Environmental stress,ageing and glial cell senescence: a novel mechanistic link to Parkinson's disease?

Exposure to environmental toxins is associated with a variety of age‐related diseases including cancer and neurodegeneration. For example, in Parkinson's disease (PD), chronic environmental exposure to certain toxins has been linked to the age‐related development of neuropathology. Neuronal damage is believed to involve the induction of neuroinflammatory events as a consequence of glial cell activation. Cellular senescence is a potent anti‐cancer mechanism that occurs in a number of proliferative cell types and causes the arrest of proliferation of cells at risk of malignant transformation following exposure to potentially oncogenic stimuli. With age, senescent cells accumulate and express a senescence‐associated secretory phenotype (SASP; that is the robust secretion of many inflammatory cytokines, growth factors and proteases). Whereas cell senescence in peripheral tissues has been causally linked to a number of age‐related pathologies, little is known about the induction of cellular senescence and the SASP in the brain. On the basis of recently reported findings, we propose that environmental stressors associated with PD may act in part by eliciting senescence and the SASP within non neuronal glial cells in the ageing brain, thus contributing to the characteristic decline in neuronal integrity that occurs in this disorder.     

PGE2 promotes angiogenesis through EP4 and PKA Cγ pathway

Inflammation is increasingly recognized as a critical mediator of angiogenesis, and unregulated angiogenic response is involved in human diseases, including cancer. Proinflammatory prostaglandin E2 (PGE2) is secreted by many cell types and plays important roles in the process of angiogenesis via activation of cognate EP1-4 receptors. Here, we provide evidence that PGE2 promotes the in vitro tube formation of human microvascular endothelial cells, ex vivo vessel outgrowth of aortic rings, and actual in vivo angiogenesis. Use of EP subtype-selective agonists and antagonists suggested EP4 mediates the prostaglandin-induced tube formation, and this conclusion was substantiated with small interfering RNA to specifically knockdown the EP4 expression. EP4 couples to Gαs, leading to activation of protein kinase A (PKA). Inhibition of PKA activity or knockdown of PKA catalytic subunit γ with RNAi attenuates the PGE2-induced tube formation. Further, knocking down the expression of Rap1A, HSPB6, or endothelial NO synthase, which serve as PKA-activatable substrates, inhibits the tube formation, whereas knockdown of RhoA or glycogen synthase kinase 3β that are inactivated after phosphorylation by PKA increases the tube formation. These results support the existence of EP4-to-PKA angiogenic signal and provide rationale for use of selective EP4 signal inhibitors as a probable strategy to control pathologic angiogenesis.     

The ��parallel pathway��: a novel nutritional and metabolic approach to cancer patients

Cancer-associated malnutrition results from a deadly combination of anorexia, which leads to reduced food intake, and derangements of host metabolism inducing body weight loss, and hindering its reversal with nutrient supplementation. Cancer patients often experience both anorexia and weight loss, contributing to the onset of the clinical feature named as anorexia–cachexia syndrome. This condition has a negative impact upon patients’ nutritional status. The pathogenesis of the anorexia–cachexia syndrome is multifactorial, and is related to: tumour-derived factors, host-derived factors inducing metabolic derangements, and side effects of anticancer therapies. In addition, the lack of awareness of cancer patients’ nutritional issues and status by many oncologists, frequently results in progressive weight loss going undiagnosed until it becomes severe. The critical involvement of host inflammatory response in the development of weight loss, and, in particular, lean body mass depletion, limits the response to the provision of standard nutrition support. A novel nutritional and metabolic approach, named “parallel pathway”, has been devised that may help maintain or improve nutritional status, and prevent or delay the onset of cancer cachexia. Such an approach may improve tolerance to aggressive anticancer therapies, and ameliorate the functional capacity and quality of life even in advanced disease stages. The “parallel pathway” implies a multiprofessional and multimodal approach aimed at ensuring early, appropriate and continuous nutritional and metabolic support to cancer patients in any phase of their cancer journey.     

Identification of a novel cellular target and a co-factor for norovirus infection – B cells & commensal bacteria

Human noroviruses are a leading cause of gastroenteritis worldwide but research on these important enteric pathogens has long been restricted by their uncultivability. Extensive efforts to infect intestinal epithelial cells with murine and human noroviruses in vitro have been thus far unsuccessful while murine noroviruses efficiently and lytically infect innate immune cells including macrophages and dendritic cells. We have recently discovered that murine and human noroviruses infect B cells in vitro. The nature of B cell infection was distinct from innate immune cell infection in that mature B cells were infected noncytopathically in contrast to the lytic infection of macrophages and dendritic cells. Human norovirus infection of B cells was facilitated by commensal bacteria expressing an appropriate histo-blood group antigen. Importantly, we used the mouse model of norovirus infection to confirm that Peyer''s patch B cells are infected, and that commensal bacteria stimulate infection, in vivo.     

Identification of a novel cellular target and a co-factor for norovirus infection – B cells & commensal bacteria

Human noroviruses are a leading cause of gastroenteritis worldwide but research on these important enteric pathogens has long been restricted by their uncultivability. Extensive efforts to infect intestinal epithelial cells with murine and human noroviruses in vitro have been thus far unsuccessful while murine noroviruses efficiently and lytically infect innate immune cells including macrophages and dendritic cells. We have recently discovered that murine and human noroviruses infect B cells in vitro. The nature of B cell infection was distinct from innate immune cell infection in that mature B cells were infected noncytopathically in contrast to the lytic infection of macrophages and dendritic cells. Human norovirus infection of B cells was facilitated by commensal bacteria expressing an appropriate histo-blood group antigen. Importantly, we used the mouse model of norovirus infection to confirm that Peyer's patch B cells are infected, and that commensal bacteria stimulate infection, in vivo.     

Bone marrow angiogenesis in aplastic anemia – a study of CD 34 and VEGF expression in bone marrow biopsies

Abstract

Introduction: Bone marrow function and the growth of hemopoietic cells depends on an intact microvasculature. A pivotal regulator of angiogenesis is vascular endothelial growth factor (VEGF). Our study assesses VEGF expression and microvessel density (MVD) in the bone marrow of patients with aplastic anemia (AA).

Materials and method: Bone marrow specimens from 25 patients with AA and 15 controls were studied. MVD was calculated on sections stained immunohistochemically for CD34. Subsequently, all the cases were studied for VEGF expression.

Results: Bone marrow MVD in patients with AA was significantly lower than that in controls (p<0·01). There was a significant MVD difference between severe AA and moderate AA (p<0·05). VEGF expression was also significantly lower in AA cases compared to controls (p<0·05).

Conclusion: Our data show that AA is associated with reduced angiogenesis and reduced VEGF expression. Defective angiogenesis may result in or aggravate bone marrow aplasia in AA patients. There are limited studies on this aspect. More studies to confirm the present hypothesis might pave the way for new treatment options in AA.     

Obstructive sleep apnoea and periodontitis: a novel association?

Purpose

Since both obstructive sleep apnoea (OSA) and periodontitis are associated with systemic inflammation and cardiovascular morbidity, we questioned whether there may be an association between these two disorders.

Materials and methods

A standard periodontal examination was undertaken in a group of 66 (54 men and 12 women) treatment-naïve patients diagnosed with OSA [apnoea–hypopnoea index (AHI) >5/h] to derive a number of quantitative variables which could then be used to determine the prevalence of periodontitis in a group of patients.

Results

The prevalence of periodontitis in our study group was 77–79%, depending on the definition used. This was almost four times that of historical controls derived from a recent national survey. When sleep-related variables were compared against periodontal variables, significant correlations were found between periodontal clinical attachment level and total sleep time.

Conclusion

Our pilot study suggests that OSA is associated with periodontitis. Further research is needed to elucidate the nature of this association.     

Genetic variation within the histamine pathway among patients with asthma – a pilot study

Objective: Histamine is an important mediator in the pathophysiology of asthma. We have previously reported that HRH1 is differentially expressed among those with asthma compared to those without asthma. Single histamine-related genes have also been associated with asthma. We aimed to evaluate known single nucleotide polymorphisms (SNPs) in genes along the histamine biotransformation and response pathway, and determine their association with asthma and HRH1 mRNA expression. Methods: We enrolled children and adults (n?=?93) with/without asthma who met inclusion/exclusion criteria. Genotyping was performed for nine known SNPs in the HDC, HRH1, HRH4, HNMT and ABP1 genes. HRH1 mRNA expression was determined on RNA from buccal tissue. General linear model, Fisher’s exact test and Chi-square test were used to determine differences in allele, genotype and haplotype frequency between subjects with and without asthma and differential HRH1 mRNA expression relative to genotype. Statistical significance was determined by p?<?0.05. Results: No difference was observed in genotype/allele frequency for the nine SNPs between subjects with and without asthma. The HNMT-1639C/-464C/314C/3′UTRA haplotype was more frequently observed in those without asthma than those with asthma (p?=?0.03). We also observed genetic differences relative to race and gender. HNMT 314 genotype CT was more frequent in males with asthma compared to those without asthma (p?=?0.04). Conclusions: Histamine pathway haplotype was associated with a diagnosis of asthma in our cohort but allele and genotype were not. Subgroup evaluations may also be important. Further studies are needed to determine the potential biological/clinical significance of our findings.