

Russell L. Delude

University of Pittsburgh

Runkuan Yang

Oslo University Hospital

Erin Bonkowski

Cincinnati Children's Hospital Medical Center

Charles M. Samson

Washington University in St. Louis

Tara Willson

Cincinnati Children's Hospital Medical Center

Cooperative Institutions

Cincinnati Children's Hospital Medical Center

University of Cincinnati

Medical University of Vienna

University of Cincinnati Medical Center

Chinese Academy of Sciences

Peking University

Chinese Academy of Medical Sciences & Peking Union Medical College

Case Western Reserve University

University of Veterinary Medicine Vienna

Hebei Medical University

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Probing Protein–DNA Conformational Dynamics in DNA Damage Recognition: Xeroderma Pigmentosum Group A Stabilizes the Damaged DNA-RPA14 Complex by Controlling Conformational Fluctuation Dynamics

The Journal of Physical Chemistry B (2022)

Sunidhi Jaiswal Xiaonan Han H. Peter Lu

DNA damage inside biological systems may result in diseases like cancer. One of the major repairing mechanisms is the nucleotide excision repair (NER) that recognizes and repairs the damage caused by several internal and external exposures, such as DNA double-strand distortion due to the chemical modifications. Recognition of lesions is the initial stage of the DNA damage repair, which occurs with the help of several proteins like Replication Protein A (RPA) and Xeroderma Pigmentosum group A (XPA). The recognition process involves complex conformational dynamics of the proteins. Studying the dynamics of damage recognition by these proteins helps us to understand the mechanism and to develop therapeutics to increase the efficiency of recognition. Here, we use single-molecule fluorescence fluctuation measurements of a dye, labeled at a damaged position on DNA, to understand the interaction of the damage site with RPA14 and XPA. Our results suggest that interactive conformational dynamics of RPA14 with damaged DNA is inhomogeneous due to its low affinity for DNA, whereas binding of XPA with the already formed DNA-RPA14 complex may increase the specificity of damage recognition by controlling the conformational fluctuation dynamics of the complex.

Dynamics

10.1021/acs.jpcb.1c07660

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Citations (1)

A centric view of JAK/STAT5 in intestinal homeostasis, infection, and inflammation

Cytokine (2021)

Marta Surbek William Ka Fai Tse Richard Moriggl Xiaonan Han

Cytokines, growth factors or hormones take action through the JAK/STAT5 signaling pathway, which plays a critical role in regulating the intestinal response to infection and inflammation. However, the way in which STAT5 regulates intestinal epithelial compartment is largely ignored due to the lack of genetic tools for proper exploration and because the two STAT5 transcription factors (STAT5A and STAT5B) have some redundant but also distinct functions. In this review article, by focusing on STAT5 functions in the intestinal undifferentiated and differentiated epithelia, we discuss major advances of the growth factor/cytokine-JAK/STAT5 research in view of intestinal mucosal inflammation and immunity. We highlight the gap in the research of the intestinal STAT5 signaling to anticipate the gastrointestinal explorative insights. Furthermore, we address the critical questions to illuminate how STAT5 signaling influences intestinal epithelial cell differentiation and stem cell regeneration during homeostasis and injury. Overall, our article provides a centric view of the relevance of the relationship between chronic inflammatory diseases and JAK/STAT5 pathway and it also gives an example of how chronic infection and inflammation pirate STAT5 signaling to worsen intestinal injuries. Importantly, our review suggests how to protect a wound healing from gastrointestinal diseases by modulating intestinal STAT5.

STAT5

Intestinal mucosa

10.1016/j.cyto.2020.155392

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Citations (19)

Clinical and molecular characterization of early onset intrahepatic cholangiocarcinoma

HPB (2024)

Diamantis I. Tsilimigras Xiaonan Han Muhammad Musaab Munir Alfredo Guglielmi Luca Aldrighetti

Intrahepatic Cholangiocarcinoma

Characterization

10.1016/j.hpb.2024.04.030

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Citations (0)

Proinflammatory Cytokines Cause No??-Dependent and -Independent Changes in Expression and Localization of Tight Junction Proteins in Intestinal Epithelial Cells

Shock (2003)

Xiaonan Han Mitchell P. Fink Russell L. Delude

Intestinal epithelial barrier function is impaired after the exposure of enterocytes to proinflammatory cytokines. The mechanism(s) responsible for this phenomenon remain incompletely understood. We used cultured monolayers of Caco-2 enterocyte-like cells to characterize the effect of cytomix, a mixture of interferon-γ, tumor necrosis factor-α, and interleukin-1β, on the expression and localization of several tight junctions proteins. Cells were stimulated with cytomix in the presence or absence of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO), an NO· scavenger. Some cells were treated with (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate] (DETA-NONOate), an NO· donor. Tight junction protein expression was measured in cellular extracts by Western blotting and localized in cells using immunofluorescence. Steady-state mRNA levels were determined using semi-quantitative reverse-transcription polymerase chain reaction. Incubation of cells with DETA-NONOate or cytomix decreased epithelial barrier function, decreased expression of ZO-1 mRNA, decreased expression of ZO-1, ZO-3, and occludin protein, and increased expression of claudin-1 protein. The effects of cytomix on barrier function and tight junction protein expression were modulated by cPTIO. Cytomix caused incorrect subcellular localization of ZO-1, occludin, and claudin-1, and this was modulated by co-incubation with cPTIO. DETA-NONOate caused similar protein mislocalization as observed with cytomix. The effectiveness of cPTIO in maintaining tight junction protein expression and correct subcellular localization was less apparent at early time points (12 h) compared with later points, suggesting an NO·-independent effect of cytokines on barrier function. Thus, cytomix appears to increase the permeability of Caco-2 monolayers through NO·-dependent and -independent mechanisms that are associated with changes in the expression and/or targeting of proteins involved in tight junction function.

Occludin

Proinflammatory cytokine

Enterocyte

Barrier function

10.1097/00024382-200303000-00006

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Citations (180)

STAT5 Signaling in Enterocytes Protects Intestinal Barrier Function by Suppressing Myosin Light Chain Kinase

Clinical Immunology (2010)

Xiaonan Han Shila Gilbert

10.1016/j.clim.2010.03.081

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[Analysis of regional differences in influencing factors of self-reporting rate of respiratory symptoms among employees in bathing place].

Zhonghua laodong weisheng zhiyebing zazhi (2020)

Xiaonan Han L Li Lijun Pan Qian Zhang

Objective: To understand the self-reporting rate of respiratory symptoms in bathing staff, and analyze the differences and influencing factors in the eastern, central and western regions. Methods: From April to December 2017, adopt the method of multistage random sampling, the selection of the national 3865 effective questionnaires were bathing places practitioners, survey from personnel of course of demographic characteristics, cultural degree, living habits, since the evaluation of environmental factors and respiratory symptoms such as self-reported rate content, using logistic regression model to analyze its influencing factors and regional differences. Results: The prevalence of self-reported respiratory symptoms among employees in the eastern, central, and western regions was 17.86% (269/1 506) , 10.66% (126/1 182) , and 31.01% (365/1 177) respectively. The influencing factors in the eastern region are age, family income, whether drinking, environment is suddenly cold and hot, dust in the air (P<0.05) ; the influencing factors in the central region are whether drinking, environment suddenly cold and hot, ventilation, dust in the air (P<0.05) . The influencing factors in the western region are gender, whether drinking, environment suddenly cold and hot, poor ventilation (P<0.05) . There are statistically significant differences in eastern, central and western regions (P<0.01) . Conclusion: The prevalence of respiratory symptoms among bathing practitioners in China varies from region to region. Economic conditions, living habits, and environmental factors are the main influencing factors.

Bathing

Questionnaire

10.3760/cma.j.cn121094-20191215-003568

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Activated STAT5 Confers Resistance to Intestinal Injury by Increasing Intestinal Stem Cell Proliferation and Regeneration

Stem Cell Reports (2015)

Shila Gilbert Harini Nivarthi Christopher N. Mayhew Yuan‐Hung Lo Taeko K. Noah

Intestinal epithelial stem cells (IESCs) control the intestinal homeostatic response to inflammation and regeneration. The underlying mechanisms are unclear. Cytokine-STAT5 signaling regulates intestinal epithelial homeostasis and responses to injury. We link STAT5 signaling to IESC replenishment upon injury by depletion or activation of Stat5 transcription factor. We found that depletion of Stat5 led to deregulation of IESC marker expression and decreased LGR5(+) IESC proliferation. STAT5-deficient mice exhibited worse intestinal histology and impaired crypt regeneration after γ-irradiation. We generated a transgenic mouse model with inducible expression of constitutively active Stat5. In contrast to Stat5 depletion, activation of STAT5 increased IESC proliferation, accelerated crypt regeneration, and conferred resistance to intestinal injury. Furthermore, ectopic activation of STAT5 in mouse or human stem cells promoted LGR5(+) IESC self-renewal. Accordingly, STAT5 promotes IESC proliferation and regeneration to mitigate intestinal inflammation. STAT5 is a functional therapeutic target to improve the IESC regenerative response to gut injury.

LGR5

STAT5

Intestinal mucosa

Ectopic expression

10.1016/j.stemcr.2014.12.004

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Citations (63)

M1696 Novel Role of Guanylyl Cyclase C (GCC) in Maintenance of Intestinal Barrier Function

Gastroenterology (2009)

Xiaonan Han Elizabeth A. Mann Shila Gilbert Yanfang Guan Marshall H. Montrose

Barrier function

10.1016/s0016-5085(09)61896-5

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Interaction of the intestinal cytokines-JAKs-STAT3 and 5 axes with RNA N6-methyladenosine to promote chronic inflammation-induced colorectal cancer

Frontiers in Oncology (2024)

Nardana Esmaeili Ahmed Bakheet William Tse Shujun Liu Xiaonan Han

Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate worldwide. Mounting evidence indicates that mRNA modifications are crucial in RNA metabolism, transcription, processing, splicing, degradation, and translation. Studies show that N6-methyladenosine (m6A) is mammalians' most common epi-transcriptomic modification. It has been demonstrated that m6A is involved in cancer formation, progression, invasion, and metastasis, suggesting it could be a potential biomarker for CRC diagnosis and developing therapeutics. Cytokines, growth factors, and hormones function in JAK/STAT3/5 signaling pathway, and they could regulate the intestinal response to infection, inflammation, and tumorigenesis. Reports show that the JAK/STAT3/5 pathway is involved in CRC development. However, the underlying mechanism is still unclear. Signal Transducer and Activator of Transcription 3/5 (STAT3, STAT5) can act as oncogenes or tumor suppressors in the context of tissue types. Also, epigenetic modifications and mutations could alter the balance between pro-oncogenic and tumor suppressor activities of the STAT3/5 signaling pathway. Thus, exploring the interaction of cytokines-JAKs-STAT3 and/or STAT5 with mRNA m6A is of great interest. This review provides a comprehensive overview of the characteristics and functions of m6A and JAKs-STAT3/5 and their relationship with gastrointestinal (GI) cancers.

10.3389/fonc.2024.1352845

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Increased iNOS activity is essential for hepatic epithelial tight junction dysfunction in endotoxemic mice

AJP Gastrointestinal and Liver Physiology (2004)

Xiaonan Han Mitchell P. Fink Takashi Uchiyama Runkuan Yang Russell L. Delude

We tested the hypothesis that increased production of nitric oxide (NO·) by inducible NO· synthase (iNOS) is a key factor responsible for alterations in the expression, localization, and function of key tight junction (TJ) proteins in mice challenged with lipopolysaccharide (LPS, endotoxin). Endotoxemia was associated with hepatobiliary epithelial barrier dysfunction, as evidenced by increased plasma-to-bile leakage of FITC-labeled dextran (relative molecular mass 40 kDa) and increased circulating levels of bile acids and conjugated bilirubin. Immunoblotting revealed decreased expression of zonula occludens (ZO)-1, ZO-2, ZO-3, and occludin in liver after injection of C57Bl/6J mice with 2 mg/kg Escherichia coli 0111:B4 LPS. Nonidet P-40-insoluble (i.e., TJ-associated) occludin and ZO-1 were virtually undetectable 12 and 18 h after injecting LPS. Immunofluorescence microscopy also revealed deranged subcellular localization of ZO-1 and occludin in endotoxemic mice. Pharmacological inhibition of iNOS activity using l- N 6 -(1-iminoethyl)lysine (5 mg/kg) or genetic ablation of iNOS ameliorated LPS-induced changes in hepatobiliary barrier function, and these strategies partially preserved TJ protein expression and localization. Steady-state levels of occludin and ZO-3 transcripts decreased transiently after injecting LPS but returned toward normal by 12 and 24 h after induction of endotoxemia, respectively. These results support the view that iNOS-dependent NO· production is an important factor contributing to hepatobiliary epithelial barrier dysfunction resulting from systemic inflammation and suggest that iNOS induction may play a role in the development of cholestatic jaundice in patients with severe sepsis.

Occludin

Barrier function

10.1152/ajpgi.00231.2003

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Citations (73)