Myocardial dysfunction is an important manifestation of sepsis. Previous studies suggest that melatonin is protective against sepsis. In addition, activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway has been reported to be beneficial in sepsis. However, the role of PI3K/Akt signaling in the protective effect of melatonin against sepsis-induced myocardial dysfunction remains unclear. Here, LY294002, a PI3K inhibitor, was used to investigate the role of PI3K/Akt signaling in mediating the effects of melatonin on sepsis-induced myocardial injury. Cecal ligation and puncture (CLP) surgery was used to establish a rat model of sepsis. Melatonin was administrated to rats intraperitoneally (30 mg/kg). The survival rate, measures of myocardial injury and cardiac performance, serum lactate dehydrogenase level, inflammatory cytokine levels, oxidative stress level, and the extent of myocardial apoptosis were assessed. The results suggest that melatonin administration after CLP surgery improved survival rates and cardiac function, attenuated myocardial injury and apoptosis, and decreased the serum lactate dehydrogenase level. Melatonin decreased the production of the inflammatory cytokines TNF-α, IL-1β, and HMGB1, increased anti-oxidant enzyme activity, and decreased the expression of markers of oxidative damage. Levels of phosphorylated Akt (p-Akt), unphosphorylated Akt (Akt), Bcl-2, and Bax were measured by Western blot. Melatonin increased p-Akt levels, which suggests Akt pathway activation. Melatonin induced higher Bcl-2 expression and lower Bax expression, suggesting inhibition of apoptosis. All protective effects of melatonin were abolished by LY294002, the PI3K inhibitor. In conclusion, our results demonstrate that melatonin mitigates myocardial injury in sepsis via PI3K/Akt signaling activation.
Seven novel half-sandwich Ir cyclopentadienyl complexes, [(η-Cp)Ir(N^N)Cl]PF, have been prepared and characterized, where Cp is Cp* or the biphenyl derivative Cp (CMeCHCH), and the N^N-chelating ligands are imino-pyridyl Schiff-bases. The X-ray crystal structures of complexes 2A, 2B, and 3A have been determined. Excitingly, most of the complexes show potent antiproliferative activity towards A549 and HeLa cancer cells, except for Cp* complex 1A towards HeLa cells. Cp complex 2B displayed the highest potency, about 19 and 6 times more active than the clinically used drug cisplatin toward A549 and HeLa cells, respectively. These complexes undergo hydrolysis, and the kinetics data have been calculated. DNA binding has been studied by interaction with nucleobases 9-ethylguanine and 9-methyladenine, cleavage of plasmid DNA, and interaction with ctDNA. Interaction with DNA does not appear to be the major mechanism of action. Protein binding (bovine serum albumin, BSA) has been established by UV-Vis, fluorescence and synchronous spectroscopic studies. The stability of complex 2B in the presence of GSH was evaluated. The complexes catalytically convert coenzyme NADH to NADvia hydride transfer. Cp complexes 2B and 4B induce cell apoptosis and arrest cell cycles at the S and G/M phases towards A549 cancer cells and increase the reactive oxygen species dramatically, which appear to contribute to the remarkable anticancer activity.
Half-sandwich metal-based anticancer complexes suffer from uncertain targets and mechanisms of action. Herein we report the observation of the images of half-sandwich iridium and ruthenium complexes in cells detected by confocal microscopy. The confocal microscopy images showed that the cyclopentadienyl iridium complex 1 mainly accumulated in nuclei in A549 lung cancer cells, whereas the arene ruthenium complex 3 is located in mitochondria and lysosomes, mostly in mitochondria, although both complexes entered A549 cells mainly through energy-dependent active transport. The nuclear morphological changes caused by Ir complex 1 were also detected by confocal microscopy. Ir complex 1 is more potent than cisplatin toward A549 and HeLa cells. DNA binding studies involved interaction with the nucleobases 9-ethylguanine, 9-methyladenine, ctDNA, and plasmid DNA. The determination of bovine serum albumin binding was also performed. Hydrolysis, stability, nucleobase binding, and catalytic NAD + / NADH hydride transfer tests for complexes 1 and 3 were also carried out. Both complexes activated depolarization of mitochondrial membrane potential and intracellular ROS overproduction and induced cell apoptosis. Complex 3 arrested the cell cycle at the G 0 /G 1 phase by inactivation of CDK 4/cyclin D1. This work paves the way to track and monitor half-sandwich metal complexes in cells, shines a light on understanding their mechanism of action, and indicates their potential application as theranostic agents.
A series of half-sandwich Ir pentamethylcyclopentadienyl and Ru arene complexes containing P^P-chelating ligands of the type [(Cp/arene)M(P^P)Cl]PF, where M = Ir, Cp is pentamethylcyclopentadienyl (Cp*), or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (Cp); M = Ru, arene is 3-phenylpropan-1-ol (bz-PA), 4-phenylbutan-1-ol (bz-BA), or p-cymene (p-cym), and P^P is 2,20-bis(diphenylphosphino)-1,10-binaphthyl (BINAP), have been synthesized and fully characterized, three of them by X-ray crystallography, and their potential as anticancer agents explored. All five complexes showed potent anticancer activity toward HeLa and A549 cancer cells. The introduction of a biphenyl substituent on the Cp* ring for the iridium complexes has no effect on the antiproliferative potency. Ruthenium complex [(η-p-cym)Ru(P^P)Cl]PF (5) displayed the highest potency, about 15 and 7.5 times more active than the clinically used cisplatin against A549 and HeLa cells, respectively. No binding to 9-MeA and 9-EtG nucleobases was observed. Although these types of complexes interact with ctDNA, DNA appears not to be the major target. Compared to iridium complex [(η-Cp*)Ir(P^P)Cl]PF (1), ruthenium complex (5) showed stronger ability to interfere with coenzyme NAD/NADH couple through transfer hydrogenation reactions and to induce ROS in cells, which is consistent with their anticancer activities. The redox properties of the complexes 1, 5, and ligand BINAP were evaluated by cyclic voltammetry. Complexes 1 and 5 arrest cell cycles at the S phase, Sub-G phase and G phase, respectively, and cause cell apoptosis toward A549 cells.
Chemotherapy is limited by its poor selectivity towards cancer cells over normal cells. Herein, we designed half-sandwich ruthenium imino-pyridyl complexes [(η-bz)Ru(N^N)Cl]PF to achieve selective cytotoxicity to cancer cells. This kind of ruthenium complex has unique characteristics and is worthy of further exploration in the design of new anticancer drugs.
We, herein, report the synthesis, characterization, luminescence properties, anticancer, and antibacterial activities of a family of novel half-sandwich iridium(III) complexes of the general formula [(η-Cp)Ir(C^N)Cl]PF [Cp = pentamethylcyclopentadienyl (Cp*) or tetramethyl(biphenyl)-cyclopentadienyl (Cp)] bearing versatile imine-N-heterocyclic carbene ligands. In this complex framework, substituents on four positions could be modulated, which distinguishes this class of complex and provides a large amount of flexibility and opportunity to tune the cytotoxicity of complexes. The X-ray crystal structures of complexes 4 and 10 exhibit the expected "piano-stool" geometry. With the exception of 1, 2, and 11, each complex shows potent cytotoxicity, with IC (half-maximum inhibitory concentration) values ranging from 1.99 to 25.86 μM toward A549 human lung cancer cells. First, the effect of four positions bearing different substituents in the complex framework on the anticancer activity, that is, structure-activity relationship, was systematically studied. Complex 8 (IC = 1.99 μM) displays the highest anticancer activities, whose cytotoxicity is more than 10-fold higher than that of the clinical platinum drug cisplatin against A549 cancer cells. Second, their chemical reactivity including nucleobases binding, catalytic activity in converting coenzyme NADH to NAD, reaction with glutathione (GSH), and bovine serum albumin (BSA) binding is investigated. No reaction with nucleobase is observed. However, these iridium(III) complexes bind rapidly to GSH and can catalyze oxidation of NADH to NAD. In addition, they show moderate binding affinity to BSA and the fluorescence quenching of BSA by the iridium (III) complexes is due to the static quenching. Third, the mode of cell death was also explored through flow cytometry experiments, including cell cycle, apoptosis induction, reactive oxygen species (ROS) and mitochondrial membrane potential. It seems that cell cycle perturbation, apoptosis induction, increase of ROS level and loss of mitochondrial membrane potential together contribute to the anticancer potency of these complexes. Last, the use of confocal microscopy provides insights into the microscopic mechanism that the typical and most active complex 8 enters A549 lung cancer cells mainly through energy-dependent pathway and is located in lysosome. Furthermore, lysosome damage and nuclear morphology were detected by confocal microscopy. Nuclear condensation and apoptotic bodies may finally induce cells apoptosis. Interestingly, complex 8 also shows antibacterial activity against Gram-positive Staphylococcus aureus. This work may provide an alternative and effective strategy to smart design of potent organometallic half-sandwich iridium(III) anticancer drugs.
The rational design of the ligands around transition metals has achieved success in the development of anticancer complexes. In this contribution, a series of organometallic half-sandwich iridium(iii) complexes with various corresponding counteranions have been prepared and characterized. The size and coordination ability of the counteranions exert a great influence on the chemical reactivity and anticancer activity of these complexes. The influence of the counteranions on the cell cycle, apoptosis, ROS and mitochondrial membrane potential is also discussed. This work has shown for the first time that the modification of counteranions can affect the anticancer activity of transition metal-based complexes.
Poor selectivity between cancer cells and normal cells is one of the major limitations of cancer chemotherapy. Lysosome-targeted ruthenium-based complexes target tumor cells selectively, only displaying rather weak cytotoxicity or inactivity toward normal cells. Confocal microscopy was employed for the first time to determine the cellular localization of the half-sandwich Ru complex.
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