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

Air pollution associated with hospital visits for mental and behavioral disorders in Northeast China

BackgroundRelated studies have found that air pollution is an important factor affecting mental and behavioral disorders. Thus, we performed this time-series study to evaluate the relationship between short-term exposure to ambient air pollutants and visits to hospital by patients with mental and behavioral disorders in northeastern China.MethodsWe used quasi-Poisson regression models and generalized additive models to probe the links between air pollution and mental and behavioral disorders. The possible influences were also explored stratified by season, age and gender.ResultsWe found that sulfur dioxide (SO2) had a cumulative effect on mental and behavioral disorders at lag04–lag07 and had the greatest effect at lag07 [Relative risk (RR) = 1.068, 95%CI = 1.021–1.117]. Particulate matter of size 2.5 μm (PM2.5) and SO2 had a cumulative effect on depression and both had the largest effect at lag07 (RR = 1.021, 95%CI = 1.002–1.041; RR = 1.103, 95%CI = 1.032–1.178); SO2 also had a cumulative effect on anxiety disorders, with the largest effect at lag06 (RR = 1.058, 95%CI = 1.009–1.110). In the stratified analysis, people are more susceptible in the cold season compared to the warm season and females and the 18–60-year age group are more sensitive to air pollutants. It is suggested to strengthen management and preventive measures to decrease air pollution exposure.ConclusionThis study found an association between increased concentrations of air pollutants and increased outpatient visits for mental and behavioral disorders. We recommend that preventive and protective measures should be strengthened in an effort to reduce exposure to air pollution in order to maintain physical and mental health

Hypomethylation of IL10 and IL13 Promoters in CD4+ T Cells of Patients with Systemic Lupus Erythematosus

Interleukin- (IL-)10 and IL-13 play important roles in Th2 cell differentiation and production of autoantibodies in patients with (SLE). However, the mechanisms leading to IL10 and IL13 overexpression in SLE patients are not well understood. In this study, we confirm that the levels of both IL10 and IL13 mRNA in CD4+ T cells and of serum IL10 and IL13 proteins are increased in SLE patients. We show that the DNA methylation levels within IL10 and IL13 gene regulatory domains are reduced in SLE CD4+ T cells relative to healthy controls and negatively correlate with IL10 and IL13 mRNA expression. Moreover, treating healthy CD4+ T cells with the demethylating agent 5-azacytidine (5-azaC) increased IL10 and IL13 mRNA transcription. Together, our results show that promoter methylation is a determinant of IL10 and IL13 expression in CD4+ T cells, and we propose that DNA hypomethylation leads to IL10 and IL13 overexpression in SLE patients

Comparison of the Therapeutic Effects of Acupuncture at PC6 and ST36 for Chronic Myocardial Ischemia

We aimed to compare the differences of the effects on chronic myocardial ischemia (MI) of acupuncture at PC6 and ST36. The chronic MI model of minipigs was created by implanting an Ameroid constrictor on the left anterior descending coronary artery (LAD) and then two weeks’ acupuncture was stimulated at PC6 or ST36, respectively. The results showed that both acupoints’ stimulation decreased the serous cardiac troponin T (cTnT) and ischemia modified albumin (IMA) significantly and improved the ischemic ECG changes. The amplitude of pathological Q wave in the PC6 group decreased more significantly than that of the ST36 group. The cardiovascular magnetic resonance imaging (cMRI) results showed that the decreased left ventricular ejection fraction (LVEF) was not improved obviously in both groups. The left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) enlarged progressively even after acupuncture. The left ventricular wall mass (LVWM) in the ST36 group increased more obviously than that of the PC6 group, which paralleled the decreasing angiotensin II (Ang II) concentration in the plasma. These results suggested that acupuncture at PC6 or ST36 was effective for protecting the myocardium from chronic ischemic injury, and the effect of PC6 seemed to be better