Inflammation & Allergy-Drug Targets (Discontinued) - Volume 13, Issue 1, 2014

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.

The submandibular salivary glands of non-obese diabetic (NOD) mice, a model for Sjogren’s syndrome and type-1 diabetes, show an elevated level of proliferating cell nuclear antigen (PCNA), a protein involved in cell proliferation and repair of DNA damage. We reported previously that epigallocatechin-3-gallate (EGCG), the most abundant green tea catechin, normalizes the PCNA level. PCNA’s activity can be regulated by the cyclin-dependent kinase inhibitor p21, which is also important for epithelial cell differentiation. In turn, expression of p21 and PCNA are partially regulated by Rb phosphorylation levels. EGCG was found to modulate p21 expression in epithelial cells, suggesting that EGCG-induced p21 could be associated with down-regulation of PCNA in vivo. The current study examined the protein levels of p21 and p53 (which can up-regulate p21) in NOD mice fed with either water or EGCG, and the effect of EGCG on p21 and p53 in cell line models with either normal or defective Rb. In NOD mice, the p21 level was low, and EGCG normalized it. In contrast to HSG cells with functional Rb, negligible expression of p21 in NS-SVAC cells that lack Rb was not altered by EGCG treatment. Inhibition of p53 by siRNA demonstrated that p21 and p53 were induced independently in HSG cells by a physiological concentration range of EGCG, suggesting p53 could be an important but not conditional factor associated with p21 expression. In conclusion, PCNA and p21 levels are altered inversely in the NOD model for SS and in HSG cells, and warrant further study as candidate new markers for salivary dysfunction associated with xerostomia. Induction of p21 by EGCG could provide clinically useful normalization of salivary glands by promoting differentiation and reducing PCNA levels.

Purpose: Our knowledge on bronchoalveolar lavage (BAL) of methotrexate-induced pneumonitis (MTX-P) is fragmentary and based on data that are sometimes apparently conflicting. Aim of this review was to provide a comprehensive overview on the BAL features of MTX-P arising from cases published to date, and to determine the cytological patterns and any differences between cancer and rheumatoid arthritis patients, the two patient subsets among which this complication more often occurs. Methods: English-language articles published up to November 2013 were systematically searched through PUBMED, EMBASE, and other databases. Adult patients with a proven diagnosis of MTX-P and careful mention of each BAL parameter were examined. Results: Seventeen articles for a total of 47 patients were included. Four BAL patterns with a variably combined lymphocytosis and two with prominent neutrophilia were identified. A more intense lymphocytosis (P=0.004) and a more depressed CD4/CD8 ratio (P=0.01) were found in cancer patients compared with rheumatoid arthritis patients. Conclusions: In MTX-P, cytological analysis of BAL may disclose up to six different patterns. In MTX-P affecting cancer patients, BAL tends to show the typical features of hypersensitivity pneumonitis, while, in rheumatoid arthritis patients, it is more heterogeneous, with a less intense lymphocytosis, a more pronounced neutrophilia, and a higher CD4/CD8 ratio. These differences could be related to a disparity in baseline pulmonary conditions between the two background diseases, i.e., to the presence of previously healthy lungs in cancer patients, and lungs already involved by the immune-mediated inflammatory processes, often not manifestly, in rheumatoid arthritis patients.

Through pattern recognition receptors, infections and tissue injuries drive innate immune cells to trigger inflammation with elevated cytokines, chemokines, growth factors, and other mediators. Inflammation resolves upon removal of pathogenic signals and the presence of pro-resolving conditions including combating adaptive immunity. Failure of resolution progresses into chronic inflammation, manifesting as detrimental disease development known as inflammatory diseases including cardiovascular diseases, diabetes, obesity, cancers, etc. Inflammation typically involves activations of many intracellular signaling pathways such as PI3K/AkT/mTORC1, PI3K/AkT/IKK(JNK), Ras/Raf/MEK/ERK, JAK/STAT, etc.; these pathways could in turn mediate the upregulations of proinflammatory transcription factors (e.g., NFκB, activator protein 1 (AP-1), HIF, signal transducer and activator of transcription (STAT), etc.). Furthermore, the resulting FOXO inactivation ensures inflammatory proceeding. This review provides a systematic view that polyphenols target multiple inflammatory components and reinforce anti-inflammatory mechanisms by antioxidant potentials, AMPK activation, PI3K/AkT inhibition, IKK/JNK inhibition, mTORC1 inhibition, JAK/STAT inhibition, TLR suppression, and ACE inhibition. As a result, polyphenols readily lead to NFκB, AP-1, HIF, and STAT inactivations with reduced proinflammatory mediator generation. In conclusion, polyphenols sustain resolution of inflammation and antagonize against proinflammation, which is readily consistent with diverse anti-inflammatory actions. The promoted, restored, and maintained tissue homeostasis beyond its anti-inflammatory effects also extends to diverse health benefits for disease preventions and interventions.

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.

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.