Evangelos Kazakos

Impact of reactive oxygen species generation on Helicobacter pylori-related extragastric diseases: a hypothesis.

Abstract Helicobacter pylori (H. pylori) induces reactive oxygen species (ROS) production that contribute to pathogenesis of a variety of H. pylori-related gastric diseases, as shown in animal and human studies. Helicobacter pylori infection is also associated with variety of systemic extragastric diseases in which H. pylori-related ROS production might also be involved in the pathogenesis of these systemic conditions. We proposed that Hp-related ROS may play a crucial role in the pathophysiology of Hp-related systemic diseases including Alzheimer’s disease, multiple sclerosis, glaucoma and other relative neurodegenerative diseases, thereby suggesting introduction of relative ROS scavengers as therapeutic strategies against these diseases which are among the leading causes of disability and are associated with a large public health global burden. Moreover, we postulated that H. pylori-related ROS might also be involved in the pathogenesis of extragastric common malignancies, thereby suggesting that H. pylori eradication might inhibit the development or delay the progression of aforementioned diseases. However, large-scale future studies are warranted to elucidate the proposed pathophysiological mechanisms, including H. pylori-related ROS, involved in H. pylori-associated systemic and malignant conditions.

Potential impact of Helicobacter pylori-related metabolic syndrome on upper and lower gastrointestinal tract oncogenesis

Both Helicobacter pylori infection and metabolic syndrome present significant global public health burdens. Metabolic syndrome is closely related to insulin resistance, the major underlying mechanism responsible for metabolic abnormalities, and Helicobacter pylori infection has been proposed to be a contributing factor. There is growing evidence for a potential association between Helicobacter pylori infection and insulin resistance, metabolic syndrome and related morbidity, including abdominal obesity, type 2 diabetes mellitus, dyslipidemia, hypertension, all of which increase mortality related to cardio-cerebrovascular disease, neurodegenerative disorders, nonalcoholic fatty liver disease and malignancies. More specifically, insulin resistance, metabolic syndrome and hyperinsulinemia have been associated with upper and lower gastrointestinal tract oncogenesis. Apart from cardio-cerebrovascular, degenerative diseases and nonalcoholic fatty liver disease, a number of studies claim that Helicobacter pylori infection is implicated in metabolic syndrome-related Barretts esophagus and esophageal adenocarcinoma development, gastric and duodenal ulcers and gastric oncogenesis as well as lower gastrointestinal tract oncogenesis. This review summarizes evidence on the potential impact of Helicobacter pylori-related metabolic syndrome on gastroesophageal reflux disease-Barretts esophagus-esophageal adenocarcinoma, gastric atrophy-intestinal metaplasia-dysplasia-gastric cancer and colorectal adenoma-dysplasia-colorectal cancer sequences. Helicobacter pylori eradication might inhibit these oncogenic processes, and thus further studies are warranted.

Novel aspects of defensins’ involvement in virus-induced autoimmunity in the central nervous system

Recent research on re-circulation of interstitial fluid from the brain parenchyma to the periphery and its inferred importance in immune surveillance dysregulation are changing our conceptualization of the pathophysiology of virus-induced autoimmunity. In this context, it is necessary to reassess the immunomodulatory properties of human defensins that are variably expressed by cerebral microglia, astrocytes and choroid plexus epithelial cells and exhibit complex and often confounding roles in neuroinflammatory processes. Therefore, in this review we describe current contributions in this field and we propose novel hypotheses regarding the potential impact of defensin-related pathways on virus-driven autoimmune neurodegeneration. In this regard, we have previously proposed that abnormal expression of defensins by penetrating the blood-brain barrier (BBB) may contribute to the pathophysiology of Helicobacter pylori-related brain neurodegenerative disorders through variable modulations of innate and adaptive immune responses. We hereby propose that impaired expression of defensins by structural components of the BBB may impede glymphatic circulation and disrupt receptor signalling in pericytes that is essential for microvascular stability, thereby retaining blood-derived toxins and bystander activated T-cells in the brain and further impairing BBB integrity and hampering viral clearance. Autoreactive T-cell infiltrates in neuronaxonal lesions characteristic of chronic central nervous system diseases, such as multiple sclerosis, are directed against both, myelin and non-myelin, antigens the precise nature of which remains enigmatic. Inadequate expression of the autoimmune regulator (AIRE), a gene expressed in medullary thymic epithelial cells, induces the recruitment of defensin-specific T-cells. These cells may access the brain, thereby causing a decrease in defensin expression and subsequent down-regulation of CD91/LRP1-mediated clearance of amyloid-β that ultimately accumulates as protein deposits. It should be highlighted that β-amyloid brain deposits are a hallmark of many neurodegenerative diseases. During human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections, selective elicitation of the VH1-69 antibody subfamily directed against specific, viral glycoprotein epitopes, often correlates with a higher likelihood of developing autoimmune disorders. In addition, we propose that recently described defensin affinity towards the same epitopes may prevent proper viral fusion, but at the expense of augmenting autoimmune reactivity. Moreover, in the context of complex and largely unknown symbiotic relations between host microbiota and pathogenic viruses, we propose that co-stimulation of defensin expression may modulate adaptive immune responses thereby enhancing inflammatory cascades responsible for autoimmunity. Finally, we describe current evidence that supports the hypothesis of a possible involvement of defensins in HCV-related autoimmunity. Exploring further potential implications of human defensins in virus-related autoimmunity may lead to improved strategies for the treatment of neurodegenerative disorders.

Letter: Helicobacter pylori-related non-alcoholic fatty liver disease with concomitant metabolic syndrome as risk factor for colorectal neoplasia.

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A potential impact of Helicobacter pylori -related galectin-3 in neurodegeneration

&NA; Neurodegeneration represents a component of the central nervous system (CNS) diseases pathogenesis, either as a disability primary source in the frame of prototype neurodegenerative disorders, or as a secondary effect, following inflammation, hypoxia or neurotoxicity. Galectins are members of the lectin superfamily, a group of endogenous glycan‐binding proteins, able to interact with glycosylated receptors expressed by several immune cell types. Glycan‐lectin interactions play critical roles in the living systems by involving and mediating a variety of biologically important normal and pathological processes, including cell‐cell signaling shaping cell communication, proliferation and migration, immune responses and fertilization, host‐pathogen interactions and diseases such as neurodegenerative disorders and tumors. This review focuses in the role of Galectin‐3 in shaping responses of the immune system against microbial agents, and concretely, Helicobacter pylori (Hp), thereby potentiating effect of the microbe in areas distant from the ordinary site of colonization, like the CNS. We hereby postulate that gastrointestinal Hp alterations in terms of immune cell functional phenotype, cytokine and chemokine secretion, may trigger systemic responses, thereby conferring implications for remote processes susceptible in immunity disequilibrium, namely, the CNS inflammation and/or neurodegeneration.

Comment on “Effect of biofilm formation by clinical isolates of Helicobacter pylori on the efflux-mediated resistance to commonly used antibiotics”

Attaran et al[1] have recently shown that decreased susceptibility of established Helicobacter pylori (H. pylori) biofilms to specific antibiotics, was associated with the overtly enhanced transcription of two efflux pump genes, hp1165 and hefA, involved in specific resistance to tetracycline and multiple antibiotics, respectively. Apart from antibiotic exposure, secretion of multiple antimicrobial peptides, such as human β-defensins (hβDs), by the gastric epithelium upon Hp challenge, may act as early triggering events that positively impact biofilm formation and thus, antibiotic resistance. In this regard, we undertook genomic transcriptional studies using Hp 26695 strain following exposure to sublethal, similar to those present in the gastric niche, concentrations of hβDs in an attempt to provide preliminary data regarding possible mechanisms of immune evasion and selective sensitivity of Hp. Our preliminary results indicate that hβD exposure ignites a rapid response that is largely due to the activation of several, possibly interconnected transcriptional regulatory networks – origons - that ultimately coordinate cellular processes needed to maintain homeostasis and successful adaptation of the bacterium in the gastric environment. In addition, we have shown that both antibiotic and hβD resistance are mediated by dedicated periplasmic transporters, including the aforementioned efflux pump genes hp1165 and hefA, involved in active export of antibiotics from the cell membrane and/or, as recently suggested, substrate sensing and signalling. Furthermore, it appears that sublethal doses of hβDs may enhance biofilm formation by the sustained expression of, mainly, quorum sensing-related genes. In conclusion, we provide additional data regarding the role of specific innate immune molecules in antibiotic cross-resistance mechanisms that may deepen our understanding in the context of the development of novel eradication regimens.

Novel Insights into the Role of Defensins in Virus-Induced Autoimmunity in the Central Nervous System

Virus-induced autoimmunity in the brain, an immune-privileged site, occurs primarily from a breach in thymic selection mechanisms that constitute peripheral tolerance, culminating in a self-directed, Tcell- mediated immune response traditionally thought to occur via molecular or epitope mimicry; immune recognition of novel selfantigens; bystander activation of autoreactive defensin-specific, Tlymphocytes (ATLs); and aberrant expression of cytokines in polyclonically expanded T-cell subsets.

The emerging role of helicobacter pylori-induced metabolic gastrointestinal dysmotility and neurodegeneration.

Helicobacter pylori infection (Hp-I) is a prevalent disorder identified in the majority of the population in many countries around the world and is responsible for substantial gastrointestinal morbidity. Likewise, neurodegenerative diseases such as Alzheimers disease, Parkinsons diseases, multiple sclerosis or glaucoma defined as ocular Alzheimers disease, are associated with a large public health burden and are among the leading causes of disability. Emerging evidences suggest that Hp-I may be associated with neurodegenerative conditions. Moreover, Hp-I could be a predictor of metabolic syndrome (MetS). Hp-I and its related MetS may induce gastrointestinal tract dys-motility disorders with systemic complications possibly including central nervous system neurodegenerative pathologies. We hereby explore the emerging role of Hprelated metabolic gastrointestinal dys-motilities on the molecular pathophysiology of Hprelated neurodegenerative and gastrointestinal disorders. Improving understanding of such Hp-I pathophysiology in brain pathologies may offer benefits by application of new relative therapeutic strategies including novel opportunities toward enhancing Hp eradication.

Letter: Helicobacter pylori in lean and obese patients with non-alcoholic fatty liver disease

SIRS, In their review, Sookoian and Pirola concluded that lean and obese non-alcoholic fatty liver disease (NAFLD) patients share a common altered metabolic and cardiovascular profile. This profile is similar to that observed in the traditional metabolic syndrome-associated NAFLD. Investigating the pathophysiological mechanisms underlying the above-mentioned profiles, we wish to share some relative data on the potential role of Helicobacter pylori infection. Evidence suggests a probable association between H. pylori infection and insulin resistance or metabolic syndrome and its related morbidity (ie, NAFLD, abdominal obesity, type 2 diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease, the end-point of metabolic syndrome). In terms of epidemiology, both H. pylori and metabolic syndrome are very common worldwide. Also, the increasing prevalence of metabolic syndrome follows the ongoing epidemics of obesity and type 2 diabetes mellitus. Metabolic syndrome decreases the lifespan, mainly due to type 2 diabetes mellitus, cardiovascular disease, and certain malignancies. Likewise, H. pylori infection prevalence is still high in most countries including South and East Europe, South America and Asia. Moreover, there are still contradictory data on the association between H. pylori and overweight/obesity that require further elucidation. At a cellular level, impaired gastric ghrelin production is associated with ghrelin-immunoreactive cells reduction in the oxyntic mucosa of lean patients with chronic H. pylori associated gastritis. In a study, we reported that NAFLD patients had higher anti-H. pylori IgG, lower circulating adiponectin, and higher tumour necrosis factor (TNF)-a levels, thereby indicating that H. pylori infection might represent one further hit in NAFLD pathogenesis. Furthermore, we recently showed that H. pylori-positive patients had increased risk of cardiovascular disease, since H. pylori infection increased the levels of fibrinogen, an independent risk factor for cardiovascular disease. Helicobacter pylori-related metabolic syndrome could also influence the cardio-cerebrovascular disease pathophysiology through several mechanisms, such as TNF-a involvement in atherosclerosis and atrial fibrillation-related stroke. Helicobacter pylori eradication: first, decreases fibrinogen, increases high-density lipoprotein-cholesterol, and it decreases Creactive protein levels significantly; second, it improves NAFLD fibrosis score and HSENSI (homocysteine, serum glutamic oxaloacetic transaminase, erythrocyte sedimentation rate, non-alcoholic steatohepatitis index); third, it improves homoeostatic model of assessment and insulin resistance, also mentioned by the authors, and might display a positive effect on H. pylori-related NAFLD and CVD development/progression by inhibiting various prothrombotic and proinflammatory agents; and finally, it might benefit metabolic syndrome-related morbidity. In summary, H. pylori infection as a risk factor for NAFLD, appears to be a common denominator underlying the shared altered metabolic syndrome and cardiovascular profile between lean and obese patients. Its eradication might benefit the aforementioned profile, and these findings merit further investigation.