Pathogenic molecular mechanisms in an animal model of fulminant hepatic failure: rabbit hemorrhagic viral disease

In this study we sought to determine whether molecular mechanisms involved in the pathogenesis of fulminant hepatic failure are present in rabbits experimentally infected with rabbit hemorrhagic disease virus (RHDV). The activities of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, as well as bilirubin concentration, were found to be significantly increased 36 hours after infection. Infected animals also demonstrated significant decreases in factor VII activity, in the Fischer index, and in the deterioration of prothrombin time. The concentration of reduced glutathione was significantly decreased 36 hours after infection, and we noted a marked increase in the ratio of oxidized to reduced glutathione. Infected animals showed progressive decreases in liver activity of the antioxidant enzyme superoxide dismutase. Expression of hepatocyte growth factor and c-met was found to be progressively reduced from 24 hours after infection, during which time we detected no modification in messenger RNA (mRNA) levels of transforming growth factor (TGF)-alpha. TFG-beta 1 was overexpressed 24 and 36 hours after infection, and 36 hours after infection we detected a significant increase in TNF-alpha mRNA levels. Experimental RHDV infection also induced marked activation of nuclear factor-kappaB and a significant increase in inducible nitric oxide synthase mRNA levels from 24 hours after infection. Data obtained from this animal model support its usefulness in the investigation of potential novel therapeutical modalities aimed at neutralizing reactive oxygen species and hepatocyte growth inhibitors or enhancing hepatocyte responsiveness to mitogens.     

Emodin induces apoptosis of human osteosarcoma cells via mitochondria- and endoplasmic reticulum stress-related pathways

Aim: Emodin showed anti-cancer activity against multiple human malignant tumors by inducing apoptosis. However, the apoptotic inducing effect against human osteosarcoma and related mechanism are still not studied. This study was aimed to investigate them. Methods: Emodin was used to incubate human OS cell U2OS cells at serially diluted concentrations. Hoechst staining was used to evaluate apoptosis; flow cytometry was applied to assess the collapse of mitochondrial membrane potential (MMP); intracellular ROS generation was detected by DCFH-DA staining; endoplasmic reticulum stress activation was examined by western blotting. Results: Cell apoptosis of U2OS cells was induced by emodin incubation in a concentration-dependent manner; MMP collapse and ROS generation were identified at starting concentration of 80 μmol/L of emodin in a concentration-dependent manner. ER stress activation was found at beginning concentration of 40 μmol/L of emodin. The MMP collapse was inhibited while the ER stress was not inhibited by NAC administration. Conclusions: Emodin induces death of human osteosarcoma cells by initiating ROS-dependent mitochondria-induced and ROS-independent ER stress-induced apoptosis.     

Danshen (Radix Salviae Miltiorrhizae) reverses renal injury induced by myocardial infarction

OBJECTIVE:To evaluate the protection of Danshen{Radix Salviae Miltiorrhizae)(SM) injection in myocardial infarction(Ml) induced renal damage.METHODS:Forty male C57 mice were divided into control group,Ml group and SM group.In Ml group,the left coronary artery was occluded for 8weeks;the same procedure was used for the SM group,with the additional step of SM(0.2 mL) administered intraperitoneally for 56 days.Before surgery and 8 weeks later,transthoracic echocardiography was performed and urine protein and albumin was measured.At the end of the time,all mice were killed and kidneys removed for reactive oxygen species(ROS) and fibrosis analysis,plasma was collected for blood urea nitrogen and serum creatinine determination.RESULTS:Ml slightly decreased renal function and increased production of ROS,accompanied with renal fibrosis.Administration of SM reduced production of ROS and increased renal function,it also reduced renal fibrosis.CONCLUSION:Ml plays a causal role in renal injury and SM exerts renal-protective effects,probably by its antioxidant activities.     

Cancer may be a pathway to cell survival under persistent hypoxia and elevated ROS: A model for solid‐cancer initiation and early development

A number of proposals have been made in the past century regarding what may drive sporadic cancers to initiate and develop. Yet the problem remains largely unsolved as none of the proposals have been widely accepted as cancer‐initiation drivers. We propose here a driver model for the initiation and early development of solid cancers associated with inflammation‐induced chronic hypoxia and reactive oxygen species (ROS) accumulation. The model consists of five key elements: (i)human cells tend to have a substantial gap between ATP demand and supply during chronic hypoxia, which would inevitably lead to increased uptake of glucose and accumulation of its metabolites; (ii) the accumulation of these metabolites will cast mounting pressure on the cells and ultimately result in the production and export of hyaluronic acid; (iii) the exported hyaluronic acid will be degraded into fragments of various sizes, serving as tissue‐repair signals, including signals for cell proliferation, cell survival and angiogenesis, which lead to the initial proliferation of the underlying cells; (iv) cell division provides an exit for the accumulated glucose metabolites using them towards macromolecular synthesis for the new cell, and hence alleviate the pressure from the metabolite accumulation; and (v) this process continues as long as the hypoxic condition persists. In tandem, genetic mutations may be selected to make cell divisions and hence survival more sustainable and efficient, also increasingly more uncontrollable. This model also applies to some hereditary cancers as their key mutations, such as BRCA for breast cancer, generally lead to increased ROS and ultimately to repression of mitochondrial activities and up‐regulation of glycolysis, as well as hypoxia; hence the energy gap, glucose‐metabolite accumulation, hyaluronic acid production and continuous cell division for survival.     

Survival variations by country and age for lymphoid and myeloid malignancies in Europe 2000–2007: Results of EUROCARE-5 population-based study

BackgroundSignificant advances in the management of patients with lymphoid and myeloid malignancies entered clinical practice in the early 2000’s. The EUROCARE-5 study database provides an opportunity to assess the impact of these changes at the population level by country in Europe. We provide survival estimates for clinically relevant haematological malignancies (HM), using the International Classification of Diseases for Oncology 3, by country, gender and age in Europe.MethodsWe estimated age-standardised relative survival using the complete cohort approach for 625,000 adult patients diagnosed in 2000–2007 and followed up to 2008. Survival information was provided by 89 participating cancer registries from 29 European countries. Mean survival in Europe was calculated as the population weighted average of country-specific estimates.ResultsOn average in Europe, 5-year relative survival was highest for Hodgkin lymphoma (81%; 40,625 cases), poorest for acute myeloid leukaemia (17%; 57,026 cases), and intermediate for non-Hodgkin lymphoma (59%; 329,204 cases), chronic myeloid leukaemia (53%; 17,713 cases) and plasma cell neoplasms (39%; 94,024 cases). Survival was generally lower in Eastern Europe and highest in Central and Northern Europe. Wider between country differences (>10%) were observed for malignancies that benefited from therapeutic advances, such as chronic myeloid leukaemia, chronic lymphocytic leukaemia, follicular lymphoma, diffuse large B-cell lymphoma and multiple myeloma. Lower differences (<10%) were observed for Hodgkin lymphoma.ConclusionsDelayed or reduced access to innovative and appropriate therapies could plausibly have contributed to the observed geographical disparities between European regions and countries. Population based survival by morphological sub-type is important for measuring outcomes of HM management. To better inform quality of care research, the collection of detailed clinical information at the population level should be prioritised.     

Dichloroacetate,a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment

Reprogramming of metabolism is a well-established property of cancer cells that is receiving growing attention as potential therapeutic target. Oral squamous cell carcinomas (OSCC) are aggressive and drugs-resistant human tumours displaying wide metabolic heterogeneity depending on their malignant genotype and stage of development. Dichloroacetate (DCA) is a specific inhibitor of the PDH-regulator PDK proved to foster mitochondrial oxidation of pyruvate. In this study we tested comparatively the effects of DCA on three different OSCC-derived cell lines, HSC-2, HSC-3, PE15. Characterization of the three cell lines unveiled for HSC-2 and HSC-3 a glycolysis-reliant metabolism whereas PE15 accomplished an efficient mitochondrial oxidative phosphorylation. DCA treatment of the three OSCC cell lines, at pharmacological concentrations, resulted in stimulation of the respiratory activity and caused a remarkably distinctive pro-apoptotic/cytostatic effect on HSC-2 and HSC-3. This was accompanied with a large remodeling of the mitochondrial network, never documented before, leading to organelle fragmentation and with enhanced production of reactive oxygen species. The data here presented indicate that the therapeutic efficacy of DCA may depend on the specific metabolic profile adopted by the cancer cells with those exhibiting a deficient mitochondrial oxidative phosphorylation resulting more sensitive to the drug treatment.     

Forced expression of fibroblast growth factor 21 reverses the sustained impairment of liver regeneration in hPPARαPAC mice due to dysregulated bile acid synthesis

Peroxisome proliferator activated receptor α (PPARα) stimulates hepatocellular proliferation is species-specific. Activation of mouse, but not human, PPARα induces hepatocellular proliferation, hepatomegaly, and liver cancer. Here we tested the hypothesis that human and mouse PPARα affects liver regeneration differentially. PPARα-humanized mice (hPPARα^PAC) were similar to wild type mice in responding to fasting-induced PPARα signaling. However, these mouse livers failed to regenerate in response to partial hepatectomy (PH). The liver-to-body weight ratios did not recover even 3 months after PH in hPPARα^PAC. The mouse PPARα-mediated down-regulation of let-7c was absent in hPPARα^PAC, which might partially be responsible for impaired proliferation. After PH, hPPARα^PAC displayed steatosis, necrosis, and inflammation mainly in periportal zone 1, which suggested bile-induced toxicity. Quantification of hepatic bile acids (BA) revealed BA overload with increased hydrophobic BA in hPPARα^PAC. Forced FGF21 expression in partial hepatectomized hPPARα^PAC reduced hepatic steatosis, prevented focal necrosis, and restored liver mass. Compared to mouse PPARα, human PPARα has a reduced capacity to regulate metabolic pathways required for liver regeneration. In addition, FGF21 can compensate for the reduced ability of human PPARα in stimulating liver regeneration, which suggests the potential application of FGF21 in promoting hepatic growth in injured and steatotic livers in humans.     

DNA strand breaks induced by nuclear hijacking of neuronal NOS as an anti-cancer effect of 2-methoxyestradiol

2-Methoxyestradiol (2-ME) is a physiological metabolite of 17β-estradiol. At pharmacological concentrations, 2-ME inhibits colon, breast and lung cancer in tumor models. Here we investigated the effect of physiologically relevant concentrations of 2-ME in osteosarcoma cell model. We demonstrated that 2-ME increased nuclear localization of neuronal nitric oxide synthase, resulting in nitro-oxidative DNA damage. This in turn caused cell cycle arrest and apoptosis in osteosarcoma cells. We suggest that 2-ME is a naturally occurring hormone with potential anti-cancer properties.     

Modulation of Reactive Oxygen Species to Overcome 5-Fluorouracil Resistance

5-Fluorouracil (5-FU) remains to be an important chemotherapeutic drug for treating several cancers when targeted therapy is unavailable. Chemoresistance limits the clinical utility of 5-FU, and new strategies are required to overcome the resistance. Reactive oxygen species (ROS) and antioxidants are balanced differently in both normal and cancer cells. Modulating ROS can be one method of overcoming 5-FU resistance. This review summarizes selected compounds and endogenous cellular targets modulating ROS generation to overcome 5-FU resistance.