ABSTRACT
Based on memorial to emperors, letters, official documents and telegrams between Yuan Shikai and his colleagues, this essay reviews Yuan's practice on governance of army medical service and public health.During his army garrisoning in Korea, Yuan Shikai hired physicians to take medical care for wounded soldiers, and conducted port quarantine. In Tianjin, Yuan Shikai set physical examination standards, operated army medical schools. During the Republican era, as the President of China, Yuan Shikai issued laws on prevention of infectious diseases, prohibited opium-smoking, selected excellent Chinese physicians as technocrats. He improved the management of Chinese public health.
Subject(s)
Military Personnel , Public Health , Sanitation , China , Humans , Male , Schools, MedicalABSTRACT
Inhibition of protein neddylation, particularly cullin neddylation, has emerged as a promising anticancer strategy, as evidenced by the antitumor activity in preclinical studies of the Nedd8-activating enzyme (NAE) inhibitor MLN4924. This small molecule can block the protein neddylation pathway and is now in clinical trials. We and others have previously shown that the antitumor activity of MLN4924 is mediated by its ability to induce apoptosis, autophagy and senescence in a cell context-dependent manner. However, whether MLN4924 has any effect on tumor angiogenesis remains unexplored. Here we report that MLN4924 inhibits angiogenesis in various in vitro and in vivo models, leading to the suppression of tumor growth and metastasis in highly malignant pancreatic cancer, indicating that blockage of angiogenesis is yet another mechanism contributing to its antitumor activity. At the molecular level, MLN4924 inhibits Cullin-RING E3 ligases (CRLs) by cullin deneddylation, causing accumulation of RhoA at an early stage to impair angiogenic activity of vascular endothelial cells and subsequently DNA damage response, cell cycle arrest and apoptosis due to accumulation of other tumor-suppressive substrates of CRLs. Furthermore, we showed that inactivation of CRLs, via small interfering RNA (siRNA) silencing of its essential subunit ROC1/RBX1, recapitulates the antiangiogenic effect of MLN4924. Taken together, our study demonstrates a previously unrecognized role of neddylation in the regulation of tumor angiogenesis using both pharmaceutical and genetic approaches, and provides proof of concept evidence for future development of neddylation inhibitors (such as MLN4924) as a novel class of antiangiogenic agents.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Chorioallantoic Membrane/blood supply , Cyclopentanes/pharmacology , Endothelial Cells/drug effects , Neovascularization, Pathologic , Neovascularization, Physiologic/drug effects , Pancreatic Neoplasms/blood supply , Pancreatic Neoplasms/drug therapy , Pyrimidines/pharmacology , Ubiquitin-Activating Enzymes/antagonists & inhibitors , Animals , Apoptosis/drug effects , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Chick Embryo , Cullin Proteins/metabolism , DNA Damage , Dose-Response Relationship, Drug , Endothelial Cells/enzymology , Endothelial Cells/pathology , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/enzymology , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Nude , NEDD8 Protein , Pancreatic Neoplasms/pathology , Protein Processing, Post-Translational , RNA Interference , Rats , Rats, Sprague-Dawley , Time Factors , Tissue Culture Techniques , Transfection , Tumor Burden/drug effects , Ubiquitin-Activating Enzymes/metabolism , Ubiquitins/metabolism , Xenograft Model Antitumor Assays , rhoA GTP-Binding Protein/genetics , rhoA GTP-Binding Protein/metabolismABSTRACT
A series of 3-(1H-benzimidazole-2)-2-propenoic acid derivatives were prepared and tested for schistosomicidal activity. The acid was proved to be a cis-isomer. Preliminary pharmacological tests showed that these compounds were in effective.
Subject(s)
Benzimidazoles/chemical synthesis , Schistosomicides/chemical synthesis , Animals , Benzimidazoles/chemistry , Benzimidazoles/therapeutic use , Mice , Molecular Structure , Schistosomiasis japonica/prevention & control , Schistosomicides/therapeutic use , StereoisomerismABSTRACT
A series of trihydroxynaphthaldehydes, polyhydroxybiphenol-asdehydes, polyhydroxybinaphthyl aldehydes and some gossypol derivatives were synthesized for antifertility experimental studies.
