Generation Of Anti-inflammatory Drugs Research Articles

Cordyceps militaris as a Bio Functional Food Source: Pharmacological Potential, Anti-Inflammatory Actions and Related Molecular Mechanisms.

Cordyceps militaris (C. militaris) is a medicinal mushroom possessing a variety of biofunctionalities. It has several biologically important components such as polysaccharides and others. The diverse pharmacological potential of C. militaris has generated interest in reviewing the current scientific literature, with a particular focus on prevention and associated molecular mechanisms in inflammatory diseases. Due to rising global demand, research on C. militaris has continued to increase in recent years. C. militaris has shown the potential for inhibiting inflammation-related events, both in in vivo and in vitro experiments. Inflammation is a multifaceted biological process that contributes to the development and severity of diseases, including cancer, colitis, and allergies. These functions make C. militaris a suitable functional food for inhibiting inflammatory responses such as the regulation of proinflammatory cytokines. Therefore, on the basis of existing information, the current study provides insights towards the understanding of anti-inflammatory activity-related mechanisms. This article presents a foundation for clinical use, and analyzes the roadmap for future studies concerning the medical use of C. militaris and its constituents in the next generation of anti-inflammatory drugs.

Abstract 13612: An mPGES-1 Inhibitor Halts Abdominal Aortic Aneurysm Formation in Mice

Background: Abdominal aortic aneurysm (AAA) is a deadly, permanent balloon of the aortic artery. Surgery is the only option available to patients, but it is risky. In addition, there are currently no FDA-approved pharmacological treatments for AAA available. Notably, microsomal prostaglandin E 2 synthase-1 (mPGES-1) is recognized as a promising target for development of a next generation of anti-inflammatory drugs. Through computational modeling and in vitro experiments, we have recently discovered a novel type of mPGES-1 inhibitors as possible anti-inflammatory drug candidates. Objectives: The purpose of this study was to assess the capability of an mPGES-1 inhibitor to alter the growth of AAA in the angiotensin (Ang)-II induced mouse model. Methods: For 28 days, 12-week-old male ApoE-/- were infused with Ang-II (1,000 ng/kg/min) plus either an mPGES-1 inhibitor (UK4b) starting day 7 (10 mg/kg SC, BID; N = 6) or no drug (control group, N = 9). Maximal aortic diameter was measured by ultrasound (Vevo 3100) on day 0 (baseline), 2, 5, 7, 12, 16, 21, and 28. Aorta tissues were collected after sacrifice on day 28 and measured. Results: On day 28, there was a significant difference between the maximal aortic diameters of the control and drug treated groups (2.08±0.22 mm, 1.34±0.02 mm; p < 0.005). Comparing day 28 in vivo and ex vivo measurements of aortas, there was no significant difference ( p = 0.898), validating the use of ultrasound as an in vivo measurement method in this study. Conclusions: In summary, the mPGES-1 inhibitor UK4b, was able to halt the progression of AAA in these mice. There was a significant difference in the size of aortas between the two groups which was validated by ex vivo assessment. These preliminary results show promise for the use of an mPGES-1 inhibitor in the treatment of AAA.

Clinical data mining reveals analgesic effects of lapatinib in cancer patients

Microsomal prostaglandin E2 synthase 1 (mPGES-1) is recognized as a promising target for a next generation of anti-inflammatory drugs that are not expected to have the side effects of currently available anti-inflammatory drugs. Lapatinib, an FDA-approved drug for cancer treatment, has recently been identified as an mPGES-1 inhibitor. But the efficacy of lapatinib as an analgesic remains to be evaluated. In the present clinical data mining (CDM) study, we have collected and analyzed all lapatinib-related clinical data retrieved from clinicaltrials.gov. Our CDM utilized a meta-analysis protocol, but the clinical data analyzed were not limited to the primary and secondary outcomes of clinical trials, unlike conventional meta-analyses. All the pain-related data were used to determine the numbers and odd ratios (ORs) of various forms of pain in cancer patients with lapatinib treatment. The ORs, 95% confidence intervals, and P values for the differences in pain were calculated and the heterogeneous data across the trials were evaluated. For all forms of pain analyzed, the patients received lapatinib treatment have a reduced occurrence (OR 0.79; CI 0.70–0.89; P = 0.0002 for the overall effect). According to our CDM results, available clinical data for 12,765 patients enrolled in 20 randomized clinical trials indicate that lapatinib therapy is associated with a significant reduction in various forms of pain, including musculoskeletal pain, bone pain, headache, arthralgia, and pain in extremity, in cancer patients. Our CDM results have demonstrated the significant analgesic effects of lapatinib, suggesting that lapatinib may be repurposed as a novel type of analgesic.

Discovery and Development of a Novel mPGES-1/5-LOX Dual Inhibitor LFA-9 for Prevention and Treatment of Chronic Inflammatory Diseases.

BackgroundNon-steroidal anti-inflammatory drugs, cyclooxygenase (COX)-2 selective inhibitors, have been explored for prevention and treatment of several inflammatory chronic conditions including arthritis, and cancer. However, the long-term use of these drugs is associated with gastrointestinal, renal, and cardiovascular side effects. Later, COX/5-lipoxygenase (5-LOX) dual inhibitors (eg, licofelone) have been developed but did not enter into the market from the clinical trails due to COX-1/2 inhibition-associated side effects. Hence, targeting microsomal prostaglandin E synthase-1 (mPGES-1) and 5-LOX can be an ideal approach while sparing COX-1/2 activities for development of the next generation of anti-inflammatory drugs with better efficacy and safety.Materials and MethodsIn silico (molecular modelling) studies were used to design a mPGES-1/5-LOX dual inhibitory and COX-1/2 sparing lead molecule licofelone analogue-9 (LFA-9) by modifying the pharmacophore of licofelone. In vitro cell-free enzymatic (mPGES-1, 5-LOX, COX-1/2) assays using fluorometric/colorimetric methods and cell-based assays (LPS-induced PGE2, LTB4, and PGI2 productions from macrophages) using ELISA technique, isothermal calorimetry, and circular dichroism techniques were performed to determine the mPGES-1/5-LOX inhibitory efficacy and selectivity. Anti-inflammatory efficacy of LFA-9 was evaluated using a carrageenan (inflammogen)-induced rat paw edema model. Infiltration/expression of CD68 immune cells and TNF-α in paw tissues were evaluated using confocal microscope and immunoblot analysis. Anti-cancer effect of LFA-9 was evaluated using colon spheroids in vitro.ResultsLFA‐9 inhibited mPGES-1/5-LOX and their products PGE2 and LTB4, spared COX-1/2 and its product PGI2. LFA‐9 bound strongly with human mPGES‐1/5‐LOX enzymes and induced changes in their secondary structure, thereby inhibited their enzymatic activities. LFA-9 inhibited carrageenan-induced inflammation (70.4%) in rats and suppressed CD68 immune cell infiltration (P ≤ 0.0001) and TNF-α expression. LFA-9 suppressed colon tumor stemness (60.2%) in vitro through inhibition of PGE2 (82%) levels.ConclusionOverall study results suggest that LFA-9 is a mPGES-1/5-LOX dual inhibitor and showed anti-inflammatory and colorectal cancer preventive activities, and warranted detailed studies.

Structure-based discovery of mPGES-1 inhibitors suitable for preclinical testing in wild-type mice as a new generation of anti-inflammatory drugs

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs without the side effects of currently available anti-inflammatory drugs, and various inhibitors have been reported in the literature. However, none of the reported potent inhibitors of human mPGES-1 has shown to be also a potent inhibitor of mouse or rat mPGES-1, which prevents using the well-established mouse/rat models of inflammation-related diseases for preclinical studies. Hence, despite of extensive efforts to design and discover various human mPGES-1 inhibitors, the promise of mPGES-1 as a target for the next generation of anti-inflammatory drugs has never been demonstrated in any wild-type mouse/rat model using an mPGES-1 inhibitor. Here we report discovery of a novel type of selective mPGES-1 inhibitors potent for both human and mouse mPGES-1 enzymes through structure-based rational design. Based on in vivo studies using wild-type mice, the lead compound is indeed non-toxic, orally bioavailable, and more potent in decreasing the PGE2 (an inflammatory marker) levels compared to the currently available drug celecoxib. This is the first demonstration in wild-type mice that mPGES-1 is truly a promising target for the next generation of anti-inflammatory drugs.

Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1

Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE2 without blocking the normal biosynthesis of other prostanoids including homeostatic PGE2. Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold was used as lead in rational design of novel inhibitors. Besides, we further designed, synthesized, and evaluated 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and structurally related derivatives for their in vitro inhibitory activities. According to in vitro activity assays, a number of these compounds were capable of inhibiting human mPGES-1, with the desirable selectivity for mPGES-1 over COX isozymes.

Selective inhibitors of human mPGES-1 from structure-based computational screening

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs. Although various mPGES-1 inhibitors have been reported in literature, few have entered clinical trials and none has been proven clinically useful so far. It is highly desired for developing the next generation of therapeutics for inflammation-related diseases to design and discover novel inhibitors of mPGES-1 with new scaffolds. Here, we report the identification of a series of new, potent and selective inhibitors of human mPGES-1 with diverse scaffolds through combined computational and experimental studies. The computationally modeled binding structures of these new inhibitors of mPGES-1 provide some interesting clues for rational design of modified structures of the inhibitors to more favorably bind with mPGES-1.

Design, Synthesis, and Biological Evaluation of Novel Disubstituted Dibenzosuberones as Highly Potent and Selective Inhibitors of p38 Mitogen Activated Protein Kinase

Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical properties as well as potency. Extremely potent inhibitors were obtained, with half-maximal inhibitory concentration (IC(50)) values in the low nM range in a whole blood assay measuring the inhibition of cytokine release. The high potency of the target compounds together with the outstanding selectivity of this novel class of compounds toward p38 mitogen activated protein (MAP) kinase as compared to other kinases indicate them to be most applicable as tools in pharmacological research and eventually they may foster a new generation of anti-inflammatory drugs.

Leukocyte integrin activation and deactivation: novel mechanisms of balancing inflammation

Leukocyte recruitment into tissue forms the basis of immune surveillance and direct immune defense. It proceeds in a cascade-like fashion. The first contact of leukocytes with the endothelium is mediated by selectins and their counter receptors, followed by rolling and integrin-mediated arrest. While rolling, neutrophils collect different inflammatory signals which can activate several signaling pathways leading to leukocyte adhesion to the endothelium and transmigration through the blood vessel wall into the inflamed tissue. Whereas inflammatory reactions are beneficial and necessary for host defense, they need to be balanced and controlled to prevent harmful consequences and tissue destruction. In this article, we discuss the different signaling pathways that ensure rapid and efficient integrin activation on leukocytes. In addition, we report on a recently identified novel endogenous mechanism that counteracts and balances integrin activation, thereby limiting leukocyte recruitment and the extent of inflammation. Further investigation of this new mechanism may allow providing new approaches for the development of the next generation of anti-inflammatory drugs.

Small Molecule Antagonists of Chemokine Receptors - is Promiscuity a Virtue?

A major function of the chemokine system is to coordinate the recruitment of leukocytes to specific locations within the tissues. The involvement of chemokine receptors in a multitude of inflammatory diseases, coupled with their belonging to the highly "druggable" GPCR superfamily, makes them excellent candidates for the development of novel drugs by the pharmaceutical industry. Despite descriptions in the literature of many specific small molecule chemokine receptor antagonists, none have yet shown efficacy in the clinical inflammatory setting. In this article, we discuss the successes and failures of chemokine receptor antagonists in the clinic and review a subset of molecules that are documented as having activity at two or more chemokine receptors. It may be that a more permissive approach, targeting several chemokine receptors with a single molecule will provide the next generation of anti-inflammatory drugs.

EPAC proteins transduce diverse cellular actions of cAMP

It has now been over 10 years since efforts to completely understand the signalling actions of cAMP (3'-5'-cyclic adenosine monophosphate) led to the discovery of exchange protein directly activated by cAMP (EPAC) proteins. In the current review we will highlight important advances in the understanding of EPAC structure and function and demonstrate that EPAC proteins mediate multiple actions of cAMP in cells, revealing future targets for pharmaceutical intervention. It has been known for some time that drugs that elevate intracellular cAMP levels have proven therapeutic benefit for diseases ranging from depression to inflammation. The challenge now is to determine which of these positive actions of cAMP involve activation of EPAC-regulated signal transduction pathways. EPACs are specific guanine nucleotide exchange factors for the Ras GTPase homologues, Rap1 and Rap2, which they activate independently of the classical routes for cAMP signalling, cyclic nucleotide-gated ion channels and protein kinase A. Rather, EPAC activation is triggered by internal conformational changes induced by direct interaction with cAMP. Leading from this has been the development of EPAC-specific agonists, which has helped to delineate numerous cellular actions of cAMP that rely on subsequent activation of EPAC. These include regulation of exocytosis and the control of cell adhesion, growth, division and differentiation. Recent work also implicates EPAC in the regulation of anti-inflammatory signalling in the vascular endothelium, namely negative regulation of pro-inflammatory cytokine signalling and positive support of barrier function. Further elucidation of these important signalling mechanisms will no doubt support the development of the next generation of anti-inflammatory drugs.

A Malignant Flame

This article explores research in chronic inflammation. Cancer researchers have found that a developing tumor can commandeer the immune system's inflammatory component which would normally be part of the wound healing process and use it to foster carcinogenesis. Using this information, a new generation of anti-inflammatory drugs may be added to traditional chemotherapy to keep tumors localized. INSETS: KEY CONCEPTS;THE PLAYERS;Immune System as Cancer Fighter.

PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond?

Dysregulated signal transduction in innate and adaptive immune cells is known to be associated with the development of various autoimmune and inflammatory diseases. Consequently, targeting intracellular signalling of the pro-inflammatory cytokine network heralds hope for the next generation of anti-inflammatory drugs. Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are known to have important roles in leukocytes. In light of the recent progress in the development of selective PI3K inhibitors, and the beneficial effects of these inhibitors in models of acute and chronic inflammatory disorders, we discuss the therapeutic potential of blocking PI3K isoforms for the treatment of rheumatoid arthritis and other immune-mediated diseases.

Novel Molecular Targets in the Search for Anti-Inflammatory Agents

In the chronic state of inflammatory diseases, cellular signaling networks aimed at combating invading pathogens are often constitutively active and transmit their signals even in the absence of inflammatory agents. Thus, many anti-inflammatory drugs interfere with these dys- and hyperactivated cellular signaling networks or transcription factors. As many signaling molecules fulfill important and essential functions in normal cell physiology, their systemic and long-term inhibition may lead to severe side effects including an impaired immune response. To circumvent these pitfalls, two possibilities are proposed and discussed here: (I) Since many inflammatory diseases such as rheumatoid arthritis or inflammatory bowel disease are restricted to certain cell types or tissues, a new generation of anti-inflammatory drugs would target enzymes that are only operational in these affected tissues. (II) As some signaling pathways affect solely a small subset of inflammatory target genes, their inhibition bears the potential of limiting potential side effects.