Inflammation & Allergy-Drug Targets (v.14, #2)

Meet Our Editorial Board Member by Dolores Pérez-Sala (65-65).

A Systematic Review of the Molecular Mechanisms of Uranium -Induced Reproductive Toxicity by Mohammad Hossein Asghari, Soodabeh Saeidnia, Mohammad Amin Rezvanfar, Mohammad Abdollahi (67-76).
Uranium is the heaviest metal known as nuclear fuel, and employed in the production of glass tinting compounds, ceramic glazes, gyroscope wheels, chemical catalysts and X-ray tube targets. Inhalation and ingestion are two of the most usual ways of exposure. Uranium may be released into drinking water through the mining leading to contamination. Uranium is able to damage the DNA by generation of free radicals and acting as a catalyst in the Fenton reactions causing oxidative stress. In fact, reproductive system contains high amount of polyunsaturated fatty acids, and therefore it is highly vulnerable to reactive oxygen species (ROS) and sensitive to uranium toxicity. Toxic effects of uranium are generally reported through different mechanisms of action including inflammation, degeneration of testis, vacuolization of Leydig cells, spermatocytes necrosis, and oocyte dysmorphism. The present article provides a comprehensive review of the recent findings mostly about the molecular and biochemical toxicity of uranium on the reproductive system.

Inducible Nitric Oxide Synthase Expression in Liver Injury: Liver Protective Effects on Primary Rat Hepatocytes by Masaki Kaibori, Tadayoshi Okumura, Kenji Sato, Mikio Nishizawa, Masanori Kon (77-83).
Background/Aims: Following injury to the liver, liver cells, including Kupffer cells and hepatocytes express inducible nitric oxide synthase (iNOS), followed by the production of excess levels of nitric oxide (NO). NO produced by iNOS has been found to contribute to liver injury. Treatment of primary cultures of rat hepatocytes with the proinflammatory cytokine interleukin (IL)-1? stimulated iNOS expression and NO production. Experiments with this in vitro hepatocyte model of liver injury and with in vivo animal models of liver injury have demonstrated that drugs showing a liver-protective effect in vivo also inhibited the induction of iNOS expression and NO production both in vivo and in vitro. Thus, in this in vitro hepatocyte model, the prevention of iNOS expression and NO production are considered indicators of liver protection.
Results/Conclusion: This review describes a simple in vitro liver injury model, consisting of IL-1?-stimulated cultured hepatocytes, and methods used to analyze the mechanisms of action of drugs that inhibit iNOS expression. This in vitro hepatocyte model may be used to assess the liver-protective effects of pharmaceutical agents, herbal medicines, and certain types of foods.

Microbiome Regulation of Autoimmune, Gut and Liver Associated Diseases by Bhagirath Singh, Nan Qin, Gregor Reid (84-93).
Extensive analysis of the complexity and diversity of microbiota using metagenomics in the gut and other body sites has provided evidence that dysbiosis occurs in many disease states. With the application of next generation sequencing technology this research is starting to uncover the impact of microbiota on metabolic, physiological and immunological pathways and elucidate the cellular and molecular mechanisms involved. To highlight these advances we have focused on autoimmunity and gut and liver related diseases and discuss the opportunities and challenges of translating microbiome research towards its application in humans. Towards this goal we discuss the application of fecal microbiome transplantation (FMT) for the treatment of multiple chronic gut associated inflammatory diseases such as Clostridium difficile infection (CDI) and inflammatory bowel disease (IBD). The potential role of human migration across continents and cultures leading to alteration in their microbiome and its implication in health and disease is also discussed.

Vaccination and Induction of Autoimmune Diseases by Éric Toussirot, Matthieu Bereau (94-98).
Vaccines have been suspected of playing a role in inducing autoimmune disease (AID) for a long time. However, apart from certain specific vaccine strains and complications (such as the swine flu vaccine and Guillain- Barre syndrome in 1976, thrombocytopenia and the Measles-Mumps-Rubella vaccine), this role has not been established. In spite of this, many isolated cases or series of cases of arthritis, vasculitis, and central or peripheral nervous system symptoms following vaccination have been reported. These cases tend to be very infrequent and usually only the shortterm outcomes are described. This paper will examine the arguments for and against the relationship between vaccines and AID, bearing in mind that no association between the two has been clearly identified up to now. The role of adjuvants in vaccines has been described by other teams and in a more general syndrome (Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants). Thus, cases of AID triggered by vaccines are highly rare and raise questions about the interaction between vaccines and/or their adjuvants and the genetic context of autoimmune disease. These observations should therefore not undermine the benefits of vaccination.

LPS Up-Regulates Cystathionine ? -Lyase Gene Expression in Primary Human Macrophages via NF-?B/ERK Pathway by Alireza Badiei, Steven Gieseg, Sian Davies, Mohd Izani Othman, Madhav Bhatia (99-104).
Hydrogen sulfide (H2S) is an endogenous inflammatory mediator produced by the activity of cystathionine ?-lyase (CSE) in mammals. Macrophages are a key element of the immune system and play a crucial role in inflammation. To determine the role of H2S and macrophages in inflammation, we investigated the expression of CSE in human primary macrophages. Our results show that H2S is produced by the activity of CSE in these cells. To investigate the role of common signalling pathway in biosynthesis of CSE in human primary macrophages, specific inhibitors were used to block NF-?B, ERK, p38 and JNK. Inhibition of NF-?B, ERK significantly reduced levels of CSE gene and protein expression in these cells but inhibition of JNK and p38 did not have an inhibitory effect on the expression of CSE gene in macrophages. Inhibition of NF-?B and ERK prevented the effect of LPS on H2S synthesizing activity in human primary macrophages. These data showed that H2S acts as an inflammatory mediator via NF-?B/ERK pathway in macrophages.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease that mimics many of the clinical and pathological features of multiple sclerosis. We have previously described a significant diminution in the GABAergic regulation of glutamate release from synaptosomes of EAE rats isolated during the acute stage of the disease. In order to explore the possible metabolic pathways responsible for this alteration, in this work we evaluate the direct effect of different GABAergic agonists on the glutamate release and concomitant synapsin I phosphorylation in synaptosomes from the frontal cortex of control and EAE animals. The results show that GABA as well as the GABA receptor agonists Muscimol (GABAA agonist) and Baclofen (GABAB agonist) caused a decrease in glutamate release in control rats paralleled by a similar reduction in synapsin I phosphorylation. Meanwhile synaptosomes from EAE animals are responsive only to Baclofen with respect to nontreated EAE synaptosomes, since glutamate release from the synaptosomes treated with Muscimol was similar to that observed in EAE rat synaptosomes which was already reduced as consequence of the disease. In the case of the benzodiazepines Diazepam and Clonazepam (GABAA allosteric agonists), both of them induced a reduction in glutamate release in synaptosomes from the CFA rats, effect that was only observed in synaptosomes of EAE rats treated with Clonazepam. In all cases both benzodiazepines showed a higher effect on synapsin I phosphorylation than in glutamate release. These results indicate that the extent of GABAergic modulation of presynaptic terminals depends on the type of agonist employed and this regulation is altered in the frontal cortex during the acute phase of EAE with respect to control animals.

Imaging Patterns of Cardiovascular Involvement in Mixed Connective Tissue Disease Evaluated by Cardiovascular Magnetic Resonance by Sophie Mavrogeni, Petros P. Sfikakis, Theodoros Dimitroulas, Loukia Koutsogeorgopoulou, Georgia Karabela, Gikas Katsifis, Efthymios Stavropoulos, Elias Gialafos, George Spiliotis, Genovefa Kolovou, George D. Kitas (111-116).
Background: To clarify the imaging patterns of cardiovascular lesions in patients with mixed connective tissue disease (MCTD) and cardiovascular symptoms with or/ without abnormal routine non-invasive evaluation.
Patients-Methods: Twenty-two MCTD patients (19F/3M), aged 38±4 yrs with cardiovascular symptoms were evaluated using a 1.5 T scanner. Of them, 8/22 had systemic lupus erythematosus (SLE), 5/22 rheumatoid arthritis (RA), 5/22 scleroderma (SSc) and 4/22 myositis (MY) overlap syndromes; 10/22 patients with MCTD presented with Raynaud phenomenon (RP) and all were positive for Anti-RNP antibodies. The cardiovascular magnetic resonance study (CMR) included evaluation of function, inflammation and fibrosis. Myocardial stress perfusion-fibrosis evaluation was performed only in MCTD patients with RP.
Results: A positive CMR study was identified in 4/8 with SLE, 1/5 with RA, 4/5 with SSc and in 1/4 with MY like MCTD. The CMR lesions were subendocardial or transmural LGE following the distribution of coronary arteries, intramyocardial LGE and diffuse subendocardial LGE in SLE-RA, MY and SSc like MCTD, respectively. Although no evidence of fibrosis was identified in patients with RP, adenosine stress myocardial perfusion revealed diffuse subendocardial perfusion defects. No correlation between disease duration and/or inflammatory indices and cardiac lesions was identified.
Conclusion: CMR can reveal myocardial lesions in MCTD patients with cardiac symptoms including myocardial infarction, inflammation, diffuse subendocardial fibrosis and diffuse perfusion defects, necessitating further cardiac investigation and/or treatment.

Anti-Inflammatory Role of Thyroid Hormones on Rat Air Pouch Model of Inflammation by Bhagyashree Nijampurkar, Farheen Qureshi, Neha Jain, Tushar Banerjee, Anil Kumar, Hamendra Singh Parmar (117-124).
Background: Many studies showed anti-inflammatory potential of thyroid hormones, but no direct report available showing influence of thyroid hormones on inflammation state. Therefore, in present study anti-inflammatory and antioxidative role of thyroid hormones being evaluated on rat air pouch model of inflammation.
Methods: Reference doses of both the thyroid hormones triiodothyronine (T3) and thyroxine (T4) were administered to rat airpouches. Air pouch model was developed by injecting air into intra-scapular region of animals, followed by carrageenan administration (AP+C). Control animals injected only with air (AP).
Results: In AP+C, group an increase was observed in exudate levels of TNF-?, total leukocytes, polymophonuclear cells and mononuclear cells. An increase was also observed in exudates and tissue lipid peroxidation, nitrite and reduced glutathione. These changes were reverted back by the administration of indomethacin (I) or T3or T4. However, effect was more pronounced in case of T3, as compared to other groups on most of the studied parameters. Histopathological changes were also observed in AP+C group, as compared to AP alone and these alterations were also normalized by the administration of I or T3 or T4. In silico interaction of both the thyroid hormones with cyclooxygenase (COX-2) was studied and compared with standard drugs indomethacin and celecoxib.
Conclusion: We conclude thyroid hormones have anti-inflammatory potential i.e. mainly mediated through their structural similarity with anti-inflammatory drugs.

Heliotropium subulatum is an erect or procumbent perennial herb; leaves contain foliar trichomes and its resinous exudate is used in traditional medicine. The anti-inflammatory activity of dichloromethane fraction and isolated flavonoids was evaluated by using carrageenan and CFA-induced paw oedema models. Similarly, the disc diffusion and microdilution methods were used for the assessment of antimicrobial activity. Five isolated flavonoids were investigated for their antiinflammatory and antimicrobial activities. Eriodictyol demonstrated maximum anti-inflammatory activity (53.09%) at 30.0 mg/kg dose on 6th h and similarly, it inhibited the CFA-induced arthritis swelling (41.84%) with 30.0 mg/kg dose on 8th day respectively. As per disc diffusion and microdilution methods used for antimicrobial activity determination, the pinocembrin was found to be most active against Staphylococcus aureus (IZ=27±0.7 mm, 08 ?g/ml dose) and Candida albicans (IZ=17±0.9 mm; 12 ?g/ml dose). These investigated results revealed that the eriodictyol and pinocembrin showed significant anti-inflammatory and antimicrobial activities. Further studies which aimed to investigate the mechanism of action of these isolated flavonoids in the treatment of inflammations and various types of infections have been initiated.

Thiopurines have been shown to effectively maintain remission of both Crohn's disease (CD) and ulcerative colitis (UC), and to behave as disease modifiers if used for >12 months in UC. Gastric intolerance manifesting as nausea constitutes a demanding drawback of thiopurines, at times forcing treatment discontinuance. A few studies have now indicated that some patients might tolerate mercaptopurine (6-MP) for azathioprine. In this paper, we review the literature, and reappraise our own data against the published figures.
The data which form the basis for this study span over all visit reports that were released between January 2008 and December 2011 in a primary care Hospital, in Turin, Italy. For the aim of this study we searched our own database and the MedLine using the key-words “azathioprine”, “mercaptopurine”, “thiopurine”, “inflammatory bowel disease”, “Crohn's disease”, “ulcerative colitis”.
We retrieved 85 azathioprine prescriptions for 42 UC, 37 CD, and 6 miscellaneous patients. There were 10 episodes of gastric intolerance to azathioprine, which were switched to 6-MP: 6 out of 10 (60%) responded and tolerated the switch drug in a median follow-up of 66 months. Female gender prevailed (p=0.038) in the azathioprine intolerant subset.
A trial with 6-MP is worth being offered to azathioprine intolerant inflammatory bowel disease subjects at any center matching the standard figures of specific performance.