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Chinese Journal of Chemistry 2022年第22期40卷 2625-2632页

作者： Huan He Mengting Xie Mengting Zhang Haiqin Zhang Huan Zhu Yuxian Fang Zihao Shen Rui Wang Zhenjiang Zhao Lili Zhu Xuhong Qian Honglin Li Shanghai Key Laboratory of New Drug Design School of PharmacyEast China University of Science&TechnologyShanghai 200237China Innovation Center for Al and Drug Discovery(ICAlDD) East China Normal UniversityShanghai 200062China

The binding of Sphingosine-1-phosphate(S1P)with the S1PR1-5 plays a fundamental physiological role in a number of processes including vascular development and stabilization,lymphocyte migration and distribution.S1P-S1PR1 signal axis established roles in immune cell trafficking thus playing a therapeutic role in multiple sclerosis and inflammatory bowel *** this study,a series of oxadiazole derivatives were designed and synthesized as S1PR1 agonists based on rational drug *** them,compound 9i was identified as a potent and selective S1PR1 agonist with activities onβ-arrestin recruitment(EC50=0.36 nmol/L)and receptor internalization(EC50=8.09 nmol/L).Meanwhile,compound 9i displayed an oral bioavailability up to 93.6%.Based on its excellent activity to S1PR1 and pharmacokinetic properties,compound 9i effectively alleviated dextran sulfate sodium(DSS)-induced ulcerative colitis in mice at a dose of 0.1 mg/kg.

关键词： ulcerativecolitis S1PR1 Inflammation Drugdesign Structure-activity relationships

Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors:Pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take"toll"?

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World Journal of Gastroenterology 2006年第12期12卷 1829-1841页

作者： Peter Laszlo Lakatos Simon Fischer Janos Papp Laszlo Lakatos Istvan Gal Department of Medicine Semmelweis UniversityBudapestHungary Department of Medicine Csolnoky F.County HospitalVeszpremHungary Department of Medicine Kenezi Gy.County HospitalDebrecenHungary

The pathogenesis of inflammatory bowel disease （IBD） is only partially understood. Various environmental and host （e.g. genetic-, epithelial-, immune and nonimmune） factors are involved. It is a multifactorial polygenic disease with probable genetic heterogeneity. Some genes are associated with IBD itself, while others increase the risk of ulcerative colitis （UC） or Crohn＇ s disease （CD） or are associated with disease location and/or behaviour. This review addresses recent advances in the genetics of IBD. The article discusses the current information on the crosstalk between microbial and genetic factors （e.g. NOD2/CARD15, SLC22A46A5 and DLG5）. The genetic data acquired in recent years help in understanding the pathogenesis of IBD and can identify a number of potential targets for therapeutic intervention. In the future, genetics may help more accurately diagnose and predict disease course in IBD.

关键词： Inflammatory bowel disease ulcerativecolitis Crohn's disease Pathogenesis Microbial factors Genetics NOD2/CARD15 SLC22A4/A5 DLG5

-449 C>G polymorphism of NFKB1 gene,coding nuclear factor-kappa-B,is associated with the susceptibility to ulcerative colitis

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World Journal of Gastroenterology 2012年第47期18卷 6981-6986页

作者： Ranji Hayashi Tomomitsu Tahara Tsukasa Yamaaki Takashi Saito Kazuhiro Matsunaga Nobuhiko Hayashi Atsushi Fukumura Kazuaki Ozaki Masakatsu Nakamura Hisakazu Shiroeda Mikihiro Tsutsumi Tomoyuki Shibata Tomiyasu Arisawa Department of Gastroenterology Kanazawa Medical UniversityIshikawa 920-0293Japan Department of Gastroenterology Fujita Health University1-98 Dengakugakubo Katsukake-ChoToyoakeAichi 470-1192Japan

AIM:To clarify the association between a polymorphism-449 C>G(rs72696119) in 5'-UTR of NFKB1 with ulcerative colitis(UC).METHODS:The studied population comprised 639 subjects,including patients with UC(UC cases,n = 174) and subjects without UC(controls,n = 465).We employed polymerase chain reaction-single strand conformation polymorphism to detect the gene ***:The rs72696119 G allele frequencies in controls and UC cases were 33.4% and 38.5%,respectively(P = 0.10).Genotype frequency of the GG homozygote in UC cases was significantly higher than that in controls(P = 0.017),and the GG homozygote was significantly associated with susceptibility to UC [odds ratio(OR),1.88;95%CI,1.13-3.14].In male subjects,the GG homozygote was associated with an increased risk for UC(OR,3.10;95%CI,1.47-6.54;P = 0.0053),whereas this association was not found in female *** addition,the GG homozygote was significantly associated with the risk of non-continuous disease(OR,2.06;95%CI,1.12-3.79;P = 0.029),not having total colitis(OR,2.40;95%CI,1.09-3.80,P = 0.040),disease which developed before 20 years of age(OR,2.80;95%CI,1.07-7.32,P = 0.041),no hospitalization(OR,2.28;95%CI,1.29-4.05;P = 0.0090) and with a maximum of 8 or less on the UCDAI score(OR,2.45;95%CI,1.23-4.93;P = 0.022).CONCLUSION:Our results provide evidence that NFKB1 polymorphism rs72696119 was significantly associated with the development of *** polymorphism influences the susceptibility to and pathophysiological features of UC.

关键词： Genetic polymorphism NFKB1 ulcerativecolitis

Role of the intestinal barrier in inflammatory bowel disease

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World Journal of Gastroenterology 2008年第3期14卷 401-407页

作者： Mike G Laukoetter Porfirio Nava Asma Nusrat Epithelial Pathobiology Research Unit Department of Pathology and Laboratory Medicine Emory University Atlanta GA 30322 United States Department of General Surgery University of Muenster Muenster 48149 Germany Epithelial Pathobiology Research Unit Department of Pathology and Laboratory Medicine Emory University Atlanta GA 30322 United States

A critical function of the intestinal mucosa is to form a barrier that separates luminal contents from the interstitium. The single layer of intestinal epithelial cells (IECs) serves as a dynamic interface between the host and its environment. Cell polarity and structural properties of the epithelium is complex and is important in the development of epithelial barrier function. Epithelial cells associate with each other via a series of intercellular junctions. The apical most intercellular junctional complex referred to as the Apical Junction Complex (AJC) is important in not only cell-cell recognition, but also in the regulation of paracellular movement of fluid and solutes. Defects in the intestinal epithelial barrier function have been observed in a number of intestinal disorders such as inflammatory bowel disease (IBD). It is now becoming evident that an aberrant epithelial barrier function plays a central role in the pathophysiology of IBD. Thus, a better understanding of the intestinal epithelial barrier structure and function in healthy and disease states such as IBD will foster new ideas for the development of therapies for such chronic disorders.

关键词： Intestine Barrier function Tight Junction InflammatorY bowel disease Crohn's disease ulcerativecolitis

Use of infliximab in the prevention and delay of colectomy in severe steroid dependant and refractory ulcerative colitis

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World Journal of Gastroenterology 2008年第16期14卷 2544-2549页

作者： Robert P Willert Ian Craig Lawrance Department of Gastroenterology Fremantle Hospital

AIM: To determine if infliximab can prevent or delay surgery in refractory ulcerative colitis (UC). METHODS: UC patients who failed to have their disease controlled with conventional therapies and were to undergo colectomy if infliximab failed to induce a clinical improvement were reviewed. Patients were primarily treated with a single 5 mg/kg infliximab dose. The Colitis Activity Index (CAI) was used to determine response and remission. Data of 8 wk response and colectomy rates at 6 mo and 12 mo were collected. RESULTS: Fifteen patients were included, 7 with UC unresponsive or intolerant to Ⅳ hydrocortisone, and 8 with active disease despite oral steroids (all but one with therapeutic dosage and duration of immunomodulation). All the Ⅳ hydrocortisone-resistant/intolerant patients had been on azathioprine/6-MP < 8 wk. At 8 wk, infliximab induced a response in 86.7% (13/15) with 40% in remission (6/15). Within 6 mo of treatment 26.7% (4/15) had undergone colectomy and surgery was avoided in 46.6% (7/15) at 12 mo. The colectomy rate at 12 mo in those on immunomodulatory therapy < 8 wk at time of infliximab was 12.5% (1/8) compared with 100% (7/7) in patients who were on long-term maintenance immunomodulators (P < 0.02). CONCLUSION: Infliximab prevented colectomy due to active disease in immunomodulatory-na?ve, refractory UC patients comparable to the use of Cyclosporine. In patients, however, on effective dosage and duration of immunomodulation at time of infliximab therapy colectomy was not avoided.

关键词： Inflammatory bowel disease ulcerativecolitis Therapy Infliximab Colectomy

Is infliximab safe to use while breastfeeding?

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World Journal of Gastroenterology 2008年第19期14卷 3085-3087页

作者： Joel Z Stengel Hays L ArnoldJ Brooke Army Medical Cente3851 Roger Brooke Drive

Inflammatory bowel disease (IBD) often affects women around the age of conception and pregnancy. Most drugs used to treat IBD are safe in pregnancy, but physicians must consider the clinical implications of certain treatment regimens in young, fertile females. We report an informative case of a pregnant patient with IBD who underwent treatment with infliximab during her pregnancy and while nursing her infant. Serum and breast milk infliximab levels were monitored throughout this time period. This case report suggests that targeted monoclonal antibodies and other biologic agents can be used with caution in pregnant and breastfeeding patients.

关键词： Inflammatory bowel disease ulcerativecolitis Crohn's disease Pregnancy Breast-feeding Monoclonal antibodies

Promoter polymorphism of transforming growth factor-β1 gene and ulcerative colitis

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World Journal of Gastroenterology 2008年第2期14卷 243-247页

作者： B Tamizifar KB Lankarani S Naeimi M Rismankar Zadeh A Taghavi A Ghaderi Department of Internal Medicine Namazee Hospital Shiraz Iran Shiraz Institute of Cancer Research School of Medicine Shiraz University of Medical SciencesShiraz Iran

AIM: To elucidate the possible difference in two promoter polymorphisms of the transforming growth factor-β1 (TGF-β1) gene (-800G > A, -509C > T) between ulcerative colitis (UC) patients and normal ***: A total of 155 patients with established ulcerative colitis and 139 normal subjects were selected as controls. Two single nucleotide polymorphisms within the promoter region of TGF-β1 gene (-509C > T and -800G > A) were genotyped using PCR-RFLP. RESULTS: There was a statistically significant difference in genotype and allele frequency distributions between UC patients and controls for the -800G > A polymorphism of the TGF-β1 gene (P A of TGF-β1 gene promoter between Iranian patients with UC and normal subjects.

关键词： Transforming growth factor-β1 ulcerativecolitis Promoter Polymorphism Iran

Changes of plasma fasting carnitine ester profile in patients with ulcerative colitis

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World Journal of Gastroenterology 2006年第1期12卷 110-113页

作者： Judit Bene Katalin Komlósi Viktória Havasi Gábor Talián Beáta Gasztonyi Krisztina Horváth Gyula Mózsik Béla Hunyady Béla Melegh Mária Figler MTA PTE Clinical Genetics Research Group of Hungarian Academy of Sciences at the University of Pécs PécsHungary Department of Medical Genetics and Child DevelopmentUniversity of PécsPécsHungary Department of Medical Genetics and Child Development University of PécsPécsHungary Department of Medicine School of MedicineUniversity of PécsPécsHungary

AIM： To determine the plasma carnitine ester profile in adult patients with ulcerative culitis （UC） and compared with healthy control subjects. METHOD： Using ESI triple quadrupole tandem mass spectrometry, the carnitine ester profile was measured in 44 patients with UC and 44 age- and sex-matched healthy controls. RESULTS： There was no significant difference in the fasting free carnitine level between the patients with UC and the healthy controls. The fasting propionyl- （0.331 ± 0.019 vs 0.392 ± 0.017 μmol/L）, butyryl- （0.219 ± 0.014 vs 0.265 ± 0.012）, and isovalerylcarniUne （0.111 ± 0.008 vs 0.134 ± 0.008） levels were decreased in the UC patients. By contrast, the level of octanoyl- （0.147 ± 0.009 vs 0.114 ± 0.008）, decanoyl- （0.180 ± 0.012 vs 0.137 ± 0.008）, myristoyl- （0.048 ± 0.003 vs 0.039 ± 0.003）, palmitoyl- （0.128 ± 0.006 vs 0.109 ± 0.004）, palmitoleyl- （0.042±0.003 vs 0.031 ± 0.002） and oleylcarnitine （0.183 ± 0.007 vs 0.163 ± 0.007; P 〈 0.05 in all comparisons） were increased in the patients with UC. CONCLUSION： Our data suggest selective involvement of the carnitine esters in UC patients, probably due to their altered metabolism.

关键词： Carnitine Carnitine ester profile ulcerativecolitis

Hepatic portal venous gas: Physiopathology, etiology, prognosis and treatment

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World Journal of Gastroenterology 2009年第29期15卷 3585-3590页

作者： Bassam Abboud Jad El Hachem Thierry Yazbeck Corinne Doumit Department of General Surgery Hotel-Dieu de France Hospital Boulevard Alfred Naccache Beirut 16-6830 Lebanon

Hepatic portal venous gas (HPVG), an ominous radiologic sign, is associated in some cases with a severe underlying abdominal disease requiring urgent operative intervention. HPVG has been reported with increasing frequency in medical literature and usually accompanies severe or lethal conditions. The diagnosis of HPVG is usually made by plain abdominal radiography, sonography, color Doppler flow imaging or computed tomography (CT) scan. Currently, the increased use of CT scan and ultrasound in the inpatient setting allows early and highly sensitive detection of such severe illnesses and also the recognition of an increasing number of benign and non-life threatening causes of HPVG. HPVG is not by itself a surgical indication and the treatment depends mainly on the underlying disease. The prognosis is related to the pathology itself and is not influenced by the presence of HPVG. Based on a review of the literature, we discuss in this paper the pathophysiology, risk factors, radiographic findings, management, and prognosis of pathologies associated with HPVG.

关键词： Hepatic portal venous gas Bowel ischemia/necrosis Diverticulitis Gastric pathologies ulcerativecolitis Abdominal computed tomography scan Crohn'sdisease Liver transplantation Chemotherapy

Anal transition zone in the surgical management of ulcerative colitis

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World Journal of Gastroenterology 2009年第7期15卷 769-773页

作者： Jennifer Holder-Murray Alessandro Fichera Department of Surgery University of Chicago

Preservation of the anal transition zone has long been a significant source of controversy in the surgical management of ulcerative *** two techniques for restorative proctocolectomy and ileal pouch anal anastomosis(RPC IPAA) in common practice are a stapled anastomosis and a handsewn anastomosis;these techniques differ in the amount of remaining rectal mucosa and therefore the presence of the anal transition zone following *** technique has advantages and disadvantages in long-term functional outcomes,operative and postoperative complications,and risk of ***,we propose a selective approach to performing a stapled RPC IPAA based on the presence of dysplasia in the preoperative endoscopic evaluation.

关键词： Anal transition zone Ileal pouch analanastomosis Restorative proctocolectomy ulcerativecolitis