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Inflammatory pathways of importance for management of inflammatory bowel disease

World Journal of Gastroenterology 2014年第1期20卷 64-77页

作者： Jannie pedersen mehmet Coskun Christoffer Soendergaard mohammad Salem Ole Haagen Nielsen Department of Gastroenterology Medical SectionUniversity of CopenhagenHerlev HospitalDK-2730 HerlevDenmark Department of Cellular and molecular medicine the Panum InstituteUniversity of CopenhagenDK-2200 CopenhagenDenmark

Inflammatory bowel disease (IBD) is a group of chronic disorders of the gastrointestinal tract comprising Crohn’s disease (CD) and ulcerative colitis (UC). Their etiologies are unknown, but they are characterised by an imbalanced production of pro-inflammatory mediators, e.g., tumor necrosis factor (TNF)-α, as well as increased recruitment of leukocytes to the site of inflammation. Advantages in understanding the role of the inflammatory pathways in IBD and an inadequate response to conventional therapy in a large portion of patients, has over the last two decades lead to new therapies which includes the TNF inhibitors (TNFi), designed to target and neutralise the effect of TNF-α. TNFi have shown to be efficient in treating moderate to severe CD and UC. However, convenient alternative therapeutics targeting other immune pathways are needed for patients with IBD refractory to conventional therapy including TNFi. Indeed, several therapeutics are currently under development, and have shown success in clinical trials. These include antibodies targeting and neutralising interleukin-12/23, small pharmacologic Janus kinase inhibitors designed to block intracellular signaling of several pro-inflammatory cytokines, antibodies targeting integrins, and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium, reducing their infiltration into the inflamed mucosa. In this review we have elucidated the major signaling pathways of clinical importance for IBD therapy and highlighted the new promising therapies available. As stated in this paper several new treatment options are under development for the treatment of CD and UC, however, no drug fits all patients. Hence, optimisations of treatment regimens are warranted for the benefit of the patients either through biomarker establishment or other rationales to maximise the effect of the broad range of mode-of-actions of the present and future drugs in IBD.

关键词： Anti-tumor necrosis factor, Biologics, Crohn’ s disease, pro-inflammatory cytokines, Signaling pathways, Treatment, Ulcerative colitis

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Development of an active-site titrant for SARS-CoV-2 main protease as an indispensable tool for evaluating enzyme kinetics

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Acta pharmaceutica Sinica B 2024年第5期14卷 2349-2357页

作者： Rabea Voget Julian Breidenbach Tobias Claff Alexandra Hingst Katharina Sylvester Christian Steinebach Lan phuong Vu Renato H.Weiße Ulrike Bartz Norbert Sträter Christa E.müller michael Gütschow pharmaceutical Institute Pharmaceutical&Medicinal ChemistryUniversity of BonnBonn 53121Germany Institute of Bioanalytical Chemistry Center for Biotechnology and BiomedicineLeipzig UniversityLeipzig 04103Germany Department of Natural Sciences University of Applied Sciences Bonn-Rhein-SiegRheinbach 53359Germany

A titrant for the SARS-CoV-2 main protease(m^(pro))was developed that enables,for the first time,the exact determination of the concentration of the enzymatically active m^(pro) by active-site *** covalent binding mode of the tetrapeptidic titrant was elucidated by the determination of the crystal structure of the enzyme–titrant *** fluorogenic substrates of m^(pro),including a prototypical,internally quenched Dabcyl-EDANS peptide,were compared in terms of solubility under typical assay *** exploiting the new titrant,key kinetic parameters for the m^(pro)-catalyzed cleavage of these substrates were determined.

关键词： COVID-19 SARS-CoV-2 main protease peptide nitriles Fluorogenic substrates Active-site titration X-ray crystallography Inner filter effect

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polymorphisms in NF-κB,pXR,LXR,ppARγ and risk of inflammatory bowel disease

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World Journal of Gastroenterology 2011年第2期17卷 197-206页

作者： Vibeke Andersen Jane Christensen Anja Ernst Bent A Jacobsen Anne Tjφnneland Henrik B Krarup Ulla Vogel Department of medical Viborg Regional Hospital Institute of Cancer Epidemiology Danish Cancer Society Department of Clinical Biochemistry Aarhus University Hospital Department of medical Gastroenterology Aarhus University Hospital National Food Institute Technical University of Denmark Institute for Science Systems and ModelsUniversity of Roskilde National Research Centre for the Working Environment

AIm:To investigate the contribution of polymorphisms in nuclear receptors to risk of inflammatory bowel disease(IBD) . mETHODS:Genotypes of nuclear factor(NF) -κB(NFKB1) NFκB-94ins/del(rs28362491) ;peroxisome proliferatoractivated receptor(ppAR) -γ(ppARγ) ppARγpro12Ala(rs1801282) and C1431T(rs 3856806) ;pregnane X receptor(pXR) (NR1I2) pXR A-24381C(rs1523127) ,C8055T(2276707) ,and A7635G(rs 6785049) ;and liver X receptor(LXR) (NR1H2) LXR T-rs1405655-C and T-rs2695121-C were assessed in a Danish case-control study of 327 Crohn's disease patients,495 ulcerative colitis(UC) patients,and 779 healthy *** ratio(OR) and 95%CI were estimated by logistic regression models. RESULTS:The pXR A7635G variant,the ppARγpro12Ala and LXR T-rs2695121-C homozygous variant genotypes were associated with risk of UC(OR:1.31,95% CI:1.03-1.66,p=0.03,OR:2.30,95%CI:1.04-5.08,p=0.04,and OR:1.41,95%CI:1.00-1.98,p=0.05,respectively) compared to the corresponding homozygous wild-type *** never smokers,pXR A7635G and the LXR T-rs1405655-C and T-rs2695121-C variant genotypes were associated with risk of IBD(OR:1.41,95%CI:1.05-1.91,p=0.02,OR:1.63,95%CI:1.21-2.20,p=0.001,and OR:2.02,95%CI:1.36-2.99,p=0.0005,respectively) compared to the respective homozygous variant *** A7635G(rs6785049) variant genotype was associated with a higher risk of UC diagnosis before the age of 40 years and with a higher risk of extensive disease(OR:1.34,95%CI:1.03-1.75 and OR:2.49,95%CI:1.24-5.03,respectively) . CONCLUSION:Common pXR and LXR polymorphisms may contribute to risk of IBD,especially among never smokers.

关键词： Crohn's disease Genetic susceptibility Single nucleotide polymorphisms Smoking status Transcription factors Ulcerative colitis

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