BACKGROUND Patients with Crohn’s disease(CD)are at risk of developing complications such as perianal fistulas.Patients with Crohn’s perianal fistulas(CPF)are affected by fecal incontinence(FI),bleeding,pain,swelling...BACKGROUND Patients with Crohn’s disease(CD)are at risk of developing complications such as perianal fistulas.Patients with Crohn’s perianal fistulas(CPF)are affected by fecal incontinence(FI),bleeding,pain,swelling,and purulent perianal discharge,and METHODS This cross-sectional observational study was conducted in patients with CD aged 21-90 years via a web-enabled questionnaire in seven countries(April-August 2021).Patients were recruited into three cohorts:Cohort 1 included patients without perianal fistulas;cohort 2 included patients with perianal fistulas without fistula-related surgery;and cohort 3 included patients with perianal fistulas and fistula-related surgery.Validated patient-reported outcome measures were used to assess quality of life.Drivers of treatment preferences were measured using a discrete choice experiment(DCE).RESULTS In total,929 patients were recruited(cohort 1,n=620;cohort 2,n=174;cohort 3,n=135).Short Inflammatory Bowel Disease Questionnaire scores were worse for patients with CPF(cohorts 2 and 3)than for those with CD without CPF(cohort 1):Mean score 3.8 and 3.7 vs 4.1,respectively,(P<0.001).Similarly,mean Revised FI and FI Quality of Life scores were worse for patients with CPF than for those with CD without CPF.Quality of Life with Anal Fistula scores were similar in patients with CPF with or without CPF-related surgery(cohorts 2 and 3):Mean score 41 and 42,respectively.In the DCE,postoperative discomfort and fistula healing rate were the most important treatment attributes influencing treatment choice:Mean relative importance 35.7 and 24.7,respectively.CONCLUSION The burden of illness in CD is significantly higher for patients with CPF and patients rate lower postoperative discomfort and higher healing rates as the most desirable treatment attributes.展开更多
AIM： To investigate the effects of Tat-NEMO-binding domain （NBD） peptide on taurocholate-induced pancreatitis and lipopolysaccharide （LPS）-stimulated AR42J acinus ceils inflammatory response in rats. METHODS： So...AIM： To investigate the effects of Tat-NEMO-binding domain （NBD） peptide on taurocholate-induced pancreatitis and lipopolysaccharide （LPS）-stimulated AR42J acinus ceils inflammatory response in rats. METHODS： Sodium taurocholate （5%） was used to induce the pancreatitis model. Forty-eight rats from the taurocholate group received an intravenous bolus of 13 mg/kg Tat-NBD （wild-type, WT） peptide, Tat- NBD （mutant-type, MT） peptide, NBD peptide or Tat peptide. The pancreatic histopathology was analyzed by hematoxylin staining. LPS was added to the culture medium to stimulate the AR42J cells. For pretreatment, cells were incubated with different peptides for 2 h before LPS stimulation. Expression of IL-1β and TNF-α mRNA was analyzed using a semi-quantitative reverse-transcript polymerase chain reaction （RT-PCR） method. IL-1β and TNF-α protein in culture medium were detected by enzyme linked immunosorbent assay （ELISA）. NF-KB DNA-binding in pancreas was examined by electrophoretic mobility shift assays. P65 expression of AR42J was determined by Strept Actividin-Biotin Complex （SABC） method. RESULTS： Pretreatment with Tat-NBD （WT） peptide at a concentration of 13 mg/kg body wt showed beneficial effect in pancreaitis model. LPS （10 mg/L） resulted in an increase of IL-1β mRNA, IL-1β protein, TNF-α mRNA and TNF-α protein, whereas significantly inhibitory effects were observed when cells were incubated with Tat-NBD （WT）. Consisting with p65 expression decrease analyzed by SABC method, NF-KB DNA-binding activity significantly decreased in Tat-NBD （WT） pretreatment group, especially at the largest dose. No significant changes were found in the control peptide group. CONCLUSION： Our result supports that active NF-KB participates in the pathogenesis of STC-induced acute pancreatitis in rats. Tat-NBD （WT） peptide has anti- inflammatory effects in this model and inhibits the inflammation of acinus simulated by LPS.展开更多
Ciprofloxacin (CPFX) and pazufloxacin (PZFX) have strong antibacterial activity against Pseudomonas aeruginosa. We investigated the sensitivity of P. aeruginosa to CPFX and PZFX in 373 strains isolated from inpatients...Ciprofloxacin (CPFX) and pazufloxacin (PZFX) have strong antibacterial activity against Pseudomonas aeruginosa. We investigated the sensitivity of P. aeruginosa to CPFX and PZFX in 373 strains isolated from inpatients (321 strains) and outpatients (52 strains) during September 2010 to September 2011 at Toho University Ohashi Medical Center. The percentage of CPFX-non-susceptible (≥3.91 μg/mL) among inpatients was 22.4%, but that among outpatients was 1.9%. As the major resistance mechanism to fluoroquinolones in P. aeruginosa involves modification of type II topoisomerases (DNA gyrase and topoisomerase IV), we examined mutations in the quinolone-resistance-determining regions (QRDRs) of gyrA and parC of P. aeruginosa isolates. Among the 373 isolates, 73 isolates had reduced CPFX-susceptibility and 88 had reduced PZFX-susceptibility. Sequencing of gyrA and parC revealed base substitutions that resulted in amino acid replacements in QRDR of GyrA in 70 P. aeruginosa isolates, while Thr83Ile (in GyrA) and Ser87Leu (in ParC) substitutions were found in 12 strains. These replacements were clearly associated with reduced susceptibility to CPFX and PZFX. However, we also found strains with high MICs to quinolones without mutations in either gyrA or parC. We then investigated the effect of efflux pumps in CPFX-resistance in these isolates. In the presence of an efflux pump inhibitor, MIC values in 12 of 66 strains decreased to 1/23. We also sequenced genes related to overexpression of efflux pumps, viz., mexZ, mexR, and nfxB. Eight of the strains without mutations in QRDRs had a mutation in mexZ, 7 strains had a mutation in mexR, but no mutation was identified in nfxB.展开更多
Despite the vigorous research and development, as of 2017, there is currently no widely available antimalarial vaccine. An effective, commercially available vaccine would be a huge game changer;however, it seems like ...Despite the vigorous research and development, as of 2017, there is currently no widely available antimalarial vaccine. An effective, commercially available vaccine would be a huge game changer;however, it seems like there is still a long way to go until that target is reached. Therefore, the purpose of this study was to use molecular docking technique to identify new inhibitors for a novel antimalarial target with the overall aim of finding hit compounds which could be further optimized to become potential drug candidates. The docking protocol AutoDockVina was used alongside the molecular visualisation software UCSF Chimera to dock 100 naphthoquinones (labelled TM1-100) and 66 aryl diketones (labelled TM101-166) with the chosen target, Plasmodium vivax N-myristoyltransferase (PvNMT). Each docking session yielded the best 9 binding modes between the ligand and target. The hydrogen bond interactions of all binding modes were analysed, and the top six target molecules (TM) were short listed as the possible hit compounds (TM40, TM65, TM66, TM81, TM94 and TM165). These compounds displayed more than six hydrogen bonds under 3 angstroms over the 9 binding modes. Using Lipinski’s rule of 5, the potential hit compounds were further analysed to determine the drug-likeness and all were found to obey the parameters. Following the same method used to dock the ligands, twelve FDA approved antimalarial drugs were also docked with PvNMT for comparison purposes. Apart from proguanil, the other eleven antimalarial drugs displayed fewer hydrogen bonds under 3 angstroms over the 9 binding modes compared to all six of the potential hit compounds. This study discovered six compounds which displayed stronger interactions with the target protein compared to majority of the FDA approved drugs. The results of this investigation gave us new molecules that could be further investigated for the designing of novel drug-like compounds for the treatment of Malaria.展开更多
The main purpose of the study was to enhance the stability and therapeutic effects of Curcumin(Cur)through nanoformulation with gum Arabic(GA)as a coating agent through an efficient synthetic approach.The antioxidant ...The main purpose of the study was to enhance the stability and therapeutic effects of Curcumin(Cur)through nanoformulation with gum Arabic(GA)as a coating agent through an efficient synthetic approach.The antioxidant properties of the developed nanoparticles(Cur/GANPs)were assessed through several in vitro assays,such asβ-carotene bleaching activity,DPPH,and nitric oxide scavenging activities in addition to evaluating its inhibitory activity on angiotensinconverting enzyme(ACE).The cytotoxicity of Cur/GANPs was evaluated in vitro using different types of human cancer cells including breast cancer(MCF7,MDA-MB231),liver cancer(HepG2),and colon cancer(HT29)cells.The prepared particles displayed an elliptical shape with a size ranging between 20–260 nm and a potential difference of–15 mV.The Cur/GANPs exhibited significant antioxidant activity compared to free curcumin when using concentrations between 31.5 and 500μg/mL.The Cur/GANPs also had inhibited the growth of all cancer cell lines in a proportional trend with concentrations used.Hence,the encapsulation with gum Arabic has augmented the antioxidant and anti-neoplastic effects of Curcumin.Therefore,Cur/GANPs may have effective therapeutic properties in diseases attributed to oxidative stress like cancer and hypertension.展开更多
Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venule...Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venules is highly dependent on the interaction between the chemokines CCL19, CCL21, CXCL12, and CXCL13, and their receptors CCR7, CXCR4 and CXCR5. However, the molecular mechanism（s） of lymphocyte egress from secondary lymphoid tissues to lymph remained unclear. We have found a new class of immunomodulator, FTY720 by chemical modification of vegetative wasp-derived natural product, ISP-I （myriocin）. FTY720 has been shown to be highly effective in experimental allograft and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating activity in these models. The reduction of circulating lymphocytes by FTY720 is caused by sequestration of lymphocytes into secondary lymphoid tissues and thymus. FTY720 is rapidly converted to （S）-enantiomer of FTY720-phosphate [（S）-FTY720-P] by sphingosine kinase 2 in vivo. （S）-FTY720-P acting as a potent agonist of S1P receptor type 1 （S1P1）, induces long-term down-regulation of S1P1 on lymphocytes, and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is presumed that FTY720-induced lymphocyte sequestration is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus by its active metabolite （S）-FTY720-P. Throughout the analysis of the mechanism of action of FTY720, it is clarified that S1P/S1P1 interaction plays an important role for lymphocyte egress from secondary lymphoid tissues and thymus.展开更多
FTY720, a sphingosine 1-phosphate receptor modulator, induces a marked decrease in the number of peripheral blood lymphocytes and exerts immunomodulating activity in various experimental allograft and autoimmune disea...FTY720, a sphingosine 1-phosphate receptor modulator, induces a marked decrease in the number of peripheral blood lymphocytes and exerts immunomodulating activity in various experimental allograft and autoimmune disease models. In this study, we evaluated the effect of FTY720 and its active metabolite, （S）-enantiomer of FTY720-phosphate [（S）-FTY720-P] on experimental autoimmune encephalomyelitis （EAE） in rats and mice. Prophylactic administration of FTY720 at 0.1 to 1 mg/kg almost completely prevented the development of EAE, and therapeutic treatment with FTY720 significantly inhibited the progression of EAE and EAE-associated histological change in the spinal cords of LEW rats induced by immunization with myelin basic protein. Consistent with rat EAE, the development of proteolipid protein-induced EAE in SJL/J mice was almost completely prevented and infiltration of CD4^＋ T cells into spinal cord was decreased by prophylactic treatment with FTY720 and （S）-FTY720-P. When FTY720 or （S）-FTY720-P was given after establishment of EAE in SJL/J mice, the relapse of EAE was markedly inhibited as compared with interferon-β, and the area of demyelination and the infiltration of CD4^＋ T cells were decreased in spinal cords of EAE mice. Similar therapeutic effect by FTY720 was obtained in myelin oligodendrocyte glycoprotein-induced EAE in C57BL/6 mice. These results indicate that FTY720 exhibits not only a prophylactic but also a therapeutic effect on EAE in rats and mice, and that the effect of FTY720 on EAE appears to be due to a reduction of the infiltration of myelin antigen-specific CD4^＋ T cells into the inflammation site. Cellular ＆ Molecular Immunology. 2005;2（6）：439-448.展开更多
文摘BACKGROUND Patients with Crohn’s disease(CD)are at risk of developing complications such as perianal fistulas.Patients with Crohn’s perianal fistulas(CPF)are affected by fecal incontinence(FI),bleeding,pain,swelling,and purulent perianal discharge,and METHODS This cross-sectional observational study was conducted in patients with CD aged 21-90 years via a web-enabled questionnaire in seven countries(April-August 2021).Patients were recruited into three cohorts:Cohort 1 included patients without perianal fistulas;cohort 2 included patients with perianal fistulas without fistula-related surgery;and cohort 3 included patients with perianal fistulas and fistula-related surgery.Validated patient-reported outcome measures were used to assess quality of life.Drivers of treatment preferences were measured using a discrete choice experiment(DCE).RESULTS In total,929 patients were recruited(cohort 1,n=620;cohort 2,n=174;cohort 3,n=135).Short Inflammatory Bowel Disease Questionnaire scores were worse for patients with CPF(cohorts 2 and 3)than for those with CD without CPF(cohort 1):Mean score 3.8 and 3.7 vs 4.1,respectively,(P<0.001).Similarly,mean Revised FI and FI Quality of Life scores were worse for patients with CPF than for those with CD without CPF.Quality of Life with Anal Fistula scores were similar in patients with CPF with or without CPF-related surgery(cohorts 2 and 3):Mean score 41 and 42,respectively.In the DCE,postoperative discomfort and fistula healing rate were the most important treatment attributes influencing treatment choice:Mean relative importance 35.7 and 24.7,respectively.CONCLUSION The burden of illness in CD is significantly higher for patients with CPF and patients rate lower postoperative discomfort and higher healing rates as the most desirable treatment attributes.
基金Supported by The Natural Science Foundation, No. 04009624
文摘AIM： To investigate the effects of Tat-NEMO-binding domain （NBD） peptide on taurocholate-induced pancreatitis and lipopolysaccharide （LPS）-stimulated AR42J acinus ceils inflammatory response in rats. METHODS： Sodium taurocholate （5%） was used to induce the pancreatitis model. Forty-eight rats from the taurocholate group received an intravenous bolus of 13 mg/kg Tat-NBD （wild-type, WT） peptide, Tat- NBD （mutant-type, MT） peptide, NBD peptide or Tat peptide. The pancreatic histopathology was analyzed by hematoxylin staining. LPS was added to the culture medium to stimulate the AR42J cells. For pretreatment, cells were incubated with different peptides for 2 h before LPS stimulation. Expression of IL-1β and TNF-α mRNA was analyzed using a semi-quantitative reverse-transcript polymerase chain reaction （RT-PCR） method. IL-1β and TNF-α protein in culture medium were detected by enzyme linked immunosorbent assay （ELISA）. NF-KB DNA-binding in pancreas was examined by electrophoretic mobility shift assays. P65 expression of AR42J was determined by Strept Actividin-Biotin Complex （SABC） method. RESULTS： Pretreatment with Tat-NBD （WT） peptide at a concentration of 13 mg/kg body wt showed beneficial effect in pancreaitis model. LPS （10 mg/L） resulted in an increase of IL-1β mRNA, IL-1β protein, TNF-α mRNA and TNF-α protein, whereas significantly inhibitory effects were observed when cells were incubated with Tat-NBD （WT）. Consisting with p65 expression decrease analyzed by SABC method, NF-KB DNA-binding activity significantly decreased in Tat-NBD （WT） pretreatment group, especially at the largest dose. No significant changes were found in the control peptide group. CONCLUSION： Our result supports that active NF-KB participates in the pathogenesis of STC-induced acute pancreatitis in rats. Tat-NBD （WT） peptide has anti- inflammatory effects in this model and inhibits the inflammation of acinus simulated by LPS.
文摘Ciprofloxacin (CPFX) and pazufloxacin (PZFX) have strong antibacterial activity against Pseudomonas aeruginosa. We investigated the sensitivity of P. aeruginosa to CPFX and PZFX in 373 strains isolated from inpatients (321 strains) and outpatients (52 strains) during September 2010 to September 2011 at Toho University Ohashi Medical Center. The percentage of CPFX-non-susceptible (≥3.91 μg/mL) among inpatients was 22.4%, but that among outpatients was 1.9%. As the major resistance mechanism to fluoroquinolones in P. aeruginosa involves modification of type II topoisomerases (DNA gyrase and topoisomerase IV), we examined mutations in the quinolone-resistance-determining regions (QRDRs) of gyrA and parC of P. aeruginosa isolates. Among the 373 isolates, 73 isolates had reduced CPFX-susceptibility and 88 had reduced PZFX-susceptibility. Sequencing of gyrA and parC revealed base substitutions that resulted in amino acid replacements in QRDR of GyrA in 70 P. aeruginosa isolates, while Thr83Ile (in GyrA) and Ser87Leu (in ParC) substitutions were found in 12 strains. These replacements were clearly associated with reduced susceptibility to CPFX and PZFX. However, we also found strains with high MICs to quinolones without mutations in either gyrA or parC. We then investigated the effect of efflux pumps in CPFX-resistance in these isolates. In the presence of an efflux pump inhibitor, MIC values in 12 of 66 strains decreased to 1/23. We also sequenced genes related to overexpression of efflux pumps, viz., mexZ, mexR, and nfxB. Eight of the strains without mutations in QRDRs had a mutation in mexZ, 7 strains had a mutation in mexR, but no mutation was identified in nfxB.
文摘Despite the vigorous research and development, as of 2017, there is currently no widely available antimalarial vaccine. An effective, commercially available vaccine would be a huge game changer;however, it seems like there is still a long way to go until that target is reached. Therefore, the purpose of this study was to use molecular docking technique to identify new inhibitors for a novel antimalarial target with the overall aim of finding hit compounds which could be further optimized to become potential drug candidates. The docking protocol AutoDockVina was used alongside the molecular visualisation software UCSF Chimera to dock 100 naphthoquinones (labelled TM1-100) and 66 aryl diketones (labelled TM101-166) with the chosen target, Plasmodium vivax N-myristoyltransferase (PvNMT). Each docking session yielded the best 9 binding modes between the ligand and target. The hydrogen bond interactions of all binding modes were analysed, and the top six target molecules (TM) were short listed as the possible hit compounds (TM40, TM65, TM66, TM81, TM94 and TM165). These compounds displayed more than six hydrogen bonds under 3 angstroms over the 9 binding modes. Using Lipinski’s rule of 5, the potential hit compounds were further analysed to determine the drug-likeness and all were found to obey the parameters. Following the same method used to dock the ligands, twelve FDA approved antimalarial drugs were also docked with PvNMT for comparison purposes. Apart from proguanil, the other eleven antimalarial drugs displayed fewer hydrogen bonds under 3 angstroms over the 9 binding modes compared to all six of the potential hit compounds. This study discovered six compounds which displayed stronger interactions with the target protein compared to majority of the FDA approved drugs. The results of this investigation gave us new molecules that could be further investigated for the designing of novel drug-like compounds for the treatment of Malaria.
基金supported by the Malaysian Ministry of Higher Education Fundamental Research Grant Scheme(FRGS17-005-0571)Prototype Research Grant Scheme(PRGS19-005-0049)Ministry of Science,Technology,and Innovation(MOSTI)Grant No.SMF18-001-0001.
文摘The main purpose of the study was to enhance the stability and therapeutic effects of Curcumin(Cur)through nanoformulation with gum Arabic(GA)as a coating agent through an efficient synthetic approach.The antioxidant properties of the developed nanoparticles(Cur/GANPs)were assessed through several in vitro assays,such asβ-carotene bleaching activity,DPPH,and nitric oxide scavenging activities in addition to evaluating its inhibitory activity on angiotensinconverting enzyme(ACE).The cytotoxicity of Cur/GANPs was evaluated in vitro using different types of human cancer cells including breast cancer(MCF7,MDA-MB231),liver cancer(HepG2),and colon cancer(HT29)cells.The prepared particles displayed an elliptical shape with a size ranging between 20–260 nm and a potential difference of–15 mV.The Cur/GANPs exhibited significant antioxidant activity compared to free curcumin when using concentrations between 31.5 and 500μg/mL.The Cur/GANPs also had inhibited the growth of all cancer cell lines in a proportional trend with concentrations used.Hence,the encapsulation with gum Arabic has augmented the antioxidant and anti-neoplastic effects of Curcumin.Therefore,Cur/GANPs may have effective therapeutic properties in diseases attributed to oxidative stress like cancer and hypertension.
文摘Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venules is highly dependent on the interaction between the chemokines CCL19, CCL21, CXCL12, and CXCL13, and their receptors CCR7, CXCR4 and CXCR5. However, the molecular mechanism（s） of lymphocyte egress from secondary lymphoid tissues to lymph remained unclear. We have found a new class of immunomodulator, FTY720 by chemical modification of vegetative wasp-derived natural product, ISP-I （myriocin）. FTY720 has been shown to be highly effective in experimental allograft and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating activity in these models. The reduction of circulating lymphocytes by FTY720 is caused by sequestration of lymphocytes into secondary lymphoid tissues and thymus. FTY720 is rapidly converted to （S）-enantiomer of FTY720-phosphate [（S）-FTY720-P] by sphingosine kinase 2 in vivo. （S）-FTY720-P acting as a potent agonist of S1P receptor type 1 （S1P1）, induces long-term down-regulation of S1P1 on lymphocytes, and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is presumed that FTY720-induced lymphocyte sequestration is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus by its active metabolite （S）-FTY720-P. Throughout the analysis of the mechanism of action of FTY720, it is clarified that S1P/S1P1 interaction plays an important role for lymphocyte egress from secondary lymphoid tissues and thymus.
文摘FTY720, a sphingosine 1-phosphate receptor modulator, induces a marked decrease in the number of peripheral blood lymphocytes and exerts immunomodulating activity in various experimental allograft and autoimmune disease models. In this study, we evaluated the effect of FTY720 and its active metabolite, （S）-enantiomer of FTY720-phosphate [（S）-FTY720-P] on experimental autoimmune encephalomyelitis （EAE） in rats and mice. Prophylactic administration of FTY720 at 0.1 to 1 mg/kg almost completely prevented the development of EAE, and therapeutic treatment with FTY720 significantly inhibited the progression of EAE and EAE-associated histological change in the spinal cords of LEW rats induced by immunization with myelin basic protein. Consistent with rat EAE, the development of proteolipid protein-induced EAE in SJL/J mice was almost completely prevented and infiltration of CD4^＋ T cells into spinal cord was decreased by prophylactic treatment with FTY720 and （S）-FTY720-P. When FTY720 or （S）-FTY720-P was given after establishment of EAE in SJL/J mice, the relapse of EAE was markedly inhibited as compared with interferon-β, and the area of demyelination and the infiltration of CD4^＋ T cells were decreased in spinal cords of EAE mice. Similar therapeutic effect by FTY720 was obtained in myelin oligodendrocyte glycoprotein-induced EAE in C57BL/6 mice. These results indicate that FTY720 exhibits not only a prophylactic but also a therapeutic effect on EAE in rats and mice, and that the effect of FTY720 on EAE appears to be due to a reduction of the infiltration of myelin antigen-specific CD4^＋ T cells into the inflammation site. Cellular ＆ Molecular Immunology. 2005;2（6）：439-448.
