Inflammation & allergy drug targets最新文献

Historical background: The clinical recognition of a form of dementia closely resembling Alzheimer's disease dates from around 1800. The role of analgesics derived from coal-tar in the spread of the pandemic is traced in terms of the introduction of phenacetin (PN) in 1887; its nephrotoxicity; the observation of lesions characteristic of the disease by Fischer and Alzheimer; the discovery of paracetamol (PA) as the major metabolite of PN; the linking of kidney injury and dementia with high PN usage; and the failure of PN replacement by PA to halt and reverse the exponential, inexorable rise in the incidence of Alzheimer-type dementia. Fischer observed his first case before Alzheimer; it is proposed to rename the syndrome Fischer-Alzheimer disease (F-AD). Disease development: PA-metabolising enzymes are localised in the synaptic areas of the frontal cortex and hippocampus, where F-AD lesions arise. The initiating chemical lesions in liver poisoning comprise covalent binding of a highly reactive product of PA metabolism to proteins; similar events are believed to occur in brain, where alterations in the antigenic profiles of cerebral proteins activate the microglia. β-Amyloid forms, and, like PA itself, induces nitric oxide synthase. Peroxynitrite modifies cerebral proteins by nitrating tyrosine residues, further challenging the microglia and exacerbating the amyloid cascade. Spontaneous reinnervation, N-acetyl cysteine administration and tyrosine supplementation may attenuate the early stages of F-AD development.

Conclusion: F-AD is primarily a man-made condition with PA as its principal risk factor.

Simvastatin has important immune-modulatory and anti-inflammatory effects independent of lipid lowering effects. Therefore, our study was conducted to investigate the anti-inflammatory effects of simvastatin either alone or in combination with aspirin. Air pouch granuloma model was used for induction of inflammation in 72 male Wistar albino rats, which were treated with simvastatin (20 mg/kg/day), aspirin (25 mg/kg/day) or both for 3 or 6 executive days. Inflammatory exudates were collected and measured. Oxidative stress was assessed by measuring exudates' malondialdehyde (MDA) and nitric oxide (NO). Inflammatory mediator C-reactive protein (CRP) was investigated using slide agglutination test. Exudates' levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-4 were measured by ELISA. We found that simvastatin alone or in combination with aspirin exerts anti-inflammatory effects by reducing volume of exudates. Simvastatin significantly reduced serum level of CRP and exudates levels of TNF-α, IL-6 and MDA as well as significantly elevated exudates level of NO and IL-4. The results of simvastain were comparable to those of aspirin. In conclusion, air pouch granuloma interrupted the balance between inflammatory and anti-inflammatory markers, which is restored by simvastatin. The anti-inflammatory effects of simvastatin are comparable to aspirin and their combination may produce better effects especially in the attenuation of the oxidative stress and IL-6.

The intestines harbor over trillions of commensal bacteria, which co-evolve and form a mutualistic relationship with the host, with microbial-host interaction shaping immune adaption and bacterial communities. The intestinal microbiota not only benefits the host and contributes to the maintenance of intestinal homeostasis, but also causes chronic intestinal inflammation under certain conditions. Thus, understanding the microbiota regulation of inflammatory bowel disease (IBD) will provide great insights into the pathogenesis of IBD as well as potential therapeutics for IBD patients.

Substance P, a neuropeptide belonging to the tachykinin family is a pleiotropic peptide with specific neural activities and involved in immunomodulation and antimicrobial host defense. It has been found to modulate a variety of inflammatory processes, including acute pancreatitis, sepsis, systemic inflammatory response syndrome and asthma. Also notably, substance P shares common bio-physical and -chemical properties such as low molecular mass, cathionicity and amphipathicity with antimicrobial peptides. It is therefore suggested to take part in host defense at specialized locations. The review aims to highlight undated understanding on substance P in inflammation, allergy and its antimicrobial activities with potential implications in infection and host defense. Therapeutic implications of the peptide, modulators of peptide expression and receptor signalling will be highlighted in each topic. Taken together, these topics will be of significant values for future pharmaceutical investigation and application of the field.

Rheumatoid arthritis (RA) is a systemic, inflammatory disease with female preponderance, characterized by severe articular and extraarticular manifestations. Cardiovascular (CV) disease in RA usually occurs a decade earlier than age- and sex-matched controls and patients with RA are twice more likely to develop myocardial infarction irrespective of age, history of prior CVD events and traditional CV risk factors. It has been shown that atherosclerotic CV disease in RA shares similarities with CV disease in diabetes mellitus (DM) in terms of clinical presentation and preclinical atherosclerosis. In addition to atherosclerosis, RA also increases risk of non-ischemic heart failure, valvular disease and myopericardial disease. Therefore, RA is considered at least a cardiovascular equivalent to diabetes mellitus. Cardiovascular magnetic resonance (CMR), a non-invasive, nonradiating technique, and due to its capability to perform tissue characterisation, can effectively identify CVdisease acuity and etiology during the course of RA. CMR, by using a combination of function evaluation, oedema-fibrosis detection and stress perfusion-fibrosis imaging can unveil myocarditis, cardiomyopathy, diffuse subendocardial vasculitis, coronary and peripheral artery disease in RA patients, who usually are oligo-asymptomatic. Additionally, CMR is the ideal technique for operator independent, reproducible diagnostic and follow up assessment. However, lack of availability, expertise and high cost still remain serious drawbacks of CMR.

Glucocorticoids are used to treat chronic and severe forms of allergic conjunctivitis. Although they exert a rapid and powerful therapeutic activity, relevant side effects may limit their ocular use: increase of intraocular pressure, cataract formation and reduced resistance to infections. New glucocorticoids displaying the same potency of classical glucocorticoids but with fewer adverse effects are needed for the treatment of ocular disorders. Mapracorat (also known as ZK245186 or BOL-303242-X) is a novel non-steroidal selective glucocorticoid receptor agonist that is in the first phases of clinical evaluation (Phase II Clinical trials) for topical treatment of inflammatory skin and ocular disorders. Mapracorat binds selectively to human glucocorticoid receptor and displays powerful anti-inflammatory effects. In experimental models of ocular diseases, mapracorat reduces clinical symptoms, eosinophil recruitment, chemokines and pro-inflammatory cytokines production at ocular level, confirming that it acts preventing both the early and late phase of allergic response. Interestingly, mapracorat induces a lower increase of intraocular pressure in comparison to the classical glucocorticoid dexamethasone. Several clinical trials are ongoing to investigate the efficacy and safety of mapracorat for the treatment of several ocular diseases. Transrepressive mechanisms are thought to account for the majority of mapracorat's antiinflammatory effects; however, the induction of anti-inflammatory proteins likely involved in transactivation events may contribute to mapracorat-mediated anti-inflammatory properties and deserve to be further investigated in suitable in vivo and in vitro models. These observations may influence how novel "differential" ligands are discovered, identified and evaluated.

Under physiological conditions, the balance between ROS production and removal properly maintains the intracellular redox-sensitive signaling as well as the appropriate status of protein thiols and disulfides. However, inflammation among other factors can modify this balance causing a rapid increase in intracellular ROS levels and hence thiol oxidation, eventually leading to oxidative stress. In the case of acute pancreatitis, both redox signaling and oxidative stress seem to contribute to the progression of the severe form of the disease. In this review we will focus on the reversible oxidation of protein cysteines during the course of acute pancreatitis. We describe disulfide stress in an acute inflammatory process, which is characterized by thiol oxidation in proteins, particularly protein cysteinylation, without significant changes in the glutathione redox status.

Since the discovery and use of the microscope in the 17(th) century, we know that we host trillions of micro-organisms mostly in the form of bacteria indwelling the "barrier organs" skin, gut, and airways. They exert regulatory functions, are in a continuous dialogue with the intestinal epithelia, influence energy handling, produce nutrients, and may cause diabetes and obesity. The human microbiome has developed by modulating or avoiding inflammatory responses; the host senses bacterial presence through cell surface sensors (the Toll-like receptors) as well as by refining mucous barriers as passive defense mechanisms. The cell density and composition of the microbiome are variable and multifactored. The way of delivery establishes the type of initial flora; use of antibiotics is another factor; diet composition after weaning will shape the adult's microbiome composition, depending on the subject's life-style. Short-chain fatty acids participate in the favoring action exerted by microbiome in the pathogenesis of type-2 diabetes and obesity. Clinical observation has pinpointed a sharp rise of various dysimmune conditions in the last decades, including IBD and rheumatoid arthritis, changes that outweigh the input of simple heritability. It is nowadays proposed that the microbiome, incapable to keep up with the changes of our life-style and feeding sources in the past few decades might have contributed to these immune imbalances, finding itself inadequate to handle the changed gut environment. Another pathway to pathology is the rise of directly pathogenic phyla within a given microbiome: growth of adherent E. coli, of C. concisus, and of C. jejuni, might be examples of causes of local enteropathy, whereas the genus Prevotella copri is now suspected to be linked to rise of arthritic disorders. Inflammasomes are required to shape a non colitogenic flora. Treatment of IBD and infectious enteritides by the use of fecal transplant is warranted by this knowledge.

Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO) syndrome is a rare and often unrecognized disease with prominent inflammatory cutaneous and articular manifestations. Since the identification of the syndrome many immunosuppressive drugs have been used for the management of SAPHO, with variable results. The use of anti- TNF-α agents as a therapeutic option for SAPHO cases unresponsive or refractory to conventional drugs, demonstrated their efficacy for bone, skin and joints manifestations. TNF-α is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 β , IL-6 and IL-8, involved in inflammation, acute-phase response induction and chemotaxis. IL-1 inhibition strategies with Anakinra have proven their efficacy as first and second line treatment. We herein review the literature concerning the use of biological drugs in patients with SAPHO syndrome. In addition, we describe for the first time the use of Ustekinumab, an antibody against the p40 subunit of IL-12 and IL-23, after failure of multiple drugs including anti-TNF-α and Anakinra. This anti-IL12/IL23 agent could be a promising therapeutic option, also considering the opportunity to interfere with the IL23/TH17 pathway, which we recently found disturbed. Furthermore, a rationale emerges for the use of the new anti-IL-1 antagonists or the IL-17 blockade, in particular for the most difficult-to-treat SAPHO cases.