Role Of Hp Research Articles

Efficiency of ferrotherapy when using different groups of iron drugs in patients with Helicobacter pylori

To date, a number of scientific studies are being conducted in the world devoted to the study of various variants of the manifestation of helicobacteriosis. Special attention should be paid to studies on the pathogenesis of iron drugs (ID) in helicobacteriosis and the role of eradication therapy in improving the effectiveness of iron therapy. Despite the fact that there are results of numerous studies confirming the role of HP in the development of ID, there are still unresolved issues related to determining the exact indications for specific therapy aimed at eradicating this infection in cases where patients with clinical and laboratory signs of ID do not have obvious symptoms damage to the gastric mucosa.

In silico Characterization of a Hypothetical Protein (PBJ89160.1) from Neisseria meningitidis Exhibits a New Insight on Nutritional Virulence and Molecular Docking to Uncover a Therapeutic Target.

Neisseria meningitidis is an encapsulated, diplococcus, kidney bean-shaped bacteria that causes bacterial meningitis. Our study hopes to advance our understanding of disease progression, the spread frequency of the bacteria in people, and the interactions between the bacteria and human body by identifying a functional protein, potentially serving as a target for meningococcal medicine in the future. A hypothetical protein HP (PBJ89160.1) from N. meningitidis was employed in this study for extensive structural and functional characterization. In the predictive functional role of HP, several constitutive bioinformatics approaches are applied, such as prediction of physiological properties, domain and motif family function, secondary and tertiary structure prediction, energy minimization, quality validation, docking, and ADMET analysis. To create the protein's three-dimensional (3D) structure, a template protein (PDB_ID: 3GXA) is used with 99% sequence identity by homology modeling technique with the HHpred server. To mitigate the pathogenicity associated with the HP function, it was docked with the natural ligand methionine and five other drug compounds like Verapamil, Loperamide, Thioridazine, Chlorpromazine, and Auranofine. The protein is predicted to be acidic, soluble and hydrophilic by physicochemical properties analysis. Subcellular localization analysis demonstrated the protein to be periplasmic. The HP has an ATP-binding cassette transporter (also known as ABC transporter) involved in uptake of methionine (MetQ) that creates nutritional virulence in host. Energy minimization, multiple quality assessments, and validation value determination led to the conclusion that the HP model had a workable and acceptable quality. Following ADMET analysis and binding affinity assessments from the docking studies, Loperamide emerged as the most promising therapeutic compound, effectively inhibiting the ATP transporter activity of the HP. Comparative genomic analysis revealed that this protein is specific to N. meningitidis and has no homologs in human proteins, thereby identifying it as a potential target for therapeutic intervention.

Helicobacter pylori infection may influence prevalence and disease course in myelin oligodendrocyte glycoprotein antibody associated disorder (MOGAD) similar to MS but not AQP4-IgG associated NMOSD.

Helicobacter pylori (Hp) persists after colonizing the gut in childhood, and potentially regulates host immune system through this process. Earlier studies have shown that Hp infection in childhood, may protect against MS in later life. Such an association was not seen with AQP4-IgG positive NMOSD, while the association with MOGAD is unclear. To evaluate frequency of Hp IgG among patients with MOGAD, MS, NMOSD and matched controls and its effect on disease course. To ascertain whether childhood socio economic factors were linked to prevalence of Hp infection. In all, 99 patients diagnosed to have MOGAD, 99 AQP4 IgG+ NMOSD, 254MS and 243 matched controls were included. Patient demographics, diagnosis, age at disease onset, duration and the last recorded expanded disability status scale (EDSS) were obtained from our records. Socioeconomic and educational status was queried using a previously validated questionnaire. Serum HpIgG was detected using ELISA kits (Vircell, Spain). Frequency of Hp IgG was significantly lower among MOGAD (28.3% vs 44%, p-0.007) and MS (21.2% vs 44%, p-0.0001) but not AQP4-IgG+ NMOSD patients (42.4% vs 44%, p-0.78) when compared to controls. Frequency of Hp IgG in MOGAD & MS patients combined (MOGAD-MS) was significantly lower than those with NMOSD (23.2% vs 42.4%, p- 0.0001). Seropositive patients with MOGAD- MS were older (p-0.001. OR -1.04, 95% CI- 1.01- 1.06) and had longer disease duration (p- 0.04, OR- 1.04, 95% CI- 1.002- 1.08) at time of testing. Educational status was lower among parents/caregivers of this study cohort (p- 0.001, OR -2.34, 95% CI- 1.48-3.69) who were Hp IgG+. In developing countries Hp infection may be a significant environmental factor related to autoimmune demyelinating CNS disease. Our preliminary data suggests that Hp may exert a differential influence -a largely protective role for MS-MOGAD but not NMOSD and may influence disease onset and course. This differential response maybe related to immuno-pathological similarities between MOGAD and MS in contrast to NMOSD. Our study further underscores the role of Hp as a surrogate marker for poor gut hygiene in childhood and its association with later onset of autoimmune diseases.

Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients.

This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology. Hp is a blood serum glycoprotein responsible for binding and removing toxic free hemoglobin from the vasculature. The role of Hp in patients with SCD is critical in combating blood toxicity, inflammation, oxidative stress, and even stroke. Ischemic stroke occurs when a blocked vessel decreases oxygen delivery in the blood to cerebral tissue and is commonly associated with SCD. Due to the malformed red blood cells of sickle hemoglobin S, blockage of blood flow is much more prevalent in patients with SCD. This review is the first to evaluate the role of the Hp polymorphism in the incidence of stroke in patients with SCD. Overall, the data compiled in this review suggest that further studies should be conducted to reveal and evaluate potential clinical advancements for gene therapy and Hp infusions.

Helicobacter pylori Infection Acts Synergistically with a High-Fat Diet in the Development of a Proinflammatory and Potentially Proatherogenic Endothelial Cell Environment in an Experimental Model.

Classic atherosclerosis risk factors do not explain all cases of chronic heart disease. There is significant evidence that gut microbiota may influence the development of atherosclerosis. The widespread prevalence of chronic Helicobacter pylori (H. pylori, HP) infections suggests that HP can be the source of components that stimulate local and systemic inflammatory responses. Elevated production of reactive oxygen species during HP infection leads to cholesterol oxidation, which drives atherogenesis. The aim of this study is to explore the link between persistent HP infection and a high-fat diet in the development of proinflammatory conditions that are potentially proatherogenic. An in vivo model of Caviae porcellus infected with HP and exposed to an experimental diet was investigated for the occurrence of a proinflammatory and proatherogenic endothelial environment. Vascular endothelial primary cells exposed to HP components were tested in vitro for oxidative stress, cell activation and apoptosis. The infiltration of inflammatory cells into the vascular endothelium of animals infected with HP and exposed to a high-fat diet was observed in conjunction with an increased level of inflammatory markers systemically. The arteries of such animals were the least elastic, suggesting the role of HP in arterial stiffness. Soluble HP components induced transformation of macrophages to foam cells in vitro and influenced the endothelial life span, which was correlated with Collagen I upregulation. These preliminary results support the hypothesis that HP antigens act synergistically with a high-fat diet in the development of proatherogenic conditions.

Sustained Helicobacter pylori infection accelerates gastric dysplasia in a mouse model.

More than 80% of gastric cancer is attributable to stomach infection with Helicobacter pylori (Hp). Gastric preneoplastic progression involves sequential tissue changes, including loss of parietal cells, metaplasia and dysplasia. In transgenic mice, active KRAS expression recapitulates these tissue changes in the absence of Hp infection. This model provides an experimental system to investigate additional roles of Hp in preneoplastic progression, beyond its known role in initiating inflammation. Tissue histology, gene expression, the immune cell repertoire, and metaplasia and dysplasia marker expression were assessed in KRAS+ mice +/-Hp infection. Hp+/KRAS+ mice had severe T-cell infiltration and altered macrophage polarization; a different trajectory of metaplasia; more dysplastic glands; and greater proliferation of metaplastic and dysplastic glands. Eradication of Hp with antibiotics, even after onset of metaplasia, prevented or reversed these tissue phenotypes. These results suggest that gastric preneoplastic progression differs between Hp+ and Hp- cases, and that sustained Hp infection can promote the later stages of gastric preneoplastic progression.

The Double-Edged Sword of a Calling: The Mediating Role of Harmonious and Obsessive Passions in the Relationship between a Calling, Workaholism, and Work Engagement.

Even though research on perceiving a calling has been growing, our understanding of its double-edged sword effects and psychological mechanisms remain unclear, especially in terms of work engagement and workaholism. Based on the heavy working investment (HWI) and dualistic model of passion (DMP) theories, we established a dual-path structural model to examine the effects of callings on work engagement and workaholism through two types of passion: harmonious (HP) and obsessive (OP) passions. Our results showed that the association between perceiving a calling and work engagement was partially mediated by HP, while the association between perceiving a calling and workaholism was fully mediated by OP. This study contributes to the literature in that it reveals how perceiving a calling has different effects on work engagement and workaholism through the HWI theoretical lens, as well as the mediating roles of HP and OP, based on the DMP theory. Our findings can be practically applied in organizations and counseling.

On Emotion Regulation Strategies and Well-Being: The Role of Passion

Emotion regulation entails using specific strategies to manage emotions, impacting on well-being. Research has uncovered important factors that may affect one’s use of emotion regulation strategies. Because passionate individuals experience positive and negative emotions while engaging in the activity that they deeply care about (Vallerand in The psychology of passion: a dualistic model, Oxford University Press, New York, 2015), it was proposed that they should be more likely to make use of emotion regulation strategies. Using the Dualistic Model of Passion (Vallerand et al. in J Personal Soc Psychol 85:756–767, 2003. https://doi.org/10.1037/0022-3514.85.4.756 ), this research tested an integrated model of passion, emotion regulated strategies, and psychological well-being. Three online studies were conducted. Study 1 (n = 370) used a cross-sectional design in order to explore the relationships between passion, emotion regulation strategies, and well-being in the context of various leisure activities. Using the same design, Study 2 (n = 253) aimed at replicating the findings from Study 1 within the specific context of romantic relationships. Finally, the goal of Study 3 (n = 253) was to replicate the findings from Studies 1 and 2 while using a prospective design. Overall, results from path analyses uncovered that HP was positively associated with cognitive reappraisal whereas OP was positively related to expressive suppression. Cognitive reappraisal was the only strategy positively linked to well-being. Findings underscore the important role of HP in the use of cognitive reappraisal, facilitating well-being.

Temporal and age-dependent effects of haptoglobin deletion on intracerebral hemorrhage-induced brain damage and neurobehavioral outcomes

Intracerebral hemorrhage (ICH) is a devastating stroke subtype and the presence of extracorpuscular hemoglobin (Hb) exacerbates brain damage. Haptoglobin (Hp) binds Hb, which prevents its oxidation and participation in neurotoxic reactions. Multiple studies have investigated the role of Hp under conditions of intravascular hemolysis, but little is known about its role in the brain and following ICH where extravascular hemolysis is rampant. Young and aged wildtype and Hp−/− mice underwent the autologous blood or collagenase ICH model. Early after ICH, Hp−/− mice display 58.0 ± 5.6% and 36.7 ± 6.9% less brain damage in the autologous blood and collagenase ICH models, respectively. In line with these findings, Hp−/− mice display less neurological deficits on several neurobehavioral tests. Hp−/− mice have less Perl's iron content, HO1 expression, and blood brain barrier dysfunction, but no difference in brain Hb content, astrogliosis and angiogenesis/neovascularization. At the later endpoint, the young cohort displays 27.8 ± 9.3% less brain damage, while no difference is seen with the aged cohort. For both cohorts, no differences are seen in HO1 levels or iron accumulation, but young Hp−/− mice display less thalamic astrogliosis and striatal microgliosis. This study reveals that the presence or absence of Hp exerts important time- and age-dependent influences on ICH outcomes.

Haptoglobin improves acute phase response and endotoxin tolerance in response to bacterial LPS

Sepsis is characterized by delayed acute phase response and lowered immune tolerance in patients. Acute phase serum proteins, like Haptoglobin (Hp), have been associated with increased mortality in bacteria mediated acute lung inflammation and sepsis in neonates. However, it’s direct role in modulating the immune response by regulating pro-inflammatory mediators leading to immune tolerant state and if gender affects its expression levels during bacterial infection, especially in blood has not been fully explored. To understand its specific role in endotoxin-mediated immune response, we investigated the correlation between the rise in Hp levels on bacterial infection and its influence on the expression of pro-inflammatory mediators in male and female Whole blood (WHB) and PBMCs. Here, we observed pathogen-specific and gender-specific expression of Hp. Gonadal steroid hormones differentially influenced the Hp expression in LPS-induced WHB, where the addition of Estrogen increased Hp expression, with suppression of TNFα, in both genders. Further on evaluating, the influence of Hp on TNFα expression in endotoxin tolerance (ET), we show that increased Hp levels directly reduced TNFα expression in ET models. Interestingly, blockade of secreted Hp significantly reversed the (ET) state, confirmed by a significant rise in TNFα expression in both ex vivo and in vitro ET models, indicating a possible feedback inhibition by Hp on inflammatory mediators like TNFα. We also investigated the role of PKCδ in the regulation of LPS induced secretion of acute phase proteins (Hp) in serum, where inhibition of PKCδ, reduced secretion of anti-microbial proteins in response to LPS shown by restored bacterial growth. These findings clearly highlight the crucial role of Hp in maintaining immune tolerance via suppressing the pro-inflammatory mediators and also in preventing bacterial proliferation in blood during infection.

ACTUAL HYGIENIC AND EPIDEMIOLOGICAL PROBLEMS OF HELICOBACTERIOSIS

This work is devoted to the problems of hygiene and epidemiology of the Helicobacter pylori infection. In recent years among the causative agents of infectious diseases, Helicobacter pylori (lat. Helicobacter pylori, HP.) takes a special place. Analysis of domestic and foreign literature had shown that at this time there is a high prevalence of Helicobacter infection (HI). It has been diagnosed in almost half of the world’s population. Published data of the Russian researchers point out its high occurrence among the population of Russia (56-88%). Analysis of the annual report of the Federal Service for Supervision in Protection of the Rights of Consumer and Man Wellbeing of the Russian Federation for 2017 showed an effective system of epidemiological and social and hygienic control of HI to have not been developed yet. Considering multiple mechanisms, ways and factors of transmission of the causative agent of HI, directions of scientific researches on the prevention of its distribution are planned. The solution of the hygienic and epidemiological problems of preventing helicobacteriosis can be carried out only by the consolidated participation of specialists of all directions of hygiene and laboratory science, as well as epidemiologists, microbiologists, and public health specialists. Clinical observations and laboratory results suggest a significant role of HP in human pathology: it is an etiological factor of more than half of all gastritis; it is found in more than 95% of patients suffering from duodenal ulcer, in 70-80% of persons with gastric ulcer, and in 60-70% of cases with gastric cancer. Accumulated over last 3 decades data indicates that up to 60-90% of all cases of stomach cancer may be associated with this infection. Against the background of such high numbers of the detection of this pathogen, questions arise why measures of hygienic prevention of Helicobacter pylori have not yet been developed, and scientific institutions of the epidemiological and hygienic profile are not sufficiently puzzled by their development.

Haptoglobin Is a Divergent MASP Family Member That Neofunctionalized To Recycle Hemoglobin via CD163 in Mammals.

In mammals, haptoglobin (Hp) is an acute-phase plasma protein that binds with high affinity to hemoglobin (Hb) released by intravascular hemolysis. The resultant Hp-Hb complexes are bound and cleared by the scavenger receptor CD163, limiting Hb-induced oxidative damage. In this study, we show that Hp is a divergent member of the complement-initiating MASP family of proteins, which emerged in the ancestor of jawed vertebrates. We demonstrate that Hp has been independently lost from multiple vertebrate lineages, that characterized Hb-interacting residues of mammals are poorly conserved in nonmammalian species maintaining Hp, and that the extended loop 3 region of Hp, which mediates CD163 binding, is present only in mammals. We show that the Hb-binding ability of cartilaginous fish (nurse shark, Ginglymostoma cirratum; small-spotted catshark, Scyliorhinus canicula; and thornback ray, Raja clavata) and teleost fish (rainbow trout, Oncorhynchus mykiss) Hp is species specific, and where binding does occur it is likely mediated through a different structural mechanism to mammalian Hp. The continued, high-level expression of Hp in cartilaginous fishes in which Hb binding is not evident signals that Hp has (an)other, yet unstudied, role(s) in these species. Previous work indicates that mammalian Hp also has secondary, immunomodulatory functions that are independent of Hb binding; our work suggests these may be remnants of evolutionary more ancient functions, retained after Hb removal became the primary role of Hp in mammals.

The protean role of haptoglobin and haptoglobin genotypes on vascular complications in diabetes mellitus.

Introduction and background Haptoglobin (Hp) is considered to be an antioxidant and protective against cardiovascular complications. Polymorphisms in the Hp gene interact with diabetes mellitus to affect the risk of vascular complications. Methods We review the updated literature about the protean role of Hp and Hp genotypes spanning genomics, molecular, translational and clinical studies. We searched Pubmed, SCOPUS and Google Scholar for all articles using the keywords: haptoglobin and/or haptoglobin polymorphism and diabetes. We review the diverse Hp genotypes, phenotypes and the impact on diabetes complications, including lessons from animal models and invitro models. We describe the clinical studies on the associations of Hp genotypes with vascular complications in type 1 and type 2 diabetes comprehensively. We review the studies looking at vitamin E supplementation in a personalized manner in Hp2-2 diabetes individuals. Results and conclusion Hp genotypes have evolved as a result of deletions in the traditional Hp genes. The Hp genotypes have been associated with microvascular and macrovascular complications in type 1 diabetes mellitus but the association in type 2 diabetes is more consistent with cardiovascular complications. A preferential benefit of vitamin E and other antioxidants in the Hp2-2 genotype for cardiovascular complications in type 2 diabetes has been seen presumably secondary to interaction with high-density lipoprotein function. Hence, the Hp genotype can be used to personalize antioxidant therapeutics in diabetes patients. These results need to be corroborated in large, global, pragmatic, prospective, cardiovascular outcome trials in type 2 diabetes patients.

Association between haptoglobin genotype and coronary artery stenosis in patient with premature coronary artery disease

Background: Accumulating evidence implicates Haptoglobin (Hp) gene polymorphism as a potential risk predictor for Coronary Artery Disease (CAD). We explored the association of Hp polymorphism with premature CAD and its severity within 165 unrelated Chinese patients and 116 healthy controls using genotyping, biochemical parameters, and the Gensini scoring system. Levels of HP and IL-17 in plasma were determined by ELISA. Results: The frequencies of Hp genotypes and Alleles, Hp levels and IL-17 levels were significantly different between CVD group and control group, and among the three subgroups. Hp2-2 was associated with the highest Gensini score but the lowest Hp concentrations. After adjustments for confounding parameters, the OR of premature CAD associated with Hp2-2 was 0.630 (95% CI 0.449-0.884; P<0.05). The Hp2-2 genotype was associated with an increase in coronary artery stenosis especially in group C (OR=2.319; 95% CI 1.278-4.209; P<0.05). Gensini score was associated with Hp and IL-17 levels when we considered the entire patients. r-values were 0.296 and 0.140, respectively (P<0.05). Conclusions: Hp polymorphism is independently associated with increasing CAD severity. Hp and IL-17 may be biomarker of coronary artery stenosis. Further studies are warranted to study the role of Hp and IL-17 in the pathogenesis of CAD.

Effects of the cannabinoid 1 receptor peptide ligands hemopressin, (m)RVD-hemopressin(α) and (m)VD-hemopressin(α) on memory in novel object and object location recognition tasks in normal young and Aβ1–42-treated mice

The cannabinoid system plays an important role in memory processes, many studies have indicated that cannabinoid receptor ligands have ability to modulate memory in rodents. A nonapeptide hemopressin (Hp) derived from rat brain, acts as a peptide antagonist or selective inverse peptide agonist of cannabinoid 1 (CB1) receptor. N-terminally extended forms of Hp isolated from mouse brain, (m)RVD-hemopressin(α) (RVD) and (m)VD-hemopressin(α) (VD) also bind CB1 receptor, however, as peptide agonists. Here, we investigated the roles of Hp, RVD, and VD on memory in mice using novel object recognition (NOR) and object location recognition (OLR) tasks.In normal young mice, intracerebroventricular (i.c.v.) infusion of Hp before training not only improved memory formation, but also prolonged memory retention in the tasks, these effects could be inhibited by RVD or VD at the same dose and intraperitoneal (i.p.) injection of a small molecule agonist of CB1 receptor WIN55, 212-2 15min before administration of Hp inhibited the memory-improving effect of Hp. In addition, under the same experimental conditions, i.c.v. RVD or VD displayed memory-impairing effects, which could be prevented by Hp (i.c.v.) or AM251 (i.p.), a small molecule antagonist of CB1 receptor.Infusion of amyloid-β (1–42) (Aβ1–42) 14days before training resulted in impairment of memory in mice which could be used as animal model of Alzheimer’s disease (AD). In these mice, RVD or VD (i.c.v.) reversed the memory impairment induced by Aβ1–42, and the effects of RVD and VD could be suppressed by Hp (i.c.v.) or AM251 (2mg/kg, i.p.). Separate administration of Hp had no effect in Aβ1–42-treated mice.The above results suggested that Hp, RVD and VD, as CB1 receptor peptide ligands, may be potential drugs to treatment of the memory deficit-involving disease, just as AD.

Role of Haptoglobin in Health and Disease: A Focus on Diabetes.

In Brief Prospective identification of individuals with diabetes who are at greatest risk for developing complications would have considerable public health importance by allowing appropriate resources to be focused on those who would benefit most from aggressive intervention. Haptoglobin (Hp) is an acute-phase protein that is crucial for the elimination of free hemoglobin and the neutralization of oxidative damage. In the past two decades, associations have been made between polymorphisms in Hp and complications arising from diabetes. Individuals with polymorphism in Hp have been shown to have significantly higher risk of developing cardiovascular disease. This review summarizes the current literature on the role of Hp in health and disease, with a focus on diabetes.

Abstract TP111: Haptoglobin Improves Intracerebral Hemorrhage Outcomes by Modulating Angiogenic Responses

Intracerebral hemorrhage (ICH) most often occurs spontaneously and is one of the most devastating stroke subtypes. Following ICH, toxic blood components must be cleared from the brain as part of the tissue repair/scar formation healing process. Angiogenesis is a key physiologic mechanism that facilitates tissue repair following acute injury, but must be tightly regulated to prevent excessive activity and deleterious consequences. After ICH, regulation of angiogenesis within the appropriate range in injured brain regions would allow for delivery of glucose and oxygen to support the energy-requiring reparative processes and facilitate the necessary entry of peripheral cells involved. Haptoglobin (Hp) is an acute phase protein that binds extracorpuscular hemoglobin, thereby directly reducing its oxidative potential, and Hp has also been shown to have potent angiogenic, vasculogenic, and wound healing properties. Using the autologous blood model of ICH, we have shown that Hp overexpression significantly improves ICH outcomes and reduces oxidative processes. Here, we aimed to confirm our previous results and further characterize the mechanisms by which Hp exerts these neuroprotective effects. Hp was overexpressed in the brain using adeno-associated viral vectors and ICH was induced using the collagenase-induced spontaneous bleeding model, which is accompanied by clinically relevant intraventricular hemorrhage. In line with our previous study, Hp-overexpressing mice demonstrate significantly smaller lesion volumes (p&lt;0.01) and less residual blood (p&lt;0.05). This reduced ICH-induced brain injury is accompanied by trends towards improved ambulatory ability and less focal neurological deficits at 72h post-ICH (p&lt;0.07). Hp-overexpressing mice have significantly reduced PECAM-1 expression and tend to have less VEGF immunoreactivity. After correcting for lesion volume, Hp-overexpressing mice retain the decreased PECAM-1 expression, but VEGF expression is increased, collectively suggesting a direct role of Hp in positively modulating angiogenesis after ICH. Hp therapy could represent a new treatment strategy for ICH through a multifactorial mechanism that includes the modulation of important angiogenic processes.

Different target specificities of haptoglobin and hemopexin define a sequential protection system against vascular hemoglobin toxicity

Free hemoglobin (Hb) triggered vascular damage occurs in many hemolytic diseases, such as sickle cell disease, with an unmet need for specific therapeutic interventions. Based on clinical observations the Hb and heme scavenger proteins haptoglobin (Hp) and hemopexin (Hx) have been characterized as a sequential defense system with Hp as the primary protector and Hx as a backup when all Hp is depleted during more severe intravascular hemolysis. In this study we present a mechanistic rationale for this paradigm based on a combined biochemical and cell biological approach directed at understanding the unique roles of Hp and Hx in Hb detoxification. Using a novel in vitro model of Hb triggered endothelial damage, which recapitulates the well-characterized pathophysiologic sequence of oxyHb(Fe2+) transformation to ferric Hb(Fe3+), free heme transfer from ferric Hb(Fe3+) to lipoprotein and subsequent oxidative reactions in the lipophilic phase. The accumulation of toxic lipid peroxidation products liberated during oxidation reactions ultimately lead to endothelial damage characterized by a specific gene expression pattern with reduced cellular ATP and monolayer disintegration. Quantitative analysis of key chemical and biological parameters allowed us to precisely define the mechanisms and concentrations required for Hp and Hx to prevent this toxicity. In the case of Hp we defined an exponential relationship between Hp availability relative to oxyHb(Fe2+) and related protective activity. This exponential relationship demonstrates that large Hp quantities are required to prevent Hb toxicity. In contrast, the linear relationship between Hx concentration and protection defines a highly efficient backup scavenger system during conditions of large excess of free oxyHb(Fe2+) that occurs when all Hp is consumed. The diverse protective function of Hp and Hx in this model can be explained by the different target specificities of the two proteins.

Understanding the role of haptoglobin in psoriasis: effects of ultraviolet B.

Haptoglobin (Hp) is one of the acute phase proteins, whose main function is to bind free haemoglobin (Hb) and transport it to the liver for degradation and iron recycling. In addition to its role as an Hb scavenger, Hp has been shown to behave as an anti-inflammatory, antioxidant and angiogenic factor. We previously investigated the role of Hp in the pathogenesis of psoriasis, and found that it displays some structural modifications that might be associated with protein function in the disease. Phototherapy is an efficacious treatment for psoriasis, although the biological mechanisms by which phototherapy improves psoriasis are still unclear. To investigate the effects of ultraviolet (UV)B on Hp to clarify the role of Hp in psoriasis. Expression of the genes encoding Hp, interleukin (IL)-6 and IL-10 was assessed in UVB-irradiated and unirradiated HaCaT cells. The biological significance of Hp modulation of UVB treatment was confirmed by ELISA and Western blotting. The Hp gene and protein expression in the skin of patients with psoriasis was also investigated. In vitro results showed that UVB modulated IL-6 and IL-10 gene expression and Hp gene and protein expression in HaCaT cells. The invivo data also showed that Hp levels were increased in the skin of patients with psoriasis compared with healthy controls. UVB irradiation was able to modulate Hp production in immortalized keratinocytes. The higher levels of Hp invivo in both lesional and nonlesional skin suggest that it might have a role in the pathogenesis of the disease.

Modulation of immune responses toward Helicobacter pylori infection by NLRs (INM6P.339)

Abstract Helicobacter pylori (HP) colonizes 50% of the world’s population resulting in a decades-long gastric infection. Bacterial interaction with host intracellular environment occurs via injection of bacterial components through a TIVSS or intracellular replication. HP has been recognized for its ability to modulate intracellular NOD-like receptors (NLR). Host responses toward the bacterium can result in asymptomatic, pathogenic or even favorable immunity. Mechanisms underlying the dual role of HP as a commensal versus pathogen are not completely understood. We combined computational modeling, bioinformatics and experimental validation to investigate intracellular host-HP interactions. Global transcriptomic analysis on bone marrow-derived macrophages (BMDM) in a gentamycin protection assay unveiled that intracellular colonization of HP upregulated NOD1, NOD2, NLRP3, NLRC5 and inflammasome components (Caspase-1 and -11) but suppressed regulatory NLRX1 which was inversely correlated to TRAF6, NF-B, proinflammatory cytokines and reactive oxygen species. Loss of NLRX1 facilitates bacterial clearance in BMDM and infected mice. Lastly, we constructed a computational model to shed light on complex immune responses and pathway crosstalk regulated by NLRX1 during infection. In conclusion, NLRX1 is associated with chronic bacterial persistence during H. pylori infection and it may represent an immune evasion mechanism employed by the bacterium to facilitate long-term host colonization.