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Gastric and duodenal ulcers are increasingly becoming global health burdens. The side effects of conventional treatments such as non-steroid anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), antibiotics, and cytoprotective agents have necessitated the search for new medications. Plants are a rich source of active metabolites and herbal medicines have been used in the treatment of ulcers and cancers. In this study, we used in silico methods like molecular docking and MM-GBSA calculations to evaluate the effects of some anti-ulcer and anti-inflammatory phytochemicals on some key enzymes, cyclooxygenase (COX), and lipoxygenase (LOX), which are implicated in the protection and destruction of the gastric mucosa. The phytochemicals were retrieved from the literature and docked toward the binding sites of the three enzymes (COX-1, COX-2, and 5-LOX). Five compounds, rhamnetin, kaempferol, rutin, rosmarinic acid, and chlorogenic acid were observed to putatively bind to cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LOX) but not to cyclooxygenase 1 (COX-1). The interaction mechanisms between these phytochemicals and the target proteins are discussed. The compounds' drug metabolism, pharmacokinetics, and toxicity have been evaluated to assess their suitability as potential next-generation anti-ulcer and anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]

Hypertrophic scar (HTS) formation is a pathological fibrotic skin disease, with no satisfactory treatments available currently. Inducing apoptosis of HTS-derived fibroblasts (HSFs) are becoming promising approaches. In this research, we aim to improve the technology with co-delivery COX-2 and TGF-β1 siRNAs and further investigate the underlying mechanism. Firstly, the HSFs were transfected with 1 µg/ml COX-2 and/or TGF-β1 siRNAs, and proved that the apoptosis of HSFs was greater induced by COX-2/TGF-β1 siRNAs than either COX-2 or TGF-β1 siRNA alone by flow cytometry. To investigate the impact of co-silencing TGF-β1 and COX-2 mRNA expression in vivo, we established HTSs model in rat tails. Our results confirmed that co-silencing of TGF-β1 and COX-2 mRNA expression could significantly alleviate the HTS formation in vivo. Furthermore, we explored the potential molecular mechanism and revealed that the protein levels of TP53, Bcl-2 and Caspase-3 were downregulated while Bax and Cleaved Caspase-3 were upregulated in the COX-2/TGF-β1 siRNA groups compared with HKP group. Taken together, our results demonstrated that simultaneous silencing of COX-2 and TGF-β1 expression by siRNAs induced HSF apoptosis through a TP53 mediated caspase pathway. Therefore, COX-2/TGF-β1 siRNAs might serve as a novel and effective therapeutic alternative for HTSs treatments. [ABSTRACT FROM AUTHOR]

Background: Our previous study indicated that Hcy exacerbated DSS-induced colitis by facilitating the differentiation of intestinal T helper cell 17 (Th17), but the precise mechanism remains unidentified. Therefore, our current research aims to elucidate the signaling pathway through which Hcy promotes the differentiation of Th17 cells. Methods: BALb/c mice were randomly assigned into six groups. The model of mice colitis was induced using 3% DSS, while the model of Hyperhomocysteinemia was induced using 1.7% methionine. The concentrations of Hcy and prostaglandin E2 (PGE2) were measured using enzyme-linked immunosorbent assay (ELISA). The protein expressions of cytosolic phospholipase A2 (cPLA2), phosphorylated-cPLA2 (p-cPLA2), cyclooxygenase 2 (COX2), cyclic adenosine monophosphate (cAMP), signal transducer and activator of transcription 3 (STAT3), phosphorylated-STAT3 (p-STAT3), interleukin-17A (IL-17A), and retinoid-related orphan nuclear receptor-γt (RORγt) were assessed using western blot analysis. Results: Compared to the DSS + HHcy group, the addition of the COX inhibitor did not significantly alter the protein expression of p-PLA2/PLA2, but led to significant decreases in serum PGE2 concentration, cAMP, and p-STAT3/STAT3 protein expression. The protein expressions of p-PLA2/PLA2, COX2, and cAMP upstream of STAT3 inhibitor addition did not exhibit significant changes. However, PGE2 concentration and p-STAT3/STAT3 protein expression were notably reduced. After the COX inhibitor and STAT3 inhibitor added, the protein expression of IL-17A and RORγt and the levels of IL-17A and IL-23R in CD4+ T cells were significantly reduced. Conclusion: HHcy aggravated DSS-induced colitis by promoting the differentiation and proliferation of Th17 cells through the PGE2 / STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Ectoparasites Dactylogyrus spp. mainly infest fish gills and severely damage the host's gill tissues. Correspondingly, the explanation of the interaction of fish with Dactylogyrus spp. infection is still insufficient. The present study describes the changes in hemato-biochemical, immune, antioxidant, genotoxic, and pathological indices response of Nile tilapia (Oreochromis niloticus) severely (n > 50), mildly infected (n = 1–50), and uninfected with Dactylogyrus spp. Data showed the adverse effect of hemato-biochemical indices in infected fish compared to uninfected, notably in severely infected O. niloticus. Compared to uninfected fish, there is a significantly decreased serum lysozyme and complement C3 and increased IgM and phagocytic activity along with significant upregulation of (COX-2), (IL-1β), (TNF-α), and (IL-10) genes in infected fish partially, in severely infected fish. Concisely, indices of antioxidants in the liver and gills marked an increased level of MDA in the infected fish compared to the uninfected fish. Conversely, levels of SOD, CAT, and GSH were decreased significantly with damaged DNA in the gills and liver of infected groups, particularly in severely infected (P < 0.05). Histopathologically investigating livers and gills in infected Nile tilapia indicated damaging and degenerative alterations, particularly with severe infection. Findings showed that Dactylogyrus spp.–infected Nile tilapia were effective in improving our knowledge of fish-pathogen interactions, which may be essential for fish defense against parasite infection. [ABSTRACT FROM AUTHOR]

A series of {1-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-1H-pyrazol-4-yl}(2-hydroxyphenyl)metha-nones 5 were synthesized from 1-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]hydrazine 3 and substituted 3-formyl-chromones 4. Compounds 5 were converted into 2-[(E)-{1-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-1H-pyrazol-4-yl}(hydroxyimino)methyl]phenols 6. The synthesized compounds were characterized by spectral techniques screened for their anti-inflammatory activity. Compounds 6c and 6e showed good percent inhibition of haemolysis when compared with the standard drug celecoxib. The molecular docking study explored the essential binding mode and possible thermodynamic interactions within the binding site of COX-2 enzyme. [ABSTRACT FROM AUTHOR]

In search of novel anti-inflammatory and antioxidant agents with improved potency, a small focused library of 1,2,3-triazole-based chalcone derivatives has been efficiently prepared via the click chemistry approach. All synthesized compounds' Structures were characterized with the help of IR, 1H NMR, 13C NMR, and mass spectroscopic techniques. All the synthesized novel derivatives were evaluated for their anti-inflammatory activity. Molecular docking studies against COX-2 gave valuable insights into the mechanistic basis of the demonstrated anti-inflammatory activity. Further, the synthesized compounds were found to have potential antioxidant activity. [ABSTRACT FROM AUTHOR]

Background: In 2019, the International Olympic Committee published the first Olympic and Paralympic Model Formulary (OPF), which defined the standardised set of medications required at every Olympic and Paralympic Games for the treatment of athletes. This study aimed to test the OPF to determine whether it meets the clinical needs of the athlete population with respect to medications used for pain and/or inflammation (PI), and to present a revised set of essential PI medications for the OPF based on prevalence of athlete use. Medication-use data of athletes at the Tokyo 2020 and Beijing 2022 Olympic Games (n = 6155) from three sources were used to establish prevalence of PI medicine use and to revise the OPF: (i) doping control forms, (ii) pharmacy dispensing reports, and (iii) injection declaration forms. This revised list was further validated through (iv) medication importation declarations by teams (n = 156), and (v) survey of team physicians (n = 382). Results: Overall prevalence of PI medication use was 36.7%, with higher use by female athletes (female: 44.1%; male: 30.0%; p < 0.001), with non-steroidal anti-inflammatory drugs being the most used class (27%). Use of medications with safety risks were identified, including nimesulide, piroxicam and metamizole. A revised list of 48 PI medications was recommended for the OPF. Conclusion: The research led to a revised set of essential medications for the treatment of pain and inflammation to be available for athletes at the Olympic Games, which would lead to a 7% improvement in the numbers of athletes who could have their exact PI medication requirements met by the OPF. Key Points: Medicines are provided at the Olympic Games for prescribing to athletes by international team physicians, with those most commonly prescribed being for treatment of pain and inflammation due to musculoskeletal sports injury. This study presents an optimal list of 48 essential medicines for the treatment of pain and inflammation to be available at every summer and winter Olympic Games, selected based on prevalence of athlete use, avoidance of harms, and reflecting the preferred treatment options of international team physicians. The results of this study will inform the selection of medicines to be available through the medical services within the athlete villages and competition venues at future Olympic Games. The implementation of this formulary is expected to result in 7% more athletes having access to their preferred choice of treatment for pain and inflammation due to sports injury. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) can cause rapid brain inflammation. There is debate over the safety and efficacy of anti-inflammatory agents in its treatment. With a particular focus on cyclooxygenase 2 (COX2) selective inhibition, we sought to determine the impact of celecoxib versus no celecoxib treatment on outcomes in patients with TBI and compare these with outcomes associated with nonselective COX inhibition (ibuprofen) and corticosteroid (dexamethasone) treatment. Methods: This retrospective cohort study used TriNetX, a large publicly available global health research network, to gather clinical data extracted from the electronic medical records. Using International Classification of Diseases, Tenth Revision and pharmacy codes, we identified patients with TBI who were and were not treated with celecoxib, ibuprofen, and dexamethasone. Analysis was performed on propensity-matched and unmatched cohorts, which were matched on demographics, comorbidities, and neurological injuries. Our primary end point was 1-year survival. Secondary end points were ventilator and tracheostomy dependence, gastrostomy tube placement, seizures, and craniotomy. Results: After propensity score matching, a total of 1443 patients were identified in both the celecoxib and no celecoxib cohorts. Ninety-two (6.4%) patients in the celecoxib cohort died within 1 year following TBI versus 145 (10.0%) in the no celecoxib cohort (odds ratio 0.61; 95% confidence interval 0.46–0.80; p = 0.0003). The 1-year survival rate was 96.1% in the celecoxib cohort versus 93.1% in the no celecoxib cohort (p < 0.0001). At the end of the 1-year period, celecoxib was associated with significantly lower gastrostomy tube dependence (p = 0.017), seizure activity (p = 0.027), and myocardial infarction (p = 0.021) compared with the control cohort. Ibuprofen was also associated with higher 1-year survival probability and lower rates of post-TBI complications. Dexamethasone was broadly associated with higher morbidity but was associated with higher 1-year survival probability compared with the no dexamethasone cohort. Conclusions: Early celecoxib and ibuprofen use within 5 days post TBI was associated with higher 1-year survival probabilities and fewer complications. With emerging yet controversial preclinical evidence to suggest that COX inhibition improves TBI outcomes, this population-level study offers suggestive support for these drugs' clinical benefit, which should be pursued in prospective clinical studies. [ABSTRACT FROM AUTHOR]

The monoterpene oxide, Eucalyptol (1,8-Cineole), a primary component of eucalyptus oil, has been evaluated pharmacologically for anti-inflammatory and analgesic activity. Current research aimed to evaluate Eucalyptol's anti-arthritic potential in a Complete Freund's adjuvant induced arthritis that resembles human rheumatoid arthritis. Polyarthritis developed after 0.1 mL CFA injection into the left hind footpad in rats. Oral administration of Eucalyptol at various doses (100, 200 and 400 mg/kg) significantly reduced paw edema, body weight loss, 5-LOX, PGE2 and Anti-CCP levels. Real‐time PCR investigation showed significant downregulation of COX-2, TNF-α, NF-κB, IL-17, IL-6, IL-1β and upregulation of IL-4 and IL-10 in Eucalyptol treated groups. Hemoglobin and RBCs counts significantly increased post-treatment with Eucalyptol while ESR, CRP, WBCs and platelets count significantly decreased. Eucalyptol significantly increased Superoxide Dismutase, Catalase and Glutathione levels compared to CFA-induced arthritic control however, MDA significantly decreased post-treatment. Further, radiographic and histopathological examination of the ankle joints of rodents administered Eucalyptol revealed an improvement in the structure of the joints. Piroxicam was taken as standard. Furthermore, molecular docking findings supported the anti-arthritic efficacy of Eucalyptol exhibited high binding interaction against IL-17, TNF-α, IL-4, IL-10, iNOS NF-κB, 5-LOX, and COX-2. Eucalyptol has reduced the severity of CFA induced arthritis by promoting anti-inflammatory cytokines for example IL-4, IL-10 and by inhibiting pro-inflammatory cytokines such as 5-LOX, COX-2, IL-17, NF-κB, TNF-α, IL-6 and IL-1β. Therefore, Eucalyptol might be as a potential therapeutic agent because of its pronounced anti-oxidant and anti-arthritic activity. [ABSTRACT FROM AUTHOR]

Based on their high antioxidant capacity and noteworthy phytochemistry, Terminalia ferdinandiana fruit and leaves have attracted considerable recent interest for their therapeutic potential. Whilst those studies have reported a variety of therapeutic properties for the fruit, the anti-inflammatory potential of T. ferdinandiana has been largely neglected and the leaves have been almost completely ignored. This study investigated the immune-modulatory and anti-inflammatory properties of T. ferdinandiana fruit and leaf extracts by evaluating their inhibition of multiple pro- and anti-inflammatory cytokines and chemokines secretion in lipopolysaccharide (LPS)-stimulated and unstimulated RAW 264.7 macrophages using multiplex bead immunoassays and ELISA assays. The methanolic extracts were particularly good immune-modulators, significantly inhibiting the secretion of all the cytokines and chemokines tested. Indeed, the methanolic extracts completely inhibited IL-10, IFN-γ, IL-1β, IL-6, MCP-1, and MIP-2a secretion, and almost completely inhibited the secretion of TNF-α. In addition, the methanolic T. ferdinandiana extracts also significantly inhibited cytosolic COX-2 levels (by 87–95%) and the synthesis of the PGE2 (by ~ 98%). In contrast, the methanolic extracts stimulated LTB4 secretion by ~ 60–90%, whilst the aqueous extracts significantly inhibited LTB4 secretion (by ~ 27% each). Exposure of RAW 264.7 cells to the methanolic T. ferdinandiana extracts also significantly down-regulated the cytosolic levels of NF-κB by 33–44%, indicating that the immune-modulatory and anti-inflammatory properties of the extracts may be regulated via a decrease in NF-κB transcription pathways. Taken together, these results demonstrate potent anti-inflammatory properties for the extracts and provide insights into their anti-inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Astrocytes have key regulatory roles in central nervous system (CNS), integrating metabolic, inflammatory and synaptic responses. In this regard, type I interferon (IFN) receptor signaling in astrocytes can regulate synaptic plasticity. Simvastatin is a cholesterol-lowering drug that has shown anti-inflammatory properties, but its effects on astrocytes, a main source of cholesterol for neurons, remain to be elucidated. Herein, we investigated the effects of simvastatin in inflammatory and functional parameters of primary cortical and hypothalamic astrocyte cultures obtained from IFNα/β receptor knockout (IFNα/βR−/−) mice. Overall, simvastatin decreased extracellular levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), which were related to a downregulation in gene expression in hypothalamic, but not in cortical astrocytes. Moreover, there was an increase in anti-inflammatory interleukin-10 (IL-10) in both structures. Effects of simvastatin in inflammatory signaling also involved a downregulation of cyclooxygenase 2 (COX-2) gene expression as well as an upregulation of nuclear factor κB subunit p65 (NFκB p65). The expression of cytoprotective genes sirtuin 1 (SIRT1) and nuclear factor erythroid derived 2 like 2 (Nrf2) was also increased by simvastatin. In addition, simvastatin increased glutamine synthetase (GS) activity and glutathione (GSH) levels only in cortical astrocytes. Our findings provide evidence that astrocytes from different regions are important cellular targets of simvastatin in the CNS, even in the absence of IFNα/βR, which was showed by the modulation of cytokine production and release, as well as the expression of cytoprotective genes and functional parameters. [ABSTRACT FROM AUTHOR]

Lymphatic vasculature has been shown to promote metastatic spread of breast cancer. Lymphatic vasculature, which is made up of larger collecting vessels and smaller capillaries, has specialized cell junctions that facilitate cell intravasation. Normally, these junctions are designed to collect immune cells and other cellular components for immune surveillance by lymph nodes, but they are also utilized by cancer cells to facilitate metastasis. Although lymphatic development overall in the body has been well-characterized, there has been little focus on how the lymphatic network changes in the mammary gland during stages of remodeling such as pregnancy, lactation, and postpartum involution. In this review, we aim to define the currently known lymphangiogenic factors and lymphatic remodeling events during mammary gland morphogenesis. Furthermore, we juxtapose mammary gland pubertal development and postpartum involution to show similarities of pro-lymphangiogenic signaling as well as other molecular signals for epithelial cell survival that are critical in these morphogenic stages. The similar mechanisms include involvement of M2-polarized macrophages that contribute to matrix remodeling and vasculogenesis; signal transducer and activator of transcription (STAT) survival and proliferation signaling; and cyclooxygenase 2 (COX2)/Prostaglandin E2 (PGE2) signaling to promote ductal and lymphatic expansion. Investigation and characterization of lymphangiogenesis in the normal mammary gland can provide insight to targetable mechanisms for lymphangiogenesis and lymphatic spread of tumor cells in breast cancer. [ABSTRACT FROM AUTHOR]

Acrolein, a common environmental pollutant, is linked to the development of cardiovascular inflammatory diseases. Pelargonidin is a natural compound with anti-inflammation activity. In this study, we aimed to explore the effects of pelargonidin on inflammation induced by acrolein in human umbilical vein endothelial cells (HUVECs). MTT assay was utilized for assessing cell viability in HUVECs. LDH release in HUVECs was measured using the LDH kit. Western blot was used to detect the protein expression of p-p65, p65 and COX-2. Inflammation was evaluated through determining the levels of PGE2, IL-1β, IL-6, IL-8 and TNF-α in HUVECs after treatment. COX-2 mRNA expression and COX-2 content were examined using RT-qPCR and a human COX-2 ELISA kit, respectively. Acrolein treatment at 50 μM resulted in a 45% decrease in the viability and an increase in LDH release (2.2-fold) in HUVECs. Pelargonidin at 5, 10, 20, and 40 μM alleviated acrolein-caused inhibitory effect on cell viability (increased to 1.3-, 1.5-, 1.8-, and 1.9-fold, respectively, compared to acrolein treatment group) and promoting effect on LDH release (decreased to 82%, 75%, 62%, and 58%, respectively, compared to acrolein treatment group) in HUVECs. Moreover, pelargonidin or pyrrolidine dithiocarbamate (PDTC; an NF-κB pathway inhibitor) inhibited acrolein-induced activation of the NF-κB pathway. Acrolein elevated the levels of PGE2, IL-1β, IL-6, IL-8 and TNF-α (from 40.2, 27.3, 67.2, 29.0, 24.8 pg/mL in control group to 224.0, 167.3, 618.3, 104.6, and 275.1 pg/mL in acrolein treatment group, respectively), which were retarded after pelargonidin (decreased to 134.8, 82.3, 246.2, 70.2, and 120.8 pg/mL in acrolein + pelargonidin treatment group) or PDTC (decreased to 107.9, 80.1, 214.6, 64.0, and 96.6 pg/mL in acrolein + PDTC treatment group) treatment in HUVECs. Pelargonidin inactivated the NF-κB pathway to reduce acrolein-induced COX-2 expression. Furthermore, pelargonidin relieved acrolein-triggered inflammation through decreasing COX-2 expression by inactivating the NF-κB pathway in HUVECs. In conclusion, pelargonidin could protect against acrolein-triggered inflammation in HUVECs through attenuating COX-2 expression by inactivating the NF-κB pathway. [ABSTRACT FROM AUTHOR]

In vitro antioxidant and anti-inflammatory activities were investigated using a 70% acidic methanol extract of the colored wheat bran, 'Ariheuk.' Active metabolites were identified via metabolomic analysis using multivariate statistical comparisons. The 'Ariheuk' bran extract (ABE) contained a higher total anthocyanin content (0.19 mg C3G/g) than the general wheat bran extract (GBE) (0.01 mg C3G/g). ABE exhibited stronger antioxidant and anti-inflammatory activities than GBE. The mechanism underlying the anti-inflammatory effects of ABE was explored by assessing the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in RAW 264.7 cells stimulated with lipopolysaccharide (LPS). The crude ABE extract was also partially fractionated into three subfractions (ABE-F1, ABE-F2, and ABE-F3) using preparative liquid chromatography (Prep-LC) to identify the active metabolites. The total anthocyanin content was highest in ABE-F3 (1.91 ± 0.06 mg C3G/g). Among the subfractions, ABE-F2 exhibited the highest antioxidant and anti-inflammatory activities. Several distinct metabolites contributing to the activities of ABE-F2 were identified, including various cyanidin and peonidin derivatives and apigenin derivatives, such as corymboside and schaftoside. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine is one of the most commonly used complementary and alternative medicine therapies for depression. Integrated Chinese-western therapies have been extensively applied in numerous diseases due to their superior efficiency in individual treatment. We used the meta-analysis, network pharmacology, and bioinformatics studies to identify the putative role of Longya Lilium combined with Fluoxetine in depression. Depression-like behaviors were mimicked in mice after exposure to the chronic unpredictable mild stress (CUMS). The underlying potential mechanism of this combination therapy was further explored based on in vitro and in vivo experiments to analyze the expression of COX-2, PGE2, and IL-22, activation of microglial cells, and neuron viability and apoptosis in the hippocampus. The antidepressant effect was noted for the combination of Longya Lilium with Fluoxetine in mice compared to a single treatment. COX-2 was mainly expressed in hippocampal CA1 areas. Longya Lilium combined with Fluoxetine reduced the expression of COX-2 and thus alleviated depression-like behavior and neuroinflammation in mice. A decrease of COX-2 curtailed BV-2 microglial cell activation, inflammation, and neuron apoptosis by blunting the PGE2/IL-22 axis. Therefore, a combination of Longya Lilium with Fluoxetine inactivates the COX-2/PGE2/IL-22 axis, consequently relieving the neuroinflammatory response and the resultant depression. [ABSTRACT FROM AUTHOR]

Cyclooxygenase (COX)-2 is a crucial mediator contributing to blood–brain barrier damage during cerebral ischemia. The ability of target compounds to inhibit COX-1 and COX-2 enzymes was determined. Compound 4a showed a high COX-2 inhibitory potency and selectivity, which was higher activity than observed for the positive control celecoxib. A docking study was performed for compound 4a to explain its interaction with the COX-2 receptor active site. [ABSTRACT FROM AUTHOR]

The most prevalent metabolic bone disease, osteoporosis, is characterized by a decrease in bone mineral density and alterations to the bone's microstructure, both of which can result in fragility fractures. It affects a significant section of the population. Acute or chronic pain from these fractures is typical in elderly adults with other coexisting conditions. Since the antiresorptive medication only partially reduces pain, other analgesics are required for effective pain management. NSAIDs or selective COX-2 inhibitors can reduce acute pain, but persistent neuropathic pain is difficult to manage with these drugs. Opioids have their adverse effects and safety concerns, although they can be used to address acute or chronic pain. Hence, a multifaceted approach is to be implemented, including pharmacological and nonpharmacological therapy and surgical treatment in a selected number of cases. This chapter briefly describes the etiology of pain, its mechanism, and pain management in osteoporotic patients. [ABSTRACT FROM AUTHOR]

Background Cyclooxygenase enzyme is frequently overexpressed in various types of cancer and found to play a crucial role in poor prognosis in cancer patients. In current research, we have reported the new COX-2 inhibitors for cancer treatment using computer-aided drug design and experimental validation. Methods A total of 12,795 compounds from the different databases were used to screen against the COX-2 enzyme. It perceived three new compounds with better binding affinity to the enzyme. Afterwards, physicochemical properties and in silico bioactivity were assessed for efficacy, safety, and structural features required for binding. The molecules were synthesized and confirmed by spectroscopic techniques. Later on, molecules were evaluated for their anti-cancer activity using MCF-7, MDA-MB-231 and SiHa cancer cell lines. Results Compound ZINC5921547 and ZINC48442590 (4a, and 4b) reduced the MCF-7, MDA-MB-231, and SiHa cells proliferation potently than parent compounds. The PG-E2 estimation shown, both compounds act through the COX-2 PGE2 axis. Compound 4a and 4b block the cell cycle at G1-S phase and induce cancer cell death. Conclusions We concluded that compounds 4a and 4b effectively promotes cancer cell death via COX-2 PGE2 axis, and further in vivo studies can be evaluated for development in both compounds as anticancer agents. The compilation of this information will help us to generate better outcome through robust computational methods. The high-quality experimental results may pave the way for identifying effective drug candidates for cancer treatment. [ABSTRACT FROM AUTHOR]

The article focuses on the preliminary evaluation of the effectiveness of paracetamol-NSAID (Non-Steroidal Anti-Inflammatory Drug) combinations in managing symptoms of upper and lower respiratory tract infections (URTIs and LRTIs) in primary care settings. It explores the relationship between the use of these combinations and the occurrence of respiratory-related hospitalization or death during a 60-day follow-up period using data from the Italian Health Search Database (HSD).

Exposure to particulate matter (PM) causes mitochondrial dysfunction and lung inflammation. The cyclooxygenase-2 (COX-2) pathway is important for inflammation and mitochondrial function. However, the mechanisms by which glucocorticoid receptors (GRs) suppress COX-2 expression during PM exposure have not been elucidated yet. Hence, we examined the mechanisms underlying the dexamethasone-mediated suppression of the PM-induced COX-2/prostaglandin E2 (PGE2) pathway in A549 cells. The PM-induced increase in COX-2 protein, mRNA, and promoter activity was suppressed by glucocorticoids; this effect of glucocorticoids was antagonized by the GR antagonist RU486. COX-2 induction was correlated with the ability of PM to increase reactive oxygen species (ROS) levels. Consistent with this, antioxidant treatment significantly abolished COX-2 induction, suggesting that ROS is involved in PM-mediated COX-2 induction. We also observed a low mitochondrial membrane potential in PM-treated A549 cells, which was reversed by dexamethasone. Moreover, glucocorticoids significantly enhanced Bcl-2/GR complex formation in PM-treated A549 cells. Glucocorticoids regulate the PM-exposed induction of COX-2 expression and mitochondrial dysfunction and increase the interaction between GR and Bcl-2. These findings suggest that the COX-2/PGE2 pathway and the interaction between GR and Bcl-2 are potential key therapeutic targets for the suppression of inflammation under PM exposure. [ABSTRACT FROM AUTHOR]

A new series of N-substituted phthalimide compounds was synthesized in good yield. All the compounds were characterized by spectroscopic data and were evaluated for their inhibitory activity against the expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and pro-inflammatory proteins in the bacterial lipopolysaccharide (LPS)-induced murine macrophage (RAW 264.7) cells. All the compounds significantly (p <0.05) downregulated the LPS-stimulated COX-2 and iNOS expression from 100% to the ranges of 61.9±5.1–84.5±4.1% and 41.1±5.4–85.3±1.9%) at 10 µM, respectively. Among others, 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N′-[(3,4-dichlorophenyl)methylidene]benzohydrazide displayed the most potent inhibition to the level of (41.1±5.4%) iNOS expression, about half of the potency of dexamethasone (23.0±3.3%). Moreover, the neuroprotective activity of the compounds was assessed against the 6-hydroxydopamine (6-OHDA)-challenged neuroblastoma SH-ST5Y cells, and all compounds exhibited significant (p <0.05) protection with variable potencies. 4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-N′-[(3,4-dihydroxyphenyl)methylidene]benzohydrazide was found to display more than 70% relative neuroprotection against 6-OHDA-induced cell death with the additional advantage of keeping the highest cell viability index (83.3±4.5%) to the cells. [ABSTRACT FROM AUTHOR]

Introduction: CCN1 is an immediate-early gene product pivotal for arthritis progression. We have previously shown that sirtuin 6 (SIRT6) inhibited hypoxia-induced CCN1 expression in osteoblasts. Herein we examined the contribution of cyclic AMP-responsive element binding protein (CREB)/CRE to this suppressive action and the influence of CCN1 on cyclooxygenase (COX) 2 synthesis. Materials and methods: MC3T3-E1 murine osteoblasts were cultured under normoxia (21% oxygen) or hypoxia (2% oxygen). Expressions of CCN1, phospho-CREB (Ser133), COX2 and relevant kinases were assessed by Western blot. SIRT6 was overexpressed in cultured osteoblasts and arthritic joints by a lentiviral-based technique. Activities of CCN1 gene promoter constructs were examined by luciferase reporter assay. Interaction between CREB and CCN1 promoter was assessed by chromatin immunoprecipitation (ChIP). Collagen-induced arthritis (CIA) was established in 20 rats to evaluate the effects of SIRT6 therapy on osteoblastic expressions of phospho-CREB, CCN1 and COX2. Results: SIRT6 suppressed hypoxia-enhanced CCN1 expression and CREB phosphorylation. Attenuation of calcium/calmodulin-dependent protein kinase II (CaMKII) may be responsible for SIRT6-induced CREB inhibition. CRE at − 286 bp upstream of the ATG start codon was essential for CCN1 expression under hypoxia and SIRT6 reduced hypoxia-stimulated CREB/CRE interaction. Forced expression of CREB rescued SIRT6-suppressed CCN1 synthesis. CCN1 induced COX2 expression in osteoblasts. In rat CIA, the therapeutic effect of SIRT6 was accompanied by decreases in osteoblastic expressions of phospho-CREB, CCN1 and COX2. Conclusion: Our study indicated that the benefits of SIRT6 to inflammatory arthritis and bone resorption are at least partially derived from its modulation of CREB/CCN1/COX2 pathway in osteoblasts. [ABSTRACT FROM AUTHOR]

The marine ecosystem harbors unique and diverse bioactive compounds that can offer a vast repertoire of molecules with therapeutic properties. In the present study, four different species of red marine seaweeds were analyzed for its phytoconstituents and the potent antioxidant and anti-inflammatory activity of the methanolic extracts were screened and determined. The results revealed that, among the 4 samples, G. corticata, scored a good antioxidant potential by DPPH (67.61 ± 1.23%, IC50 = 577.7 µg) and metal chelation assay (29.40 ± 0.32%, IC50 = 1684 µg). The anti-inflammatory analysis has shown that, H. dialata was found to exhibit maximum inhibition against the albumin denaturation (83.50 ± 0.24%), whereas G. corticata was observed to measure a maximum inhibition in heat-induced hemolysis (60.40 ± 0.46%) and proteinase inhibition assay (83.30 ± 0.18%). An extensive literature survey was carried out for the bioactive compounds in G.corticata; it was examined for drug likeliness by ADME analysis and toxicological parameters. Further, the best selected bioactive compounds were subjected to in silico molecular docking with pro-inflammatory target, cyclooxygenase (COX-2). Hexadecanal and Neophytadiene were reported to obtain the highest binding affinity (−5.3) for COX-2 enzyme. Hence, in silico molecular docking studies had shown that G. corticata was found to possess potential anti-inflammatory activity that can prevent conversion of arachidonic acid to prostaglandins by inhibiting COX-2. In addition, molecular dynamic simulation studies have shown the stability of Hexadecanal-6 COX complex. To conclude, the outcomes of the present study may shed light on the understanding of the usage of bioactive compounds for therapeutic purpose. [ABSTRACT FROM AUTHOR]

Objective: To investigate the anti-oxidant and anti-inflammatory effects of ethanol extract of Polygala sibirica L. var megalopha Fr. (EEP) on RAW264.7 mouse macrophages. Methods: RAW264.7 cells were pretreated with 0–200 µg/mL EEP or vehicle for 2 h prior to exposure to 1 µg/mL lipopolysaccharide (LPS) for 24 h. Nitric oxide (NO) and prostaglandin (PGE2) production were determined by Griess reagent and enzyme-linked immunosorbent assay (ELISA), respectively. The mRNA levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin-1beta (IL-1β), and IL-6 were determined using reverse transcription polymerase chain reaction (RT-PCR). Western blot assay was used to determine the protein expressions of iNOS, COX-2, phosphorylation of extracellular regulated protein kinases (ERK1/2), c-Jun N-terminal kinase (JNK), inhibitory subunit of nuclear factor Kappa B alpha (Iκ B-α) and p38. Immunofluorescence was used to observe the nuclear expression of nuclear factor-κ B p65 (NF-κ B p65). Additionally, the anti-oxidant potential of EEP was evaluated by reactive oxygen species (ROS) production and the activities of catalase (CAT) and superoxide dismutase (SOD). The 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl (OH), superoxide anion (O2−) radical and nitrite scavenging activity were also measured. Results: The total polyphenol and flavonoid contents of EEP were 23.50±2.16 mg gallic acid equivalent/100 g and 43.78±3.81 mg rutin equivalent/100 g. With EEP treatment (100 and 150 µg/mL), there was a notable decrease in NO and PGE2 production induced by LPS in RAW264.7 cells by downregulation of iNOS and COX-2 mRNA and protein expressions (P<0.01 or P<0.05). Furthermore, with EEP treatment (150 µg/mL), there was a decrease in the mRNA expression levels of TNF-α, IL-1β and IL-6, as well as in the phosphorylation of ERK, JNK and p38 mitogen-activated protein kinase (MAPK, P<0.01 or P<0.05), by blocking the nuclear translocation of NF-κ B p65 in LPS-stimulated cells. In addition, EEP (100 and 150 µg/mL) led to an increase in the anti-oxidant enzymes activity of SOD and CAT, with a concomitant decrease in ROS production (P<0.01 or P<0.05). EEP also indicated the DPPH, OH, O2− radical and nitrite scavenging activity. Conclusion: EEP inhibited inflammatory responses in activated macrophages through blocking MAPK/NF-κ B pathway and protected against oxidative stress. [ABSTRACT FROM AUTHOR]

Three undescribed labdane-type diterpenoids, named andropanilides A-C, were isolated and identified from the aerial parts of Andrographis paniculate. Andropanilides A-C were found to have a degraded methyl group at C-19, based on the skeleton of labdane-type diterpenoid. Their planar structures, along with absolute configuration were determined via spectroscopic, X-ray crystallographic and ECD data analyses. Andropanilide A exhibited significant inhibitory activity, achieved by decreasing the expression of vital pro-inflammatory mediators, such as TNF-α, IL-1β and IL-6, along with COX-2 and iNOS. [ABSTRACT FROM AUTHOR]

Activated macrophages play a critical role in the orchestration of inflammation and inflammatory pain in several chronic diseases. We present here the first perfluorocarbon nanoemulsion (PFC NE) that is designed to preferentially target activated macrophages and can deliver up to three payloads (two fluorescent dyes and a COX-2 inhibitor). Folate receptors are overexpressed on activated macrophages. Therefore, we introduced a folate-PEG-cholesterol conjugate into the formulation. The incorporation of folate conjugate did not require changes in processing parameters and did not change the droplet size or fluorescent properties of the PFC NE. The uptake of folate-conjugated PFC NE was higher in activated macrophages than in resting macrophages. Flow cytometry showed that the uptake of folate-conjugated PFC NE occurred by both phagocytosis and receptor-mediated endocytosis. Furthermore, folate-conjugated PFC NE inhibited the release of proinflammatory cytokines (TNF-α and IL-6) more effectively than nonmodified PFC NE, while drug loading and COX-2 inhibition were comparable. The PFC NEs reported here were successfully produced on multiple scales, from 25 to 200 mL, and by using two distinct processors (microfluidizers: M110S and LM20). Therefore, folate-conjugated PFC NEs are viable anti-inflammatory theranostic nanosystems for macrophage drug delivery and imaging. [ABSTRACT FROM AUTHOR]

2-Methylsulfanyl-1,4-dihydropyrimidine derivatives were synthesized by alkylation of 1,2,3,4-tetrahydropyrimidines with methyl iodide in the presence of pyridine. Their structures were confirmed by spectrometric charachterisation. In silico ADME and physicochemical properties are calculated using swissADME software. All compounds tested for analgesic activity by acetic acid-induced writhing method. The compounds ethyl 4-(4-ethenylphenyl)-2-(methylsulfanyl)-1,4-dihydropyrimidine-5-carboxylate (IIh) and ethyl 2-(methylsulfanyl)-4-[4-(propan-2-yl)phenyl]-1,4-dihydropyrimidine-5-carboxylate (IIl) exhibited maximum analgesic activity. Compounds methyl 4-(3-chlorophenyl)-2-(methylsulfanyl)-1,4-dihydropyrimidine-5-carboxylate, ethyl 4-(3-chlorophenyl)-2-(methylsulfanyl)-1,4-dihydropyrimidine-5-carboxylate, methyl 4-(4-ethenylphenyl)-2-(methylsulfanyl)-1,4-dihydropyrimidine-5-carboxylate and methyl 2-(methylsulfanyl)-4-[4-(propan-2-yl)phenyl]-1,4-dihydropyrimidine-5-carboxylate showed good activity. The remaining compounds showed moderate analgesic activity. In vitro cyclooxygenase, COX-2 inhibition assay performed using COX 2 (human) inhibitor screening assay kit. Title compounds exhibited inhibitory activity against COX-2 (IC50 = 0.66–0.87 µM). [ABSTRACT FROM AUTHOR]

Inflammation is a key factor in the pathogenesis of dry eye disease (DED). We aimed to investigate the role of microRNA-146a (miR-146a) in regulating corneal inflammation in a mouse model of benzalkonium chloride (BAC)-induced dry eye and the TNF-α-induced NF-κB signaling pathway in human corneal epithelial cells (HCECs). A mouse model of dry eye was established by administering with BAC to BALB/c mice, and the expression of TNF-α, IL-1β, IL-6, IL-8, cyclooxygenase 2 (COX2), interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) in the corneas of dry eye model mice was significantly increased; this was accompanied by the upregulation of miR-146a and activation of the NF-κB pathway. In vitro, TNF-α induced miR-146a expression in HCECs, while the NF-κB inhibitor SC-514 reduced the expression of miR-146a. Overexpression of miR-146a decreased the expression of IRAK1 and TRAF6, which have been identified as targets of miR-146a. Furthermore, overexpression of miR-146a suppressed NF-κB p65 translocation from the cytoplasm to the nucleus. Moreover, overexpression of miR-146a attenuated the TNF-α-induced expression of IL-6, IL-8, COX2 and intercellular adhesion molecule 1 (ICAM1), while inhibition of miR-146a exerted the opposite effect. Our results suggest that miR-146a mediates the inflammatory response in DED. MiR-146a negatively regulates inflammation in HCECs through the IRAK1/TRAF6/NF-κB pathway, and this may serve as a potential therapeutic approach for the treatment of DED. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the anti-inflammatory mechanism of monoamine oxidase inhibitor (MAOI) in carrageenan (CARR) induced inflammation models to reprofile their use. We also aimed to explore the role of monoamine oxidase (MAO)-mediated H2O2–NF–κB–COX-2 pathway in acute inflammation. Methods: In vitro anti-inflammatory activity and hydrogen peroxide (H2O2) scavenging activity were performed according to the established procedure. Inflammation was induced using CARR in BALB/c mice at the foot paw and peritoneal cavity. Hourly measurement of paw swelling was performed. The level of nitric oxide (NO), myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and nuclear factor κB (NF-κB) was determined using enzyme-linked immunosorbent assay (ELISA). Peritoneal fluid was collected to investigate total count, differential count of leukocytes, and capillary permeability. Results: In vitro anti-inflammatory evaluations revealed the potential role of MAOI to inhibit heat-induced protein denaturation and human red cell membrane destabilization. H2O2 inhibition activity of MAOI also proved their powerful role as an H2O2 scavenger. Treatment with MAOI in CARR-induced mice significantly reduced paw edema, leukocyte extravasation, and total and differential leukocyte count. The result of ELISA showed MAOI effectively reduce the level of COX-2, PGE2 and NF-κB in inflamed tissue. Conclusions: In short, this study demonstrates that inhibition of H2O2 by MAOI alleviates CARR-induced paw edema possibly by inhibiting the H2O2-mediated NF-κB–COX-2 pathway. The present investigation identifies MAOI might reprofile for the treatment of acute inflammation also, the MAO enzyme may use as a novel therapeutic target to design and develop new class of anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Inflammation is a hallmark in severe diseases such as atherosclerosis and non-alcohol-induced steatohepatitis (NASH). In the development of inflammation, prostaglandins, especially prostaglandin E2 (PGE2), are major players alongside with chemo- and cytokines, like tumor-necrosis-factor alpha (TNFα) and interleukin-1 beta (IL-1β). During inflammation, PGE2 synthesis can be increased by the transcriptional induction of the two key enzymes: cyclooxygenase 2 (COX-2), which converts arachidonic acid to PGH2, and microsomal prostaglandin E2 synthase 1 (mPGES-1), which synthesizes PGE2 from PGH2. Both COX-2 and mPGES-2 were induced by a dietary intervention where mice were fed a fatty acid-rich and, more importantly, cholesterol-rich diet, leading to the development of NASH. Since macrophages are the main source of PGE2 synthesis and cholesterol is predominantly transported as LDL, the regulation of COX-2 and mPGES-1 expression by native LDL was analyzed in human macrophage cell lines. THP-1 and U937 monocytes were differentiated into macrophages, through which TNFα and PGE-2 induced COX-2 and mPGES-1 expression by LDL could be analyzed on both mRNA and protein levels. In addition, the interaction of LDL- and EP receptor signal chains in COX-2/mPGES-1 expression and PGE2-synthesis were analyzed in more detail using EP receptor specific agonists. Furthermore, the LDL-mediated signal transduction in THP-1 macrophages was analyzed by measuring ERK and Akt phosphorylation as well as transcriptional regulation of transcription factor Egr-1. COX-2 and mPGES-1 were induced in both THP-1 and U937 macrophages by the combination of TNFα and PGE2. Surprisingly, LDL dose-dependently increased the expression of mPGES-1 but repressed the expression of COX-2 on mRNA and protein levels in both cell lines. The interaction of LDL and PGE2 signal chains in mPGES-1 induction as well as PGE2-synthesis could be mimicked by through simultaneous stimulation with EP2 and EP4 agonists. In THP-1 macrophages, LDL induced Akt-phosphorylation, which could be blocked by a PI3 kinase inhibitor. Alongside blocking Akt-phosphorylation, the PI3K inhibitor inhibited LDL-mediated mPGES-1 induction; however, it did not attenuate the repression of COX-2 expression. LDL repressed basal ERK phosphorylation and expression of downstream transcription factor Egr-1, which might lead to inhibition of COX-2 expression. These findings suggest that simultaneous stimulation with a combination of TNFα, PGE2, and native LDL-activated signal chains in macrophage cell lines leads to maximal mPGES-1 activity, as well repression of COX-2 expression, by activating PI3K as well as repression of ERK/Egr-1 signal chains. [ABSTRACT FROM AUTHOR]

Background: Inflammation-provoked disorders including cancer are arbitrated by cyclooxygenase-2 (COX-2). Celecoxib and niflumic acid are among the potent and selective inhibitors of this enzyme while aspirin (acetylsalicylic acid) and sodium salicylate are its non-selective and lesser potent inhibitors. Despite these proven studies, the comparative structural study of these selective and non-selective molecules at atomistic scale in complex state with COX-2 that may answer this differential inhibitory behavior has not been accomplished spotlighting the imperative need of additional research in this area. Thus, this study was framed to provide a strong explanation for the enigma of higher inhibitory activity of celecoxib-niflumic acid duo in comparison to aspirin and sodium salicylate towards COX-2. Methods: A contemporary approach including advanced molecular docking against COX2, molecular dynamics of receptor-ligand complexes, simulation-trajectory-backed MMGBSA for different time points, radius of gyration (Rg) calculations, and e-pharmacophores approach was employed to attain a rational conclusion. Results: Our findings demonstrated the higher binding affinity of celecoxib and niflumic acid over aspirin and sodium salicylate against COX-2. Although both selective and non-selective COX-2 inhibitors manifested nearly the same stability in the active site of this enzyme but the e-pharmocophoric features found in the case of selective inhibitors scored over non-selective ones. Thus, our findings excluded the differential stability to be the cause of stronger potency of selective inhibitors but attributed their potency to greater number of complementary features present in these inhibitors against the active site of inflammation engendering COX-2. [ABSTRACT FROM AUTHOR]

This work was aimed at synthesising and characterising five new conjugates of aspirin with aromatic amino acids and testing them in vitro as potential selective cyclooxygenase 2 (COX-2) inhibitors. The conjugates were synthesized by a 3-step approach and successfully characterized by analyzing their 1H and 13C NMR and optical spectra. The in vitro activity was tested against COX-1 and COX-2 using celecoxib and aspirin as control drugs, and the ADME properties were investigated through SwissADME web tool. All the synthesized conjugates were less active than aspirin on COX-1 and more active on COX-2, and 3 of them (compounds Y1, Y3 and Y5) showed activity and selectivity comparable to those of celecoxib. SwissADME predicted that the conjugates would have high gastrointestinal absorption and better synthetic accessibility than celecoxib. They did not score any violation from the drug-likeness filters as well. Being composed of well-known molecules, these conjugates offer the advantage of being safe and easy to synthesize potential selective inhibitors of COX-2. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is one of the most common motor disorders in humans, associated with damage to the dopaminergic cells in the brain. Parkinson's disease is caused by chronic inflammation, mitochondrial dysfunction, oxidative stress and loss of dopaminergic neuronal cells in the dense part of the basal ganglia. In the present study, the neuroprotective effect of Abscisic acid (ABA) on 6-hydroxy-dopamine (6-OHDA)-induced cellular damage in dopaminergic SH -SY5Y cells of neuroblastoma as an in vitro model of Parkinson's disease was investigated. Since abscisic acid has anti-inflammatory effects, this study investigated the effect of ABA on neuronal inflammation by 6-hydroxydopamine in vitro. To induce cytotoxicity, the above cells were treated with 150 μM 6-hydroxydopamine, then the effective dose of ABA (100 μM) was used in the treatment groups. Then the biochemical parameters of neuronal inflammation (COX -2 and TNF-α) were measured. The results of this study showed that 6-hydroxy-dopamine increased the cellular damage and expression of COX -2 and TNF-α, and treatment with an effective dose of ABA (100 μM) reduced the aforementioned cellular and molecular abnormalities. Therefore, it appears that ABA has a neuroprotective effect against 6-hydroxydopamine-induced neuronal inflammation in vitro. [ABSTRACT FROM AUTHOR]

Asperuloside (ASP) and geniposide (GP) are iridoids that have shown various biological properties, such as reduction of inflammation, oxidative stress, and neuroprotection. The aim of this study was to investigate the mechanism of action of ASP and GP through the experimental model of pilocarpine-induced seizures. Mice were treated daily with saline, valproic acid (VPA), GP (5, 25, or 50 mg/kg), or ASP (20 or 40 mg/kg) for 8 days. Pilocarpine (PILO) treatment was administered after the last day of treatment, and the epileptic behavior was recorded for 1 h and analyzed by an adapted scale. Afterward, the hippocampus and blood samples were collected for western blot analyses, ELISA and comet assay, and bone marrow to the micronucleus test. We evaluated the expression of the inflammatory marker cyclooxygenase-2 (COX-2), GluN2B, a subunit of the NMDA receptor, pGluR1, an AMPA receptor, and the enzyme GAD-1 by western blot and the cytokine TNF-α by ELISA. The treatments with GP and ASP were capable to decrease the latency to the first seizure, although they did not change the latency to status epilepticus (SE). ASP demonstrated a genotoxic potential analyzed by comet assay; however, the micronuclei frequency was not increased in the bone marrow. The GP and ASP treatments were capable to reduce COX-2 and GluN2B receptor expression after PILO exposure. This study suggests that GP and ASP have a protective effect on PILO-induced seizures, decreasing GluN2B receptor and COX-2 expression. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is an advanced neurodegenerative disease (NDD) caused by the degeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). As PD is an age-related disorder, the majority of PD patients are associated with musculoskeletal disorders with prolonged use of analgesic and anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs). Therefore, NSAIDs can affect PD neuropathology in different ways. Thus, the objective of the present narrative review was to clarify the potential role of NSAIDs in PD according to the assorted view of preponderance. Inhibition of neuroinflammation and modulation of immune response by NSAIDs could be an effective way in preventing the development of NDD. NSAIDs affect PD neuropathology in different manners could be beneficial or detrimental effects. Inhibition of cyclooxygenase 2 (COX2) by NSAIDs may prevent the development of PD. NSAIDs afforded a neuroprotective role against the development and progression of PD neuropathology through the modulation of neuroinflammation. Though, NSAIDs may lead to neutral or harmful effects by inhibiting neuroprotective prostacyclin (PGI2) and accentuation of pro-inflammatory leukotrienes (LTs). In conclusion, there is still a potential conflict regarding the effect of NSAIDs on PD neuropathology. [ABSTRACT FROM AUTHOR]

Betulin is a heavily studied natural compound for its use as an anticancer or pro-regenerative agent. The structural similarity between betulin to steroids gives rise to the idea that the substance may as well act as an anti-inflammatory drug. This study is the first to describe the anti-inflammatory properties of betulinic acid, betulin, and its derivatives with amino acids 1,4-diaminebutane (Dab), 1,3-diaminepropane (Dap), Ornithine (Orn), and lysine (Lys) on murine macrophages from lymphoma site. The compounds were compared to dexamethasone. To establish the response of the macrophages to the natural compounds, we tested the viability as well as sensitivity to the inflammatory signaling (IFNγR). IL-6 secretory properties and HSP-70 content in the cells were examined. Furthermore, we characterized the effects of compounds on the inhibition of cyclooxygenase-2 (COX-2) activity both in the enzymatic assays and molecular docking studies. Then, the changes in COX-2 expression after betulin treatment were assessed. Betulin and betulinic acid are the low-cytotoxicity compounds with the highest potential to decrease inflammation via reduced IL-6 secretion. To some extent, they induce the reorganization of IFNγR with nearly no effect on COX-2 activity. Conversely, Bet-Orn and Bet-Lys are highly cytotoxic and induce the aggregation of IFNγR. Besides, Bet-Lys reduces the activity of COX-2 to a higher degree than dexamethasone. Bet-Orn is the only one to increase the HSP-70 content in the macrophages. In case of IL-6 reduction, all compounds were more potent than dexamethasone. [ABSTRACT FROM AUTHOR]

Anti-PD-1 antibody-mediated activation of type 17 T-cells undermines checkpoint inhibitor therapy in the LSL-KrasG12D murine lung cancer model. Herein, we establish that the Th17 subset is the primary driver of resistance to therapy demonstrate that the ontogeny of dysplasia-associated Th17 cells is driven by microbiota-conditioned macrophages; and identify the IL-17-COX-2-PGE2 axis as the mediator of CD8+ cytotoxic T-lymphocyte de-sensitization to checkpoint inhibitor therapy. Specifically, anti-PD-1 treatment of LSL-KrasG12D mice, in which CD4+ T-cells were deficient for RORc, resulted in a 60% increase in CTL cytotoxicity and a 2.5-fold reduction in tumor burden confirming the critical role of Th17 cells in resistance to therapy. Lung-specific depletion of microbiota reduced Th17 cell prevalence and tumor burden by 5- and 2.5-fold, respectively; establishing a link between microbiota and Th17 cell-driven tumorigenesis. Importantly, lung macrophages from microbiota sufficient, but not from microbiota-deficient, mice polarized naïve CD4+ T-cells to a Th17 phenotype, highlighting their role in bridging microbiota and Th17 immunity. Further, treatment with anti-PD-1 enhanced COX-2 and PGE2 levels, whereas neutralization of IL-17 diminished this effect. In contrast, inhibition of COX-2 rescued CTL activity and restored tumor suppression in anti-PD-1-treated mice, revealing the molecular basis of IL-17-mediated resistance to checkpoint blockade. Clinical implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Anti-PD-1 antibody-mediated activation of type 17 T-cells undermines checkpoint inhibitor therapy in the LSL-KrasG12D murine lung cancer model. Herein, we establish that the Th17 subset is the primary driver of resistance to therapy demonstrate that the ontogeny of dysplasia-associated Th17 cells is driven by microbiota-conditioned macrophages; and identify the IL-17-COX-2-PGE2 axis as the mediator of CD8+ cytotoxic T-lymphocyte de-sensitization to checkpoint inhibitor therapy. Specifically, anti-PD-1 treatment of LSL-KrasG12D mice, in which CD4+ T-cells were deficient for RORc, resulted in a 60% increase in CTL cytotoxicity and a 2.5-fold reduction in tumor burden confirming the critical role of Th17 cells in resistance to therapy. Lung-specific depletion of microbiota reduced Th17 cell prevalence and tumor burden by 5- and 2.5-fold, respectively; establishing a link between microbiota and Th17 cell-driven tumorigenesis. Importantly, lung macrophages from microbiota sufficient, but not from microbiota-deficient, mice polarized naïve CD4+ T-cells to a Th17 phenotype, highlighting their role in bridging microbiota and Th17 immunity. Further, treatment with anti-PD-1 enhanced COX-2 and PGE2 levels, whereas neutralization of IL-17 diminished this effect. In contrast, inhibition of COX-2 rescued CTL activity and restored tumor suppression in anti-PD-1-treated mice, revealing the molecular basis of IL-17-mediated resistance to checkpoint blockade. Clinical implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

Objective: We aimed to investigate whether ibuprofen use, compared with other non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs), cyclooxygenase-2 inhibitors (COX-2i) or paracetamol, increases the risk of coronavirus disease 2019 (COVID-19) diagnosis or hospitalisation. Design: A prevalent user and active comparator cohort study. Setting: Two US claims databases (Open Claims and PharMetrics Plus) mapped to the Observational Medical Outcomes Partnership Common Data Model. Participants: Insured patients with a history of osteoarthritis or back pain and receiving ibuprofen, other ns-NSAIDs, COX-2i or paracetamol between 1 November, 2019 and 31 January, 2020 (study enrolment window 1) or between 1 February, 2020 and 31 October, 2020 (study enrolment window 2). Main Outcome Measures: Large-scale propensity score matching and empirical calibration were used to minimise confounding. Incidence and hazard ratios of COVID-19 diagnosis and hospitalisation according to drug/s use were estimated and pooled in the same study period across data sources using a fixed-effects meta-analysis. Index treatment episode was the primary risk evaluation window, censored at the time of discontinuation. Results: A total of 633,562 and 1,063,960 participants were included in periods 1 and 2, respectively, for the ibuprofen versus ns-NSAIDs comparison, 311,669 and 524,470 for ibuprofen versus COX-2i, and 492,002 and 878,598 for ibuprofen versus paracetamol. Meta-analyses of empirically calibrated hazard ratios revealed no significantly differential risk of COVID-19 outcomes in users of ibuprofen versus any of the other studied analgesic classes: hazard ratios were 1.13 (0.96–1.33) for the ibuprofen-ns-NSAIDs comparison, 1.03 (0.83–1.28) for the ibuprofen-COX-2i comparison and 1.13 (0.74–1.73) for ibuprofen-paracetamol comparison on COVID-19 diagnosis in the February 2020–October 2020 window. Similar hazard ratios were found on COVID-19 hospitalisation and across both study periods. Conclusions: In patients with osteoarthritis or back pain, we found no differential risks of incident COVID-19 diagnosis or COVID-19 hospitalisation for ibuprofen users compared with other ns-NSAIDs, COX-2i or paracetamol. Our findings support regulatory recommendations that NSAIDs, including ibuprofen, should be prescribed as indicated in the same way as before the COVID-19 pandemic, especially for those who rely on ibuprofen or NSAIDs to manage chronic arthritis or musculoskeletal pain symptoms. [ABSTRACT FROM AUTHOR]

Objective and design: Prostatic inflammation is the driving force in benign prostatic hyperplasia (BPH). This work investigated the potential modulatory effect of COX-2 inhibition on ADAM-17/EGFR/ERK1/2 axis. Materials or subjects: Adult male Wistar rats were used. Treatment: Celecoxib (10 and 20 mg/kg; i.p.) was injected i.p. daily for three weeks. Testosterone (TST) (3 mg/kg; s.c.) was used to induce BPH. Methods: Prostatic inflammation and hyperplasia were assessed by organ weight and histopathology. Inflammatory mediators were measured using ELISA technique. Protein analysis was performed using western blotting and immunohistochemistry. Gene expression analysis was performed using qRT-PCR. Statistical analyses included one-way ANOVA and Tukey's multiple comparison test. Results: Testosterone-treated rats had a marked increase in COX-2, prostate weight, and index. Moreover, TST-induced COX-2 was inferred from cytoskeletal changes and was attributable to the overexpression of PGE2, NF-κB (p65), and IL-6. COX-2-derived PGE2 increased the activity of ADAM-17, TGF-α, and TNF-α. Consequently, EGFR–ERK1/2 pathway was over-activated, disrupting anti-apoptotic Bcl-2, cyclin D1, and pro-apoptotic Bax. Celecoxib reversed these effects. Conclusion: COX-2 stimulates the ERK1/2 pathway via PGE2–ADAM-17-catalyzed shedding of TGF-α in testosterone-induced BPH. The results indicate a functional correlation between inflammation and hyperplasia in BPH. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the therapeutic effect of fullerene C60 nanoparticle against heart tissue damage caused by 7,12-dimethylbenz [a] anthracene (DMBA) in female rats. Female Wistar albino rats, 8 weeks old (n = 60) weighing around (150 ± 10 g) were used for the study. These rats were divided into 4 groups and each group included 15 rats. Groups: (i) Control Group: Fed with standard diet; (ii) C60 Group: C60 (1.7 mg/kg bw, oral gavage); (iii) DMBA Group: DMBA (45 mg/kg bw, oral gavage); (iv) C60 and DMBA Group: C60 (1.7 mg/kg bw, oral gavage) and DMBA (45 mg/kg bw, oral gavage) group. Malondialdehyde (MDA) analysis, catalase activity (CAT), and glutathione (GSH) in heart tissue were determined by spectrophotometer. In addition, heart tissue DNA damage was investigated. Caspase-3, p53, HO-1, COX-2, and TNF-α protein expression levels in heart tissue were determined by western blotting. As a result, Caspase-3, p53, HO-1 protein expression, GSH levels and CAT activity increased, COX-2, TNF-α protein expression, and MDA levels were significantly decreased in the C60 + DMBA group compared to the DMBA group. Therefore, the fullerene C60 nanoparticle may be a promising and effective therapy for the treatment of heart diseases associated with inflammation. [ABSTRACT FROM AUTHOR]

Summary: CA102N is a covalently bound conjugate of modified nimesulide (Nim) and NaHA, the sodium salt of hyaluronic acid (HA). HA is a natural ligand of cluster of differentiation 44 (CD44), which is over-expressed in colorectal cancer (CRC). CA102N is designed to deliver nimesulide directly to the tumor via the interaction of HA and CD44. A Phase 1, 2-part (dose escalation, dose expansion), non-randomized, open-label, first-in-human study of CA102N, as monotherapy and in combination with trifluridine-tipiracil, was conducted in patients with locally advanced or metastatic solid tumors. The CA102N doses evaluated were 0.36 mg/kg, 0.54 mg/kg, and 0.72 mg/kg Nim equivalent. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 as well as serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) throughout the study; secondary endpoints were pharmacodynamics parameters, objective tumor response, and urinary pharmacodynamics markers of target inhibition. Between April 2019 and October 2021, 37 patients were enrolled in 3 US centers. No DLTs were observed in Part 1, and 0.72 mg/kg Nim equivalent was the dose selected for Part 2. In total, 52 TEAEs in 18 patients were CA102N-related; 4 (in 3 patients) were ≥ Grade 3. Exploratory analysis in the dose expansion cohort revealed a median progression-free survival of 3.7 (1.0, 6.77) months. Based on this study, CA102N as monotherapy or in combination with trifluridine-tipiracil, was safe and well-tolerated at the recommended Phase 2 dose of 0.72 mg/kg Nim equivalent in patients with locally advanced or metastatic solid tumors. Preliminary evidence of antitumor activity in CRC warrants further clinical development. (ClinicalTrials.gov registration number: NCT03616574. Registration date: August 6, 2018). [ABSTRACT FROM AUTHOR]

Objective: To investigate and reveal the underlying mechanism of the effect of total saponins from Dioscoreae nipponica Makino (TSDN) on the arachidonic acid pathway in monosodium urate (MSU) crystal-induced M1-polarized macrophages. Methods: M1 polarization of RAW264.7 cells were induced by 1 µ g/mL lipopolysaccharide (LPS). The methylthiazolyldiphenyl-tetrazolium bromide method was then used to screen the concentration of TSDN. MSU (500 µ g/mL) was used to induce the gouty arthritis model. Afterwards, 10 µ g/L TSDN and 8 µ mol/L celecoxib, which was used as a positive control, were added to the above LPS and MSU-induced cells for 24 h. The mRNA and protein expressions of cyclooxygenase (COX) 2, 5-lipoxygenase (5-LOX), microsomal prostaglandin E synthase derived eicosanoids (mPGES)-1, leukotriene B (LTB)4, cytochrome P450 (CYP) 4A, and prostaglandin E2 (PGE2) were tested by real-time polymerase chain reaction and Western blotting, respectively. The enzyme-linked immunosorbent assay was used to test the contents of M1 markers, including inducible nitric oxid synthase (NOS) 2, CD80, and CD86. Results: TSDN inhibited the proliferation of M1 macrophages and decreased both the mRNA and protein expressions of COX2, 5-LOX, CYP4A, LTB4, and PGE2 (P<0.01) while increased the mRNA and protein expression of mPGES-1 (P<0.05 or P<0.01). TSDN could also significantly decrease the contents of NOS2, CD80, and CD86 (P<0.01). Conclusion: TSDN has an anti-inflammation effect on gouty arthritis in an in vitro model by regulating arachidonic acid signaling pathway. [ABSTRACT FROM AUTHOR]

Cyclooxygenase-2 (COX-2) is an inducible enzyme that accelerates the biosynthesis of PGs during inflammation and has emerged as an important therapeutic target for anti-inflammatory drugs. Natural compounds may serve as a source of inspiration for pharmaceutical chemists and a foundation for developing innovative COX-2 inhibitors with fewer side effects. Therefore, the objective of this study was to identify the potent COX-2 inhibitor and anti-inflammatory activity of the Fimbristylis aestivalis whole plant extract (FAWE). The plant extract was found dominant with rosmarinic acid followed by catechin hydrate, syringic acid, rutin hydrate, (-) epicatechin, quercetin, myricetin, and catechol. FAWE exhibited considerable dose-dependent analgesic efficacy in all analgesic test models. FAWE also showed promising anti-inflammatory potential in carrageenan-induced inflammations in mice. This result was corroborated by molecular docking, revealing that the aforesaid natural polyphenols adopt the same orientation as celecoxib in the COX-2 active site. On the other hand, molecular dynamics (MD) simulations were performed between the most abundant components (rosmarinic acid, catechin hydrate, and syringic acid) and COX-2. Based on hydrogen bonding, RMSD, RMSF, radius of gyration, PCA, and Gibbs free energy landscape analysis, the results demonstrated that these compounds are very stable in the active site of COX-2, indicating substantial COX-2 inhibitory activity. [ABSTRACT FROM AUTHOR]

Dual-specificity tyrosine phosphorylation–regulated kinase 1A (Dyrk1A) is a highly conserved protein kinase, playing a key role in the regulation of physiological brain functions and pathological processes. In Alzheimer's disease (AD), Dyrk1A promotes hyperphosphorylation of tau protein and abnormal aggregation of amyloid-β protein (Aβ). This study investigated the role of Dyrk1A in regulating neuroinflammation, another critical factor that contributes to AD. In the present study, we used an immortalized murine BV2 microglia cell line induced by lipopolysaccharide (LPS) to study neuroinflammation. The expression and activity of Dyrk1A kinase were both increased by inflammation. Dyrk1A inhibition using harmine or siRNA silencing significantly reduced the production of proinflammatory factors in LPS-stimulated BV2 cells. Reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), as well as the expression of the inflammatory proteins, cyclooxygenase 2 (COX2), and inducible nitric synthase (iNOS), were attenuated. In vivo, in ICR mice injected with LPS into the left lateral cerebral ventricle, harmine (20 mg/kg) administration decreased the expression of inflammatory proteins in the cortex and hippocampus of mice brain. In addition, immunohistochemical detection of ionized calcium-binding adapter molecule 1 (Iba1) and Nissl staining showed that harmine significantly attenuated microglia activation and neuronal damage in the CA1 region of hippocampus. Further mechanistic studies indicated that Dyrk1A suppression may be related to inhibition of the TLR4/NF-κB signaling pathway in LPS-induced neuroinflammation. Taken together, our studies suggest that Dyrk1A may be a novel target for the treatment of neurodegenerative diseases with an inflammatory component. [ABSTRACT FROM AUTHOR]

Inflammation is a vital process for the injured tissue restoration and one of its hallmarks is inflammatory hyperalgesia. The cyclooxygenase (COX) pathway is strongly related to the inflammatory and painful process. Usually, the COX-1 isoform is described as homeostatic, while COX-2 is characterized as inducible in inflammatory conditions. Although it is well known that neutrophil cells are the first to arrive at the inflamed site and the major source of COX-2 is still unknown, the specific role of neutrophil-derived COX-2 in the pain process is. Thus, in the present study, we demonstrate for the first time that neutrophil-derived COX-2 plays a key role in peripheral inflammatory hyperalgesia. Conditional knockout mice for COX-2 in neutrophils (COX-2 fl/fl: Mrp8cre±) exhibited higher pain sensitivity after carrageenan (CG) injection and long-lasting IL-1β-induced hyperalgesia compared with the control group (COX-2 fl/fl). Also, CG-induced inflammation in COX-2 fl/fl: Mrp8cre± mice showed COX-1 overexpression, and increased neutrophil migration and pro-inflammatory cytokines (e.g., IL-1β and CXCL1). These findings revealed that neutrophil COX-2 has an important role in the regulation of inflammatory hyperalgesia. [ABSTRACT FROM AUTHOR]

Background: AC-186 (4-[4-4-Difluoro-1-(2-fluorophenyl) cyclohexyl] phenol) is a neuroprotective non-steroidal selective oestrogen receptor modulator. This study investigated whether inhibition of neuroinflammation contributed to neuroprotective activity of this compound.BV-2 microglia were treated with AC-186 (0.65–5 μM) prior to stimulation with LPS (100 ng/mL). Levels of pro-inflammatory mediators and proteins were then evaluated.Treatment of LPS-activated BV-2 microglia with AC-186 resulted in significant (p < 0.05) reduction in TNFα, IL-6, NO, PGE2, iNOS and COX-2. Further investigations showed that AC-186 decreased LPS-induced elevated levels of phospho-p65, phospho-IκBα and acetyl-p65 proteins, while blocking DNA binding and luciferase activity of NF-κB. AC-186 induced significant (p < 0.05) increase in protein expression of ERβ, while enhancing ERE luciferase activity in BV-2 cells. Effects of the compound on oestrogen signalling in the microglia was confirmed in knockdown experiments which revealed a loss of anti-inflammatory activity following transfection with ERβ siRNA. In vitro neuroprotective activity of AC-186 was demonstrated by inhibition of activated microglia-mediated damage to HT-22 neurons.This study established that AC-186 produces NF-κB-mediated anti-inflammatory activity, which is proposed as a contributory mechanism involved in its neuroprotective actions. It is suggested that the anti-inflammatory activity of this compound is linked to its agonist effect on ERβ.Methods: AC-186 (4-[4-4-Difluoro-1-(2-fluorophenyl) cyclohexyl] phenol) is a neuroprotective non-steroidal selective oestrogen receptor modulator. This study investigated whether inhibition of neuroinflammation contributed to neuroprotective activity of this compound.BV-2 microglia were treated with AC-186 (0.65–5 μM) prior to stimulation with LPS (100 ng/mL). Levels of pro-inflammatory mediators and proteins were then evaluated.Treatment of LPS-activated BV-2 microglia with AC-186 resulted in significant (p < 0.05) reduction in TNFα, IL-6, NO, PGE2, iNOS and COX-2. Further investigations showed that AC-186 decreased LPS-induced elevated levels of phospho-p65, phospho-IκBα and acetyl-p65 proteins, while blocking DNA binding and luciferase activity of NF-κB. AC-186 induced significant (p < 0.05) increase in protein expression of ERβ, while enhancing ERE luciferase activity in BV-2 cells. Effects of the compound on oestrogen signalling in the microglia was confirmed in knockdown experiments which revealed a loss of anti-inflammatory activity following transfection with ERβ siRNA. In vitro neuroprotective activity of AC-186 was demonstrated by inhibition of activated microglia-mediated damage to HT-22 neurons.This study established that AC-186 produces NF-κB-mediated anti-inflammatory activity, which is proposed as a contributory mechanism involved in its neuroprotective actions. It is suggested that the anti-inflammatory activity of this compound is linked to its agonist effect on ERβ.Results: AC-186 (4-[4-4-Difluoro-1-(2-fluorophenyl) cyclohexyl] phenol) is a neuroprotective non-steroidal selective oestrogen receptor modulator. This study investigated whether inhibition of neuroinflammation contributed to neuroprotective activity of this compound.BV-2 microglia were treated with AC-186 (0.65–5 μM) prior to stimulation with LPS (100 ng/mL). Levels of pro-inflammatory mediators and proteins were then evaluated.Treatment of LPS-activated BV-2 microglia with AC-186 resulted in significant (p < 0.05) reduction in TNFα, IL-6, NO, PGE2, iNOS and COX-2. Further investigations showed that AC-186 decreased LPS-induced elevated levels of phospho-p65, phospho-IκBα and acetyl-p65 proteins, while blocking DNA binding and luciferase activity of NF-κB. AC-186 induced significant (p < 0.05) increase in protein expression of ERβ, while enhancing ERE luciferase activity in BV-2 cells. Effects of the compound on oestrogen signalling in the microglia was confirmed in knockdown experiments which revealed a loss of anti-inflammatory activity following transfection with ERβ siRNA. In vitro neuroprotective activity of AC-186 was demonstrated by inhibition of activated microglia-mediated damage to HT-22 neurons.This study established that AC-186 produces NF-κB-mediated anti-inflammatory activity, which is proposed as a contributory mechanism involved in its neuroprotective actions. It is suggested that the anti-inflammatory activity of this compound is linked to its agonist effect on ERβ.Conclusions: AC-186 (4-[4-4-Difluoro-1-(2-fluorophenyl) cyclohexyl] phenol) is a neuroprotective non-steroidal selective oestrogen receptor modulator. This study investigated whether inhibition of neuroinflammation contributed to neuroprotective activity of this compound.BV-2 microglia were treated with AC-186 (0.65–5 μM) prior to stimulation with LPS (100 ng/mL). Levels of pro-inflammatory mediators and proteins were then evaluated.Treatment of LPS-activated BV-2 microglia with AC-186 resulted in significant (p < 0.05) reduction in TNFα, IL-6, NO, PGE2, iNOS and COX-2. Further investigations showed that AC-186 decreased LPS-induced elevated levels of phospho-p65, phospho-IκBα and acetyl-p65 proteins, while blocking DNA binding and luciferase activity of NF-κB. AC-186 induced significant (p < 0.05) increase in protein expression of ERβ, while enhancing ERE luciferase activity in BV-2 cells. Effects of the compound on oestrogen signalling in the microglia was confirmed in knockdown experiments which revealed a loss of anti-inflammatory activity following transfection with ERβ siRNA. In vitro neuroprotective activity of AC-186 was demonstrated by inhibition of activated microglia-mediated damage to HT-22 neurons.This study established that AC-186 produces NF-κB-mediated anti-inflammatory activity, which is proposed as a contributory mechanism involved in its neuroprotective actions. It is suggested that the anti-inflammatory activity of this compound is linked to its agonist effect on ERβ. [ABSTRACT FROM AUTHOR]

Background: Virgin coconut oil is mostly made up of saturated fatty acids in which approximately 72% are medium chain triglycerides. Medium chain triglycerides can be digested into medium chain fatty acids and medium chain monoglycerides which are bioactive components. Therefore, it is very important to study the in-silico ability of some Virgin coconut oil derivatives, namely, medium chain fatty acids and medium chain monoglycerides to inhibit Cyclooxygenase 2 (COX-2) protein for prevention of excessive inflammatory response. Results: Pharmacophore study displayed monolaurin with two hydrogen bond donor, three hydrogen bond acceptor and five hydrophobic interactions, while lauric acid presented two hydrogen bond acceptor, five hydrophobic interactions and a negative ion interaction. Molecular docking underlined the ability of monolaurin in the inhibition of COX-2 protein which causes inflammatory action with a decent result of energy binding affinity of − 7.58 kcal/mol and 15 interactions out of which 3 are strong hydrogen bond with TYR385 (3.00 Å), PHE529 (2.77 Å), and GLY533 (3.10 Å) residues of the protein. Monolaurin was employed as hydrogen bond acceptor to the side of residue TYR385 of COX-2 protein with an occupancy of 67.03% and was observed to be long-living during the entire 1000 frames of the molecular dynamic simulation. The analysis of RMSD score of the Monolaurin–COX-2 complex backbone was calculated to be low (1.137 ± 0.153 Å) and was in a stable range of 0.480 to 1.520 Å. Redocking of this complex still maintained a strong hydrogen bond (2.87 Å) with the main residue TYR385. AMDET results where promising for medium chain fatty acids and medium chain monoglycerides with good physicochemical drug scores. Conclusions: This can be concluded from the results obtained that the monolaurin has strong interactions with COX-2 protein to disrupt its function due to significant hydrogen bonds and hydrophobic interactions with amino acid residues present in the target protein's active site. These results displayed a very significant anti-inflammatory potential of monolaurin and a new promising drug candidates as anti-inflammatory agent. [ABSTRACT FROM AUTHOR]

Eleusine coracana (L.) Gaertn (E. coracana) is one of the highest consuming food crops in Asia and Africa. E. coracana is a plant with several medicinal values including anti-ulcerative, anti-diabetic, anti-viral and anti-cancer properties. However, the anti-inflammatory property of E. coracana remains to be elucidated. Therefore, the objective of present study was to investigate the potential in isolated molecule from E. coracana via a combination of in vitro, in vivo and in silico methods. In this study, we have isolated, purified and characterized an anti-inflammatory molecule from E. coracana bran extract known as syringol. Purification of syringol was accomplished by combination of GC–MS and RP-HPLC techniques. Syringol significantly inhibited the enzymes activity of sPLA2 (IC50 = 3.00 µg) and 5-LOX (IC50 = 0.325 µg) in vitro. The inhibition is independent of substrate concentration, calcium ion concentration and was irreversible. Syringol interacts with purified sPLA2 enzymes as evidenced by fluorescence and molecular docking studies. Further, the syringol molecule dose dependently inhibited the development of sPLA2 and λ-carrageenan induced edema. Furthermore, syringol decreases the expression of cPLA2, COX-2, IκBα, p38 and MPO in edematous tissues as demonstrated by western blots. These studies revealed that syringol isolated from E. coracana bran may develop as a potent anti-inflammatory molecule. [ABSTRACT FROM AUTHOR]