Inhibition Of Cyclooxygenase Enzymes Research Articles

Current Pharmaceutical Options for the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis is an inflammatory and autoimmune disease that describes the joints persistent inflammation and tendon sheets synovial lining. The primary symptoms of rheumatoid arthritis are stiffness, pain, and swelling of peripheral joints. Persistent inflammation results in many systemic and extra-articular manifestations involving many organ systems. Rheumatoid arthritis treatment goals are symptomatic management of pain, stiffness and restricted mobility. NSAIDs are commonly prescribed for people with rheumatoid arthritis. Analgesic effects of NSAIDs are based mainly on the inhibition of COX-enzyme and consequently the production of prostaglandins.

Pharmacological evaluation underlying the antinociceptive activity of two new hybrids NSAIDs tetrahydropyran derivatives.

The development of analgesic drugs is still a necessity due to the inefficiency of the current treatments for some pathological conditions and also due to the adverse effects produced by these drugs. The aim of this study was to deepen the pharmacological study of two new hybrids NSAIDs tetrahydropyran derivatives, regarding their antinociceptive effects on acute pain in mice. Male swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail-flick, open-field, glutamate- and capsaicin-induced paw licking tests, and in vitro Cox inhibition assay, besides the acute toxicological evaluation. The compounds had an effect on the acetic acid-induced abdominal writhing, formalin (both phases), and tail-flick tests. In the study of the mechanism of action was observed reversion of the antinociceptive effect of the compounds from the previous administration of naloxone, L-NAME (L-nitro-arginine methyl ester), ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), glibenclamide, and nor-binaltorphimine, by the intrathecal and intraperitoneal routes. The prior administration of MK-801 suggests that the modulation of NMDA receptor contributes to the antinociceptive effect of compounds. In summary, hybrid compounds presented central antinociceptive effect, demonstrating participation of the NO-cGMP-K+ ATP pathway, κ-opioid, and NMDA receptors. In addition, the compounds showed inhibition of cyclo-oxygenase enzymes and adverse effects were not observed with dose 300 times greater than the dose used experimentally.

P098 Worsening Colitis and Congestive Heart Failure Related to Mesalamine Use

BACKGROUND: Five-amino salicylic acid derivatives are generally well-tolerated agents commonly used to treat ulcerative colitis. Serious reactions are rare. We present a case of paradoxical worsening of ulcerative colitis and acute heart failure in a young woman on mesalamine therapy. CASE: A 37-year old white female with a history of sleeve gastrectomy and recently diagnosed mild to moderate extensive ulcerative colitis (UC) had been on oral mesalamine for 1 month. She endorsed worsening symptoms, with 10-12 watery bowel movements daily along with 3-4 episodes of hematochezia and generalized abdominal cramps. Lack of response to prednisone prompted admission. She was found to be severely dehydrated, hyponatremic with a sodium of 132 mEq/L, and anemic with a hemoglobin of 10.2 g/dL (from normal three months earlier). Albumin was decreased at 3.1 g/dL and C-reactive protein (CRP) was elevated at 4.2 mg/dL. Stool tests for Clostridioides difficile, other bacteria, and viruses, were negative. Flexible sigmoidoscopy showed Mayo 3 colitis despite 3 days of IV methylprednisolone. Her hospital course was complicated by acute heart failure presenting as leg edema and shortness of breath. Brain natruretic peptide level was elevated at 550 pg/mL. Echocardiogram revealed global hypokinesis of the left ventricle and an estimated ejection fraction of 30-35%. Given this contraindication to anti-tumor necrosis factor agents, she was started on tofacitinib 10 mg thrice daily. Surgical consultation was also obtained. After three doses her abdominal pain improved, diarrhea decreased to 5 bowel movements daily, and CRP decreased to 1.9 mg/dL. After three days, the dose was decreased to 10 mg twice daily. On clinic follow-up 3 weeks later, she was pain-free and bowel movements were back to baseline with no blood and no diarrhea. CRP and albumin normalized. Her shortness of breath and leg edema had also resolved. Multigated acquisition scan 3 months after discharge showed resolution of left ventricle wall motion abnormalities, and a normal ejection fraction of 61%. DISCUSSION: Five-amino salicylic acids (5-ASA) are relatively safe medications. Serious reactions including pancreatitis, interstitial nephritis, blood dyscrasias, pneumonitis, and Stevens Johnson syndrome, are rare. Infrequently, paradoxical worsening of colitis is seen. This phenomenon is not well understood and there is no consistency in the presence of inflammatory markers. Confirmation requires a mesalamine challenge, which is not often feasible. Acute cardiac side effects from mesalamine are extremely uncommon, potentially serious, and appear dose-independent. The exact mechanism by which it might induce myocardial inflammation and heart failure is unclear. Existing hypotheses include: a hypersensitivity reaction due to inhibition of COX enzyme and subsequent acceleration in metabolism of arachidonic acid to lipoxygenases, humoral-mediated hypersensitivity wherein antibodies against mesalamine cross-react with the myocardium, cell-mediated hypersensitivity, and immunoglobulin E-mediated allergic reaction. Symptoms usually manifest within 2-4 weeks of starting the drug. CONCLUSION: The temporal relationship between our patient’s symptom onset and initiation of mesalamine indicates a causal relationship. Mesalamine should remain on the differential of worsening UC, and acute heart failure, after evaluating for more common causes.

Molecular Dynamics Studies on COX-2 Protein-tyrosine Analogue Complex and Ligand-based Computational Analysis of Halo-substituted Tyrosine Analogues

Background: The quest for new drug entities and novel structural fragments with applications in therapeutic areas is always at the core of medicinal chemistry. Methods: As part of our efforts to develop novel selective cyclooxygenase-2 (COX-2) inhibitors containing tyrosine scaffold. The objective of this study was to identify potent COX-2 inhibitors by dynamic simulation, pharmacophore and 3D-QSAR methodologies. Dynamics simulation was performed for COX-2/tyrosine derivatives complex to characterise structure validation and binding stability. Certainly, Arg120 and Tyr355 residue of COX-2 protein formed a constant interaction with tyrosine inhibitor throughout the dynamic simulation phase. A four-point pharmacophore with one hydrogen bond acceptor, two hydrophobic and one aromatic ring was developed using the HypoGen algorithm. The generated, statistically significant pharmacophore model, Hypo 1 with a correlation coefficient of r2, 0.941, root mean square deviation, 1.15 and total cost value of 96.85. Results: The QSAR results exhibited good internal (r2, 0.992) and external predictions (r2pred, 0.814). The results of this study concluded the COX-2 docked complex was stable and interactive like experimental protein structure. Also, it offered vital chemical features with geometric constraints responsible for the inhibition of the selective COX-2 enzyme by tyrosine derivatives. Conclusion: In principle, this work offers significant structural understandings to design and develop novel COX-2 inhibitors.

Growth inhibitory effects of PC-NSAIDs on human breast cancer subtypes in cell culture.

The potential role of non-steroidal anti-inflammatory drug (NSAID) therapy in the prevention and treatment of cancer has generated considerable research interest. Phosphatidylcholine (PC)-associated NSAIDs decrease the gastrointestinal side effects of NSAID therapy, and may be more effective than traditional NSAIDs in limiting tumor growth. In the present study, human cells representing three major breast cancer subtypes were cultured with aspirin, indomethacin and PC-associated forms of each drug, with PC alone as a control. All tested drugs decreased the tumor cell number after 8 days of culture, with PC-NSAIDs having the greatest inhibitory effect, and NSAIDs alone, particularly aspirin, having the least effect. PC alone was effective in limiting the proliferation of all cell lines, suggesting that the two components of PC-NSAIDs have an additive effect. The ELISA results did not support a strong role for inhibition of cyclooxygenase enzymes in the decrease in cancer cell proliferation, which may account for the limited effectiveness of aspirin alone. PC-NSAIDs, particularly indomethacin-PC, are attractive candidate drugs in the prevention and treatment of different types of breast cancer, including triple negative breast cancer.

Синтез и биологическая активность N-алкил(арил)-4-R-оксо-2-(2-фениламинобензоилгидразоно)бутанамидов

First of all, the main task of pharmacy is search for new compounds, including those with high biological activity. Although lots of known compounds have antinociceptive and anti-inflammatory effects, almost all of them have a toxic effect on the gastrointestinal tract and cause a large number of side effects from various organs and systems of the body, since they are non-selective inhibitors of cyclooxygenase enzyme. The relief of pain and inflammatory processes as well the following search for safe and more efficient compounds is the significant task of pharmacology. It was found that hydrazonamides have very effective anti-inflammatory and antinociceptive activity; they will be perspective for following pharmacological screening. Objective: synthesis and study of anti-inflammatory and antinociceptive activity of N-alkyl(aryl)-4-R-4-oxo-2-(2-phenylaminobenzoylhydrazono)butanamides. Materials and methods. We synthesized the compounds investigated by means of classic organic synthesis; their structures were analyzed with IR, NMR 1 H, NMR 13 C spectroscopy and mass spectrometry. We studied the antinociceptive activity on outbred white mice by «hot plate» method, and anti-inflammatory activity on outbred white rats by the model of acute inflammatory edema. Results. N-alkyl(aryl)-4-R-4-oxo-2-(2-phenylaminobenzoylhydrazono)butanamides showed the high antinociceptive activity, several compounds exhibited anti-inflammatory effect. Conclusion. N-alkyl(aryl)-4-R-4-oxo-2-(2-phenylaminobenzoylhydrazono)butanamides have perspective for the following in-depth study, including on acute toxicity and other types of biological activity.

Design, Synthesis and Pharmacological Evaluation of Novel Antiinflammatory and Analgesic O-Benzyloxime Compounds Derived From Natural Eugenol

Background: : A new series of O-benzyloximes derived from eugenol was synthesized and was evaluated for its antinociceptive and anti-inflammatory properties. Methods: : The target compounds were obtained in good global 25-28% yields over 6 steps, which led us to identify compounds (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-(4- (methylthio)benzyloxime (8b), (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- bromobenzyloxime (8d) and (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- (methylsulfonyl)benzyloxime (8f) as promising bioactive prototypes. Results:: These compounds have significant analgesic and anti-inflammatory effects, as evidenced by formalin-induced mice paw edema and carrageenan-induced mice paw edema tests. In the formalin test, compounds 8b and 8f evidenced both anti-inflammatory and direct analgesic activities and in the carrageenan-induced paw edema, with compounds 8c, 8d, and 8f showing the best inhibitory effects, exceeding the standard drugs indomethacin and celecoxib. Conclusion: : Molecular docking studies have provided additional evidence that the pharmacological profile of these compounds may be related to inhibition of COX enzymes, with slight preference for COX-1. These results led us to identify the new O-benzyloxime ethers 8b, 8d and 8f as orally bioactive prototypes, with a novel structural pattern capable of being explored in further studies aiming at their optimization and development as drug candidates.

The Impact of Immunological Factors on Depression Treatment - Relation Between Antidepressants and Immunomodulation Agents.

It is determined that 30% of patients with depression are resistant to antidepressant medication. The increased concentration of inflammation factors, such as C-reactive protein, and pro-inflammatory cytokines, have been detected in serum in these patients. It is necessary to establish new therapeutic possibilities and protocols that are created to overcome the difficulties caused by increased concentration of inflammatory biomarkers in depressive patients. The Selective Serotonin Reuptake Inhibitors (SSRIs) are considered to be the most powerful antidepressants, increasing the level of serotonin in endogenous depression, as well as in that caused by immunological mechanisms. It is believed that agents that influence cytokines, immunological signal pathways and cytokine syntheses, like the inhibitors of cyclooxygenase enzyme and other non-steroidal anti-inflammatory drugs (NSAIDs), are very important in the potential treatment of residual symptoms of depression. Treatment with cytokine antagonists is one of the potential adjuvant therapies, along with antidepressants. Signal pathways blockers, such as the inhibitors of cyclooxygenase and other NSAIDs, are in the phase of research, in terms of their antidepressant effects. Also, it has been shown that the inhibition of indolamin-2,3 deoxygenase (IDO) and kynurenine (KYN) signal pathways in the synthesis of neurotransmitters, by application of IDO antagonists, are leading to suppression of pro-inflammatory cytokine effects. Antidepressants may have anti-inflammatory effects, depending on dose and type, and they achieve this effect through the decrease of pro-inflammatory cytokine production and increase of anti-inflammatory cytokines. Also, antidepressants modulate the humoral and cellular immune system. This work aims to summarise certain neurobiological and neuroimmunological specificities that have been observed in patients with depression, antidepressants and immunomodulation agents. The understanding of complex and heterogenic pathophysiology of depression through the prism of the altered immune system, is of major importance, in terms of better optimisation of pharmacotherapy, and options for a personalised approach in depressive disorder treatment.

Insights into the weak Csp3–H···H–Csp3 mediated supramolecular architecture in ethyl 2-(5-bromopentanamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate, a probable selective COX-2 lead molecule: An integrated crystallographic and theoretical approach

We report a detailed investigation of the weak noncovalent interactions exist in the crystal structure of the title benzo[b]thiophene derivative. It crystallizes in triclinic system with the centrosymmetric space group P-1. The planar conformation of the molecule is maintained by intramolecular 1,5-S···O chalcogen bond and N–H⋯O and C–H⋯O hydrogen bonding interactions. The crystal structure is primarily stabilized by C–H⋯S, C–H···π, C–H⋯O, Csp3–Br···OC, C–H⋯Br and Csp3–H···H–Csp3 interactions. The relative stability of the Csp3–Br···OC halogen bond is stronger in the crystal structure. Analysis of intermolecular interactions and topological properties show that the Csp3–H···H–Csp3 interactions play vital role in the construction of supramolecular architecture in the crystalline state. The structure based ligand docking and free energy calculation suggests that the title compound could display anti-inflammatory activity via selective inhibition of COX-2 enzyme. The selective inhibitory potential of the title molecule is further validated through theoretical charge density analysis.

3D-QSAR and Molecular Docking Studies on Oxadiazole Substituted Benzimidazole Derivatives: Validation of Experimental Inhibitory Potencies Towards COX-2.

In past few decades, computational chemistry has seen significant advancements in design and development of novel therapeutics. Benzimidazole derivatives showed promising anti-inflammatory activity through the inhibition of COX-2 enzyme. The structural features necessary for COX-2 inhibitory activity for a series of oxadiazole substituted benzimidazoles were explored through 3D-QSAR, combinatorial library generation (Combi Lab) and molecular docking. 3D-QSAR (using kNN-MFA (SW-FB) and PLSR (GA) methods) and Combi Lab studies were performed by using VLife MDS Molecular Design Suite. The molecular docking study was performed by using AutoDockVina. Significant QSAR models generated by PLSR exhibited r2 = 0.79, q2 = 0.68 and pred_r2 = 0. 84 values whereas kNN showed q2 = 0.71 and pred_r2 = 0.84. External validation of developed models by various parameters assures their reliability and predictive efficacy. A library of 72 compounds was generated by combinatorial technique in which 11 compounds (A1-A5 and B1-B6) showed better predicted biological activity than the most active compound 27 (pIC50 = 7.22) from the dataset. These compounds showed proximal interaction with amino acid residues like TYR355 and/or ARG120 on COX-2(PDB ID: 4RS0). The present work resulted in the design of more potent benzimidazoles as COX-2 inhibitors with good interaction as compared to reference ligand. The results of the study may be helpful in the development of novel COX-2 inhibitors for inflammatory disorders.

Anti-nociceptive and Anti-inflammatory Activities of Asparacosin A Involve Selective Cyclooxygenase 2 and Inflammatory Cytokines Inhibition: An in-vitro, in-vivo, and in-silico Approach.

Triterpenes possess anti-inflammatory and anti-nociceptive effects. In this study anti-inflammatory activities of Asparacosin A were evaluated' using in-vitro cyclooxygenases 1 and 2 (COX-1/2) inhibition assays. Moreover, anti-nociceptive activities were assessed in-vivo by carrageenan-induced paw edema test, xylene-induced ear edema tests, and acetic acid-induced writhing and formalin tests. Additionally molecular docking was conducted to elucidate the binding mechanism of the compound and to correlate the in-vitro findings with the in-silico data. Oral administration of Asparacosin A at the doses of 10, 20, and 40 mg/kg induced significant anti-inflammatory effects (*p < 0.05, **p < 0.01, and ***p < 0.001) in a dose-dependent manner in both models. Asparacosin A also inhibited the human recombinant COX-2 enzyme and caused a dose-dependent decrease in the levels of TNF-α, IL-1β, and PGE2 in the carrageenan-induced paws. Moreover, Asparacosin A displayed significant anti-nociceptive effects (*p < 0.05, **p < 0.01, ***p < 0.001) at the doses of 10, 20, and 40 mg/kg in acetic-acid induced writhing test. However, in formalin test, Asparacosin A (10–40 mg/kg, p.o) produced anti-nociceptive effects only in the late phase, similar to the effect observed with the reference drug celecoxib (50 mg/kg, p.o). Molecular docking was carried out on both COX-1 and COX-2 structures which revealed that Asparacosin A targets allosteric binding site similar to the binding mode of the selective COX inhibitor. In conclusion, Asparacosin A exhibits anti-inflammatory and peripheral anti-nociceptive activities which are likely mediated via inhibition of COX-2 enzyme and inflammatory cytokines. Furthermore, Asparacosin A can serve as a model to obtain new and more selective potent anti-inflammatory and anti-nociceptive drugs.

New pyrazole derivatives: Synthesis, anti-inflammatory activity, cycloxygenase inhibition assay and evaluation of mPGES

New pyrazole derivatives 2–5 were synthesized and evaluated for their COX-1 and COX-2 inhibitory activity in vitro. All compounds showed good inhibitory activity at a nanomolar level and most compounds exhibited selectivity towards COX-2 inhibition. Compounds 2a, 3b, 4a, 5b and 5e exhibited IC50 towards COX-2 enzyme of 19.87, 39.43, 61.24, 38.73 and 39.14 nM, respectively. Furthermore, compounds 3b, 4a, 5b and 5e exhibited a selectivity index of 22.21, 14.35, 17.47 and 13.10, respectively. The most active compounds were further subjected to in vivo anti-inflammatory assay. The tested compounds showed better or comparable activity to celecoxib as positive control. In order to explore their binding mode and selectivity behaviour, molecular docking in the active site of COX-2 was carried out for these derivatives. Analysis of the docked poses of the compounds showed that they adopt similar conformations to the highly selective COX-2 inhibitor, SC-558. The docking pose of compound 3b was confirmed by molecular dynamics. All the tested compounds exhibited potent inhibitory effect on the production of PGE2, in addition to their inhibition of COX-2 enzyme.

Aspirin and Prostate Cancer Mortality: The Role of Tumor Grading Misclassification?

Editorials2 April 2019Aspirin and Prostate Cancer Mortality: The Role of Tumor Grading Misclassification?Teemu J. Murtola, MD, PhD and Thea Veitonmäki, MD, PhDTeemu J. Murtola, MD, PhDTampere University and Tampere University Hospital and Seinäjoki Central Hospital, Tampere and Seinäjoki, Finland (T.J.M.)Search for more papers by this author and Thea Veitonmäki, MD, PhDTampere University Hospital, Tampere, Finland (T.V.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M19-0525 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail In their current Annals article, Skriver and colleagues report results from a Danish population-based cohort study estimating prostate cancer–specific survival by aspirin use among 29 136 patients with prostate cancer (1). Aspirin, also known as acetylsalicylic acid, has been linked to a decrease in prostate cancer risk (2) and, in some studies, prostate cancer mortality (2). However, these associations have been controversial; thus, further study is needed.In theory, aspirin is a very interesting drug for preventing prostate cancer progression. It is a noncompetitive inhibitor of cyclooxygenase enzyme 1 (COX-1) and also modifies the action of COX-2, an enzyme thought to ...

Vitamin B12 as a Treatment for Pain

Background: First isolated as cyanocobalamin in 1948, vitamin B12 has been explored for pain treatment almost since its discovery. With the advent of the opioid epidemic, safer treatments for pain are needed. Objectives: Our objective was to compile the latest information on potential mechanisms from animal studies and clinical trial data on vitamin B12 for the treatment of pain conditions. Study Design: We conducted a narrative review. Methods: PubMed was searched using the terms “methylcobalamin pain”, “hydroxycobalamin pain”, “cyanocobalamin pain”, and “vitamin B12 pain.” Animal studies that identified mechanisms of action for the effects of pain were collected. Clinical trials utilizing larger, pharmaceutical doses of vitamin B12 (&gt; 100 µg/dose) in pain treatment were identified and reviewed. Results: Animal studies support multiple beneficial effects of vitamin B12 including the regeneration of nerves and the inhibition of cyclooxygenase enzymes and other pain-signaling pathways. In addition, animal studies have demonstrated synergistic benefits of vitamin B12 combined with other pain medications, including nonsteroidal anti-inflammatory drugs and opiates. Clinical trials provide evidence for the effectiveness of vitamin B12 for the treatment of low back pain and neuralgia, although data is still fairly limited and optimal treatment regimens have not been identified. Limitations: More large, double-blind placebo-controlled trials are needed to fully establish efficacy and best dosing parameters. Conclusion: Vitamin B12 may prove to be an adjunctive or integrative treatment for pain conditions. While more research is needed, considering the low incidence of side effects and overall safety, B12 may be an additional tool to consider for pain treatment. Key words: Vitamin B12, cyanocobalamin, methylcobalamin, hydroxycobalamin, pain, chronic pain, neuropathy, low back pain

In vitro vasoactive effects of dexmedetomidine on isolated human umbilical arteries

We aimed to investigate the vasoactive effects of dexmedetomidine on isolated human umbilical arteries and possible mechanisms involved. Human umbilical artery strips were suspended in Krebs-Henseleit solution and dose-response curves were obtained for cumulative dexmedetomidine before and after incubation with different agents; propranolol, atropine, yohimbine, prazosin, indomethacin, verapamil. Effects of calcium on cumulative dexmedetomidine-induced contractions were also studied. Cumulative dexmedetomidine resulted in dose dependent contraction responses. Incubation with propranolol (Emax: 93.3 ± 3.26 %), atropine (Emax: 92.0 ± 6.54 %), or indomethacin (Emax: 94.25 ± 2.62 %), did not attenuate dexmedetomidine-elicited contractions (p > 0.05). There were significant decreases in the contraction responses of cumulative dexmedetomidine with yohimbine (Emax: 12.1 ± 11.9 %), prazosin (Emax: 28.8 ± 4.6 %) and verapamil (Emax: 11.2 ± 13.6 %) (p < 0.05). In Ca+2 free medium contraction responses to cumulative dexmedetomidine was insignificant (Emax: 5.20 ± 3.42 %). Addition of cumulative calcium to the Ca+2 free medium resulted in concentration dependent increase in contractions (Emax: 64.83 ± 37.7 %) (p < 0.05). Dexmedetomidine induces vasoconstriction in endothelial-free umbilical arteries via both, α1- and α2-adrenergic receptors and also extracellular Ca+2 concentrations play a major role. β-adrenergic receptors, muscarinic cholinergic receptors, and inhibition of cyclooxygenase enzyme are not involved in this vasoconstriction (Fig. 3, Ref. 36).

Antibacterial, anti-inflammatory and peroxidase-mediated cyclooxygenase-1 inhibitory properties of Fusarium solani extract

Context: Nigerian soil fungi population is unexplored. It is hypothesized that they harbour new bioactive chemicals. This hypothesis is based on the large percentage of currently approved medicines that originated from soil-inhabiting micro-organismsObjectives: To investigate the antimicrobial and anti-inflammatory properties of Fusarium solani ethyl acetate (EtOAc) extract selected based on its broad spectrum of antimicrobial potential in an overlay experiment with seven other soil fungi strains.Materials and methods: Fungus number 6 (F6), identified by molecular characterization as Fusarium solani (Mart.) Sacc (Nectriaceae) was selected for studies from eight purified soil fungi due to its superior broad-spectrum antibiotics producing potential following agar overlay experiment. F6 was fermented for 21 d and the minimum inhibitory concentration (MIC) of its EtOAc fermentation extract (dose range: 12.5–100 µg/mL) was determined using agar dilution method for Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli, Salmonella typhi and anti-inflammatory properties determined using rat-paw (250–500 mg/kg) and xylene induced oedema (250–500 µg/kg) (in Swiss albino rats and mice) models, respectively. The ability of the extract to inhibit cyclooxygenase (COX) enzyme was also determined in vitro using Cayman test kit-760111.Result: The MIC of the EtOAc extract was <12.5 µg/mL for S. aureus, P. aeruginosa and Escherichia coli. It inhibited xylene induced oedema by 65% compared with 61% observed for diclofenac and was significantly (p < 0.05) better than diclofenac in rat-paw-oedema model within the first phase of inflammation. The extract inhibited COX-1 peroxidase-mediated activities with an IC50 below 5 µg/mL.Conclusions: The extract exhibited strong antibacterial and anti-inflammatory properties, warranting further investigations into therapeutic potential of this fungus. This study design can be adapted in soil fungi metabolomic investigations. We report for the first time the potent anti-inflammatory property of the ethyl acetate extract of soil strain of F. solani with a possible mechanism of action that involves the inhibition of COX enzyme.

Potential Cyclooxygenase (COX-2) enzyme inhibitors from Myrica nagi-from in-silico to in-vitro investigation

Introduction: Myrica nagi Thunb. (family Myricaceae) are actinorhizal plants showing symbiotic interaction with Frankia. Inhibition of cyclooxygenase-2 (COX-2) enzyme is known to be significant in preventing inflammation and in therapeutics. Objectives: Our principal focus was to identify COX-2 enzyme inhibitors, safer and natural anti-inflammatory compounds from M. nagi. Protein–ligand interaction has a significant role in structure-based drug design. Materials and Methods: Sixty-eight phytochemicals were therefore screened and evaluated for their binding energies with COX-2. These phytoconstituents were screened and analyzed for drug Likeliness along with Lipinski's rule of five. The X-ray crystallographic structure of the target COX-2 (protein data bank [PDB] ID: 4PH9), obtained from PDB, was docked with PubChem structures of phytochemicals using AutoDock 4.2 that uses Lamarckian genetic algorithm. Further, myricetin was subjected to in vitro anti-inflammatory assay using RAW-264.7 cell lines and inhibitory concentration (IC50) value was also determined. Results: The myricetin, myricitrin, and corchoionoside-C inhibited COX-2 with − 6.52, −4.94, and − 4.94 Kcal/mol binding energies, respectively, comparable to ibuprofen. Eventually, bioactivity score and absorption distribution metabolism excretion-toxicity properties showed considerable biological activities as G protein-coupled receptor, nuclear receptor, protease inhibitor, and enzyme inhibitors for myricetin, myricitrin, and corchoionoside-C phytochemicals. Molecular docking revealed hydrophobic interactions followed by four, nine, and four numbers of hydrogen bonds between myricetin, myricitrin, and corchoionoside-C, respectively, within the binding site of COX-2. Flavonol myricetin showed 112 μg/mL as IC50 value when it was subjected to in vitro cytotoxicity assay. These results clearly demonstrated that myricetin, myricitrin, and corchoionoside-C could act as highly potential COX-2 inhibitors. Therefore, in silico and in vitro studies revealed that of three best phytochemicals, myricetin could be promising candidate.

Biphenyl Derivatives from the Aerial Parts of Oenanthe javanica and Their COX-2 Inhibitory Activities.

Four new biphenyl derivatives (1-4), along with six known biphenyl derivatives (5-10) were isolated and elucidated by their detailed analyses of spectroscopic data and references from the aerial parts of Oenanthe javanica for the first time. Compounds (1-10) were assayed for their activities about the inhibition of COX-2 enzyme in vitro for the first time. Compounds 1, 2, 4, and 6 showed inhibitory activities against COX-2 with IC50 values ranging from 22.18±0.29 to 108.54±0.42 μm.

α-Tocopherol Potentiates the Cervical Resistance Decreasing Effects of COX Inhibitors in Pregnant Rats: The Putative Role of Cyclooxygenase-2 Inhibition.

Vitamin E and their analogs as antioxidant and lipid-soluble compounds can have diverse effects on the physiologic processes. By binding to receptors and enzymes, they may modify the action of drugs. It has been proved that α-tocopherol succinate modifies the effects of β 2 agonist terbutaline and cyclooxygenase (COX) inhibitors on rat trachea and myometrium. Our aim was to investigate how α-tocopherol and COX inhibitors may influence cervical resistance in rats. The cervical resistance of nonpregnant and 22 day-pregnant Sprague-Dawley rats was determined in an isolated organ bath in vitro. α-Tocopherol-succinate (10-7 M) was used, whereas the COX-nonselective diclofenac (10-6 M), the COX-2-selective rofecoxib (10-6 M), and the COX-1-selective SC-560 (10-6 M) were applied as inhibitors. The COX activities of the cervices were measured by enzyme immunoassay. The modifying effect of single doses of COX inhibitors and tocopherol on the onset of labor was investigated in vivo. The cervical resistance of nonpregnant samples was not changed by either α-tocopherol or COX inhibitors. On pregnant cervices, tocopherol, diclofenac, or rofecoxib pretreatment decreased cervical resistance that was further reduced by COX inhibitors after pretreatment with tocopherol. α-Tocopherol elicited a significant COX-2 enzyme inhibition in cervical samples from pregnant rats. By coadministration of tocopherol and rofecoxib, the parturition was initiated earlier than in the other groups. It is supposed that COXs play a significant role not only in cervical ripening, but also in the contraction of the cervical smooth muscle a few hours before parturition. This latter action may be developed by COX-2-liberated prostaglandins.

FTY720P inhibits the Na+/K+ ATPase in Caco-2 cells via S1PR2: PGE2 and NO are along the signaling pathway

AimsSphingosine-1-phosphate (S1P) has been implicated lately in inflammatory bowel disease which has diarrhea as one of its symptoms. Diarrhea is due to altered water movements as a result of altered electrolyte transport, and in particular sodium. Sodium movements are geared by the sodium gradient established by the Na+/K+ ATPase. The aim of this work was to investigate if S1P can modulate the activity of the ATPase, using Caco-2 cells as a model and the S1P analogue, FTY720P. Materials and methodsThe activity of the ATPase was assayed by measuring the amount of inorganic phosphate liberated in presence and absence of ouabain. Protein expression of the various S1P receptors was studied by western blot analysis. Key findingsCaco-2 cells were found to express mainly S1PR2 and S1PR3. FTY720P (7.5 nM) reduced significantly the activity of the Na+/K+ ATPase when applied for 15 min. This inhibitory effect disappeared in presence of JTE-013, a specific blocker of S1PR2, and indomethacin, an inhibitor of cyclooxygenase enzymes, and was mimicked by CYM5520, a S1PR2 agonist and by exogenous PGE2. The inhibitory effect of PGE2 did not appear when EP3 receptors were blocked or when a nitric oxide scavenger was added. RpcAMP, a PKA inhibitor, reduced the activity of the Na+/K+ ATPase, while dbcAMP, a PKA activator was without any effect and when added, abrogated the effect of PGE2. SignificanceIt was concluded that FTY720P inhibits the Na+/K+ ATPase via activation of S1PR2 and generation of PGE2 nitric oxide.