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| 1 | Extracellular histones stimulate collagen expression in vitro and promote liver fibrogenesis in a mouse model via the TLR4-MyD88 signaling pathway显示文摘BACKGROUND Liver fibrosis progressing to liver cirrhosis and hepatic carcinoma is very common and causes more than one million deaths annually.Fibrosis develops from recurrent liver injury but the molecular mechanisms are not fully understood.Recently,the TLR4-MyD88 signaling pathway has been reported to contribute to fibrosis.Extracellular histones are ligands of TLR4 but their roles in liver fibrosis have not been investigated.AIM To investigate the roles and potential mechanisms of extracellular histones in liver fibrosis.METHODS In vitro,LX2 human hepatic stellate cells(HSCs)were treated with histones in the presence or absence of non-anticoagulant heparin(NAHP)for neutralizing histones or TLR4-blocking antibody.The resultant cellular expression of collagen I was detected using western blotting and immunofluorescent staining.In vivo,the CCl4-induced liver fibrosis model was generated in male 6-week-old ICR mice and in TLR4 or MyD88 knockout and parental mice.Circulating histones were detected and the effect of NAHP was evaluated.RESULTS Extracellular histones strongly stimulated LX2 cells to produce collagen I.Histone-enhanced collagen expression was significantly reduced by NAHP and TLR4-blocking antibody.In CCl4-treated wild type mice,circulating histones were dramatically increased and maintained high levels during the duration of fibrosisinduction.Injection of NAHP not only reduced alanine aminotransferase and liver injury scores,but also significantly reduced fibrogenesis.Since the TLR4-blocking antibody reduced histone-enhanced collagen I production in HSC,the CCl4 model with TLR4 and MyD88 knockout mice was used to demonstrate the roles of the TLR4-MyD88 signaling pathway in CCl4-induced liver fibrosis.The levels of liver fibrosis were indeed significantly reduced in knockout mice compared to wild type parental mice.CONCLUSION Extracellular histones potentially enhance fibrogenesis via the TLR4–MyD88 signaling pathway and NAHP has therapeutic potential by detoxifying extracellular histones. | Zhi Wang Zhen-Xing Cheng Simon T Abrams Zi-Qi Lin ED Yates Qian Yu Wei-Ping Yu Ping-Sheng Chen Cheng-Hock Toh Guo-Zheng Wang | 2020 | World Journal of Gastroenterology2020，26，47： | 3 |
| 2 | Sursical treatment for injuries of the middle and lower cervical spine显示文摘 | Toh E Nomura T Watanabe M | 2006 | Int Orthop2006，30，1： | 1 |
| 3 | Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinoma显示文摘 | Toh Y Ohga T Endo K | 2004 | Int J Cancer2004，110，： | 1 |
| 4 | Retroperito- neal bronchogenie cyst: report of a case and literature review 显示文摘 | TOH H SHITAMURA T KATAOKA H | 1999 | PatholInt1999，49，： | 1 |
| 5 | Beneficial effects of exoge- nous tetrahydrobiopterin on left ventrlcular remodeling after myo- cardial infarction in rats: the possible role of oxidative stress caused by uncoupled endothelial nitric oxide synthase 显示文摘 | Masano T Kawashima S Toh R | 2008 | Circ J2008，72，9： | 1 |
| 6 | Optimum magnetic flux density in quality control of casts with level DC magnetic field in continuous casting mold 显示文摘 | Yamamura H Toh T | 2001 | ISU International2001，41，10： | 1 |
| 7 | Effect of Magnetic Field Conditions on the Electromagnetic Braking Efficiency 显示文摘 | Harada H Toh T Ishii T | 2001 | ISIJ International2001，41，10： | 1 |
| 8 | Recent progress of EPM i n steelmaking, casting, and solidification processing 显示文摘 | Yasuda H Toh T Iwai K | 2007 | ISIJ Intemational2007，47，4： | 1 |
| 9 | Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinomas显示文摘 | TOH Y OHGA T ENDO K | 2004 | Int J Cancer2004，110，3： | 1 |
| 10 | Validation of the Japanese Society for Surgery of the Hand version of the Disability of the Arm, Shoulder, and Hand questionnaire显示文摘 | IMAEDA T TOH S NAKAO Y | 2005 | J Orthop Sci2005，10，4： | 1 |
| 11 | Magnetohydrodynamic calcula-tion for electromagnetic stirring of molten metal显示文摘 | Fujisaki K Ueyama T Toh T | 1998 | IEEE TransMagn1998，34，4： | 1 |
| 12 | Selective peroxiseme proliferator- activated receptor-gamma modulation to reduce cardiovascular risk in patients with insulin resistance 显示文摘 | Yew T Toh SA Millar JS | 2012 | Recent Pat Cardiovasc Drug Discov2012，7，1： | 1 |
| 13 | Angiopoietin - 2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases显示文摘 | toh T Inoue H Tnanka S | 2001 | Cancer Res2001，61，： | 1 |
| 14 | Surgical treatment for injuries of the middle and lower cervical spine显示文摘 | Toh E Nomura T Watanabe M | 2006 | Int Orthop2006，1，： | 1 |
| 15 | Genome of anendosymbiont coupling N2 fixation to cellulolysis within protist cells intermite gut 显示文摘 | Hongoh Y Sharma VK Prakash T Noda S Toh H Taylor TD Kudo T Sakaki Y Toyoda A Hattori M Ohkuma M | 2008 | Science2008，322，5904： | 1 |
| 16 | Binding of biliverdin, bilirubin, and thyroid hormones to lipocalin-type prostaglandin D synthase显示文摘 | Beuckmann CT Aoyagi M Okazaki I Hiroike T Toh H Hayaishi O Urade Y | 1999 | Biochemistry1999，2238，： | 1 |
| 17 | Expression of the metastasis-associated MTAl protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinomas显示文摘 | TOH Y OHGA T ENDO K | 2004 | Int J Cancer2004，110，： | 1 |
| 18 | Organization and nucleotide sequence of the DNA polymerase gene from the archaeon Pyrococcus furious 显示文摘 | Uemori T Ishino Y Toh H Asada F Kato I | 1993 | Nucleic Acids Research1993，21，2： | 1 |
| 19 | High Sensitivity and Fast Response Sn O2and La-Sn O2catalytic pellet sensots in detecting volatile organic compounds显示文摘 | ANG G T TOH G H BAKAR M Z A | 2011 | Process Safety and Environmengtal Protection2011，89，3： | 1 |
| 20 | Appropriate indications for the use of a percutaneous cardiopulmonary support system in cases with cardiogenic shock complicating acute myocardial infarction显示文摘 | Aiba T Nonogi H Tomonri I TOH | 2001 | Jpn Circ J2001，65，： | 1 |
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