Inflammation & allergy drug targets最新文献

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.

We have reported the synthesis, characterization, in vitro release profile and preliminary pharmacological investigations of an antioxidant mutual prodrug of diacerein with thymol in our earlier communication. The present work reports the results of in vivo release studies and extensive pharmacological evaluation of this prodrug in collagenase- induced osteoarthritis and monosodium iodoacetate- induced hyperalgesia in Wistar rats. In vivo release was thoroughly studied in Wistar rats upon oral administration of the prodrug. In rat blood, release of 92.7% of diacerein and 20.5% of thymol was observed. From these studies we hypothesized that activation of prodrug could be mediated by physiological pH of blood (7.4) and serum esterases. Pharmacological screening of prodrug in collagenase and monoiodoacetate-induced osteoarthritis at a dose of 6.8 mg/kg, (BID) exhibited significant reduction in knee diameter (p<0.001), increase in paw withdrawal latency (p<0.001), and locomotor activity (p<0.001) with significantly higher anti-inflammatory and anti-osteoarthritic activities as compared to parent drug. The biochemical studies indicated a significant step-up in glucosaminoglycan level (p<0.001) and reduction in the C-reactive protein (p<0.001) and sulfated alkaline phosphatase levels (p<0.001). The histopathological and radiological studies confirmed the additive anti-osteoarthritic effect of prodrug as compared to plain diacerein. Antioxidant potential of prodrug was significantly more (p<0.001) while ulcer index was significantly lower (p<0.01) than diacerein. Interestingly, the diarrhea observed in diacerein- treated animals was not evident in animalstreated with prodrug, thymol and their physical mixture. Our findings indicate promising potential of this antioxidant prodrug to be used for long-term and safer management of OA.

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.

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.

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.

During cardiac surgery different factors, such as the aortic clamp, the extracorporeal circulation and the surgical injury itself, produce complex inflammatory responses which can lead to varying degrees of ischemia-reperfusion injury and/or systemic inflammatory response. This may have clinical implications due to hemodynamic changes related with an enlarged vasodilatory response. Thus, maintaining adequate levels of blood pressure during and after cardiac surgery represents a challenge for physicians when inflammatory response appears. The use of noradrenaline to raise arterial pressure is the most current pharmacological approach in the operating room and ICU. However, it is not always effective and other drugs, such as methylene blue, have to be used among others in specific cases as rescue therapy. The aim of our research is to review briefly the pathophysiology and clinical implications in the treatment of the inflammatory response in cardiac surgery, together with the mechanisms involved in those treatments.

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 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.