Ulcerative colitis (UC) has reactive oxygen species (ROS) and immunologic pathways implicated in its pathogenesis. The search for new therapeutic protocols in managing UC is tailored in suppressing or preventing these...Ulcerative colitis (UC) has reactive oxygen species (ROS) and immunologic pathways implicated in its pathogenesis. The search for new therapeutic protocols in managing UC is tailored in suppressing or preventing these pathways. The influence of trivalent chromium (Cr3+), an essential mineral on experimental colitis was investigated. Mice were grouped into 3;group 1 (control) received clean drinking water while groups 2 and 3 received 10 and 100 ppm Cr3+ respectively for 12 weeks through drinking water. After Cr3+ administration, 5 animals per group were sacrificed on day 0. Thereafter, experimental colitis was induced intra-rectally using acetic acid (4%, 0.3mL) and 5 mice per group were subsequently sacrificed on days 3, 7 and 14. Blood and colonic tissues were obtained and processed appropriately. Blood Cr3+ level, haematological variables, gross and microscopic colitis scores, colonic myeloperoxidase (MPO), Superoxide Dismutase (SOD) and malondialdehyde (MDA) levels were determined using standard methods. Colon cytokine mRNA genes were quantified using real-time PCR. There was a significant decrease in colon gross and histology scores on days 3 and 7 in chromium treated compared with control. The MPO and MDA in chromium groups reduced significantly compared with control while SOD activities increased significantly in Cr3+ groups compared with control. Total RNA increased in chromium groups compared with control on day 3 post-colitis. There was up-regulation of IL-10, down-regulation of TNF-α and IFN-λ in chromium administered groups compared with control. Chromium enhanced healing of colitis by suppression of ROS, inflammation and promotion of antioxidant activities.展开更多
Cancer immunotherapy has greatly advanced in recent years,and PD-1/PD-L1 blocking therapy has become a major pillar of immunotherapy.Successful clinical trials of PD-1/PD-L1 blocking therapies in cancer treatments hav...Cancer immunotherapy has greatly advanced in recent years,and PD-1/PD-L1 blocking therapy has become a major pillar of immunotherapy.Successful clinical trials of PD-1/PD-L1 blocking therapies in cancer treatments have benefited many patients,which promoted the Food and Drug Administration(FDA)approval of PD-1/PD-L1 blocking drugs.In this review,we provide a detailed introduction of five PD-1/PD-L1 blocking drugs,with indications and studies,as a valuable reference for doctors and medical investigators.Moreover,the characteristics of PD-1/PD-L1 blocking therapies,including their universality and sustainability,are discussed in this review.Furthermore,we also discuss and predict the possibility of PD-L1 as an indication marker of PD-1/PD-L1 blocking therapy for pan-cancer treatment,and the current status of combination therapies.展开更多
Cysteine-rich secretory protein-1 （CRISP-1） is a glycoprotein secreted by the epididymal epithelium. It is a member of a large family of proteins characterized by two conserved domains and a set of 16 conserved cyst...Cysteine-rich secretory protein-1 （CRISP-1） is a glycoprotein secreted by the epididymal epithelium. It is a member of a large family of proteins characterized by two conserved domains and a set of 16 conserved cysteine residues. In mammals, CRISP-1 inhibits sperm-egg fusion and can suppress sperm capacitation. The molecular mechanism of action of the mammalian CRISP proteins remains unknown, but certain non-mammalian CRISP proteins can block ion channels. In the rat, CRISP-1 comprises two forms referred to as Proteins D and E. Recent work in our laboratory demonstrates that the D form of CRISP-1 associates transiently with the sperm surface, whereas the E form binds tightly. When the spermatozoa are washed, the E form of CRISP-1 persists on the sperm surface after all D form has dissociated. Cross-linking studies demonstrate different protein-protein interaction patterns for D and E, although no binding partners for either protein have yet been identified. Mass spectrometric analyses revealed a potential post-translational modification on the E form that is not present on the D form. This is the only discernable difference between Proteins D and E, and presumably is responsible for the difference in behavior of these two forms of rat CRISP- 1. These studies demonstrate that the more abundant D form interacts with spermatozoa transiently, possibly with a specific receptor on the sperm surface, consistent with a capacitation-suppressing function during sperm transit and storage in the epididymis, and also confirm a tightly bound population of the E form that could act in the female reproductive tract. （Asian J Androl 2007 July; 9： 508-514）展开更多
AIM:To assess the effect of sitagliptin therapy on seasonal fluctuation of glycemic control in Japanese type 2 diabetic patients.METHODS:Participating patients(age:29-80 years) had been treated with conventional oral ...AIM:To assess the effect of sitagliptin therapy on seasonal fluctuation of glycemic control in Japanese type 2 diabetic patients.METHODS:Participating patients(age:29-80 years) had been treated with conventional oral antidiabetic agents and/or diet and exercise therapy for over 6 mo.From December 2009,35 patients were additionally prescribed oral sitagliptin starting from 50 mg once daily,while 19 patients taking-glucosidase inhibitors were switched to sitagliptin.Twenty-four patients who refused sitagliptin formed the control group.Changes of mean monthly hemoglobin A 1c(HbA 1c) during the "winter holiday season" were compared between groups using Student's t-test(2008-2009 vs 2009-2010).Statistical significance was accepted at P < 0.05.Multivariate analysis was performed to assess whether sitagliptin use was associated with deterioration or improvement of glycemic control.RESULTS:Both add-on sitagliptin and switching from-glucosidase inhibitors to sitagliptin prevented the seasonal deterioration of glycemic control and tended to improve HbA 1c.Multivariate analysis revealed that both adding and switching to sitagliptin were negatively correlated with deterioration of glycemic control.In 44 patients who continued sitagliptin therapy for another year,elevation of HbA 1c was suppressed without adverse effects.CONCLUSION:Sitagliptin is a suitable oral agent for preventing deterioration of glycemic control during the winter holiday season.展开更多
We present the case of a 74 year old woman suffering from severe mitral valve incompetence and rapid atrial fibrillation. After an appropriate vitamin K antagonist(VKA) therapy, the patient underwent mitral valve repl...We present the case of a 74 year old woman suffering from severe mitral valve incompetence and rapid atrial fibrillation. After an appropriate vitamin K antagonist(VKA) therapy, the patient underwent mitral valve replacement by bioprosthesis. Then, the patient was rehospitalized for jaundice. Suspecting hepatotoxicity, VKA was discontinued and fondaparinux was started. During this treatment, the patient developed a symptomatic atrial thrombus. After exclusion of a hepatic disease, VKA was re-established with hemodynamic and liver enzymes normalization and atrial thrombus resolution. Caution has to be used when considering fondaparinux as an alternative strategy to VKA in patients with multiple thrombotic risk factors.展开更多
Objective:To identify whether Canova medication changes TNF-α and IL-10 serum levels in mice infected with Trypanosoma cruzi Y strain.Methods:Animals were divided into five groups:non-treated infected animals(I); ben...Objective:To identify whether Canova medication changes TNF-α and IL-10 serum levels in mice infected with Trypanosoma cruzi Y strain.Methods:Animals were divided into five groups:non-treated infected animals(I); benznidazole-treated infected animals(Bz; 100 mg/kg body weight,single daily dose by gavage); Canova medication(CM) treated infected animals(CM;0.2 mL/animal,single daily dose by gavage); benznidazole- and Canova medication–treated infected animals with the above-mentioned dose(Bz+CM);and non-infected animals(C).TNF-α and IL-10 levels were determined in serum aliquots after 4,7,10,13,and 29 days of infection.An ELISA technique was employed with R&D System Inc.antibody pairs.Results:A high increase in TNF-α and IL-10 levels occurred in the infected and CM-treated groups within the treatment employed on the 10 th day after infection,coupled with a IL-10 decrease on the 13 th day after infection when compared with the other experimental groups.Conclusions:CM may change the balance between plasma cytokine levels(TNF-α and IL-10) in mice infected with Y strain T.cruzi,with important consequences leading towards a more severe infection.展开更多
Runt-related transcription factor-1(RUNX1),also known as the core-binding factor alpha 2 subunit,is closely related to human leukemia.The functions of RUNX1 in modulating cell proliferation,differentiation,and surviva...Runt-related transcription factor-1(RUNX1),also known as the core-binding factor alpha 2 subunit,is closely related to human leukemia.The functions of RUNX1 in modulating cell proliferation,differentiation,and survival in multiple systems have been gradually discovered with the emergence of transgenic mice.RUNX1 is a powerful transcription factor implicated in diverse signaling pathways and cellular mechanisms that participate in lung development and pulmonary diseases.RUNX1 has recently been identified as a target regulator of fibrotic remodeling diseases,particularly in the kidney.However,the role of RUNX1 in pulmonary fibrosis is unclear.Pulmonary fibrosis is characterized by obscure nosogenesis,limited therapy,and poor prognosis.Moreover,the population of patients with pulmonary fibrosis is gradually increasing.Thus,there is an unmet need for therapeutic targets.In this review,we retrospectively discuss the alteration in RUNX1 mRNA expression in the RNA sequencing data of human fibrotic lungs and the protein levels in mouse pulmonary fibrosis.Subsequently,we focused on the interaction between RUNX1 and several signaling pathways involved in pulmonary fibrosis.Finally,this review highlights the therapeutic potential of RUNX1 as a target for slowing the progression of fibrotic lung disease.展开更多
Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis(OA), and osteomodulin(OMD), a proteoglycan involved in extracellular matrix mineralization, is associated with the scleroti...Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis(OA), and osteomodulin(OMD), a proteoglycan involved in extracellular matrix mineralization, is associated with the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used Omd knockout and overexpressing male mice and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated with bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis, thus controlling the balance of bone remodeling. In conclusion, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis by acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.展开更多
SUMOylation is recently found to function as a targeting signal for the degradation of substrates through the ubiquitin-proteasome system. RNF4 is the most studied human SUMO-targeted ubiquitin E3 ligase. However, the...SUMOylation is recently found to function as a targeting signal for the degradation of substrates through the ubiquitin-proteasome system. RNF4 is the most studied human SUMO-targeted ubiquitin E3 ligase. However, the relationship between SUMO proteases, SENPs, and RNF4 remains obscure. There are limited examples of the SENP regulation of SUMO2/3-targeted proteolysis mediated by RNF4. The present study investigated the role of SENP3 in the global protein turnover related to SUMO2/3-targeted ubiquitination and focused in particular on the SENP3 regulation of the stability of Spl. Our data demonstrated that SENP3 impaired the global ubiquitination profile and promoted the accumulation of many proteins. Spl, a cancer-associated transcription factor, was among these proteins. SENP3 increased the level of Spl protein via antagonizing the SUMO2/3-targeted ubiquitination and the consequent proteasome-dependent degradation that was mediated by RNF4. De-conjugation of SUMO2/3 by SENP3 attenuated the interaction of Spl with RNF4. In gastric cancer cell lines and specimens derived from patients and nude mice, the level of Spl was generally increased in parallel to the level of SENP3. These results provided a new explanation for the enrichment of the Spl protein in various cancers, and revealed a regulation of SUMO2/3 conjugated proteins whose levels may be tightly con- trolled by SENP3 and RNF4.展开更多
文摘Ulcerative colitis (UC) has reactive oxygen species (ROS) and immunologic pathways implicated in its pathogenesis. The search for new therapeutic protocols in managing UC is tailored in suppressing or preventing these pathways. The influence of trivalent chromium (Cr3+), an essential mineral on experimental colitis was investigated. Mice were grouped into 3;group 1 (control) received clean drinking water while groups 2 and 3 received 10 and 100 ppm Cr3+ respectively for 12 weeks through drinking water. After Cr3+ administration, 5 animals per group were sacrificed on day 0. Thereafter, experimental colitis was induced intra-rectally using acetic acid (4%, 0.3mL) and 5 mice per group were subsequently sacrificed on days 3, 7 and 14. Blood and colonic tissues were obtained and processed appropriately. Blood Cr3+ level, haematological variables, gross and microscopic colitis scores, colonic myeloperoxidase (MPO), Superoxide Dismutase (SOD) and malondialdehyde (MDA) levels were determined using standard methods. Colon cytokine mRNA genes were quantified using real-time PCR. There was a significant decrease in colon gross and histology scores on days 3 and 7 in chromium treated compared with control. The MPO and MDA in chromium groups reduced significantly compared with control while SOD activities increased significantly in Cr3+ groups compared with control. Total RNA increased in chromium groups compared with control on day 3 post-colitis. There was up-regulation of IL-10, down-regulation of TNF-α and IFN-λ in chromium administered groups compared with control. Chromium enhanced healing of colitis by suppression of ROS, inflammation and promotion of antioxidant activities.
文摘Cancer immunotherapy has greatly advanced in recent years,and PD-1/PD-L1 blocking therapy has become a major pillar of immunotherapy.Successful clinical trials of PD-1/PD-L1 blocking therapies in cancer treatments have benefited many patients,which promoted the Food and Drug Administration(FDA)approval of PD-1/PD-L1 blocking drugs.In this review,we provide a detailed introduction of five PD-1/PD-L1 blocking drugs,with indications and studies,as a valuable reference for doctors and medical investigators.Moreover,the characteristics of PD-1/PD-L1 blocking therapies,including their universality and sustainability,are discussed in this review.Furthermore,we also discuss and predict the possibility of PD-L1 as an indication marker of PD-1/PD-L1 blocking therapy for pan-cancer treatment,and the current status of combination therapies.
文摘Cysteine-rich secretory protein-1 （CRISP-1） is a glycoprotein secreted by the epididymal epithelium. It is a member of a large family of proteins characterized by two conserved domains and a set of 16 conserved cysteine residues. In mammals, CRISP-1 inhibits sperm-egg fusion and can suppress sperm capacitation. The molecular mechanism of action of the mammalian CRISP proteins remains unknown, but certain non-mammalian CRISP proteins can block ion channels. In the rat, CRISP-1 comprises two forms referred to as Proteins D and E. Recent work in our laboratory demonstrates that the D form of CRISP-1 associates transiently with the sperm surface, whereas the E form binds tightly. When the spermatozoa are washed, the E form of CRISP-1 persists on the sperm surface after all D form has dissociated. Cross-linking studies demonstrate different protein-protein interaction patterns for D and E, although no binding partners for either protein have yet been identified. Mass spectrometric analyses revealed a potential post-translational modification on the E form that is not present on the D form. This is the only discernable difference between Proteins D and E, and presumably is responsible for the difference in behavior of these two forms of rat CRISP- 1. These studies demonstrate that the more abundant D form interacts with spermatozoa transiently, possibly with a specific receptor on the sperm surface, consistent with a capacitation-suppressing function during sperm transit and storage in the epididymis, and also confirm a tightly bound population of the E form that could act in the female reproductive tract. （Asian J Androl 2007 July; 9： 508-514）
文摘AIM:To assess the effect of sitagliptin therapy on seasonal fluctuation of glycemic control in Japanese type 2 diabetic patients.METHODS:Participating patients(age:29-80 years) had been treated with conventional oral antidiabetic agents and/or diet and exercise therapy for over 6 mo.From December 2009,35 patients were additionally prescribed oral sitagliptin starting from 50 mg once daily,while 19 patients taking-glucosidase inhibitors were switched to sitagliptin.Twenty-four patients who refused sitagliptin formed the control group.Changes of mean monthly hemoglobin A 1c(HbA 1c) during the "winter holiday season" were compared between groups using Student's t-test(2008-2009 vs 2009-2010).Statistical significance was accepted at P < 0.05.Multivariate analysis was performed to assess whether sitagliptin use was associated with deterioration or improvement of glycemic control.RESULTS:Both add-on sitagliptin and switching from-glucosidase inhibitors to sitagliptin prevented the seasonal deterioration of glycemic control and tended to improve HbA 1c.Multivariate analysis revealed that both adding and switching to sitagliptin were negatively correlated with deterioration of glycemic control.In 44 patients who continued sitagliptin therapy for another year,elevation of HbA 1c was suppressed without adverse effects.CONCLUSION:Sitagliptin is a suitable oral agent for preventing deterioration of glycemic control during the winter holiday season.
基金Supported by Swiss National Science Foundation,No.310030_118245 and No.32003B_134963/1
文摘We present the case of a 74 year old woman suffering from severe mitral valve incompetence and rapid atrial fibrillation. After an appropriate vitamin K antagonist(VKA) therapy, the patient underwent mitral valve replacement by bioprosthesis. Then, the patient was rehospitalized for jaundice. Suspecting hepatotoxicity, VKA was discontinued and fondaparinux was started. During this treatment, the patient developed a symptomatic atrial thrombus. After exclusion of a hepatic disease, VKA was re-established with hemodynamic and liver enzymes normalization and atrial thrombus resolution. Caution has to be used when considering fondaparinux as an alternative strategy to VKA in patients with multiple thrombotic risk factors.
文摘Objective:To identify whether Canova medication changes TNF-α and IL-10 serum levels in mice infected with Trypanosoma cruzi Y strain.Methods:Animals were divided into five groups:non-treated infected animals(I); benznidazole-treated infected animals(Bz; 100 mg/kg body weight,single daily dose by gavage); Canova medication(CM) treated infected animals(CM;0.2 mL/animal,single daily dose by gavage); benznidazole- and Canova medication–treated infected animals with the above-mentioned dose(Bz+CM);and non-infected animals(C).TNF-α and IL-10 levels were determined in serum aliquots after 4,7,10,13,and 29 days of infection.An ELISA technique was employed with R&D System Inc.antibody pairs.Results:A high increase in TNF-α and IL-10 levels occurred in the infected and CM-treated groups within the treatment employed on the 10 th day after infection,coupled with a IL-10 decrease on the 13 th day after infection when compared with the other experimental groups.Conclusions:CM may change the balance between plasma cytokine levels(TNF-α and IL-10) in mice infected with Y strain T.cruzi,with important consequences leading towards a more severe infection.
基金funded by 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,Grant No.ZYJC18021Post-Doctoral Research Project,West China Hospital,Grant No.2021HXBH074+1 种基金the National Natural Science Foundation of China,Grant No.82100075Sichuan Science and Technology Program,Grant Nos.2020YFH0073,2021YFG0329。
文摘Runt-related transcription factor-1(RUNX1),also known as the core-binding factor alpha 2 subunit,is closely related to human leukemia.The functions of RUNX1 in modulating cell proliferation,differentiation,and survival in multiple systems have been gradually discovered with the emergence of transgenic mice.RUNX1 is a powerful transcription factor implicated in diverse signaling pathways and cellular mechanisms that participate in lung development and pulmonary diseases.RUNX1 has recently been identified as a target regulator of fibrotic remodeling diseases,particularly in the kidney.However,the role of RUNX1 in pulmonary fibrosis is unclear.Pulmonary fibrosis is characterized by obscure nosogenesis,limited therapy,and poor prognosis.Moreover,the population of patients with pulmonary fibrosis is gradually increasing.Thus,there is an unmet need for therapeutic targets.In this review,we retrospectively discuss the alteration in RUNX1 mRNA expression in the RNA sequencing data of human fibrotic lungs and the protein levels in mouse pulmonary fibrosis.Subsequently,we focused on the interaction between RUNX1 and several signaling pathways involved in pulmonary fibrosis.Finally,this review highlights the therapeutic potential of RUNX1 as a target for slowing the progression of fibrotic lung disease.
基金funded by the F.R.S.-FNRS for the “EOS: The Excellence of Science-Join-t-against-Osteoarthritis”, grant number 30480119by a research grant from the Osteoarthritis Foundation and by the University of Liege (Fonds Léon Fredericq and Fonds Speciaux à la Recherche)funded by Versus Arthritis senior fellowship 21937。
文摘Abnormal subchondral bone remodeling leading to sclerosis is a main feature of osteoarthritis(OA), and osteomodulin(OMD), a proteoglycan involved in extracellular matrix mineralization, is associated with the sclerotic phenotype. However, the functions of OMD remain poorly understood, specifically in vivo. We used Omd knockout and overexpressing male mice and mutant zebrafish to study its roles in bone and cartilage metabolism and in the development of OA. The expression of Omd is deeply correlated with bone and cartilage microarchitectures affecting the bone volume and the onset of subchondral bone sclerosis and spontaneous cartilage lesions. Mechanistically, OMD binds to RANKL and inhibits osteoclastogenesis, thus controlling the balance of bone remodeling. In conclusion, OMD is a key factor in subchondral bone sclerosis associated with OA. It participates in bone and cartilage homeostasis by acting on the regulation of osteoclastogenesis. Targeting OMD may be a promising new and personalized approach for OA.
文摘SUMOylation is recently found to function as a targeting signal for the degradation of substrates through the ubiquitin-proteasome system. RNF4 is the most studied human SUMO-targeted ubiquitin E3 ligase. However, the relationship between SUMO proteases, SENPs, and RNF4 remains obscure. There are limited examples of the SENP regulation of SUMO2/3-targeted proteolysis mediated by RNF4. The present study investigated the role of SENP3 in the global protein turnover related to SUMO2/3-targeted ubiquitination and focused in particular on the SENP3 regulation of the stability of Spl. Our data demonstrated that SENP3 impaired the global ubiquitination profile and promoted the accumulation of many proteins. Spl, a cancer-associated transcription factor, was among these proteins. SENP3 increased the level of Spl protein via antagonizing the SUMO2/3-targeted ubiquitination and the consequent proteasome-dependent degradation that was mediated by RNF4. De-conjugation of SUMO2/3 by SENP3 attenuated the interaction of Spl with RNF4. In gastric cancer cell lines and specimens derived from patients and nude mice, the level of Spl was generally increased in parallel to the level of SENP3. These results provided a new explanation for the enrichment of the Spl protein in various cancers, and revealed a regulation of SUMO2/3 conjugated proteins whose levels may be tightly con- trolled by SENP3 and RNF4.
基金supported by Fudan University Special Funds for COVID-19the National Natural Science Foundation of China(32130063)+4 种基金the National Key Research and Development Program of China(2021YFE0201900 and 2021YFC2301700)China Postdoctoral Science Foundation(2020T130017ZX)the Starry Night Science Fund at Shanghai Institute for Advanced Study of Zhejiang University(SN-ZJU-SIAS-009)the STS Regional Key Project(KFJSTS-QYZD-2021-12-001)from Chinese Academy of SciencesHubei Science and Technology Major Project(2021ACB0004)。
