Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling.

BACKGROUND: Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes. Here we describe the potential anticancer activity of rhenium-based complexes with preclinical efficacy in different types of solid malignancies. METHODS: Kinase profile assay of rhenium complexes. Toxicology studies using zebrafish. Analysis of the growth of pancreatic cancer cell line-derived xenografts generated in zebrafish and in mice upon exposure to rhenium compounds. RESULTS: We describe rhenium complexes which block cancer proliferation in vitro by inhibiting the signalling cascade induced by FGFR and Src. Initially, we tested the toxicity of rhenium complexes in vivo using a zebrafish model and identified one compound that displays anticancer activity with low toxicity even in the high micromolar range. Notably, the rhenium complex has anticancer activity in very aggressive cancers such as pancreatic ductal adenocarcinoma and neuroblastoma. We demonstrate the potential efficacy of this complex via a significant reduction in cancer growth in mouse xenografts. CONCLUSIONS: Our findings provide a basis for the development of rhenium-based chemotherapy agents with enhanced selectivity and limited side effects compared to standard platinum-based drugs.

Methane attenuates lung ischemia-reperfusion injury via regulating PI3K-AKT-NFκB signaling pathway.

Objective: This study aims to investigate the protective effects and possible mechanism of methane-rich saline (MS) on lung ischemia-reperfusion injury (LIRI) in rats.Methods: MS (2 ml/kg and 20 ml/kg) was injected intraperitoneally in rats after LIRI. Lung injury was assayed by Hematoxylin-eosin (HE) staining and wet-to-dry weight (W/D). The cells in the bronchoalveolar lavage fluid (BALF) and blood were counted. Oxidative stress was examined by the level of malondialdehyde (MDA) and superoxide dismutase (SOD). Inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-10 (IL-10) were determined by ELISA. Lung tissue apoptosis was detected by TUNEL staining and western blotting of Bcl-2, Bax, and caspase-3. The expressions of IкBα, p38, PI3K, AKT, and NF-κB were analyzed with Western blotting.Results: MS effectively decreased the lung W/D ratio as well as the lung pathological damage and reduced the localized infiltration of inflammatory cells. Methane suppressed the expression of the PI3K-AKT-NFκB signaling pathway during the lung IR injury, which inhibited the activation of NF-kB and decreased the level of inflammatory cytokines, such as TNF-α, IL-1ß, and IL-10. Moreover, we found that MS treatment relieved reactive oxygen species (ROS) damage by downregulating MDA and upregulating SOD. MS treatment also regulated apoptosis-related proteins, such as Bcl-2, Bax, and caspase-3.Conclusions: MS could repair LIRI and reduce the release of oxidative stress, inflammatory cytokines, and cell apoptosis via the PI3K-AKT-NFκB signaling pathway, which may provide a novel and promising strategy for the treatment of LIRI.

Methane ameliorates post-operative cognitive dysfunction by inhibiting microglia NF-κB/MAPKs pathway and promoting IL-10 expression in aged mice.

Postoperative cognitive dysfunction (POCD) is one of the most common complications after surgery. Accumulating evidence suggests that postoperative neuro-inflammation plays a critical role in the mechanism of POCD. Recently, exogenous methane is reported to have anti-inflammatory properties and play a neuro-protective role in acute carbon monoxide poisoning injury. Therefore, we investigated the protective effect of methane on a POCD model induced by abdominal surgery and its underlying mechanism in aged mice. Methane-rich saline (MS) or normal saline (NS) (16 ml/kg) was injected intraperitoneally 30 min after the abdominal surgery. The result showed that methane attenuated spatial memory loss in Morris water maze (MWM) with decreasing pro-inflammatory cytokines production and activation of microglia in hippocampus after surgery. Meanwhile, methane treatment suppressed lipopolysaccharide (LPS)-stimulated phosphorylation of MAPKs pathways and its downstream target TNF-α and IL-6 in BV2 cells. Moreover, methane increased expression of IL-10 in the hippocampus 24 h after surgery, and blockade of IL-10 repressed the protective effect of methane on the cognitive impairments observed in MWM test, decreased microglial activation and the pro-inflammatory cytokine in plasma and hippocampal. Blockade of IL-10 abrogated the suppression effect of methane on the pro-inflammatory cytokine production and phosphorylation of NF-κB and p38MAPK both in hippocampus and in BV2 cells. In conclusion, our study suggests exogenous methane could be a novel agent for the therapy of POCD through its anti-inflammation properties.

Methane inhalation reduces the systemic inflammatory response in a large animal model of extracorporeal circulation.

OBJECTIVES: Extracorporeal circulation induces cellular and humoral inflammatory reactions, thus possibly leading to detrimental secondary inflammatory responses. Previous data have demonstrated the bioactive potential of methane and confirmed its anti-inflammatory effects in model experiments. Our goal was to investigate the in vivo consequences of exogenous methane administration on extracorporeal circulation-induced inflammation. METHODS: Two groups of anaesthetized Vietnamese minipigs (non-treated and methane treated, n = 5 each) were included. Standard central cannulation was performed, and extracorporeal circulation was maintained for 120 min without cardiac arrest or ischaemia, followed by an additional 120-min observation period with haemodynamic monitoring. In the methane-treated group, 2.5% v/v methane-normoxic air mixture was added to the oxygenator sweep gas. Blood samples through the central venous line and tissue biopsies from the heart, ileum and kidney were taken at the end point to determine the whole blood superoxide production (chemiluminometry) and the activity of xanthine-oxidoreductase and myeloperoxidase, with substrate-specific reactions. RESULTS: Methane treatment resulted in significantly higher renal blood flow during the extracorporeal circulation period compared to the non-treated group (63.9 ± 16.4 vs 29.0 ± 9.3 ml/min). Whole blood superoxide production (548 ± 179 vs 1283 ± 193 Relative Light Unit (RLU)), ileal myeloperoxidase (2.23 ± 0.2 vs 3.26 ± 0.6 mU/(mg protein)) and cardiac (1.5 ± 0.6 vs 4.7 ± 2.5 pmol/min/mg), ileal (2.2 ± 0.6 vs 7.0 ± 3.4 pmol/min/mg) and renal (1.2 ± 0.8 vs 13.3 ± 8.0 pmol/min/mg) xanthine-oxidoreductase activity were significantly lower in the treated group. CONCLUSIONS: The addition of bioactive gases, such as methane, through the oxygenator of the extracorporeal circuit represents a novel strategy to influence the inflammatory effects of extracorporeal perfusion in cardiac surgical procedures.

Silver carbene complexes: An emerging class of anticancer agents.

Cancer is a major global health problem with large therapeutic challenges. Although substantial progress has been made in cancer therapy, there still remains a need to develop novel and effective treatment strategies to treat several relapsed and refractory cancers. Recently, there has been growing demand for considering organometallics as antineoplastic agents. This review is focused on a group of organometallics, silver N-heterocyclic carbene complexes (SCCs) and their anticancer efficacy in targeting multiple pathways in various in vitro cancer model systems. However, the precise molecular mechanism of SCCs anticancer properties remains unclear. Here, we discuss the SCCs chemistry, potential molecular targets, possible molecular mechanism of action, and their application in cancer therapies.

Methane-Rich Saline Ameliorates Sepsis-Induced Acute Kidney Injury through Anti-Inflammation, Antioxidative, and Antiapoptosis Effects by Regulating Endoplasmic Reticulum Stress.

Sepsis-induced acute kidney injury (AKI) is a severe complication of sepsis and an important cause of mortality in septic patients. Previous investigations showed that methane had protective properties against different diseases in animal models. This study is aimed at investigating whether methane-rich saline (MRS) has a protective effect against sepsis-induced AKI. Sepsis was induced in wild-type C57BL/6 mice by cecal ligation and puncture (CLP), and the mice were divided into three groups: a sham control group (sham), a surgery group with saline intraperitoneal injection (i.p.) treatment (CLP + NS), and a surgery group with MRS i.p. treatment (CLP + MRS). 24 h after the establishment of the sepsis, the blood and kidney tissues of mice in all groups were collected. According to the serum levels of blood urea nitrogen (BUN) and creatinine (CRE) and a histologic analysis, which included hematoxylin-eosin (H&E) staining and periodic acid-Schiff (PAS) staining, MRS treatment protected renal function and tissues from acute injury. Additionally, MRS treatment significantly ameliorated apoptosis, based on the levels of apoptosis-related protein makers, including cleaved caspase-3 and cleaved PARP, and the levels of Bcl-2/Bax expression and TUNEL staining. In addition, the endoplasmic reticulum (ER) stress-related glucose-regulated protein 78 (GRP78)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP)/caspase-12 apoptosis signaling pathway was significantly suppressed in the CLP + MRS group. The levels of inflammation and oxidative stress were also reduced after MRS treatment. These results showed that MRS has the potential to ameliorate sepsis-induced acute kidney injury through its anti-inflammatory, antioxidative, and antiapoptosis properties.

Methane Medicine: A Rising Star Gas with Powerful Anti-Inflammation, Antioxidant, and Antiapoptosis Properties.

Methane, the simplest organic compound, was deemed to have little physiological action for decades. However, recently, many basic studies have discovered that methane has several important biological effects that can protect cells and organs from inflammation, oxidant, and apoptosis. Heretofore, there are two delivery methods that have been applied to researches and have been proved to be feasible, including the inhalation of methane gas and injection with the methane-rich saline. This review studies on the clinical development of methane and discusses about the mechanism behind these protective effects. As a new field in gas medicine, this study also comes up with some problems and prospects on methane and further studies.

Methane alleviates carbon tetrachloride induced liver injury in mice: anti-inflammatory action demonstrated by increased PI3K/Akt/GSK-3ß-mediated IL-10 expression.

The inflammatory response plays an important role in carbon tetrachloride (CCl4)-induced acute liver injury and methane has been shown to exert beneficial effects on inflammation-associated diseases. Thus, we investigated the potential protective effects of methane-rich saline (MS) on CCl4-induced acute liver injury and explored the underlying mechanism. A CCl4-induced acute liver injury model was established by injection of CCl4 (0.6 ml/kg, ip) in mice followed by treatment with MS (16 ml/kg, ip), 24 h later. All groups of mice were sacrificed and blood and liver tissues were collected. Serum aminotransferase, necrotic areas, and inflammatory cell infiltration in liver slices were enhanced after CCl4 treatment but decreased with MS treatment. IL-6, TNF-α, IL-1ß, IFN-γ, ICAM-1, CXCL1, MPO, NF-κB p65, ERK, JNK, and MAPK P38, expression in serum or liver homogenate were greater after CCl4 treatment but comparatively less after MS treatment. Only IL-10 increased after MS treatment. Anti-IL10 blockade (1.5 mg/kg) restored MS-mediated attenuated phosphorylation of NF-ĸbB/MAPK and the protective effect of MS was abolished for all indices examined. The PI3K inhibitor, wortmannin had the same effects on MS as anti-IL-10 antibody. MS also induced phosphorylation of GSK-3ß and AKT in CCl4-treated mice. After pre-treatment with wortmannin (0.7 mg/kg), phosphorylation of GSK-3ß and AKT proteins were reduced compared to its solvent control group-DMSO-treated animals. Thus, the data provide evidence that MS may activate the PI3K-AKT-GSK-3ß pathway to induce IL-10 expression and produce anti-inflammatory effects via the NF-κB and MAPK pathways. The findings provide a new pharmacological strategy for management of inflammatory response after acute liver injury.

Protective Effects of Methane-Rich Saline on Rats with Lipopolysaccharide-Induced Acute Lung Injury.

Objective. The aim of this research is to evaluate the protective effects of methane-rich saline (MS) on lipopolysaccharide- (LPS-) induced acute lung injury (ALI) and investigate its potential antioxidative, anti-inflammatory, and antiapoptotic activities. Methods. LPS-induced (20 mg/kg) ALI rats were injected with MS (2 ml/kg and 20 ml/kg) before the initiation of LPS induction. Survival rate was determined until 96 h after LPS was induced. Lung injury was assayed by oxygenation index, lung permeability index (LPI), wet-to-dry weight (W/D), and histology. The cells in the bronchoalveolar lavage fluid (BALF) were counted. Oxidative stress was examined by the level of malondialdehyde (MDA) and superoxide dismutase (SOD). Inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) in BALF were determined by ELISA. Lung tissue apoptosis was detected by TUNEL staining and western blotting of caspase-3. Results. It was found that methane significantly prolonged the rat survival, decreased the lung W/D ratio and the content of the inflammatory factors, and reduced the amount of caspase-3 and apoptotic index. In addition, MS increased the level of SOD and decreased the level of MDA significantly. Conclusions. MS protects the LPS-challenged ALI via antioxidative, anti-inflammatory, and antiapoptotic effect, which may prove to be a novel therapy for the clinical management of ALI.

Neuroprotective effects of methane-rich saline on experimental acute carbon monoxide toxicity.

BACKGROUND: Methane has been reported to play a protective role in ischemia-reperfusion injury via anti-oxidation, anti-inflammatory and anti-apoptotic activities. This study was designed to determine the protective effects of methane-rich saline (MRS) on acute carbon monoxide (CO) poisoning. METHODS: A total of 36 male Sprague-Dawley rats were randomly divided into 3 groups: sham group, CO group and MRS group. Acute CO poisoning was induced by exposing rats to 1000ppm CO in air for 40min and then to 3000ppm CO for an additional 20min until they lost consciousness. MRS at 10ml/kg was intraperitoneally administered at 0h, 8h and 16h after CO exposure. Rats were sacrificed 24h after CO exposure. Brains were collected for Nissl staining. The cortex and hippocampus were separated for the detections of malondialdehyde (MDA), 3-nitrotyrosine (3-NT), 8-hydroxydeoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), interleukin1-ß (IL-1ß), interleukin-6 (IL-6) and superoxide dismutase (SOD) activities. RESULTS: The results showed that MRS treatment improved neuronal injury, reduced MDA, 3-NT and 8-OHdG, and increased SOD activity of the hippocampus and cortex compared with normal saline-treated rats. In addition, MRS reduced the expression of TNF-α and IL-1ß in the brain but had no effect on IL-6 expression. CONCLUSION: These findings suggest that MRS may protect the brain against acute CO poisoning-induced injury via its anti-oxidative and anti-inflammatory activities.

Cyclometalated Palladium(II) N-Heterocyclic Carbene Complexes: Anticancer Agents for Potent In†Vitro Cytotoxicity and In†Vivo Tumor Growth Suppression.

Palladium(II) complexes are generally reactive toward substitution/reduction, and their biological applications are seldom explored. A new series of palladium(II) N-heterocyclic carbene (NHC) complexes that are stable in the presence of biological thiols are reported. A representative complex, [Pd(C^N^N)(N,N'-nBu2 NHC)](CF3 SO3 ) (Pd1 d, HC^N^N=6-phenyl-2,2'-bipyridine, N,N'-nBu2 NHC=N,N'-di-n-butylimidazolylidene), displays potent killing activity toward cancer cell lines (IC50 =0.09-0.5 µm) but is less cytotoxic toward a normal human fibroblast cell line (CCD-19Lu, IC50 =11.8 µm). In vivo anticancer studies revealed that Pd1 d significantly inhibited tumor growth in a nude mice model. Proteomics data and in vitro biochemical assays reveal that Pd1 d exerts anticancer effects, including inhibition of an epidermal growth factor receptor pathway, induction of mitochondrial dysfunction, and antiangiogenic activity to endothelial cells.

N-heterocyclic carbene metal complexes as bio-organometallic antimicrobial and anticancer drugs.

Late transition metal complexes that bear N-heterocyclic carbene (NHC) ligands have seen a speedy growth in their use as both, metal-based drug candidates and potentially active homogeneous catalysts in a plethora of C-C and C-N bond forming reactions. This review article focuses on the recent developments and advances in preparation and characterization of NHC-metal complexes (metal: silver, gold, copper, palladium, nickel and ruthenium) and their biomedical applications. Their design, syntheses and characterization have been reviewed and correlated to their antimicrobial and anticancer efficacies. All these initial discoveries help validate the great potential of NHC-metal derivatives as a class of effective antimicrobial and anticancer agents.

Synthesis of ß-Carboline-Based N-Heterocyclic Carbenes and Their Antiproliferative and Antimetastatic Activities against Human Breast Cancer Cells.

A series of novel ß-carboline-based N-heterocyclic carbenes was prepared via Mannich reaction between methyl 1-(dimethoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate, formaldehyde, and primary amines. All compounds were evaluated for their antiproliferative activity using human breast cancer and lung cancer cell lines. Three compounds, 3c, 3j, and 3h, were discovered to display IC50 less than 10 µM against human breast cancer MDA-MB-231 cells at 24 h of treatment. Pharmacologically these compounds lead to G2/M phase cell cycle arrest and induction of cellular apoptosis by triggering intrinsic apoptotic pathway through depolarization of mitochondrial membrane potential and activation of caspases. At lower concentrations, these compounds also showed antimigratory and antiinvasive effects against highly metastatic human breast cancer MDA-MB-231 cells via aberration of MAP-kinase signaling and by the inhibition of matrix metalloproteinases. However, these analogues lack in vivo effect in mouse model which may be attributed to their strong affinity to HSA that was investigated spectroscopically with compound 3h.

Phosphorescent iridium(III)-bis-N-heterocyclic carbene complexes as mitochondria-targeted theranostic and photodynamic anticancer agents.

Mitochondria-targeted compounds represent a promising approach to target tumors selectively and overcome resistance to current anticancer therapies. In this work, three cyclometalated iridium(III) complexes (1-3) containing bis-N-heterocyclic carbene (NHC) ligands have been explored as theranostic and photodynamic agents targeting mitochondria. These complexes display rich photophysical properties, which greatly facilitates the study of their intracellular fate. All three complexes are more cytotoxic than cisplatin against the cancer cells screened. 1-3 can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, and they can carry out theranostic functions by simultaneously inducing and monitoring the morphological changes in mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by initiating a cascade of events related to mitochondrial dysfunction. Additionally, they display up to 3 orders of magnitude higher cytotoxicity upon irradiation at 365 nm, which is so far the highest photocytotoxic responses reported for iridium complexes.

Metal N-heterocyclic carbene complexes as potential antitumor metallodrugs.

The discovery of cisplatin's antitumor activity in 1969 prompted the search for novel metal-containing complexes as potential anticancer drugs. Among these novel complexes, metal N-heterocyclic carbene (NHC) complexes have recently gained considerable attention because they perfectly fit prerequisites for efficient drug design and fast optimization. Moreover, most of them have shown higher cytotoxicity than cisplatin. This review describes the advances that have been achieved in using transition metal (Ag, Au, Pt, Pd, Cu, Ni, and Ru) complexes containing NHC ligands as antitumor agents. Their modes of action at the cellular lever are further discussed. All these initial achievements clearly demonstrate the great potential of metal-NHC complexes as antitumor agents.

Novel antiangiogenic agents in dermatology.

Because angiogenesis underlies the pathogenesis of numerous conditions (cancer, psoriasis, macular degeneration), there is a pressing need for continued investigations into angiogenic signaling and potential drug targets. Antiangiogenic agents can be classified as either direct or indirect. Direct antiangiogenics act on untransformed endothelial cells to prevent differentiation and proliferation; indirect antiangiogenics act to inhibit factors involved in proangiogenic signaling. Agents currently available with dermatologic indications are few; while several established and novel biologics targeting various proangiogenic factors are currently being investigated for potential dermatologic uses, but the jury is still out on their efficacy and safety. In this review, we highlight our experience with a group of existing and novel, small molecules that combine several modes of action against angiogenesis in addition to other properties--triarylmethane dyes and fulvene derivatives.

The antimicrobial efficacy of sustained release silver-carbene complex-loaded L-tyrosine polyphosphate nanoparticles: characterization, in vitro and in vivo studies.

The pressing need to treat multi-drug resistant bacteria in the chronically infected lungs of cystic fibrosis (CF) patients has given rise to novel nebulized antimicrobials. We have synthesized a silver-carbene complex (SCC10) active against a variety of bacterial strains associated with CF and chronic lung infections. Our studies have demonstrated that SCC10-loaded into L-tyrosine polyphosphate nanoparticles (LTP NPs) exhibits excellent antimicrobial activity in vitro and in vivo against the CF relevant bacteria Pseudomonas aeruginosa. Encapsulation of SCC10 in LTP NPs provides sustained release of the antimicrobial over the course of several days translating into efficacious results in vivo with only two administered doses over a 72 h period.

Macrophage ablation attenuates adenoviral vector-induced pancreatitis.

BACKGROUND: The objective of these studies is to determine the effects of macrophage ablation on the course of acute viral pancreatitis. Macrophages secrete proinflammatory cytokines triggering local pancreatic and systemic inflammation in the acute phase of virus-induced pancreatitis. We hypothesized that ablation of macrophages should attenuate the host inflammatory response in a mouse model of adenovirus-induced pancreatitis. METHODS: Liposome-encapsulated dichloromethylene-diphosphonate, a macrophage-depleting agent, was used before direct pancreatic injection of a recombinant adenovirus expressing a marker gene in C57Bl/6 and IL-6 knockout (KO) mice. RESULTS: C57Bl/6 mice depleted of macrophages had diminished pancreatic inflammation in the first 24 hours after vector administration. IL-6 KO mice depleted of macrophages had more severe inflammation than similarly treated C57Bl/6 mice. C57Bl/6 mice depleted of macrophages, and IL-6 KO mice had prolonged transgene expression and diminished cytotoxic T lymphocyte responses to adenoviral vector. Mortality was highest in IL-6 KO mice depleted of macrophages. Depletion of macrophages also prevented detectable serum IL-6, IL-10, or IL-12 levels in C57Bl/6 mice. CONCLUSIONS: The data suggest that macrophages play a role in the acute inflammatory response to viral vector-induced pancreatitis and that IL-6 may be protective. Understanding of the mechanisms that initiate the host immune cascade will allow more effective use of adenoviral vector-based pancreatic gene delivery.