Therapeutic promise and principles: Metabotropic glutamate receptors

For a number of disease entities, oxidative stress becomes a significant factor in the etiology and progression of cell dysfunction and injury. Therapeutic strategies that can identify novel signal transduction pathways to ameliorate the toxic effects of oxidative stress may lead to new avenues of treatment for a spectrum of disorders that include diabetes, Alzheimer's disease, Parkinson's disease and immune system dysfunction. In this respect, metabotropic glutamate receptors (mGluRs) may offer exciting prospects for several disorders since these receptors can limit or prevent apoptotic cell injury as well as impact upon cellular development and function. Yet the role of mGluRs is complex in nature and may require specific mGluR modulation for a particular disease entity to maximize clinical efficacy and limit potential disability. Here we discuss the potential clinical translation of mGluRs and highlight the role of novel signal transduction pathways in the metabotropic glutamate system that may be vital for the clinical utility of mGluRs

A fork in the path: Developing therapeutic inroads with FoxO proteins

Advances in clinical care for disorders involving any system of the body necessitates novel therapeutic strategies that can focus upon the modulation of cellular proliferation, metabolism, inflammation and longevity. In this respect, members of the mammalian forkhead transcription factors of the O class (FoxOs) that include FoxO1, FoxO3, FoxO4 and FoxO6 are increasingly being recognized as exciting prospects for multiple disorders. These transcription factors govern development, proliferation, survival and longevity during multiple cellular environments that can involve oxidative stress. Furthermore, these transcription factors are closely integrated with several novel signal transduction pathways, such as erythropoietin and Wnt proteins, that may influence the ability of FoxOs to act as a “double-edge sword” to sometimes promote cell survival, but at other times lead to cell injury. Here we discuss the fascinating but complex role of FoxOs during cellular injury and oxidative stress, progenitor cell development, fertility, angiogenesis, cardiovascular function, cellular metabolism and diabetes, cell longevity, immune surveillance and cancer

New strategies for Alzheimer disease and cognitive impairment

Approximately five million people suffer with Alzheimer disease (AD) and more than twenty-four million people are diagnosed with AD, pre-senile dementia, and other disorders of cognitive loss worldwide. Furthermore, the annual cost per patient with AD can approach $200,000 with an annual population aggregate cost of$100 billion. Yet, complete therapeutic prevention or reversal of neurovascular injury during AD and cognitive loss is not achievable despite the current understanding of the cellular pathways that modulate nervous system injury during these disorders. As a result, identification of novel therapeutic targets for the treatment of neurovascular injury would be extremely beneficial to reduce or eliminate disability from diseases that lead to cognitive loss or impairment. Here we describe the capacity of intrinsic cellular mechanisms for the novel pathways of erythropoietin and forkhead transcription factors that may offer not only new strategies for disorders such as AD and cognitive loss, but also function as biomarkers for disease onset and progression

Dose-dependent inhibition of gastric injury by hydrogen in alkaline electrolyzed drinking water

BACKGROUND: Hydrogen has been reported to relieve damage in many disease models, and is a potential additive in drinking water to provide protective effects for patients as several clinical studies revealed. However, the absence of a dose–response relationship in the application of hydrogen is puzzling. We attempted to identify the dose–response relationship of hydrogen in alkaline electrolyzed drinking water through the aspirin induced gastric injury model. METHODS: In this study, hydrogen-rich alkaline water was obtained by adding H(2) to electrolyzed water at one atmosphere pressure. After 2 weeks of drinking, we detected the gastric mucosal damage together with MPO, MDA and 8-OHdG in rat aspirin induced gastric injury model. RESULTS: Hydrogen-dose dependent inhibition was observed in stomach mucosal. Under pH 8.5, 0.07, 0.22 and 0.84 ppm hydrogen exhibited a high correlation with inhibitory effects showed by erosion area, MPO activity and MDA content in the stomach. Gastric histology also demonstrated the inhibition of damage by hydrogen-rich alkaline water. However, 8-OHdG level in serum did not have significant hydrogen-dose dependent effect. pH 9.5 showed higher but not significant inhibitory response compared with pH 8.5. CONCLUSIONS: Hydrogen is effective in relieving the gastric injury induced by aspirin-HCl, and the inhibitory effect is dose-dependent. The reason behind this may be that hydrogen-rich water directly interacted with the target tissue, while the hydrogen concentration in blood was buffered by liver glycogen, evoking a suppressed dose–response effect. Drinking hydrogen-rich water may protect healthy individuals from gastric damage caused by oxidative stress

FoxO proteins: cunning concepts and considerations for the cardiovascular system

A B S T R A C T Dysfunction in the cardiovascular system can lead to the progression of a number of disease entities that can involve cancer, diabetes, cardiac ischaemia, neurodegeneration and immune system dysfunction. In order for new therapeutic avenues to overcome some of the limitations of present clinical treatments for these disorders, future investigations must focus upon novel cellular processes that control cellular development, proliferation, metabolism and inflammation. In this respect, members of the mammalian forkhead transcription factors of the O class (FoxOs) have increasingly become recognized as important and exciting targets for disorders of the cardiovascular system. In the present review, we describe the role of these transcription factors in the cardiovascular system during processes that involve angiogenesis, cardiovascular development, hypertension, cellular metabolism, oxidative stress, stem cell proliferation, immune system regulation and cancer. Current knowledge of FoxO protein function combined with future studies should continue to lay the foundation for the successful translation of these transcription factors into novel and robust clinical therapies

Erythropoietin, Forkhead Proteins, and Oxidative Injury: Biomarkers and Biology

Oxidative stress significantly impacts multiple cellular pathways that can lead to the initiation and progression of varied disorders throughout the body. It therefore becomes imperative to elucidate the components and function of novel therapeutic strategies against oxidative stress to further clinical diagnosis and care. In particular, both the growth factor and cytokine erythropoietin (EPO), and members of the mammalian forkhead transcription factors of the O class (FoxOs), may offer the greatest promise for new treatment regimens, since these agents and the cellular pathways they oversee cover a range of critical functions that directly influence progenitor cell development, cell survival and degeneration, metabolism, immune function, and cancer cell invasion. Furthermore, both EPO and FoxOs function not only as therapeutic targets, but also as biomarkers of disease onset and progression, since their cellular pathways are closely linked and overlap with several unique signal transduction pathways. Yet, EPO and FoxOs may sometimes have unexpected and undesirable effects that can raise caution for these agents and warrant further investigations. Here we present the exciting as well as the complex role that EPO and FoxOs possess to uncover the benefits as well as the risks of these agents for cell biology and clinical care in processes that range from stem cell development to uncontrolled cellular proliferation

Serum Metabolomics Reveals Serotonin as a Predictor of Severe Dengue in the Early Phase of Dengue Fever

Effective triage of dengue patients early in the disease course for in- or out-patient management would be useful for optimal healthcare resource utilization while minimizing poor clinical outcome due to delayed intervention. Yet, early prognosis of severe dengue is hampered by the heterogeneity in clinical presentation and routine hematological and biochemical measurements in dengue patients that collectively correlates poorly with eventual clinical outcome. Herein, untargeted liquid-chromatography mass spectrometry metabolomics of serum from patients with dengue fever (DF) and dengue hemorrhagic fever (DHF) in the febrile phase (1.5) in the serum, among which are two products of tryptophan metabolism–serotonin and kynurenine. Serotonin, involved in platelet aggregation and activation decreased significantly, whereas kynurenine, an immunomodulator, increased significantly in patients with DHF, consistent with thrombocytopenia and immunopathology in severe dengue. To sensitively and accurately evaluate serotonin levels as prognostic biomarkers, we implemented stable-isotope dilution mass spectrometry and used convalescence samples as their own controls. DHF serotonin was significantly 1.98 fold lower in febrile compared to convalescence phase, and significantly 1.76 fold lower compared to DF in the febrile phase of illness. Thus, serotonin alone provided good prognostic utility (Area Under Curve, AUC of serotonin = 0.8). Additionally, immune mediators associated with DHF may further increase the predictive ability than just serotonin alone. Nine cytokines, including IFN-γ, IL-1β, IL-4, IL-8, G-CSF, MIP-1β, FGF basic, TNFα and RANTES were significantly different between DF and DHF, among which IFN-γ ranked top by multivariate statistics. Combining serotonin and IFN-γ improved the prognosis performance (AUC = 0.92, sensitivity = 77.8%, specificity = 95.8%), suggesting this duplex panel as accurate metrics for the early prognosis of DHF

Synergistic interactions in W/O microemulsions containing imidazolium based C12mimBr and sodium lauryl sulfate

The physicochemical properties and synergistic effects of W/O microemulsion systems containing imidazolium based surfactant, 1-dodecyl-3-methylimidazolium bromide (C12mimBr)-sodium lauryl sulfate (SLS)/ alcohol/alkane/ 5% NaCl solution at different molar ratios of water-to-surfactant (ω0) are studied. The W/O microemulsions are formed at the molar fractions of SLS-to-C12mimBr+SLS (XSLS) ranges of 0.0-0.3 and 0.7-1.0. The synergism between C12mimBr and SLS can be seen from the values of (mole fraction of alcohol in the oil phase), (mole fraction of alcohol in the interfacial layer) and  (the standard free energy change of transferring alcohol from the continuous oil phase to the interfacial layer). The increase in the values of  and , and the decrease in  values with ω0 is attributed to the increasing hydrophilicity of the microemulsions. By increasing the carbon chain lengths of the alcohol molecules, or by increasing the salt concentrations, the values of  and  decrease, whereas that of  increases for the W/O microemulsions containing the mixed surfactants. On the other hand, the effect of the alkane carbon chain lengths is exactly the opposite of the effect of the alcohol carbon chain lengths on the these parameters

TAT-Ngn2 Enhances Cognitive Function Recovery and Regulates Caspase-Dependent and Mitochondrial Apoptotic Pathways After Experimental Stroke

Neurogenin-2 (Ngn2) is a basic helix-loop-helix (bHLH) transcription factor that contributes to the identification and specification of neuronal fate during neurogenesis. In our previous study, we found that Ngn2 plays an important role in alleviating neuronal apoptosis, which may be viewed as an attractive candidate target for the treatment of cerebral ischemia. However, novel strategies require an understanding of the function and mechanism of Ngn2 in mature hippocampal neurons after global cerebral ischemic injury. Here, we found that the expression of Ngn2 decreased in the hippocampus after global cerebral ischemic injury in mice and in primary hippocampal neurons after oxygen glucose deprivation (OGD) injury. Then, transactivator of transcription (TAT)-Ngn2, which was constructed by fusing a TAT domain to Ngn2, was effectively transported and incorporated into hippocampal neurons after intraperitoneal (i.p.) injection and enhanced cognitive functional recovery in the acute stage after reperfusion. Furthermore, TAT-Ngn2 alleviated hippocampal neuronal damage and apoptosis, and inhibited the cytochrome C (CytC) leak from the mitochondria to the cytoplasm through regulating the expression levels of brain-derived neurotrophic factor (BDNF), phosphorylation tropomyosin-related kinase B (pTrkB), Bcl-2, Bax and cleaved caspase-3 after reperfusion injury in vivo and in vitro. These findings suggest that the downregulation of Ngn2 expression may have an important role in triggering brain injury after ischemic stroke and that the neuroprotection of TAT-Ngn2 against stroke might involve the modulation of BDNF-TrkB signaling that regulates caspase-dependent and mitochondrial apoptotic pathways, which may be an attractive therapeutic strategy for cerebral ischemic injury

Exometabolomic analysis of decidualizing human endometrial stromal and perivascular cells

Differentiation of endometrial fibroblasts into specialized decidual cells controls embryo implantation and transforms the cycling endometrium into a semi-permanent, immune-protective matrix that accommodates the placenta throughout pregnancy. This process starts during the midluteal phase of the menstrual cycle with decidual transformation of perivascular cells (PVC) surrounding the terminal spiral arterioles and endometrial stromal cells (EnSC) underlying the luminal epithelium. Decidualization involves extensive cellular reprogramming and acquisition of a secretory phenotype, essential for coordinated placental trophoblast invasion. Secreted metabolites are an emerging class of signalling molecules. Here, we used liquid chromatography-mass spectrometry to characterise the dynamic changes in metabolite secretion (exometabolome) of primary PVC and EnSC decidualized over 8 days. We identified 79 annotated metabolites differentially secreted upon decidualization, including prostaglandin, sphingolipid, and hyaluronic acid metabolites. Secreted metabolites encompassed 21 metabolic pathways, most prominently glycerolipid and pyrimidine metabolism. Although temporal exometabolome changes were comparable between decidualizing PVC and EnSC, 32 metabolites were differentially secreted across the decidualization time-course. Further, targeted metabolomics demonstrated a conspicuous difference in xanthine secretion between decidualized PVC and EnSC. Taken together, our findings indicate that the metabolic footprints generated by different decidual subpopulations encode spatiotemporal information that may be important for optimal embryo implantation