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This study investigated the anti‐inflammatory properties of Ajuga integrifolia, an herbal preparation. Qualitative and quantitative phytochemical analyses were conducted to identify active compounds in the preparation. The researchers also assessed its ability to inhibit the production of pro‐inflammatory enzymes, cyclooxygenases (COX‐1, COX‐2), and lipoxygenase (5‐LOX) in vitro. The extracts demonstrated dose‐dependent inhibition of these enzymes, with some extracts showing IC50 values comparable to standard anti‐inflammatory drugs. The ethanol extract exhibited significant inhibition of 5‐LOX (52.99 μg/mL), compared to the standard drug zileuton (32.41 μg/mL), while the inhibition of COX‐1 (66.00 μg/mL) and COX‐2 (71.62 μg/mL) was comparable to the standard drug indomethacin (40.57 and 54.39 μg/mL, respectively). These findings suggest that A. integrifolia has the potential to be used as a herbal remedy for treating inflammatory conditions. By inhibiting pro‐inflammatory enzymes, the extracts may effectively reduce inflammation and promote tissue healing or repair. The inhibition potential of extract of this plant can be taken as a good candidate of anti‐inflammatory agent. [ABSTRACT FROM AUTHOR]

Inflammation is a body response against infection that activates other biological components that include various cytokines, chemokines and other biological compounds that trigger body response against pathological activities. The Arachidonic acid pathway is involved in the inflammation that is connected with lipoxygenase (LOX) and cyclooxygenase (COX) enzymes. The importance of the isoforms of LOX and COX in inflammation is well studied. At the cellular level, some of the thiazole derivatives showed potent anti-inflammatory activities especially to block LOX5 and COX2 in the inflammation. These factors include both acute and chronic inflammation in various tissues like the heart, kidney, pancreas, brain, intestine, lungs and other organs as well that lead to the damage of the organs or cells. Whether it's the infectious or non-infectious response it will further activate some of the downstream signaling pathways like lipoxygenase, cyclooxygenase, cytochrome 450, JAK-STAT, MAPK, JNK, TNF-α, Nfr2, and many more pathways that lead to activation of another chronic disease in the body. In this review, we will concentrate on thiazole molecules that serve as anti-inflammatory responses to both acute and chronic inflammation. Further, we discussed the evidence that correlates the possible connection with LOX and COX enzymes in the inflammatory pathways and their blocking ability especially through thiazole derivatives has been discussed in this present review. The current assessment is the best part of the present consequence of thiazole derivatives on anti-inflammatory studies, covering articles published from 1973 to 2023.

The tuberous roots of Holostemma annulare are utilized as the drug Jivanti in Ayurvedic medicine system. There is a huge demand of root tubers of this plant by pharmacies. Conversely, there are reports concerning adulteration in market samples of Jivanti resulting in damaging effect on the quality of drug formulations. Till now there is no significant study to relate the source plants available in markets as Jivanti. A meticulous phytochemical profiling especially of the roots is still a lacuna and no studies have been carried out yet regarding this. We focused on this concept and analyzed the antiinflammatory activity by means of proteinase inhibition assay, as well as COX and LOX inhibition assays in the root samples collected from homestead cultivation (HS) and from an authenticated trade shop in Thiruvananthapuram (TS). Among the two samples, TS exhibited comparable anti-inflammatory activity to HS which further confirms the authenticity of the genuine drug in the preparation of Ayurvedic formulations. The study provides a scientific rationale in using Holostemma roots in traditional drug preparations for diseases linked with inflammation and also throw light in fortifying molecular approaches in validating elite raw drugs in order to supplement genuine samples for pharma needs. [ABSTRACT FROM AUTHOR]

Advances have been made in the search for new multi-target modulators to control pain and inflammation. Therefore, compound 3,5-di-tert-butyl-4-hydroxyphenyl)(4-methylpiperazin-1-yl)methanone (LQFM202) was synthesised and evaluated. First, in vitro assays were performed for COX-1, COX-2, and 5-LOX enzymes. Subsequently, adult female Swiss albino mice treated orally with LQFM202 at doses of 25–200 mg/kg were subjected to acetic acid-induced writhing, formalin-induced pain, carrageenan-induced hyperalgesia, carrageenan- or zymosan-induced paw oedema, or pleurisy. LQFM202 inhibited COX-1, COX-2, and LOX-5 (IC50 = 3499 µM, 1565 µM, and 1343 µM, respectively). In acute animal models, LQFM202 (50, 100, or 200 mg/kg) decreased the amount of abdominal writhing (29%, 52% and 48%, respectively). Pain in the second phase of the formalin test was reduced by 46% with intermediate dose. LQFM202 (100 mg/kg) reduced the difference in nociceptive threshold in all 4 h evaluated (46%, 37%, 30%, and 26%, respectively). LQFM202 (50 mg/kg) decreased the carrageenan-oedema from the second hour (27%, 31% and 25%, respectively); however, LQFM202 (100 mg/kg) decreased the carrageenan-oedema in all hours evaluated (35%, 42%, 48% and 50%, respectively). When using zymosan, LQFM202 (50 mg/kg) decreased the oedema in all hours evaluated (33%, 32%, 31% and 20%, respectively). In the carrageenan-pleurisy test, LQFM202 (50 mg/kg) reduced significantly the number of polymorphonuclear cells (34%), the myeloperoxidase activity (53%), TNF-α levels (47%), and IL-1β levels (58.8%). When using zymosan, LQFM202 (50 mg/kg) reduced the number of polymorphonuclear and mononuclear cells (54% and 79%, respectively); and the myeloperoxidase activity (46%). These results suggest antinociceptive and anti-inflammatory effects of LQFM202. [ABSTRACT FROM AUTHOR]

Simple Summary: On a system level, multi-omics approaches allow studying oxylipins, metabolites of omega-3 or omega-6 polyunsaturated fatty acids. We compared the ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) oxylipin profile signatures in the blood plasma of 152 healthy volunteers (HC) and 169 patients with different stages of breast cancer (BC). We identified 18 differentially expressed oxylipins between BC vs. HC patients, including anandamide, prostaglandins, and hydroxydocosahexaenoic acids. To integrate lipidomics, transcriptomics, and genomics data, we analyzed a transcriptome of 10 open database datasets obtained from tissues and blood cells of BC patients and SNP data for 33 genes related to oxylipin metabolism and revealed 19 changed genes, among them CYP2C19, PTGS2, HPGD, and FAAH included in the list of DEGs in the analysis of transcriptomes and the list of SNPs associated with BC. Our data allow us to suppose that oxylipin profiles can be used to evaluate the early stages of breast cancer. The involvement of oxylipins, metabolites of polyunsaturated fatty acids, in cancer pathogenesis was known long ago, but only the development of the high-throughput methods get the opportunity to study oxylipins on a system level. The study aimed to elucidate alterations in oxylipin metabolism as characteristics of breast cancer patients. We compared the ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) oxylipin profile signatures in the blood plasma of 152 healthy volunteers (HC) and 169 patients with different stages of breast cancer (BC). To integrate lipidomics, transcriptomics, and genomics data, we analyzed a transcriptome of 10 open database datasets obtained from tissues and blood cells of BC patients and SNP data for 33 genes related to oxylipin metabolism. We identified 18 oxylipins, metabolites of omega-3 or omega-6 polyunsaturated fatty acids, that were differentially expressed between BCvsHC patients, including anandamide, prostaglandins and hydroxydocosahexaenoic acids. DEGs analysis of tissue and blood samples from BC patients revealed that 19 genes for oxylipin biosynthesis change their expression level, with CYP2C19, PTGS2, HPGD, and FAAH included in the list of DEGs in the analysis of transcriptomes and the list of SNPs associated with BC. Results allow us to suppose that oxylipin signatures reflect the organism's level of response to the disease. Our data regarding changes in oxylipins at the system level show that oxylipin profiles can be used to evaluate the early stages of breast cancer. [ABSTRACT FROM AUTHOR]

Lipid mediators are bioactive lipids which help regulate inflammation. We aimed to develop an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to quantify 58 pro-inflammatory and pro-resolving lipid mediators in plasma, determine preliminary reference ranges for adolescents, and investigate how total parenteral nutrition (TPN) containing omega-3 polyunsaturated fatty acid (n-3 PUFA) or n-6 PUFA based lipid emulsions influence lipid mediator concentrations in plasma. Lipid mediators were extracted from plasma using SPE and measured using UHPLC-MS/MS. EDTA plasma was collected from healthy adolescents between 13 and 17 years of age to determine preliminary reference ranges and from mice given intravenous TPN for seven days containing either an n-3 PUFA or n-6 PUFA based lipid emulsion. We successfully quantified 43 lipid mediators in human plasma with good precision and recovery including several leukotrienes, prostaglandins, resolvins, protectins, maresins, and lipoxins. We found that the addition of methanol to human plasma after blood separation reduces post blood draw increases in 12-hydroxyeicosatetraenoic acid (12-HETE), 12-hydroxyeicosapentaenoic acid (12-HEPE), 12S-hydroxyeicosatrienoic acid (12S-HETrE), 14-hydroxydocosahexaenoic acid (14-HDHA) and thromboxane B2 (TXB2). Compared to the n-6 PUFA based TPN, the n-3 PUFA based TPN increased specialized pro-resolving mediators such as maresin 1 (MaR1), MaR2, protectin D1 (PD1), PDX, and resolvin D5 (RvD5), and decreased inflammatory lipid mediators such as leukotriene B4 (LTB4) and prostaglandin D2 (PGD2). Our method provides an accurate and sensitive quantification of 58 lipid mediators from plasma samples, which we used to establish a preliminary reference range for lipid mediators in plasma samples of adolescents; and to show that n-3 PUFA, compared to n-6 PUFA rich TPN, leads to a less inflammatory lipid mediator profile in mice. [ABSTRACT FROM AUTHOR]

Zanthoxylum armatum (ZA) a commonly used medicinal plant was investigated for phytochemical, anti-nociceptive, anti-inflammatory and antipyretic effects. Extract and total alkaloids from fruit and leaves significantly (p < 0.001) reduced the rectal temperature in mice. The effects of bark and root extracts were less significant. In writhing and tail flick methods both the extract and total alkaloids from fruit showed significant (p < 0.05 and p < 0.001) antinociceptive activity. The fruit extract and crude alkaloids showed significant (p < 0.01) lowering of inflammation of paw edema in mice. Crude alkaloids from fruit and leaves showed significant enzyme inhibition with lower IC50 values for 15 and 69 against COX and 21 and 62 μg/ml against LOX. This study rationalize the usage of this spice in traditional medicine for management of pain and inflammation involving LOX and COX inhibition as possible mechanism. GC-MS analysis revealed the presence of various constituents which might contributed towards the pain and inflammation alleviation.

Introduction: Ocular inflammation is a key pathogenic factor in most blindness-causing visual disorders. It can manifest in the aqueous humor (AH) and tear fluid (TF) as alterations in polyunsaturated fatty acids (PUFAs) and their metabolites, oxylipins, lipid mediators, which are biosynthesized via enzymatic pathways involving lipoxygenase, cyclooxygenase or cytochrome P450 monooxygenase and specifically regulate inflammation and resolution pathways. Objectives: This study aimed to establish the baseline patterns of PUFAs and oxylipins in AH and TF by their comprehensive lipidomic identification and profiling in humans in the absence of ocular inflammation and comparatively analyze these compounds in the eye liquids of rabbits, the species often employed in investigative ophthalmology. Methods: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for qualitative and quantitative characterization of lipid compounds in the analyzed samples. Results: A total of 28 lipid compounds were identified, including phospholipid derivatives and PUFAs, as well as 22 oxylipins. Whereas the PUFAs included arachidonic, docosahexaenoic and eicosapentaenoic acids, the oxylipins were derived mainly from arachidonic, linoleic and α-linolenic acids. Remarkably, although the concentration of oxylipins in AH was lower compared to TF, these liquids showed pronounced similarity in their lipid profiles, which additionally exhibited noticeable interspecies concordance. Conclusion: The revealed correlations confirm the feasibility of rabbit models for investigating pathogenesis and trialing therapies of human eye disorders. The identified metabolite patterns suggest enzymatic mechanisms of oxylipin generation in AH and TF and might be used as a reference in ocular inflammation studies. [ABSTRACT FROM AUTHOR]

Inflammation is implicated in the pathogenesis of many diseases such as Alzheimer's disease, rheumatoid arthritis and cancer. Inflammation is a complex process, involving the activation of specific mediators such as enzymes, cytokines, as well as growth and nuclear factors. The inhibition of pro-inflammatory enzymes is regarded as an effective strategy to combat inflammation. The undesirable side effects associated with many current anti-inflammation drugs have necessitated an increased search for natural principles with the capacity to suppress or inhibit inflammation mediators and with much reduced side effects. South Africa has a rich floral biodiversity coupled with indigenous knowledge systems on the use of medicinal plants, which has become widely explored for meeting primary health care needs, especially in resource-limited areas. Using electronic search engines and library resources, this review highlights the successes, challenges and prospects associated with the exploration of the South African floral diversity for inflammatory inhibitors. Several South African plant extracts demonstrated pro-inflammatory enzyme inhibitory potential with very low cytotoxicity. However, these reports have been based largely on in vitro evaluation. This has resulted in, at least, partial valorisation of their traditional uses. Notwithstanding the vast natural endowment and the available technology in bioprospecting the floral diversity for natural inflammatory enzyme inhibitors, only a limited number of plant species has been exploited and a relatively negligible fraction has been developed into natural products. The current limited bioprospecting 'success', when examined in the light of relatively untapped opportunity, underscores the potential for the discovery of new sources of natural inflammatory enzyme inhibitors. • Partial valorisation of South African plants for inflammatory inhibition. • Strong COX-inhibitory activity demonstrated largely in in vitro -based assays. • Potential to search for inhibitors of COX-2, LOX, sPLA2 and iNOs enzymes. [ABSTRACT FROM AUTHOR]

Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms.

Cancer is one of the highest prevalent diseases in humans. The chances of surviving cancer and its prognosis are very dependent on the affected tissue, body location, and stage at which the disease is diagnosed. Researchers and pharmaceutical companies worldwide are pursuing many attempts to look for compounds to treat this malignancy. Most of the current strategies to fight cancer implicate the use of compounds acting on DNA damage checkpoints, non-receptor tyrosine kinases activities, regulators of the hedgehog signaling pathways, and metabolic adaptations placed in cancer. In the last decade, the finding of a lipid peroxidation increase linked to 15-lipoxygenases isoform 1 (15-LOX-1) activity stimulation has been found in specific successful treatments against cancer. This discovery contrasts with the production of other lipid oxidation signatures generated by stimulation of other lipoxygenases such as 5-LOX and 12-LOX, and cyclooxygenase (COX-2) activities, which have been suggested as cancer biomarkers and which inhibitors present anti-tumoral and antiproliferative activities. These findings support the previously proposed role of lipid hydroperoxides and their metabolites as cancer cell mediators. Depletion or promotion of lipid peroxidation is generally related to a specific production source associated with a cancer stage or tissue in which cancer originates. This review highlights the potential therapeutical use of chemical derivatives to stimulate or block specific cellular routes to generate lipid hydroperoxides to treat this disease.

Wilson’s disease (WD) is a rare autosomal recessive metabolic disorder resulting from mutations in the copper-transporting, P-type ATPase gene ATP7B gene, but influences of epigenetics, environment, age, and sex-related factors on the WD phenotype complicate diagnosis and clinical manifestations. Oxylipins, derivatives of omega-3, and omega-6 polyunsaturated fatty acids (PUFAs) are signaling mediators that are deeply involved in innate immunity responses; the regulation of inflammatory responses, including acute and chronic inflammation; and other disturbances related to any system diseases. Therefore, oxylipin profile tests are attractive for the diagnosis of WD. With UPLC-MS/MS lipidomics analysis, we detected 43 oxylipins in the plasma profiles of 39 patients with various clinical manifestations of WD compared with 16 healthy controls (HCs). Analyzing the similarity matrix of oxylipin profiles allowed us to cluster patients into three groups. Analysis of the data by VolcanoPlot and partial least square discriminant analysis (PLS-DA) showed that eight oxylipins and lipids stand for the variance between WD and HCs: eicosapentaenoic acid EPA, oleoylethanolamide OEA, octadecadienoic acids 9-HODE, 9-KODE, 12-hydroxyheptadecatrenoic acid 12-HHT, prostaglandins PGD2, PGE2, and 14,15-dihydroxyeicosatrienoic acids 14,15-DHET. The compounds indicate the involvement of oxidative stress damage, inflammatory processes, and peroxisome proliferator-activated receptor (PPAR) signaling pathways in this disease. The data reveal novel possible therapeutic targets and intervention strategies for treating WD.

The application of metabolomics in phytochemical analysis is an innovative strategy for targeting active compounds from a complex plant extract. Species of the Asteraceae family are well-known to exhibit potent anti-inflammatory (AI) activity. Dual inhibition of the enzymes COX-1 and 5-LOX is essential for the treatment of several inflammatory diseases, but there is not much investigation reported in the literature for natural products. In this study, 57 leaf extracts (EtOH-H2O 7:3, v/v) from different genera and species of the Asteraceae family were tested against COX-1 and 5-LOX while HPLC-ESI-HRMS analysis of the extracts indicated high diversity in their chemical compositions. Using O2PLS-DA (R2 > 0.92; VIP > 1 and positive Y-correlation values), dual inhibition potential of low-abundance metabolites was determined. The O2PLS-DA results exhibited good validation values (cross-validation = Q2 > 0.7 and external validation = P2 > 0.6) with 0% of false positive predictions. The metabolomic approach determined biomarkers for the required biological activity and detected active compounds in the extracts displaying unique mechanisms of action. In addition, the PCA data also gave insights on the chemotaxonomy of the family Asteraceae across its diverse range of genera and tribes.

Eicosanoids comprise a diverse group of bioactive lipids which orchestrate inflammation, immunity, and tissue homeostasis, and whose dysregulation has been implicated in carcinogenesis. Among the various eicosanoid metabolic pathways, studies of their role in endometrial cancer (EC) have very much been confined to the COX‐2 pathway. This study aimed to determine changes in epithelial eicosanoid metabolic gene expression in endometrial carcinogenesis; to integrate these with eicosanoid profiles in matched clinical specimens; and, finally, to investigate the prognostic value of candidate eicosanoid metabolic enzymes. Eicosanoids and related mediators were profiled using liquid chromatography–tandem mass spectrometry in fresh frozen normal, hyperplastic, and cancerous (types I and II) endometrial specimens (n = 192). Sample‐matched epithelia were isolated by laser capture microdissection and whole genome expression analysis was performed using microarrays. Integration of eicosanoid and gene expression data showed that the accepted paradigm of increased COX‐2‐mediated prostaglandin production does not apply in EC carcinogenesis. Instead, there was evidence for decreased PGE2/PGF2α inactivation via 15‐hydroxyprostaglandin dehydrogenase (HPGD) in type II ECs. Increased expression of 5‐lipoxygenase (ALOX5) mRNA was also identified in type II ECs, together with proportional increases in its product, 5‐hydroxyeicosatetraenoic acid (5‐HETE). Decreased HPGD and elevated ALOX5 mRNA expression were associated with adverse outcome, which was confirmed by immunohistochemical tissue microarray analysis of an independent series of EC specimens (n = 419). While neither COX‐1 nor COX‐2 protein expression had prognostic value, low HPGD combined with high ALOX5 expression was associated with the worst overall and progression‐free survival. These findings highlight HPGD and ALOX5 as potential therapeutic targets in aggressive EC subtypes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Tinospora cordifolia (Willd.) Miers ex Hook. f. & Thomson, a known immunomodulatory agent extensively used in ayurveda, has not been effectively validated for the mechanisms involved in immunomodulation and the identification of the active principles. The bioactive fraction of T. cordifolia (TBF) in methanol was used for nitric oxide (NO) radical scavenging activity, lipoxygenase (LOX) and cyclooxygenase (COX) dual inhibition and cytotoxicity studies. Production of the proinflammatory cytokines, tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in dendritic cell (DC) suspensions treated with lipopolysaccharide (LPS) was also studied. The bioactive principles involved were identified with ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometric (UPLC-Q-ToF MS/MS) system. The results indicate significantly higher potency of TBF as compared to positive standards for LOX/COX inhibition with moderate NO radical scavenging activity and the fraction was also found to be non-cytotoxic to monocyte cells. A significant inhibition was also observed in TNF-α and IL-1β production in LPS-treated DC suspensions as compared to standards, rolipram and dexamethasone, respectively. 11 compounds were identified from TBF by MS/MS system. The potent inhibition of LOX and COX enzymes with moderate NO scavenging was indicative of a free radical scavenging-independent mechanism of immunomodulation. Further investigations into the active principles identified would result in the development of lead candidates with potent therapeutic implications. [ABSTRACT FROM AUTHOR]

Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of non-steroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors. Almost all of them present a number of unwanted, often serious, side effects as a consequence of interference with the arachidonic acid cascade. In search for new drugs to avoid side effects, while maintaining high potency over inflammation, scientists turned their interest to the synthesis of dual COX/LOX inhibitors, which could provide numerous therapeutic advantages in terms of anti-inflammatory activity, improved gastric protection and safer cardiovascular profile compared to conventional NSAIDs. Thiazole and thiazolidinone moieties can be found in numerous biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. This review focuses on the biological activity of several thiazole and thiazolidinone derivatives as COX-1/COX-2 and LOX inhibitors. [ABSTRACT FROM AUTHOR]

Lectins are non-immune glycoproteins or proteins having a unique capacity to interact with carbohydrate ligands found on the surface of their host cells. In the present investigation, the lectin was purified from the hemolymph of freshwater crab, Oziotelphusa naga and its antimicrobial, anti-inflammatory and anti-arthritic activity was analysed. The preliminary characterization of the hemagglutinin was carried out to identify the erythrocyte and sugar specificity, optimum pH and temperature and cation dependency. The agglutinin was found to be highly specific to rabbit erythrocyte and inhibited by fetuin and α-lactose. Maximum hemagglutination activity was noted at pH 7.5–8 and temperature 20–40 °C. An O-acetyl sialic acid specific 75 kDa hemolymph lectin, designated as NagLec was isolated from the freshwater crab, Oziotelphusa naga by affinity chromatography on fetuin coupled Sepharose 4 B, with a purification fold of 185. The bacteria Staphylococcus aureus , Proteus mirabilis and fungus Candida albicans had the greatest zone of inhibition when treated with NagLec. The results of the Minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) assays showed that the purified lectin inhibited the growth of Staphylococcus aureus at 0.031 and 0.065 μg/ml, which proved the bactericidal property of NagLec. NagLec generated alterations on the bacterial cells and led to protein leakage, which was dosage (24 and 48 μg/ml) and time dependent (10–40 min). COX and LOX enzyme was inhibited to 49.43% and 61.81% with 100 μg/ml concentration of NagLec respectively, demonstrating NagLec's ability to reduce inflammation. Furthermore, NagLec (500 μg) suppressed protein denaturation up to 77.12% whereas diclofenac sodium (a standard drug) was inhibited by 89.36%. The results indicate that NagLec, a sialic acid specific lectin isolated from the freshwater crab O. naga could be formulated as a nano drug in future owing to its antimicrobial, anti-inflammatory and anti-arthritic potential that could be targeted to specific pathogenic microbes and treat arthritis. • A sialic acid specific lectin was purified from the hemolymph of freshwater crab, Oziotelphusa naga. • The purified lectin, NagLec exhibited antimicrobial activity against Staphylococcus aureus , Proteus mirabilis , and Candida albicans. • NagLec demonstrated bactericidal activity against Staphylococcus aureus , causing alterations in bacterial cells and protein leakage. • NagLec inhibited COX and LOX enzymes and protein denaturation suggesting anti-inflammatory and anti-arthritic properties. [ABSTRACT FROM AUTHOR]

Docking analysis was used to predict the effectiveness of adamantanyl insertion in improving cycloxygenase/lipoxygenase (COX/LOX) inhibitory action of previously tested 2-thiazolylimino-5-arylidene-4-thiazolidinones. The crystal structure data of human 5-LOX (3O8Y), ovine COX-1 (1EQH) and mouse COX-2 (3ln1) were used for docking analysis. All docking calculations were carried out using AutoDock 4.2 software. Following prediction results, 11 adamantanyl derivatives were synthesized and evaluated for biological action. Prediction evaluations correlated well with experimental biological results. Comparison of the novel adamantanyl derivatives with the 2-thiazolylimino-5-arylidene-4-thiazolidinones previously tested showed that insertion of the adamantanyl group led to the production of more potent COX-1 inhibitors, as well as LOX inhibitors (increased activity from 200% to 560%). Five compounds out of the 11 exhibited better activity than naproxen; while nine out of 11 showed better activity than NDGA and seven compounds possessed better anti-inflammatory activity than indomethacin. [ABSTRACT FROM PUBLISHER]

A pathogenic (biological or chemical) stimulus is the earliest information received by a cell that can result in the disruption of homeostasis with consequent development of disease. Chronic inflammation involves many cell types with numerous cytokines and signaling pathways, the release of different components by the cells, and the crosstalk provoked by such stimuli involving subclinical chronic inflammation and is mechanistically manifold. Exosomes secrete chemicals that trigger the epithelium to produce exosome-like nanoparticles promoting chronic inflammation. Small molecules, together with various cytokines, selectively target signaling pathways inducing crosstalk that suppress apoptosis. 16S rRNA gene sequencing has become routine to provide information on the composition and abundance of bacteria found in human tissues and in reservoirs. The deregulation of autophagy with chronic stimulation of inflammation is an early phenomenon in carcinogenesis. The disruption of cell–cell integrity enables transcellular CagA migration and triggers deregulation of autophagy with the net result being chronic inflammation. The complex and insidious nature of chronic inflammation can be seen both inside and outside the cell and even with intracellular nuclear fragments such as chromatin, which itself can elicit a chronic inflammatory response within the cytoplasm and affect autophagy. The ultimate result of unresolved chronic inflammation is fibrosis, a step before tissue remodeling results in the formation of a precancerous niche (PCN). Various pathogenic stimuli associated with different neoplasms result in persistent inflammation. This ongoing disruption of homeostasis in the micromilieu of cells, tissues, and organs is an essential preamble to carcinogenesis and occurs early in that process.

Schisandra rubriflora is a dioecious plant of increasing importance due to its lignan composition, and therefore, possible therapeutic properties. The aim of the work was lignan profiling of fruits, leaves and shoots of female (F) and male (M) plants using UHPLC-MS/MS. Additionally, the anti-inflammatory activity of plant extracts and individual lignans was tested in vitro for the inhibition of 15-lipooxygenase (15-LOX), phospholipases A2 (sPLA2), cyclooxygenase 1 and 2 (COX-1; COX-2) enzyme activities. The extracts of fruits, leaves and shoots of the pharmacopoeial species, S. chinensis, were tested for comparison. Twenty-four lignans were monitored. Lignan contents in S. rubriflora fruit extracts amounted to 1055.65 mg/100 g DW and the dominant compounds included schisanhenol, aneloylgomisin H, schisantherin B, schisandrin A, gomisin O, angeloylgomisin O and gomisin G. The content of lignan in leaf extracts was 853.33 (F) and 1106.80 (M) mg/100 g DW. Shoot extracts were poorer in lignans—559.97 (F) and 384.80 (M) mg/100 g DW. Schisantherin B, schisantherin A, 6-O-benzoylgomisin O and angeloylgomisin H were the dominant compounds in leaf and shoot extracts. The total content of detected lignans in S. chinensis fruit, leaf and shoot extracts was: 1686.95, 433.59 and 313.83 mg/100 g DW, respectively. Gomisin N, schisandrin A, schisandrin, gomisin D, schisantherin B, gomisin A, angeloylgomisin H and gomisin J were the dominant lignans in S. chinensis fruit extracts were. The results of anti-inflammatory assays revealed higher activity of S. rubriflora extracts. Individual lignans showed significant inhibitory activity against 15-LOX, COX-1 and COX-2 enzymes.

• Newer [1,3,4]-thiadiazoles compounds (7a-j) are synthesized and have been evaluated as XO inhibitor. • Bioactivity were evaluated for inflammatory enzymes using COX and LOX. • Compound (7i) was found to exhibited best activity. • The results were supported by In-silico docking, DFT and MEP surface studies. Xanthine oxidase (XO) is an interesting target for the synergic treatment of several diseases such as gout, hypertension, type 2 diabetes, and kidney disease. Associated complication includes hyperuricemia, which is considered one of the most common metabolic lifestyle disorders worldwide. Overproduction and insufficient excretion of uric acid during purine metabolism results in the formation of uric acid crystals in kidneys, joints, and other tissues. Allopurinol and Febuxostat, a clinically available drug used to reduce XO activity and serum uric acid level, are demonstrated to produce adverse effects including gastrointestinal distress, hypersensitivity, and skin rash, raising safety concerns. Exploring newer and novel XO inhibitors with minimum or no side effects is the aim of the current study. [1,3,4]-Thaidiazole analogs (7a-j) scaffold plays an important role in the design of efficient and potent inhibitors. In the present work, (7a-j) were evaluated for their ability to inhibit XO and found that among the series compound (7i) is selected as the best compound for inhibition of XO. Further, cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX), enzymes that generate biologically active lipid molecules termed eicosanoids, are considered inflammatory and play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types, the level of COX-2 enzyme is increased indicating that this enzyme could be a suitable target for cancer therapy. Based on these findings, we have synthesized some new novel [1,3,4]-thiadiazole analogous (7a-j) and tested them against XO, COX, and LOX. To gain insight into the activity of XO, COX, and LOX inhibition, molecular docking studies were carried out for XO, COX, and LOX enzymes utilizing the newly synthesized compounds (7a-j) , and the results inferred that among the synthesized series of [1,3,4]-thiadiazoles (7a-j) , the compound (7i) showed extremely good result in both In silico and evaluation studies of XO, COX, and LOX, which is in agreement with the experimental results. Furthermore, density functional theory (DFT) was applied to calculate HOMO-LUMO, energy gap, and other parameters under the hybrid exchange-correlation functional (B3LYP) with the triple split valence basis set (6-311G). [ABSTRACT FROM AUTHOR]

Chloramphenicol (Chl) is an effective antimicrobial agent widely used in veterinary medicine and commonly used in fish. Its use is restricted in the clinic because of adverse effects on the immune system and oxidative stress in mammals. However, the effects of Chl treatment on invertebrates remain unclear. Amphioxus, a basal chordate, is an ideal model to study the origin and evolution of the vertebrate immune system as it has a primary vertebrate-like arachidonic acid (AA) metabolic system. Here, we combined transcriptomic and lipidomic approaches to investigate the immune system and observe the oxygenated metabolites of AA to address the antibiotic effects on amphioxus. Tissue necrosis of the gill slits occurred in the Chl-treated amphioxus, but fewer epithelial cells were lost when treated with both Chl and ampicillin (Amp). The immune related pathways were dysregulated in both of the antibiotic treatment groups. The Chl alone treatment resulted in immunosuppression with down-regulation of the innate immune genes. In contrast, the Chl + Amp treatment resulted in immunostimulation to some extent, as shown by KEGG clustering. Furthermore, Chl induced a 3-fold reduction in the level of the eicosanoids, while the Chl + Amp treatment resulted in 1.7-fold increase of eicosanoid level. Thus in amphioxus, Amp might relieve the effects of the Chl-induced immune suppression and increase the level of eicosanoids from AA. Finally, the oxygenated metabolites from AA might be crucial to evaluate the effects of Chl treatment in animals. [ABSTRACT FROM AUTHOR]

Curcumin (diferuloylmethane) is the most important component of the spice turmeric and is derived from the rhizome of the East Indian plant Curcuma longa. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including antioxidant, analgesic, anti-inflammatory, and antiseptic activities. Recently, curcumin has been widely studied for its anticancer properties via its effects on a variety of biological pathways involved in apoptosis, tumor proliferation, chemo- and radiotherapy sensitization, tumor invasion, and metastases. Curcumin can be an effective adjunct in treating solid organ tumors due to its properties of regulating oncogenes like p53, egr-1, c-myc, bcl-XL, etc.; transcription factors like NF-kB, STAT-3, and AP-1; protein kinases like MAPK; and enzymes like COX and LOX. Lung cancer is the most common malignancy worldwide and a leading cause of cancer-related deaths. Seventy-five percent of lung cancer presents at an advanced stage where the existing treatment is not very effective and may result in tremendous patient morbidity. As a result, there is a significant interest in developing adjunctive chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo studies of curcumin in lung cancer. [ABSTRACT FROM AUTHOR]

Eicosanoids play an important role in inducing complex and crucial physiological processes in animals. Eicosanoid biosynthesis in animals is widely reported; however, eicosanoid production in invertebrate tissue is remarkably different to vertebrates and in certain respects remains elusive. We, for the first time, compared the orthologs involved in arachidonic acid (AA) metabolism in 14 species of invertebrates and 3 species of vertebrates. Based on parsimony, a complex AA-metabolic system may have existed in the common ancestor of the Metazoa, and then expanded and diversified through invertebrate lineages. A primary vertebrate-like AA-metabolic system via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways was further identified in the basal chordate, amphioxus. The expression profiling of AA-metabolic enzymes and lipidomic analysis of eicosanoid production in the tissues of amphioxus supported our supposition. Thus, we proposed that the ancestral complexity of AA-metabolic network diversified with the different lineages of invertebrates, adapting with the diversity of body plans and ecological opportunity, and arriving at the vertebrate-like pattern in the basal chordate, amphioxus. [ABSTRACT FROM AUTHOR]

The toxic effects of arsenic on the whole brain, as well as the discrete regions, has been previously reported for mice. We investigated the effects of acute arsenite (As(III)) on brain levels of arachidonic acid (AA) and its associated metabolites generated through cytochrome P450 (CYP), cyclooxygenase (COX), and lipoxygenase (LOX) pathways. Our results demonstrated that acute As(III) treatment (12.5 mg·(kg body mass)−1) decreases cytosolic phospholipase A2 (cPLA2) with a subsequent decrease in its catalytic activity and brain AA levels. In addition, As(III) differentially altered CYP epoxygenases and CYP ω-hydroxylases, but it did not affect brain Ephx2 mRNA or sEH catalytic activity levels. As(III)-mediated effects on Cyps caused an increase in brain 5,6-epoxyeicosatrienoic acid (5,6-EET) and 16/17-hydroxyeicosatetreinoic acid (16/17-HETE) levels, and a decrease in 18- and 20-HETE levels. Furthermore, As(III) increased cyclooxygenase-2 (COX-2) mRNA while decreasing prostaglandins F2α (PGF2α) and PGJ2. As(III) also increased brain 5-lipoxygenase (5-LOX) and 15-LOX mRNA, but decreased 12-LOX mRNA. These changes in LOX mRNA were associated with a decrease in 8/12-HETE levels only. In conclusion, this is the first demonstration that As(III) decreases AA levels coinciding with alterations to EET, HETE, and PG levels, which affects brain development and neurochemistry. [ABSTRACT FROM AUTHOR]

Abstract: KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the inhibitory activity test on Hep G2 growth. We found that KYKZL-1 inhibited the growth of Hep G2 cells via inducing apoptosis. Further studies showed that KYKZL-1 activated caspase-3 through cytochrome c release from mitochondria and down regulation of Bcl-2/Bax ratio and reduced the high level of COX-2 and 5-LOX. As shown in its anti-inflammatory effect, KYKZL-1 also exhibited inhibitory effect on the PGE2 and LTB4 production in Hep G2 cells. Accordingly, exogenous addition of PGE2 or LTB4 reversed the decreases in cell viability. In addition, KYKZL-1 caused cell cycle arrest at the S–G2 checkpoint via the activation of p21CIP1 protein and down-regulation of cyclin A expression. These data indicate that the growth inhibitory effect of KYKZL-1 is associated with inhibition of AA metabolites and caspase-3 pathway and cell cycle arrest. Combined with our previous findings, KYKZL-1 exhibiting COX/5-LOX inhibition may be a promising potential agent not only for inflammation control but also for cancer prevention/therapy with an enhanced gastric safety profile. [Copyright &y& Elsevier]

Abstract: KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the anti-inflammatory activity test focusing on its modulation of inflammatory mediators as well as intracellular MAPK and NF-κB signaling pathways. In acute ear edema model, pretreatment with KYKZL-1 (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice with a higher inhibition than diclofenac. In a three-day TPA-induced inflammation, KYKZL-1 also showed significant anti-inflammatory activity with inhibition ranging between 20% and 64%. In gastric lesion test, KYKZL-1 elicited markedly fewer stomach lesions with a low index of ulcer as compared to diclofenac in rats. In further studies, KYKZL-1 was found to significantly inhibit the production of NO, PGE2, LTB4 in LPS challenged RAW264.7, which is parallel to its attenuation of the expression of iNOS, COX-2, 5-LOX mRNAs or proteins and inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB. Taken together, our data indicate that KYKZL-1 comprises dual inhibition of COX and 5-LOX and exerts an obvious anti-inflammatory activity with an enhanced gastric safety profile via simultaneous inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB. [Copyright &y& Elsevier]

Abstract: Two faba bean (Vicia faba L.) subspecies major and minor and lentil seeds grown in Algeria were separated into cotyledons and hulls. These fractions, together with their corresponding whole seeds, were extracted with two solvents, aqueous (70%) acetone and (80%) ethanol, and evaluated for antioxidant activity in relation to their phenolic contents. Acetone selectively extracted tannins from faba beans. The hulls always exhibited high antioxidant activity, measured using the reducing power (RP), antiradical activity (DPPH) or oxygen radical absorbance capacity (ORAC) assays. Aqueous ethanol (80%) extract of lentil hulls exhibited high antioxidant and anti-inflammatory activities preferentially inhibiting 15-LOX (IC50, 55μg/ml), with moderate COX-1 (IC50, 66μg/ml) and COX-2 (IC50, 119μg/ml) inhibitory effects on the COX pathway, whereas faba bean hull extracts exerted relatively mild LOX inhibitory activity. [Copyright &y& Elsevier]

Abstract: Benfotiamine, a lipid-soluble analogue of vitamin B1, is a potent antioxidant that is used as a food supplement for the treatment of diabetic complications. Our recent study (U.C. Yadav et al., Free Radic. Biol. Med. 48:1423–1434, 2010) indicates a novel role for benfotiamine in the prevention of bacterial endotoxin, lipopolysaccharide (LPS)-induced cytotoxicity and inflammatory response in murine macrophages. Nevertheless, it remains unclear how benfotiamine mediates anti-inflammatory effects. In this study, we investigated the anti-inflammatory role of benfotiamine in regulating arachidonic acid (AA) pathway-generated inflammatory lipid mediators in RAW264.7 macrophages. Benfotiamine prevented the LPS-induced activation of cPLA2 and release of AA metabolites such as leukotrienes, prostaglandin E2, thromboxane 2 (TXB2), and prostacyclin (PGI2) in macrophages. Further, LPS-induced expression of AA-metabolizing enzymes such as COX-2, LOX-5, TXB synthase, and PGI2 synthase was significantly blocked by benfotiamine. Furthermore, benfotiamine prevented the LPS-induced phosphorylation of ERK1/2 and expression of transcription factors NF-κB and Egr-1. Benfotiamine also prevented the LPS-induced oxidative stress and protein–HNE adduct formation. Most importantly, compared to specific COX-2 and LOX-5 inhibitors, benfotiamine significantly prevented LPS-induced macrophage death and monocyte adhesion to endothelial cells. Thus, our studies indicate that the dual regulation of the COX and LOX pathways in AA metabolism could be a novel mechanism by which benfotiamine exhibits its potential anti-inflammatory response. [Copyright &y& Elsevier]

Abstract: The anti-inflammatory effect of sulphated polysaccharide (SP) isolated from an algae Padina tetrastromatica was studied. Even though the polysaccharide was found to be a fucan, the composition of this polysaccharide is different from those reported and the mechanism underlying the anti-inflammatory effect also has not been reported so far; perhaps this might be the first report in this regard. Paw edema in rats was induced by injecting 0.1mL, 1% carrageenan suspension in 0.9% NaCl solution into the sub-plantar tissue of the right hind paw. SP was given intraperitoneally (i.p), 1 hour before the injection of carrageenan. Carrageenan caused a significant increase in the activity of inflammatory marker enzymes like lipoxygenases (LOX) and cyclooxygenase (COX) in peripheral blood mononuclear cells (PBMC) and increased the concentration of serum ceruloplasmin and myeloperoxidase (MPO). SP pre-treatment when compared to the reference drug significantly reduced the concentration of COX and LOX in PBMC, ceruloplasmin and MPO in serum and also inhibited the iNOS and COX-2 expression at mRNA level. As this polysaccharide has high anti-inflammatory activity when compared to the anti-inflammatory drug diclofenac, this natural biomolecule could be recommended as a new effective drug for inflammation. [Copyright &y& Elsevier]

Targeting to the synthesis of potent dual acting COX/LOX inhibitors as future anti-inflammatory drugs, we attempted a modification of the compounds based on docking analysis results. A substitution of the oxygen of the oxo-group of the oxazin-2-one ring by sulphur resulted in a four to over ten fold improvement of COX and LOX inhibitory action. N-phenyl derivatives exhibited the best biological properties with the 4-methoxy-phenyl derivative showing the best COX-1 and LOX inhibitory action and the 4-Br-phenyl derivative exhibiting the best COX-2 inhibitory action combined with good COX-1 and LOX inhibitory capacity. [ABSTRACT FROM AUTHOR]

Abstract: Head and neck cancers are known to synthesize arachidonic acid metabolites. Interfering with arachidonic acid metabolism may inhibit growth and invasiveness of cancer cells. In this study we investigate effects of sulindac (the non-selective COX inhibitor), aspirin (the irreversible, preferential COX-1 inhibitor), NS-398 (the selective COX-2 inhibitor), NDGA (nordihydroguaiaretic acid, the selective LOX inhibitor) and ETYA (5,8,11,14-eicosatetraynoic acid, the COX and LOX inhibitor) on cell viability, MMP-2 and MMP-9 activities, and in vitro invasion of cancer cells derived from primary and metastatic head and neck, and colon cancers. The inhibitors of COX and/or LOX could inhibit cell proliferation, MMP activity and invasion in head and neck and colon cancer cells. However, the inhibitory effect was obviously observed in colon cancer cells. Inhibition of arachidonic acid metabolism caused a decrease in cancer cell motility, which partially explained by the inhibition of MMPs. Therefore, COX and LOX pathways play important roles in head and neck cancer cell growth. [ABSTRACT FROM AUTHOR]

Abstract: A series of adamantane derivatives of thiazolyl-N-substituted amides were synthesized in a three-step reaction and tested for anti-inflammatory activity as well as lipoxygenase and cycloxygenase inhibitory actions. Theoretical calculation of their lipophilicity, as C log P was performed. The effect of the synthesized compounds on inflammation, using the carrageenin-induced mouse paw oedema model was studied and compared to indomethacin. In general, the studied compounds were found to be potent anti-inflammatory agents (29.6–81.5%). Anti-inflammatory activity was influenced by some structural characteristics of the synthesized compounds. The lipoxygenase inhibitory activity was tested by the conversion of sodium linoleate to 13-hydroperoxylinoleic acid. Low inhibitory activity was observed. Evaluation of COX-1 and COX-2 inhibitory activities of the compounds revealed a COX-1 inhibitory potential, comparable to that of naproxen for some of the compounds and a low to moderate COX-2 inhibitory potential. Comparison of the in vivo and in vitro results leads to the conclusion that most compounds of this series may be involved in other mechanisms of inflammation, too. [Copyright &y& Elsevier]

Abstract: Although inflammation has long been known as a localized protective reaction of tissue to irritation, injury, or infection, characterized by pain, redness, swelling, and sometimes loss of function, there has been a new realization about its role in a wide variety of diseases, including cancer. While acute inflammation is a part of the defense response, chronic inflammation can lead to cancer, diabetes, cardiovascular, pulmonary, and neurological diseases. Several pro-inflammatory gene products have been identified that mediate a critical role in suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis. Among these gene products are TNF and members of its superfamily, IL-1α, IL-1β, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX. The expression of all these genes are mainly regulated by the transcription factor NF-κB, which is constitutively active in most tumors and is induced by carcinogens (such as cigarette smoke), tumor promoters, carcinogenic viral proteins (HIV-tat, HIV-nef, HIV-vpr, KHSV, EBV-LMP1, HTLV1-tax, HPV, HCV, and HBV), chemotherapeutic agents, and γ-irradiation. These observations imply that anti-inflammatory agents that suppress NF-κB or NF-κB-regulated products should have a potential in both the prevention and treatment of cancer. The current review describes in detail the critical link between inflammation and cancer. [Copyright &y& Elsevier]

Abstract: The release of soluble amyloid precursor protein α (sAPPα), produced during α-secretase processing by cleavage within the β amyloid peptide domain of APP, is highly regulated by several external and internal signals. Because evidence suggests the involvement of inflammatory processes in the pathology of Alzheimer''s disease and APP formation, we examined the involvement of the phospholipase A2 (PLA2) pathway and of its downstream cyclooxygenase (COX) and lipoxygenase (LOX) pathways in the regulation of sAPPα, release induced by muscarinic receptor activation in SH-SY5Y cells. The amount of sAPP released into the culture medium was analyzed using a monoclonal 6E10 antibody detecting sAPPα. Treatment with the PLA2 inhibitor, manoalide, blocked the release of oxoM (muscarinic receptor agonist)-stimulated sAPPα, and the muscarinic receptor-mediated sAPPα release was increased by the non-selective PLA2 activator mellitin. COX and LOX inhibitors inhibited exogenous AA-induced sAPPα release, but upregulated basal constitutive sAPPα release. However, treatment with COX or LOX inhibitors failed to significantly change oxoM-stimulated sAPPα release, and furthermore, muscarinic receptor activation inhibited AA-stimulated COX activity. Our results suggest that sAPPα release induced by muscarinic receptor activation is regulated by AA generation via PLA2 activation independently of COX and LOX activities, but that the COX and LOX pathways are possibly involved in the constitutive release of sAPPα. [Copyright &y& Elsevier]

Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are used primarily for the treatment of inflammatory diseases. However, certain NSAIDs also have a chemopreventive effect on the development of human colorectal and other cancers. NSAIDs inhibit cyclooxygenase-1 (COX-1) and/or cyclooxygenase-2 (COX-2) activity and considerable evidence supports a role for prostaglandins in cancer development. However, the chemopreventive effect of NSAIDs on colorectal and other cancers appears also to be partially independent of COX activity. COX inhibitors also alter the expression of a number of genes that influence cancer development. One such gene is NAG-1 (NSAID-Activated Gene), a critical gene regulated by a number of COX inhibitors and chemopreventive chemicals. Therefore, this article will discuss the evidence supporting the conclusion that the chemo-preventive activity of COX inhibitors is mediated, in part, by altered gene expression with an emphasis on NAG-1 studies. This review may also provide new insights into how chemicals and environmental factors influence cancer development. In view of the cardiovascular and gastrointestinal toxic side effects of COX-2 inhibitors and non-selective COX inhibitors, respectively, the results presented here may provide the basis for the development of a new family of anti-tumorigenic compounds acting independent of COX inhibition. [Copyright &y& Elsevier]

Abstract: Different peroxidases were used to catalyze the synthesis of neolignan. Horseradish peroxidase (type I, Sigma) was employed successfully to catalyze the formation of magnolol by the phenolic oxidative coupling of allyphenol. The effects of organic co-solvents, pH, addition rate of H2O2, and the ratio of enzyme/substrate on the yields of dimer were studied. After the peroxidase-catalyzed reaction was performed, different neolignans were isolated and identified as magnolol (3), the trimeric ortho–ortho-coupled product dunnianol (4), the ortho-O-coupled product isomagnolol (5), and the Pummerer''s ketone derivative (6). The inhibitory activities of magnolol against cyclo-oxygenase and lipoxygenase were also reported. [Copyright &y& Elsevier]

[Display omitted] • Thymol – 4-thiazolidinone hybrids as multitarget colorectal cancer inhibitors (CRC). • Inhibition of COX-2, 5-LOX and PIM-1 kinase is effective in the treatment of CRC. • 5a, 5c, 5f and 5g showed in vitro and in vivo anti-inflammatory activities. • 5d, 5e and 5g induced caspase 3\7 dependent-apoptosis in vitro in human CRC. • 5g achieved the target goal and acted as multitarget inhibitor of human CRC. Colorectal cancer (CRC) is the second cause of cancer death worldwide. Inhibitors of COX-2, 5-LOX and PIM-1 kinase were very effective in the treatment and prevention of CRC in mouse models in vivo. Furthermore, thymol was confirmed to inhibit CRC cell proliferation in cancer cell lines and inhibitory activity against COX-2 and 5-LOX. On the other hand, 4-thiazolidinone pharmacophore was incorporated in the structures of various reported COX-2, 5-LOX and PIM kinase inhibitors. Consequently, the aim of the present investigation was to combat CRC by synthesis and biological evaluation of new thymol – 4-thiazolidinone hybrids as multitarget anticancer agents that could inhibit the key COX-2, 5-LOX and PIM-1 kinase enzymes simultaneously. Compounds 5a - d and 5g displayed inhibitory activity against COX-2 nearly equal to Celecoxib with high selectivity index (SI). Moreover, compounds 5b-e showed 5-LOX inhibitory activity nearly equal to the reference Quercetin while compounds 5a , 5f and 5g elicited inhibitory activity slightly lower than Quercetin. Furthermore, in vivo formalin-induced paw edema test revealed that, compounds 5a, 5c, 5f and 5g showed higher % inhibition than Celecoxib and compounds 5a, 5f and 5g showed higher % inhibition than Diclofenac sodium. In addition, compounds 5a-c, 5e-g showed in vivo superior gastrointestinal safety profile as Celecoxib in fasted rats. Besides, compounds 5d, 5e and 5g exhibited the highest activity against human CRC cell lines (Caco-2 and HCT-116) at doses less than their EC 100 on normal human cells. Furthermore, compounds 5e and 5g induced apoptosis-dependent death by above 50% in the treated CRC cell lines. Moreover, compounds 5e and 5g induced caspase activation by >50% in human CRC. Also, compounds 5d, 5e and 5g showed in vitro inhibitory activity against both PIM-1\2 kinases comparable to the reference Staurosporine. In silico docking studies were concordant with the biological results. In conclusion, compound 5g, of simple chemical structure, achieved the target goal of inhibiting three targets leading to inhibition of human CRC cell proliferation. It inhibited the target key enzymes COX-2, 5-LOX and PIM-1\2 kinase in vitro. Besides, it revealed in vitro inhibition of cell proliferation in cancer cell lines via activation of caspase 3\7 dependent-apoptosis in human CRC cell lines. In addition, it elicited in vivo anti-inflammatory activity in formalin-induced paw edema test and in vivo oral safety in gastric ulcerogenic activity test. [ABSTRACT FROM AUTHOR]