ABSTRACT
In this study, two series of novel carbon monoxide-releasing molecules (CO-RMs) containing Co were designed and synthesized. The synthesized complexes were characterized by IR, ESI-MS, 1H NMR and 13C NMR spectroscopies. The antitumor activity of all complexes on HepG2 cells, Hela cells and MDA-MB-231 cells were assayed by MTT. IC50 values of complexes 1-13 were 4.7-548.6 µM. Among these complexes, complex 1 was presented with a high selectivity to HepG2 cells (IC50 = 4.7 ± 0.76 µM). Compared with iCORM (inactive CORM), CORM (complex 1) showed a remarkable activity against tumor cells owing to co-effect of CO and the ligand of COX-2 inhibitor. In addition, complex 1 increased ROS in mitochondria and caused a decrease of dose-dependent mitochondrial membrane potential against HepG2 cells. Complex 1 down-regulated the expression of COX-2 protein in western blot analysis. The molecular docking study suggested that the complex 1 formed a hydrogen bond with amino acid R120 in the active site of the Human cyclooxygenase-2 (COX-2). Therefore, the complex 1 could induce apoptosis of HepG2 cells through targeting COX-2 and mitochondria pathways, and it maybe a potential therapeutic agent for cancer.
Subject(s)
Antineoplastic Agents/chemical synthesis , Carbon Monoxide/metabolism , Coordination Complexes/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Binding Sites , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/metabolism , Coordination Complexes/pharmacology , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Design , Drug Screening Assays, Antitumor , Humans , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Molecular Docking Simulation , Protein Structure, Tertiary , Reactive Oxygen Species/metabolismABSTRACT
OBJECTIVE: To observe wet cupping therapy (WCT) on local blood perfusion and analgesic effects in patients with nerve-root type cervical spondylosis (NT-CS). METHODS: Fifty-seven NT-CS patients were randomly divided into WCT group and Jiaji acupoint-acupuncture (JA) group according a random number table. WCT group (30 cases) was treated with WCT for 10 min, and JA group (27 cases) was treated with acupuncture for 10 min. The treatment efficacies were evaluated with a Visual Analogue Scale (VAS). Blood perfusion at Dazhui (GV 14) and Jianjing (GB 21) acupoints (affected side) was observed with a laser speckle flowmetry, and its variations before and after treatment in both groups were compared as well. RESULTS: In both groups, the VAS scores significantly decreased after the intervention (P<0.01), while the blood perfusion at the two acupoints significantly increased after intervention (P<0.05); however, the increasement magnitude caused by WCT was obvious compared with JA (P<0.05). CONCLUSIONS: WCT could improve analgesic effects in patients with NT-CS, which might be related to increasing local blood perfusion of acupunct points.
Subject(s)
Acupuncture Therapy/methods , Analgesia , Spondylosis/therapy , Adult , Female , Humans , Male , Regional Blood Flow , Spondylosis/physiopathology , Visual Analog ScaleABSTRACT
The use of exogenous carbon monoxide releasing molecules (CORMs) provides promise for clinical application; however, the hazard potential of CORMs in vivo remains poorly understood. The developmental toxicity of CORM-3 was investigated by exposure to concentrations ranging from 6.25 to 400 µmol/L during 4-144 h post fertilization. Toxicity endpoints of mortality, spontaneous movement, heart rate, hatching rate, malformation, body length, and larval behavior were measured. CORM-3 disrupted the progression of zebrafish larval development at concentrations exceeding 50 µmol/L, resulting in embryonic developmental toxicity.
Subject(s)
Cardiotonic Agents/toxicity , Embryonic Development/drug effects , Organometallic Compounds/toxicity , Zebrafish/embryology , Animals , Carbon Monoxide/pharmacology , Dose-Response Relationship, Drug , Embryo, Nonmammalian/drug effects , Zebrafish/metabolismABSTRACT
Carbon monoxide has been proved to be an important signal molecule in body. Transition metal carbonyl compounds are solidified form of carbon monoxide. Numerous studies have shown that Ruthenium carbonyl carbon monoxide releasing molecules have a strong pharmacological activity. In this paper, five Ruthenium (II) carbonyl CORMs 1-5 were synthesized and their toxicology, tissue distribution and interaction with blood endogenous substances were investigated. The results showed CORMs' IC50 to fibroblasts are ranged from 212.9 to 2089.2 micromol x L(-1). Their oral LD50 to mouse is between 800 to 1600 mg x kg(-1). After repeated administration, CORMs 1 and CORMs 5 haven't shown an obvious influence to rats' liver and kidney function, but caused the injury to liver and kidney cells. The in vivo distribution result revealed the majority of CORMs were distributed in blood, liver and kidney, only a small part of CORMs distributed in lung, heart and spleen. They could scarcely cross the blood-brain barrier and distribute to brain. The non-CO ligands in structure have an obvious relevance to their in vivo absorption and distribution. Interestingly, CORMs could enhance the fluorescence of bovine serum albumin, and this enhancement was in direct proportion with the concentration of CORMs. Under different conditions, interaction of CORMs with glutathione got different type of products, one is Ruthenium (II) tricarbonyl complexes, and Ruthenium (II) dicarbonyl complexes.
