Osteoarthritis(OA)is the most prevalent joint disease causing major disability and medical expenditures.Synovitis is a central feature of OA and is primarily driven by macrophages.Synovial macrophages not only drive i...Osteoarthritis(OA)is the most prevalent joint disease causing major disability and medical expenditures.Synovitis is a central feature of OA and is primarily driven by macrophages.Synovial macrophages not only drive inflammation but also its resolution,through a coordinated,simultaneous expression of pro-and anti-inflammatory mechanisms that are essential to counteract damage and recover homeostasis.Current OA therapies are largely based on anti-inflammatory principles and therefore block pro-inflammatory mechanisms such as prostaglandin E2 and Nuclear factor-kappa B signaling pathways.However,such mechanisms are also innately required for mounting a pro-resolving response,and their blockage often results in chronic low-grade inflammation.Following minor injury,macrophages shield the damaged area and drive tissue repair.If the damage is more extensive,macrophages incite inflammation recruiting more macrophages from the bone marrow to maximize tissue repair and ultimately resolve inflammation.However,sustained damage and inflammation often overwhelms pro-resolving mechanisms of synovial macrophages leading to the chronic inflammation and related tissue degeneration observed in OA.Recently,experimental and clinical studies have shown that joint injection with autologous bone marrow mononuclear cells replenishes inflamed joints with macrophage and hematopoietic progenitors,enhancing mechanisms of inflammation resolution,providing remarkable and long-lasting effects.Besides creating an ideal environment for resolution with high concentrations of interleukin-10 and anabolic growth factors,macrophage progenitors also have a direct role in tissue repair.Macrophages constitute a large part of the early granulation tissue,and further transdifferentiate from myeloid into a mesenchymal phenotype.These cells,characterized as fibrocytes,are essential for repairing osteochondral defects.Ongoing“omics”studies focused on identifying key drivers of macrophagemediated resolution of joint inflammation and those required for efficient osteochondral repair,have the potential to uncover ways for developing engineered macrophages or off-the-shelf pro-resolving therapies that can benefit patients suffering from many types of arthropaties,not only OA.展开更多
Background: Toxoplasmosis is a common cause of foodborne, gastrointestinal and congenital syndrome with particularly severe or unknown health consequences. There is no safe and effective preventive or therapeutic moda...Background: Toxoplasmosis is a common cause of foodborne, gastrointestinal and congenital syndrome with particularly severe or unknown health consequences. There is no safe and effective preventive or therapeutic modality against congenital toxoplasmosis or to eliminate the persistent chronic infection. Hypothesis: Diclazuril to be safe in pregnancy and effective against gastrointestinal toxoplasmosis. Methods: CD1 programmed pregnant mice were divided into groups and administered a diet containing diclazuril, or sham control. Treatments were initiated on Day 5 of pregnancy and continued until Day 16 when dams were euthanatized. On Day 8 of pregnancy dams were infected intraperitoneally with escalating doses of tachyzoites (0, 100, 300, 600) from Type II strain. Dams were monitored daily for distress, pain, and abortion and samples collected at the end of the experiments. Results: Infected dams developed moderate to severe Toxoplasma related complications in tachyzoites dose dependent manner. Animals became anemic and showed hydrothorax, and ascities. Diclazuril effectively protected dams from ascities and anemia (p < 0.05). Infected dams showed splenomegaly, with massive infiltration of epithelioid cells compared with the protective effect of diclazuril in treated animals. Infected dams exhibited severe hepatitis (score 0 to 4 scale = 3.5 ± 0.01) with influx of inflammatory and plasma cells, dysplastic hepatocytes, multinucleated giant cell transformation and hepatic cells necrosis. Diclazuril treatment significantly protected dams from hepatitis, also in tachyzoites dose (100, 300, 600) dependent manner (respectively infected-treated versus infected controls, p < 0.001, p < 0.01 and p with infiltration of lymphocytes, and macrophages and microabscess formations in the cryptic structures, with significant improvement in diclazuril treated animals. Additionally, the number of fetuses, fetal length and fetal weight were preserved in diclazuril treated dams. Conclusions: This is the first report describing of diclazuril safety in pregnancy as well as efficacy against mild to moderate hepato-gastrointestinal syndrome in dams and fetal toxoplasmosis (Special issue, “Treatment of Liver Diseases”).展开更多
Leptospirosis is an infectious bacterial disease caused by Leptospira species. In this study, we cloned and se- quenced the gene encoding the immunodominant protein GroEL from L. interrogans serovar Autumnalis strain ...Leptospirosis is an infectious bacterial disease caused by Leptospira species. In this study, we cloned and se- quenced the gene encoding the immunodominant protein GroEL from L. interrogans serovar Autumnalis strain N2, which was isolated from the urine of a patient during an outbreak of leptospirosis in Chennai, India. This groEL gene encodes a protein of 60 kDa with a high degree of homology （99% similarity） to those of other leptospiral serovars. Recombinant GroEL was overexpressed in Escherichia coli. lmmunoblot analysis indi- cated that the sera from confirmed leptospirosis patients showed strong reactivity with the recombinant GroEL while no reactivity was observed with the sera from seronegative control patient. In addition, the 3D structure of GroEL was constructed using chaperonin complex cpn60 from Thermus thermophilus as template and vali- dated. The results indicated a Z-score of -8.35, which is in good agreement with the expected value for a pro- tein. The superposition of the Ca traces of cpn60 structure and predicted structure of leptospiral GroEL indicates good agreement of secondary structure elements with an RMSD value of 1.5A. Further study is necessary to evaluate GroEL for serological diagnosis of leptospirosis and for its potential as a vaccine component.展开更多
文摘Osteoarthritis(OA)is the most prevalent joint disease causing major disability and medical expenditures.Synovitis is a central feature of OA and is primarily driven by macrophages.Synovial macrophages not only drive inflammation but also its resolution,through a coordinated,simultaneous expression of pro-and anti-inflammatory mechanisms that are essential to counteract damage and recover homeostasis.Current OA therapies are largely based on anti-inflammatory principles and therefore block pro-inflammatory mechanisms such as prostaglandin E2 and Nuclear factor-kappa B signaling pathways.However,such mechanisms are also innately required for mounting a pro-resolving response,and their blockage often results in chronic low-grade inflammation.Following minor injury,macrophages shield the damaged area and drive tissue repair.If the damage is more extensive,macrophages incite inflammation recruiting more macrophages from the bone marrow to maximize tissue repair and ultimately resolve inflammation.However,sustained damage and inflammation often overwhelms pro-resolving mechanisms of synovial macrophages leading to the chronic inflammation and related tissue degeneration observed in OA.Recently,experimental and clinical studies have shown that joint injection with autologous bone marrow mononuclear cells replenishes inflamed joints with macrophage and hematopoietic progenitors,enhancing mechanisms of inflammation resolution,providing remarkable and long-lasting effects.Besides creating an ideal environment for resolution with high concentrations of interleukin-10 and anabolic growth factors,macrophage progenitors also have a direct role in tissue repair.Macrophages constitute a large part of the early granulation tissue,and further transdifferentiate from myeloid into a mesenchymal phenotype.These cells,characterized as fibrocytes,are essential for repairing osteochondral defects.Ongoing“omics”studies focused on identifying key drivers of macrophagemediated resolution of joint inflammation and those required for efficient osteochondral repair,have the potential to uncover ways for developing engineered macrophages or off-the-shelf pro-resolving therapies that can benefit patients suffering from many types of arthropaties,not only OA.
文摘Background: Toxoplasmosis is a common cause of foodborne, gastrointestinal and congenital syndrome with particularly severe or unknown health consequences. There is no safe and effective preventive or therapeutic modality against congenital toxoplasmosis or to eliminate the persistent chronic infection. Hypothesis: Diclazuril to be safe in pregnancy and effective against gastrointestinal toxoplasmosis. Methods: CD1 programmed pregnant mice were divided into groups and administered a diet containing diclazuril, or sham control. Treatments were initiated on Day 5 of pregnancy and continued until Day 16 when dams were euthanatized. On Day 8 of pregnancy dams were infected intraperitoneally with escalating doses of tachyzoites (0, 100, 300, 600) from Type II strain. Dams were monitored daily for distress, pain, and abortion and samples collected at the end of the experiments. Results: Infected dams developed moderate to severe Toxoplasma related complications in tachyzoites dose dependent manner. Animals became anemic and showed hydrothorax, and ascities. Diclazuril effectively protected dams from ascities and anemia (p < 0.05). Infected dams showed splenomegaly, with massive infiltration of epithelioid cells compared with the protective effect of diclazuril in treated animals. Infected dams exhibited severe hepatitis (score 0 to 4 scale = 3.5 ± 0.01) with influx of inflammatory and plasma cells, dysplastic hepatocytes, multinucleated giant cell transformation and hepatic cells necrosis. Diclazuril treatment significantly protected dams from hepatitis, also in tachyzoites dose (100, 300, 600) dependent manner (respectively infected-treated versus infected controls, p < 0.001, p < 0.01 and p with infiltration of lymphocytes, and macrophages and microabscess formations in the cryptic structures, with significant improvement in diclazuril treated animals. Additionally, the number of fetuses, fetal length and fetal weight were preserved in diclazuril treated dams. Conclusions: This is the first report describing of diclazuril safety in pregnancy as well as efficacy against mild to moderate hepato-gastrointestinal syndrome in dams and fetal toxoplasmosis (Special issue, “Treatment of Liver Diseases”).
文摘Leptospirosis is an infectious bacterial disease caused by Leptospira species. In this study, we cloned and se- quenced the gene encoding the immunodominant protein GroEL from L. interrogans serovar Autumnalis strain N2, which was isolated from the urine of a patient during an outbreak of leptospirosis in Chennai, India. This groEL gene encodes a protein of 60 kDa with a high degree of homology （99% similarity） to those of other leptospiral serovars. Recombinant GroEL was overexpressed in Escherichia coli. lmmunoblot analysis indi- cated that the sera from confirmed leptospirosis patients showed strong reactivity with the recombinant GroEL while no reactivity was observed with the sera from seronegative control patient. In addition, the 3D structure of GroEL was constructed using chaperonin complex cpn60 from Thermus thermophilus as template and vali- dated. The results indicated a Z-score of -8.35, which is in good agreement with the expected value for a pro- tein. The superposition of the Ca traces of cpn60 structure and predicted structure of leptospiral GroEL indicates good agreement of secondary structure elements with an RMSD value of 1.5A. Further study is necessary to evaluate GroEL for serological diagnosis of leptospirosis and for its potential as a vaccine component.
