Inflammation & Allergy-Drug Targets (v.14, #1)

Meet Our Editor: by Kurt S. Zaenker (1-1).

Inflammatory bowel disease is a chronic, debilitating immunological disorder for which there are few effective treatments. New therapies targeting gut homing molecules, such as CCR9 and α4β7, are currently in development, with some of these reaching clinical trials. Gut-trophic molecules and their receptors are critical to the development of both tolerant and inflammatory immune responses in the gut. However, we know little regarding the function of homing molecules as it relates to IBD. Data have suggested both pathological and protective roles for gut homing molecules in IBD development and maintenance. In addition, recent research findings have suggested that chemokines can influence T cell differentiation and function. Given the current clinical relevance, it is essential to obtain a better understanding of the role of gut homing molecules in the regulation of IBD.

Pathogenic viral infections pose major health risks to humans and livestock due to viral infection-associated illnesses such as chronic or acute inflammation in crucial organs and systems, malignant and benign lesions. These lead to large number of illnesses and deaths worldwide each year. Outbreaks of emerging lethal viruses, such as Ebola virus, severe acute respiratory syndrome (SARS) virus and Middle East respiratory syndrome (MERS) virus, could lead to epidemics or even pandemics if they are not effectively controlled. Current strategies to prevent viral entry into the human body are focused on cleansing the surface of the skin that covers hands and fingers. Surface protection and disinfection against microorganisms, including viruses, is performed by sanitization of the skin surface through hand washing with soap and water, surface disinfectants, and hand sanitizers, particularly alcohol-based hand sanitizers. However, concerns about the overall ineffectiveness, toxicity of certain ingredients of disinfectants, pollution of the environment, and the short duration of antimicrobial activity of alcohol have not been addressed, and the epidemiology of certain major viral infections are not correlated inversely with the current measures of viral prevention. In addition to a short duration on the skin surface, alcohol is ineffective against certain viruses such as norovirus, rabies virus, and polio virus. There is a need for a novel approach to protect humans and livestock from infections of pathogenic viruses that is broadly effective, long-lasting (persistent), non-toxic, and environment-friendly. A strong candidate is a group of unique compounds found in Camellia sinensis (tea plant): the green tea polyphenols, in particular epigallocatechin-3-gallate (EGCG) and its lipophilic derivatives. This review discussed the weaknesses of current hand sanitizers, gathered published results from many studies on the antiviral activities of EGCG and its lipophilic derivatives, and the potential use of these compounds as a novel strategy for disease prevention, especially against pathogenic viruses.

Analgesic and Anti-Inflammatory Properties of Arylnitroalkenes by Laura Celano, Yolanda K. Cupertino Da Silva, Nicolás Cataldo, Martín Gabay, Alicia Merlino, Magna S. Alexandre-Moreira, Lidia Moreira Lima, Hugo Cerecetto, Mercedes González, Leonor Thomson (19-28).
In a recent work, we described the design and synthesis of arylnitroalkenes, able to scavenge macrophagederived oxidants, in particular peroxynitrite and peroxynitrite derived radicals. Four compounds emerged as potential leads, 1,1-dimethylamino-4-(2-nitro-1Z-ethenyl)benzene (1), 1,1-dimethylamino-4-(2-nitro-1Z-propenyl)benzene (2), 5- (2-nitro-1Z-ethenyl)benzo[d][1,3]dioxol (3), and 5-(2-nitro-1Z-ethenyl)benzo[d][1,3]dioxol (4). In the present work, the possibility of the preclinical validation of these molecules as anti-inflammatory and analgesic was explored in appropriate in vivo mouse models. Compounds 1, 2 and 4, administered orally as a single dose (30 µmol kg-1) to the mice showed anti-inflammatory and analgesic properties similar to classic nonsteroidal anti-inflammatory agents. The pharmacological effects were consistent with the inhibitory effect observed on prostaglandin endoperoxide H synthase (PGHS). In fact, both PGHS-1 and PGHS-2 were inhibited by the compounds, with compound 2 being more specific as PGHS-2 inhibitor with a specificity index superior to 70%. Conversely to classical nonsteroidal anti-inflammatory drugs, compound 2 inhibited peroxidase half reaction of the enzyme (IC50 2.3 µM) while the cyclooxygenase activity of hrPGHS-2 remained unchanged. In vitro experiments were reinforced by docking and molecular dynamics simulations showing arylnitroalkene moiety located in the region of the peroxidase active site, competing with the peroxide intermediate. The absence of toxicity and mutagenicity of the compounds was also demonstrated.

Cardiovascular Magnetic Resonance Imaging clarifies cardiac pathophysiology in early, asymptomatic diffuse systemic sclerosis by Sophie I. Mavrogeni, Konstantinos Bratis, Georgia Karabela, George Spiliotis, Kees van Wijk, David Hautemann, Johan H.C. Reiber, Loukia Koutsogeorgopoulou, George Markousis-Mavrogenis, Genovefa Kolovou, Efthymios Stavropoulos (29-36).
Background: Myopericardial inflammation, perfusion's defects and fibrosis are major causes of cardiac disease in scleroderma (SSc). We hypothesized that using inflammation and stress perfusion-fibrosis cardiovascular magnetic resonance (CMR), we can identify the pathophysiology of heart disease in asymptomatic diffuse SSc.
Patients-Methods: 46 recently diagnosed, asymptomatic patients with diffuse SSc had a CMR examination using a 1.5T system. ECG gated breath hold cine and short tau inversion recovery (STIR) T2 images were initially acquired. If T2 ratio<2 a stress perfusion-fibrosis protocol was applied. If T2>2 a myocarditis protocol including early (EGE) and late (LGE) gadolinium imaging was applied. SSc patients' results were compared with age and sex-matched controls and patients with coronary artery disease (CAD).
Results: In 2/46 SSc with T2 ratio>2, the myocarditis protocol was positive for acute myocardial inflammation, who developed clinical signs of acute myocarditis shortly after the CMR evaluation. In the rest 44/46 with T2 ratio<2 the stress perfusion-fibrosis CMR identified a significant reduction in Myocardial Perfusion Reserve Index (MPRI) compared with matched controls (0.6±0.4 vs 3.2±0.8, p<0.001), but not with CAD (0.6±0.4 vs 0.86±0.46, p=NS) and correlated only with the presence of digital ulcers (p<0.05). The scar was diffused and greater compared to controls, but did not differ from that assessed in CAD. Two years follow up, available in 11/44 SSc, showed further asymptomatic MPRI deterioration in all and diffuse subendocardial LGE in 8/11, without any change in LV, RV volumes and ejection fractions.
Conclusion: CMR may reveal severe cardiac involvement in early, asymptomatic diffuse SSc with normal routine cardiac evaluation, presenting either as myocardial inflammation or as severe reduction of MPRI and diffuse fibrosis with further deterioration in the long term follow up.


7-prenyloxi-6-methoxycoumarin from Polygala sabulosa A.W. Bennett Regulates p38 MAPK and NF-kB Pathways Inhibiting the Inflammation Induced by Carrageenan in the Mouse Model of Pleurisy by Marcus Vinicius Pereira dos Santos Nascimento, F&#225;bio Arruda-Silva, Ana Beatriz G. Luz, Dalila Venzke, Gustavo S. Queiroz, Beatriz G. Mendes, Eduardo R. Fernandes-Ribeiro, T&#226;nia S. Fr&#246;de, Moacir G. Pizzolatti, Eduardo M. Dalmarco (37-46).
Context: Polygala sabulosa, popularly known as “timutu-pinheirinho,” has been used in Brazilian folk medicine for the treatment of bowel and kidney disorders and as an expectorant.
Objective: Evaluate the anti-inflammatory effects of the crude extract (CE), acetonic fraction (Ac), and the main compound, 7-prenyloxi-6-methoxycoumarin (PC) on a mouse model of carrageenan-induced pleurisy.
Materials and Methods: A mouse model of carrageenan-induced pleurisy was used to investigate the effects of P. sabulosa CE, Ac and PC on leukocyte migration, exudate formation, activities of myeloperoxidase (MPO), and adenosine-deaminase (ADA), levels of tumor necrosis factor-? (TNF-?), interleukin 1? (IL-1?) and nitric oxide (NO). In addition, the effect of the plant material on lung histology was also evaluated. The effects of PC on the TNF-?, IL-1? and NO synthase 2 (NOS2) mRNA expression, were also investigated. Finally, the effect of PC on the nuclear factor-kappa B (NF-?B) and p38 mitogen-activated protein kinase (p38 MAPK) was also evaluated.
Results: CE, Ac and PC reduced inflammation in the pleural cavity and lungs. This effect was evidenced by reduction on all inflammatory parameters evaluated; the exception being the inability of the CE to inhibit exudate formation. In isolation, PC showed reduction on mRNA levels of TNF-?, IL-1? and NOS2, and on activation of the NF-?B and p38 MAPK pathways.
Conclusion: The presented results show that P. sabulosa has significant anti-inflammatory activity, as does its main compound, PC. Moreover, the results suggest that PC exerts its effects mainly by inhibited the NF-?B and p38 MAPK pathways.


Design, Synthesis and In Vitro Release Studies of Co-Drugs for Rheumatoid Arthritis by Patil Kashmira, Suneela Dhaneshwar, Chopade Shakuntala, Joshi Poorvashree (47-52).
Background: Rheumatoid arthritis (RA) is an autoimmune disease that results in a chronic, systemic inflammation that may affect many tissues and organs, but principally the synovial joints. The tendency for joint destruction is greatest in the early stages of disease hence current trend is to introduce a disease-modifying anti-rheumatic drug (DMARD) immediately after the diagnosis of RA in a step- up approach which is generally followed by its combination with a corticosteroid or NSAID.
Objective: Hydroxychloroquine (HCQ) is a slow acting DMARD used in the early stage of RA. NSAIDs if given in combination with HCQ would provide immediate symptomatic relief from pain and inflammation even before HCQ starts showing its disease modifying effects. Long half life of HCQ results in its accumulation in the body while frequent intake of NSAIDs results in severe GI side effects. Present project aims at minimizing these shortcomings by designing co-drugs of HCQ and NSAIDs as a potential combination RA therapy.
Method: Synthesis of two co-drugs was achieved by CDI coupling, followed by their spectral characterization. In vitro release kinetics was studied by HPTLC in aqueous buffers and tissue homogenates of upper GIT.
Results: Prodrugs were resistant to hydrolysis in buffers (pH 1.2 and 7.4) and stomach homogenates of Wistar rat but 32- 65% hydrolysis was observed in small intestinal homogenates.
Conclusion: We propose that the mutual prodrug strategy of a DMARD with NSAID could be useful in initial management of RA wherein NSAIDs would produce their anti-inflammatory effect and simultaneously the process of joint reconstruction by hydroxychloroquine could be initiated.


In vitro effects of infrared A radiation on the synthesis of MMP-1, catalase, superoxide dismutase and GADD45 alpha protein by Adilson Costa, Samara Eberlin, Stefano P. Clerici, Beatrice M.Z. Abdalla (53-59).
Harmful influences in the process of photoaging and skin damage are associated with infrared A (IRA) radiation, such as, disturbance of dermal extracellular matrix by up regulation of matrix metalloproteinase-1 (MMP1). Furthermore, DNA damage, induction of cytotoxicity and oxidative stress by decreasing natural antioxidant ability has been reported after acute exposure to IRA. The present study provides additional evidence that IRA radiation response in human skin fibroblasts produces deleterious effects to the cell, such as accelerating aging and weakening of their antioxidant defense mechanism. Human skin fibroblasts were exposed to a non-cytotoxic dose of IRA radiation and cultured for different periods for further collection of cell-free supernatants and lysates, and quantification of MMP-1, catalase, superoxide dismutase, and GADD45a. Our results corroborate previous published data and strongly indicate a negative impact of IRA radiation on the skin physiological by mechanisms involving reduced endogenous antioxidant enzymatic defense, increased MMP-1 and decreased repair process of DNA by reducing GADD45a protein, in cultured human fibroblasts. From a clinical perspective, IRA radiation acts by mechanisms distinct from those observed in ultraviolet radiation indicating the need for developing and making available cosmetics for skin care with properties beyond protection exerted by traditional sunscreens.

Investigation of 5-HT2A gene expression in PBMCs of patients with allergic asthma by Ghasem Ahangari, Somayeh Emadi Koochak, Leila Mohammadi Amirabad, Gholamreza Derkhshan Deilami (60-64).
Background: Asthma is an inflammatory airway disorder in which different immune cells in the blood and lungs play a fundamental role. In asthma condition, the airway inflammation accompanied by bronchial smooth muscle spasm cause airway obstruction. A study showed that high concentration of blood serotonin is associated with the intensity and exacerbation of asthma disease. Other studies showed that a subtype of serotonin receptor called 5-Hydroxytriptamine 2A receptor (5- HT2A) can enhance T-cell blastogenesis and production of pro-inflammatory cytokines such as IFN?. Objective: The objective of this study was to assess the level of 5-HT2A in peripheral blood mononuclear cells (PBMCs) of asthmatic patients. Methods: PBMCs were extracted from blood of 30 patients with asthma and 30 normal people. After synthesizing cDNAs from total mRNAs, real-time PCR was performed to amplify 5-HT2A and ?-actin (as an internal control). The expression ratios were analyzed in patients with asthma in comparison with normal group. Results: The results indicated that gene expression is significantly increased in peripheral blood mononuclear cells (PBMCs) of asthma patients in comparison with normal group (P = 0.003). Conclusion: The results of this study can suggest designing a protocol by using of the 5-HT2A receptor expression in PBMCs as a biomarker of asthma, but this requires further studies on a larger number of patients. In addition, the potential role of this receptor in bronchoconstriction can lead us to use its antagonists as a new treatment in asthma.