Search

This study was to explore whether Ginkgo biloba extract (GBE) improve memory impairment by alleviating neuroinflammation signaling in mice with status epilepticus.The status epilepticus (SE) mice model was established by pilocarpine and treated with 100 mg / kg of GBE for 14 days. Spontaneous alternation of Y-maze and new object recognition were used to explore memory impairment. To examine glial cell activation, we performed immunohistochemistry and immunofluorescence staining. The activation of NF-κB signaling and the expression level of lncRNA-COX2 were detected by Western blot and qRT-PCR, respectively. Adeno-associated virus lncRNA-COX2 was injected into mice for overexpression of lncRNA-COX2.After GBE treatment, the spontaneous alternation rate and the recognition coefficient in SE mice were both increased. Moreover, activation of glial cells, NF-κB signaling and lncRNA-COX2 were significantly decreased in SE mice. In the GBE-treated SE mice with lncRNA-COX2 overexpression, NF-κB signaling was up-regulated again; the reduced level of inflammation factors was reversed; the GBE-rescued spontaneous alternation rate of Y-maze was eliminated.Our results suggested that GBE reduces the hippocampal inflammation by down-regulating lncRNA-COX2 / NF-κB signaling in the SE mice, leading to the decrease of neuronal damage and the improvement of memory functions.

Nonsteroidal anti-inflammatory drugs represent one of the most popularly used classes of drugs. However, their long-term administration is associated with various side effects including gastrointestinal ulceration. One of the major reasons of NSAIDs ulcerogenicity is direct damage of the epithelial lining cells by the acidic moieties present in many drugs. Another drawback for this acidic group is its rapid metabolism and clearance through Phase II conjugation. Three series of thiophene and thienopyrimidine derivatives were designed and synthesized as nonacidic anti-inflammatory agents. In vivo testing of their analgesic activity indicated that compounds 2b and 7a-d showed higher PI values than that of the positive control drugs, indomethacin and celecoxib. The latter compounds 2b and 7a-d were subjected to further anti-inflammatory activity testing where they showed comparable percentage edema inhibition to that of indomethacin and celecoxib. Compounds 2b, 7a, 7c, and 7d inhibited PGE2 synthesis by 61.10%-74.54% (71.47% for indomethacin, and 80.11% for celecoxib). The same compounds inhibited the expression of rat mPGES-1 and cPGES3 by 74%-83% (77% for indomethacin, and 82% for celecoxib) and 48%-70% (62% for indomethacin, and 70% for celecoxib), respectively. The stability of the most active compound 2b in Nonenzymatic gastrointestinal fluids and in human plasma was tested. Additionally, studying the metabolic stability of compound 2b in S9 rat liver fraction showed that it displayed a slow in vitro clearance with half-life time 1.5-fold longer than indomethacin. The metabolites of 2b were predicted via UPLC-MS/MS. In silico ADMET profiling study was also included.

Acute or repetitive exposure to ultraviolet (UV) cause disruptions to the skin barrier and subsequent inflammatory skin disease. 4-phenylpyridine (4-PP) is a constituent of Brassica campestris L. ssp. Pekinensis and its effect on skin inflammation and molecular target remain unclear. The purpose of this study is to confirm the anti-inflammatory efficacy of 4-PP on UVB-induced skin inflammation in human keratinocytes HaCaT and mouse skin and validation of its molecular target. 4-PP also attenuated UVB-induced phosphorylation of p38/mitogen-activated protein kinase kinase (MKK) 3/6, c-Jun N-terminal kinase 1/2, MKK 4/7, extracellular-signal-regulated kinase 1/2, mitogen-activated protein kinase 1/2. Additionally, 4-PP inhibited UVB-induced phosphorylation of epidermal growth factor receptor (EGFR) Y1068, Y1045 and 854 residues but not the proto-oncogene tyrosine-protein kinase c-Src. Drug affinity responsive target stability assay revealed that 4-PP directly binds to c-Src and inhibits pronase c-proteolysis. Knockdown of c-Src inhibited UVB-induced COX-2 expression and phosphorylation of MAPKs and EGFR in HaCaT cells. Dorsal treatment of 4-PP prevented UVB (0.5 J/cm

Obesity is a world-wide problem, especially the child obesity, with the complication of various metabolic diseases. Child obesity can be developed as early as the age between 2 and 6. The expansion of fat mass in child age includes both hyperplasia and hypertrophy of adipose tissue, suggesting the importance of proliferation and adipogenesis of preadipocytes. The changed composition of gut microbiota is associated with obesity, revealing the roles of lipopolysaccharide (LPS) on manipulating adipose tissue development. Studies suggest that LPS enters the circulation and acts as a pro-inflammatory regulator to facilitate pathologies. Nevertheless, the underlying mechanisms behind LPS-modulated obesity are yet clearly elucidated. This study showed that LPS enhanced the expression of cyclooxygenase-2 (COX-2), an inflammatory regulator of obesity, in preadipocytes. Pretreating preadipocytes with the scavenger of reactive oxygen species (ROS) or the inhibitors of NADPH oxidase or p42/p44 MAPK markedly decreased LPS-stimulated gene expression of COX-2 together with the phosphorylation of p47

Robenacoxib is a veterinary-approved non-steroidal anti-inflammatory drug (NSAID) of the coxib group. It possesses anti-hyperalgesic, anti-inflammatory and anti-pyretic properties. Robenacoxib inhibits the cyclooxygenase (COX)-2 isoform of COX selectively (in vitro IC

Background Inhibition of the microsomal prostaglandin (PG) E2 synthase (mPGES-1) introduces a promising anti-inflammatory treatment approach by specifically reducing PGE2 . The microvasculature is a central target organ for early manifestations of cardiovascular disease. Therefore, a better understanding of the prostaglandin system and characterising the effects of mPGES-1 inhibition in this vascular bed are of interest. Experimental approach The effects of mPGES-1 inhibition on constriction and relaxation of resistance arteries (O100-400μm) from patients with end stage kidney disease (ESKD) and controls (Non-ESKD) were studied using wire-myography in combination with immunological and mass-spectrometry based analyses. Key results Inhibition of mPGES-1 in arteries from ESKD patients and Non-ESKD controls significantly reduced adrenergic vasoconstriction, which was not affected by the COX-2 inhibitors NS-398 and Etoricoxib or the COX-1/COX-2 inhibitor Indomethacin, tested in Non-ESKD controls. Correspondingly, a significant increase of acetylcholine-induced dilatation was observed for mPGES-1 inhibition only. In IL-1β treated arteries, inhibition of mPGES-1 significantly reduced PGE2 levels while PGI2 levels remained unchanged. In contrast, COX-2 inhibition blocked the formation of both prostaglandins. Blockage of PGI2 signaling with an IP receptor antagonist did not restore the reduced constriction, neither did blocking of PGE2 -EP4 or signaling through PPARγ. A biphasic effect was observed for PGE2 , inducing dilatation at nmol and constriction at μmol concentrations. Immunohistochemistry demonstrated expression of mPGES-1, COX-1, PGIS, weak expression for COX-2 as well as receptor expression for PGE2 (EP1-4), thromboxane (TP) and PGI2 (IP) in ESKD and Non-ESKD. Conclusion Our study demonstrates vasodilating effects following mPGES-1 inhibition in human microvasculature and suggests that several pathways besides shunting to PGI2 may be involved.

Mycobacterium tuberoculosis (Mtb) is a contagious pathogen that causes human tuberculosis (TB). TB is a major global health threat that causes 9.6 million illnesses and 1.5 million deaths per year. Recent studies have suggested Mtb-secreted proteins as new candidates for therapeutic drugs and vaccines. LprG is a Mtb-secreted surface glycolipoprotein encoded by lprG (Rv1411c), which forms an operon with Rv1410c, where Rv1410c encodes P55, an efflux pump membrane protein. Various in vitro and in vivo studies have reported on the target-binding activity, cell envelope biosynthesis, and mycobacterial virulence of LprG. However, the anti-inflammatory effect of LprG in macrophages has not yet been investigated. In this study, we demonstrated that LprG can suppress lipopolysaccharide (LPS)-induced inflammation in a macrophage model. LprG inhibited LPS-stimulated nitric oxide (NO) production. LprG also suppressed expression of inducible cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) at the transcriptional and protein levels. In addition, LprG decreased mRNA expression of the pro-inflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). Furthermore, LprG attenuated nuclear factor kappa-B (NF-κB) translocation and IκB phosphorylation. Moreover, LprG specifically inhibited phosphorylated kinases such as c-Jun N-terminal kinase (p-JNK) and extracellular signal-regulated kinase 1/2 (p-ERK1/2), but not p-p38. Taken together, these results suggest that LprG inhibits LPS-stimulated inflammation via downregulation of NO, COX-2, iNOS, and pro-inflammatory cytokines through the NF-κB, AP-1, and MAPK signaling pathways. The present study will aid in the development of anti-inflammatory medications using Mtb. The organism, which has long been regarded as a human pathogenic or human health-threating agent, can be utilized as a future medical resource.

Enflicoxib is approved for the treatment of pain and inflammation in canine osteoarthritis. The objective of this work was to assess the mechanistic basis of enflicoxib therapy investigating the COX inhibitory activity of enflicoxib (racemate), its enantiomers and its main metabolites using the canine whole blood assay. The (R)-(+)-Enflicoxib enantiomer and metabolite M8 (hydroxylated pyrazoline) did not induce significant COX inhibition. Enflicoxib and its (S)-(-)-Enflicoxib enantiomer inhibited COX-1 and COX-2 with variable degree of preferential isoform inhibition, but no significant therapeutic effect is anticipated in vivo. The pyrazol metabolite showed the highest COX-2 inhibition and was the most selective (IC

Microglial activation has been studied extensively in diabetic retinopathy. We have previously detected activation and migration of microglia in 8-week-old diabetic rat retinas. It is widely acknowledged that microglia-mediated inflammation contributes to the progression of diabetic retinopathy. However, existing cell models do not explore the role of activated microglia in vitro. In this study, microglia were subject to various conditions mimicking diabetic retinopathy, including high glucose, glyoxal, and hypoxia. Under high glucose or glyoxal treatment, microglia demonstrated only partially functional changes, while under hypoxia, microglia became fully activated showing enlarged cell bodies, enhanced migration and phagocytosis as well as increased production of pro-inflammatory factors such as cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and inducible nitric oxide synthase (iNOS). The data indicate that hypoxia-treated microglia is an optimal in vitro model for exploration of microglia activation in diabetic retinopathy.

The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase‐2 (COX‐2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX‐2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX‐2 overexpression by COX‐2‐dependent PGE2‐EP2‐ERK1/2‐NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX‐2‐independent LKB1‐AMPK‐NRF2‐HO‐1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX‐2‐dependent and COX‐2‐independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.

BACKGROUND Cyclooxygenase-2 protein is a critically important mediator in inflammation that influences proliferation, apoptosis, angiogenesis and metastasis. Previous works showed a relationship between cyclooxygenase-2 and tumourigenesis in humans and animal models. In epithelial odontogenic tumours and cysts, increased cell proliferation and survival have been linked to its pathogenesis and tumour development. The aim of the present study was to analyse the immunohistochemical expression of cyclooxygenase-2 in solid ameloblastoma and odontogenic keratocyst and its association with proteins related to cell proliferation and apoptosis. METHODS This study was conducted on 40 cases from the Pathological Anatomy Service, University of Chile. The cases were diagnosed as solid ameloblastoma (n = 21) and odontogenic keratocyst (n = 19) according to WHO 2017. Slides prepared from paraffin-embedded sections were immunohistochemically stained for cyclooxygenase-2, cyclin D1, Ki-67, p63 and Bcl-2. Statistical evaluation was performed by the Shapiro-Wilk test, ANOVA Mann-Whitney test and Spearman's correlation coefficient (p

The use of non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of musculoskeletal injuries is commonplace in the general, athletic, and military populations. While NSAIDs have been studied in a variety of tissues, the effects of NSAIDs on skeletal muscle have not been fully defined. To address this, we investigated the degree to which the cyclooxygenase (COX)-2-selective NSAID celecoxib affects muscle cell proliferation, differentiation, anabolic signaling, and mitochondrial function in primary human skeletal myoblasts and myotubes. Primary muscle cells were treated with celecoxib or NS-398 (a pharmacological inhibitor of COX-2) as a control. Celecoxib administration significantly reduced myoblast proliferation, viability, fusion, and myotube area in a dose-dependent manner, whereas NS-398 had no effect on any of these outcomes. Celecoxib treatment was also associated with reduced phosphorylation of ribosomal protein S6 in myoblasts, and reduced phosphorylation of AKT, p70S6K, S6, and ERK in myotubes. In contrast, NS-398 did not alter phosphorylation of these molecules in myoblasts or myotubes. In myoblasts, celecoxib significantly reduced mitochondrial membrane potential and respiration, as evidenced by the decreased citric acid cycle (CAC) intermediates cis-aconitic acid, alpha-keto-glutarate acid, succinate acid, and malic acid. Similar results were observed in myotubes, although celecoxib also reduced pyruvic acid, citric acid, and fumaric acid. NS-398 did not affect CAC intermediates in myoblasts or myotubes. Together, these data reveal that celecoxib inhibits proliferation, differentiation, intracellular signaling, and mitochondrial function in primary human myoblasts and myotubes independent of its function as a COX-2 inhibitor.

This is the first study investigating the nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity of compounds containing a new scaffold, tetrahydrobenzo[b]thiophene. Eighteen compounds were synthesised and confirmed their NRF2 activation through NQO1 enzymatic activity and mRNA expression of NQO1 and HO-1 in Hepa-1c1c7 cells. The compounds disrupted the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and NRF2 via interfering with the KEAP1's Kelch domain. The compounds exhibited anti-inflammatory activity in Escherichia coli Lipopolysaccharide (LPS

2-Halogenatedphenyl benzoxazole-5-carboxylic acids with mono-halogen (chloro, bromo and fluoro) substituted at ortho-, meta- and para-positions on the phenyl ring were designed and synthesized based on significance of presence of halogen in increasing number of marketed halogenated drugs and importance of benzoxazoles. These 2-alogenatedphenylbenzoxazole-5-carboxylic acids and their methyl esters were screened for anti-inflammatory activity, and cytotoxicity. 2-(3-Chlorophenyl)benzoxaole-5-carboxylic acid (6b) exhibited significant anti-inflammatory activity with IC

Some bioactive derivatives of indeno[1,2-c]pyrazolones were synthesized through the reaction of phenylhydrazine, different aldehydes and indan-1,2,3-trione at room temperature in acetonitrile. Analytical and spectroscopic studies have confirmed the structural characteristics of the synthesized compounds. In addition, the target compounds were screened for the in-vitro antiproliferative properties against the B16F10 melanoma cancer cell lines by the standard MTT assay. The effect on inflammatory marker cyclooxygenase 2 and matrix metalloproteinase 2, 9 was also checked to determine the anti-inflammatory and anti-cell migratory properties of these compounds. The final compounds were also tested for their tyrosinase inhibitory activity. Among all compounds, screened for anticancer activity, three compounds 4e, 4f and 4h reduced the cell proliferation significantly comparable to that of the positive standard drug erlotinib (IC

Purpose Reactive microglia are an important hallmark of neuroinflammation. Reactive microglia release various inflammatory mediators, such as cytokines, chemokines, and prostaglandins, which are produced by enzymes like cyclooxygenases (COX). The inducible COX-2 subtype has been associated with inflammation, whereas the constitutively expressed COX-1 subtype is generally considered as a housekeeping enzyme. However, recent evidence suggests that COX-1 can also be upregulated and may play a prominent role in the brain during neuroinflammation. In this review, we summarize the evidence that supports this involvement of COX-1. Methods Five databases were used to retrieve relevant studies that addressed COX-1 in the context of neuroinflammation. The search resulted in 32 articles, describing in vitro, in vivo, post mortem, and in vivo imaging studies that specifically investigated the COX-1 isoform under such conditions. Results Reviewed literature generally indicated that the overexpression of COX-1 was induced by an inflammatory stimulus, which resulted in an increased production of prostaglandin E2. The pharmacological inhibition of COX-1 was shown to suppress the induction of inflammatory mediators like prostaglandin E2. Positron emission tomography (PET) imaging studies in animal models confirmed the overexpression of COX-1 during neuroinflammation. The same imaging method, however, could not detect any upregulation of COX-1 in patients with Alzheimer's disease. Conclusion Taken together, studies in cultured cells and living rodents suggest that COX-1 is involved in neuroinflammation. Most postmortem studies on human brains indicate that the concentration of COX-1-expressing microglial cells is increased near sites of inflammation. However, evidence for the involvement of COX-1 in neuroinflammation in the living human brain is still largely lacking.

Background Periodontitis is an inflammatory disease caused by multiple disease-associated bacterial species in periodontal tissues. Autophagy is known to modulate various inflammation-driven diseases and inflammatory responses, but the role of autophagy related to the pathogenesis of periodontitis is not fully established. We investigated whether autophagic flux regulated the expression of inflammatory cytokines in the gingiva of periodontitis patients and lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (HGFs) and the underlying mechanism. Methods The mRNA and protein expression of pro-inflammatory cytokines was assessed in human gingival tissues collected from patients with periodontitis and HGFs treated with LPS. The expression of signaling molecules related to autophagy was evaluated by immunofluorescence and Western blot analyses. Results The expression of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and intercellular adhesion molecule-1 (ICAM-1) was increased in the gingival tissues of patients with periodontitis. LC3B-positive cells, a typical autophagic marker, were increased in the gingival tissues of periodontitis patients and LPS-treated HGFs. The conversion ratio of LC3-I to LC3-II was higher in the gingival tissues associated with periodontitis and LPS-treated HGFs compared to the controls. The autophagy inhibitor 3-methyladenine (3MA) significantly abrogated the LPS-sustained inflammatory effect by reducing the expression of IL-6, TNF-α, COX-2, and ICAM-1 in HGFs. The phosphorylation of protein kinase B (AKT) and protein S6K1 (S6), signals involved in the mTOR-dependent mechanism, was decreased in gingiva derived from periodontitis patients and LPS-treated HGFs. Conclusions Autophagy augmented the production of inflammatory cytokines by mTOR inactivation via the AKT signaling pathway in the gingival tissues of patients with periodontitis and LPS-stimulated HGFs. These findings would provide a better understanding of the mechanism by which autophagy regulates the inflammatory response associated with periodontal pathogenesis. This article is protected by copyright. All rights reserved.

4‐Phenylbutyric acid (4‐PBA) exerts potent pharmacological effects, including anti‐inflammatory properties, via inhibition of endoplasmic reticulum (ER) stress. However, it is not known whether 4‐PBA attenuates the severity of rheumatoid arthritis. The present study aimed to determine whether the inhibition of ER stress by 4‐PBA ameliorated experimentally induced arthritis. The proliferation of synovial fibroblasts (SFs) and expression of matrix metalloproteinases (MMPs) were evaluated in the presence of interleukin (IL)‐1β with or without 4‐PBA. The effect of 4‐PBA on the phosphorylation of Mitogen‐activated protein kinase (MAPK) and the activation of Nuclear factor‐κB (NF‐κB) in IL‐1β‐stimulated SFs was assessed. In an in vivo study, the effects of 4‐PBA were investigated using DBA/1 mice with collagen‐induced arthritis (CIA). Clinical, histological, and serological assessments of CIA treated with 4‐PBA were performed to determine the therapeutic effect of 4‐PBA. In vitro, 4‐PBA inhibited the proliferation and expression of IL‐1β‐stimulated SFs and MMP‐1 and MMP‐3 through the suppression of both the phosphorylation of MAPKs and NF‐κB in IL‐1β‐stimulated SFs. The 4‐PBA treatment markedly attenuated the severity of arthritis in CIA mice. The 4‐PBA treatment ameliorated joint swelling and the degree of bone erosion and destruction and decreased the level of inflammatory cytokines and MMP‐3 and Cox‐2. Furthermore, remarkable improvements in histopathological findings occurred in 4‐PBA‐treated mice. These findings suggested that 4‐PBA could attenuate the severity of arthritis in CIA mice by partially blocking the phosphorylation of MAPKs and the activation of NF‐κB in SFs. Thus, through the inhibition of ER stress, 4‐PBA may be a potent agent for the treatment of RA.

The organic extract of the old woman octopus Cistopus indicus (Octopodidae), ubiquitous in the Central and South Indo-Pacific to the tropical Indian Ocean, was chromatographically fractionated over a reverse-phase adsorbent to yield two oxygenated spiro heterocyclic compounds, named indiculides A and B. Their structures were elucidated by using comprehensive spectroscopic methods. The radical scavenging potential displayed by indiculide A (IC

Rheumatoid arthritis (RA) is a systemic chronic disease characterized by inflammation and synovitis. More effective treatment methods with less side effects need to be developed. In this context, current study investigated the therapeutic effects of safranal in a model of complete Freund's adjuvant (CFA)-induced RA. The control group was given 1 ml of saline orally starting from the 8th day, and 0.2 ml of CFA was given to the RA, RA + Safranal and RA + Methotrexate (MTX) groups on the 0th day of the experiment. Starting from the 8th day of the experiment, 1 ml of saline was given to the RA group, safranal was given at 200 mg/kg of body weight to the RA + MTX group, and 3 mg/kg of MTX to the RA + MTX group twice a week. The results showed that weight gain decreased in the RA group compared to the control group while arthritis index score, thymus index, and planter temperature were found to be increased. Additionally, a deterioration in blood parameters, an increase in alanine aminotransferase, aspartate aminotransferase, urea, creatinine, C-reactive protein, and malondialdehyde levels, and a decrease in reduced glutathione levels and glutathione peroxidase and catalase (CAT) activities were seen while tumor necrosis factor-α, interleukin-6 (IL-6), cyclooxygenase-2, nuclear factor kappa B levels were found to be increased. However, the safranal had a regulatory effect on all the values, except IL-6 and CAT, and blood parameters. Moreover, histopathological examination revealed that safranal reduced inflammatory cell infiltration and edema.

Background Multiple drug resistance (MDR) of cancer cells is the main cause of intrinsic or acquired desensitization to chemotherapy in many cancers. A number of studies have found high expression of COX‐2 to be a factor for expression of MDR gene in several cancer. Furthermore, adipose tissue derived mesenchymal stem/stromal cells (ADSC) have been found to increase cyclo‐oxygenase‐2 (COX‐2) expression in some tumour cells. The mechanism for this, however, is not yet clear and needs further study. Objective The purpose of this study was to determine whether tumour necrosis factor‐alpha stimulated gene/protein 6 (TSG‐6) secreted from ADSCs is associated with an increase in MDR genes by inducing COX‐2 gene expression in melanoma and osteosarcoma cell lines. Methods ADSCs were transfected with TSG‐6 siRNA or Control RNA respected, and cancer cell line were transfected with COX‐2 siRNA or Control RNA respected. Using trans well coculture system, the interactions of ADSCs with tumour cells were investigated. Results Increased COX‐2 expression was observed in cancer cell co‐cultured with ADSCs. Additionally, we identified that COX‐2 expression was related to drug resistance genes (P‐glycoprotein, multidrug resistance‐associated protein). Transfecting canine ADSCs with small interfering RNA, TSG‐6 secreted from ADSCs was found to be a major factor in the regulation of COX‐2 expression and drug resistance genes in osteosarcoma and melanoma cell lines. Conclusion TSG‐6 mediated COX‐2 up‐regulation is a possible mechanism of chemoresistance development induced by ADSCs. These findings provide better understanding about the mechanism associated with ADSC‐induced chemoresistance in cancer., TSG‐6 mediated COX‐2 up‐regulation could be a possible mechanism underlying the development of chemoresistance induced by mesenchymal stem cells.

New findings What is the central question of this study? It is reported that SFTPB polymorphisms are associated with COPD. The function and its mechanism of SFTPB in COPD are still unknown. We indicate the function and underlying mechanism in controls and COPD patients, A549 cells induced by 10% CSE and a mouse model of COPD. Furthermore, we have indicated the mechanism of SFTPB in COPD by regulating the expression of SFTPB in A549 cells. What is the main finding and its importance? Under the stimulation of the risk factors of COPD, SFTPB expression is decreased, which may be involved in the formation of COPD. The progress of COPD induces an inflammatory response and reduces SFTPB expression. Otherwise, levels of PTGS2 and inflammatory responses are changed by SFTPB, which indicates that SFTPB promotes the progression of COPD by PTGS2 and inflammation. Abstract Pulmonary surfactant-associated protein B (SFTPB) is a critical protein for lung homeostasis, and its polymorphisms are associated with COPD. However, few studies have so far confirmed the functional involvement of SFTPB in COPD. Serum SFTPB and inflammatory cytokines levels were measured in 54 patients with acute exacerbation of COPD and 29 healthy controls. A549 cells were induced using 10% cigarette smoke extract (CSE) and treated with dexamethasone to investigate the effect of inflammation on SFTPB expression, and the effect of SFTPB overexpression and silencing on inflammatory cytokines was measured using real-time PCR and ELISA. Lastly, SFTPB expression was assessed in mouse lung tissues using immunofluorescence. Serum levels of SFTPB were significantly lower in COPD patients than in controls (p = 0.009). Conversely, levels of IL-6 and prostaglandin-endoperoxide synthase-2 (PTGS2) were increased in COPD patients (IL-6: p = 0.006, PTGS2: p = 0.043). After CSE treatment, SFTPB mRNA and protein levels were significantly decreased compared to controls (mRNA: p = 0.002; protein: p = 0.011), while IL-6, IL-8 and PTGS2 were elevated. Dexamethasone treatment increased SFTPB levels. Following SFTPB overexpression in A549 cells, mRNA and protein levels of IL-6, IL-8 and PTGS2 were significantly reduced, while silencing induced the opposite effect. SFTPB levels were significantly reduced in the lung tissue of a mouse model of COPD compared to controls. Reduced SFTPB levels may induce PTGS2 and inflammatory responses in COPD and could be a key protein for evaluation of COPD progression. This article is protected by copyright. All rights reserved.

Facile synthesis of 6- or 7-substituted coumarin-indomathacin hybrids (Coum-IDM) has been developed for specific cyclooxygenase-2 (COX-2) binding along with their intrinsic fluorescent properties. A mild and rapid condensation/dehydrative cyclization of 2-hydroxy benzaldehyde with activated indomethacin was carried out in one step under ultrasound irradiation. Coum-IDM4 was found to be the best of this series as it presented significant binding to COX-2 and exhibited higher fluorescent intensity in cancer cells than in normal cells. Therefore, in the light of drug development tools, this new hybrid system could be a potential targeted probe for COX-2-overexpressed inflammation and cancer-cell tracking.

Atopic dermatitis (AD) is a multifactorial chronic inflammatory skin disease characterized by skin barrier dysfunction, eczematous lesions, pruritus, and abnormal immune responses. In this study, we assessed the therapeutic effect of topical applied conjugated linoleic acid (CLA) on a murine AD model that was developed by repetitive applications of 2, 4-dinitrofluorobenzene (DNFB). 2% or 5% CLA could markedly ameliorate AD-like skin lesions, scratching behaviour and skin inflammation as evidenced by the reduced inflammatory blood cells, IgE and Th2-related cytokine levels, and the infiltration of mast cells and inflammatory cells to the dermal tissues. Moreover, topical application with CLA modulated skin barrier repair including maintaining a balanced skin pH and increasing skin hydration, partially mediated by upregulating skin barrier-related protein, filaggrin (FLG). In addition, topical CLA significantly dose-dependently inhibited pro-inflammatory cytokines including interleukin (IL)-6, IL-1β, tumour necrosis factor (TNF)-α and pro-inflammatory enzyme expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in inflamed mice skin. Its anti-inflammatory effect was associated with the inhibition of DNFB-stimulated IκBα and NF-κB p65 phosphorylation in mouse skin. Taken together, our results suggest that locally applied CLA exerts potentially protective effects against AD lesional skin at least in part, due to regulation of skin barrier function and inflammatory response.

miR‐34a‐5p up‐regulates the IL‐1β/COX2/PGE2 inflammation pathway and induces apoptosis and the release of calcitonin gene‐related peptide via inhibition of SIRT1 expression in trigeminal ganglion neurons. This suggests that miR‐34a‐5p may have potential for development into a therapeutic target for the treatment of migraine., Migraine is a debilitating neurological condition, with a global prevalence rate of 10.68% in men and 18.79% in women. Elucidation of the molecular mechanisms underlying migraines is of great importance for improving the quality of life of patients. The release of the neuropeptide calcitonin gene‐related peptide (CGRP) from trigeminal nerve terminals is involved in the pathogenesis of migraine. Recent studies have shown that up‐regulation of miR‐34a‐5p expression is associated with acute migraine attacks. Here, we investigated whether alteration of the expression of miR‐34a‐5p induces the release of the vasoactive peptide CGRP. We isolated primary rat trigeminal ganglion neurons and performed gain‐ and loss‐of‐function assays to alter the expression level of miR‐34a‐5p. Down‐regulation of miR‐34a‐5p inhibited the expression of interleukin‐1β (IL‐1β)/cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2), decreased IL‐1β, PGE2 and CGRP release, and up‐regulated the expression of silencing information regulator 1 (SIRT1) in trigeminal ganglion, whereas overexpression of miR‐34a‐5p enhanced the expression of IL‐1β/COX2/PGE2, increased the release of IL‐1β, PGE2 and CGRP, and decreased the expression of SIRT1 in trigeminal ganglion. In addition, overexpression of miR‐34a‐5p induced apoptosis in primary rat trigeminal neurons. In summary, these findings suggest that miR‐34a‐5p up‐regulates the IL‐1β/COX2/PGE2 inflammation pathway, induces apoptosis and enhances release of CGRP via inhibition of SIRT1 expression in trigeminal ganglion neurons; thus, miR‐34a‐5p may have potential as a therapeutic target for the treatment of migraine.

Hyaluronic acid (HA) is widely recognized as a therapeutic target and currently used in medicine. However, HA metabolism during intervertebral disc degeneration (IVDD) has not been completely elucidated. This study aimed to evaluate the efficacy of HA on intervertebral disc (IVD) inflammation and identify the main molecules modulating HA degradation in IVDs. To assess HA function in IVD cells in vitro, we treated human disc cells and U-CH1-N cells, a notochordal nucleus pulposus cell line, with HA or hyaluronidase. Real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis showed that tumor necrosis factor alpha (TNF-α)-mediated induction of the expression of TNF-α and cyclooxygenase-2 (COX2) was clearly neutralized by HA treatment, and the expression of TNF-α and COX2 was significantly induced by hyaluronidase treatment in both cell types. Additionally, Western blot analysis showed that hyaluronidase-induced phosphorylation of p38 and Erk1/2, and that TNF-α-mediated phosphorylation of p38 and Erk1/2 was clearly reduced by HA addition. In degenerating human IVD samples, immunohistochemistry for hyaluronidase showed that the expression of hyaluronidases including HYAL1, HYAL2, and cell migration-inducing protein (CEMIP) tended to increase in accordance with IVDD. In particular, HYAL1 showed statistically significant differences. In vitro study also confirmed a similar phenomenon that TNF-α treatment increased both messenger RNA and protein expression in both cell types. Our results demonstrated that HA could potentially suppress IVDD by regulating p38 and Erk1/2 pathways, and that the expression of HYAL1 was correlated with IVDD progression. These findings indicated that HYAL1 would be a potential molecular target for suppressing IVDD by controlling HA metabolism.

Primary cilia have been found to function as mechanosensors in low-magnitude high-frequency vibration (LMHFV)-induced osteogenesis. The PGE2 also regulates bone homeostasis and mechanical osteogenesis through its receptor EP4 signaling, but its involvement in LMHFV-induced or in primary cilia-induced osteogenesis has not been investigated. We hypothesized that LMHFV stimulates osteoblast (OB) differentiation by activating the COX2-PGE2-EP pathway in a manner dependent on primary cilia and that primary cilia are also affected by the PGE2 pathway. In this study, through western blot analysis, RNA interference, enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and cytochemical staining, we observed that COX2, mPGES-1, and PGE2 levels were markedly elevated in cells treated with LMHFV and were greatly decreased in LMHFV-treated cells following IFT88 silencing. EP4 expression was significantly increased in OBs following LMHFV treatment, but IFT88 silencing significantly blocked this increase. EP4 localized to the bases of primary cilia. LMHFV reduced the length and abundance of primary cilia, but the cells could self-repair their primary cilia after mechanical damage. EP4 antagonism significantly blocked the LMHFV-induced increase in IFT88 expression and blocked the recovery of primary cilia length and the proportion of cells with primary cilia. In addition, COX2 or EP4 antagonism disrupted LMHFV-induced osteogenesis. These results demonstrate the integration of and crosstalk between primary cilia and the COX2-PGE2-EP4 signaling pathway under mechanical stimulation.

The study aimed to establish a strategy to elucidate the in vivo constituents of Angelicae Pubescentis Radix (APR, also known as Duhuo) and reveal the probable mechanisms underlying its anti-rheumatoid arthritis activity. First recorded by Shennong Bencao Jing, APR is mainly used to treat Bi syndrome. Eleven absorbed components of APR were successfully identified using the rheumatoid arthritis (RA) rat model and the UHPLC-QTOF/MS technique. Two active ingredients (osthole and columbianadin) and five corresponding targets (PTGS1, PTGS2, RXRA, CCNA2 and ACHE) were found to construct a compound-protein interaction network in RA. In addition, a non-alcoholic fatty liver disease pathway, which was related to anti-RA activity, was eventually identified by KEGG analysis. Subsequently, molecular docking was performed by establishing a mixed matrix network, including the absorbed component, corresponding target and signaling pathway with two key compounds (osthole and columbianadin) and two important targets (PTGS2 and PTGS1). The result of molecular docking is in agreement with the network pharmacology.

Opuntia milpa alta polysaccharides (ODP) are bioactive compounds extracted from Opuntia milpa alta and widely used in the treatment of diseases, but the therapeutic mechanism of ODP on inflammatory injury remains unclear. Therefore, this study explores the effects and mechanisms of ODP in lipopolysaccharide (LPS)-induced inflammation of human keratinocytes (HaCaT). In this experiment, ODP was extracted via the water extraction and fermentation methods, respectively. LPS was then used to induce inflammatory damage in HaCaT cells, and the stimulated cells were treated with different concentrations of ODP. Cell viability was detected by MTT assay, and the concentrations of COX-2, iNOS, IL-6, IL-8, IL-10 and TNF-α were determined by enzyme-linked immunosorbent assay (ELISA). Changes in inflammatory cytokines and related mRNA expression were observed to assess LPS-induced cell damage. In the experiment, it was found that the LPS stimulation of HaCaT cells can induce cellular inflammatory response, reduce cell viability, increase cell apoptosis and increase the expression of COX-2, iNOS, IL-6, IL-8, IL-10 and TNF-α. However, the experimental data shows that ODP can reverse the above results by increasing cell viability, inhibiting cell apoptosis, reducing the expression of the above genes and inactivating antioxidant pathways, which revealed the specific mechanism of ODP repairing LPS-induced inflammatory damage to Hacat cell. In addition, The experimental results showed that fermentation could improve the anti-inflammatory effect of ODP. In conclusion, our experimental results indicate that ODP fermented by lactic acid bacteria can be used as an anti-inflammatory agent.

Endometrial cancer is the major type of gynecological cancer and ranks as the sixth most common cancer in women. Endometrial cancer usually is diagnosed in an advanced stage, complicating the treatments in many cases. The present research was focused on unveiling the in vitro anticancer role of fucoxanthin against the endometrial cancer HEC-1A cells by inhibiting the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling axis. The cytotoxicity of fucoxanthin against the endometrial cancer HEC-1A cells was studied using the MTT test. The level of reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) status, and apoptotic cell death in the 7.5 and 10 µM administered HEC-1A cells were assayed using fluorescent staining techniques. The messenger RNA expression was analyzed using RT-PCR for PI3K/Akt/mTOR signaling molecules, proapoptotic (Bax and caspase-3) antiapoptotic (cyclin D1 and Bcl-2) genes, and inflammatory markers like tumour necrosis factor α (TNFα), nuclear factor kappa B (NF-κB), Cox-2, and interleukin (IL)-6. The cell viability assay proved that fucoxanthin effectively prevented HEC-1A cell viability, where the IC

A novel series of hybrids designed on the basis of aurantiamide acetate and isopropylated genipin were synthesized and biologically evaluated as anti-inflammatory agents. Among them, compound 7o exhibited the best inhibitory activity against TNF-α secretion (IC50 = 16.90 μM), and was selected for further in vitro and in vivo functional study. The results demonstrated that 7o was capable of suppressing the expression of LPS-induced iNOS and COX-2, as well as reducing the production of NO at the concentration of 5 μM, which may be resulted from its regulation of NF-κB signaling and MAPK signaling. Moreover, compound 7o exhibited favourable in vivo anti-inflammatory activity with an inhibition rate of 53.32% against xylene-induced ear swelling in mice at the dose of 5 mg/kg.

An over-expression of COX-2 isoenzyme belonging to the Cyclooxygenase Enzyme Family triggers the overproduction of pro-inflammatory prostaglandins that instigate the development of chronic inflammation and related disorders. Hence, the rationally designed drugs for mitigating over-activity of COX-2 isoenzyme play a regulatory role toward the alleviation of the progression of these disorders. However, a selective COX-2 inhibition chemotherapy prompts several side effects that necessitate the identification of novel molecular scaffolds for deliberating state-of-the-art drug designing strategies. The heterocyclic "azole" scaffold, being polar and hydrophilic, possesses remarkable physicochemical advantages for designing physiologically active molecules capable of interacting with a wide range of biological components, including enzymes, peptides, and metabolites. The substituted derivatives of azole nuclei enable a comprehensive SAR analysis for the appraisal of bioactive profile of the deliberated molecules for obtaining the rationally designed compounds with prominent activities. The comprehensive SAR analysis readily prompted the identification of Y-shaped molecules and the eminence of bulkier group for COX-2 selective inhibition. This review presents an epigrammatic collation of the pharmacophore-profile of the chemotherapeutics based on azole motif for a selective targeting of the COX-2 isoenzyme.

Prolonged hypersecretion of catecholamine induced by chronic stress may correlate with malignant progression of cancer. β2‐adrenergic receptor (β2‐AR) overexpressed in certain cancer cells may translate the signals from neuroendocrine system to malignant signals by interacting with oncoproteins, such as Her2. In the present study, we demonstrate that catecholamine stimulation activates the expression and proteolytic activity of ADAM10 by modulating the expression of miR‐199a‐5p and SIRT1 and also confirm that catecholamine induction triggers the activities of γ‐secretase, leading to shedding of Her2 extracellular domain (ECD) by ADAM10 and subsequent intramembranous cleavage of Her2 intracellular domain (ICD) by presenilin‐dependent γ‐secretase, nuclear translocation of Her2 ICD, and enhanced transcription of tumor metastasis‐associated gene COX‐2. Chronic stimulation of catecholamine strongly promotes the invasive activities of cancer cells in vitro and spontaneous tumor lung metastasis in mice. Furthermore, nuclear localization of Her2 was significantly correlated with overexpression of β2‐AR in human breast cancer tissues, indicating that catecholamine‐induced β2‐AR activation plays decisive roles in tumor metastasis. Our data also reveal that an unknown mechanism by which the regulated intramembrane proteolysis (RIP) initiated by β2‐AR‐mediated signaling controls a novel Her2‐mediated signaling transduction., In the present study, we demonstrated that catecholamine stimulation activates the expression and proteolytic activity of ADAM10 by modulating the expression of miR‐199a‐5p and SIRT1 and also confirm that catecholamine induction triggers the activities of γ‐secretase, leading to shedding of Her2 ECD by ADAM10 and subsequent intramembranous cleavage of Her2 ICD by presenilin‐dependent γ‐secretase, nuclear translocation of Her2 ICD, and enhanced transcription of tumor metastasis‐associated gene COX‐2. Chronic stimulation of catecholamine strongly promotes the invasive activities of cancer cells in vitro and spontaneous tumor lung metastasis in mice. Furthermore, the nuclear localization of Her2 was significantly correlated with overexpression of β2‐adrenergic receptor (β2‐AR) in human breast cancer tissues, indicating that catecholamine‐induced β2‐AR activation plays decisive roles in tumor metastasis.

Acute brain ischemia accounts for most of stroke cases and constitutes a leading cause of deaths among adults and permanent disabilities in survivors. Currently, the intravenous thrombolysis is the only available medication for ischemic stroke; mechanical thrombectomy is an emerging alternative treatment for occlusion of large arteries and has shown some promise in selected subsets of patients. However, the overall narrow treatment window and potential risks largely limit the patient eligibility. New druggable targets are needed to innovate the treatment of brain ischemia. As the rate-limiting enzyme in the biosyntheses of prostanoids, cyclooxygenase (COX), particularly the inducible isoform COX-2, has long been implicated in mechanisms of acute stroke-induced brain injury and inflammation. However, the notion of therapeutically targeting COX has been diminished over the past two decades due to significant complications of the cardiovascular and cerebrovascular systems caused by long-term use of COX-2 inhibitor drugs. New treatment strategies targeting the downstream prostanoid signaling receptors regulating the deleterious effects of COX cascade have been proposed. As such, a large number of selective small molecules that negatively or positively modulate these important inflammatory regulators have been evaluated for neuroprotection and other beneficial effects in various animal models of brain ischemia. These timely preclinical studies, though not yet led to clinical innovation, provided new insights into the regulation of inflammatory reactions in the ischemic brain and could guide drug discovery efforts aiming for novel adjunctive strategies, along with current reperfusion therapy, to treat acute brain ischemia with higher specificity and longer therapeutic window.

Gouty arthritis is the one of the most painful arthritis and is caused by an inflammatory reaction. This study investigated whether astaxanthin (AXT), which has documented anti-inflammatory and antioxidant properties, exhibits protective effects against monosodium urate (MSU) crystal-induced inflammation. Cell viability of J774A.1 murine macrophages was assessed by AXT dose-dependent incubation by MTT assays, and expression levels of iNOS and COX-2 proteins as well as secretion of IL-1β were also analyzed under MSU crystals stimulation with or without AXT treatment. The production of inflammatory mediators was found to significantly decrease with AXT treatment, and the formation of the inflammasome complex was also attenuated when cells were co-stimulated with MSU crystals and AXT. Furthermore, we found that expression of the MAPK pathway was downregulated in J774A.1 cells. AXT also inhibited the induction of COX-2 and IL-6 in human chondrocytes and synovial fibroblasts by western blots. Finally, an MSU crystal intra-articular injection rat model for gouty arthritis was utilized in which treatment groups received 5-daily intraperitoneal injections of AXT prior to MSU crystal stimulation, or once intra-articular injections of AXT following MSU crystal stimulation for 6 hours. Results of synovitis score analysis revealed that inflammation was significantly attenuated in the group which received intraperitoneal AXT injection prior to MSU crystal stimulation compared to the group which received MSU only. These results indicate that AXT attenuates the effects of MSU crystal-induced inflammation by suppressing the production of pro-inflammatory cytokines and inflammatory mediators. Our findings that the anti-inflammatory activities of AXT may be beneficial in the treatment of MSU crystal-induced arthritis.

The majority of anti-cancer therapies target the proliferating tumor cells, while the tumor stroma, principally unaffected, survives, and provide a niche for surviving tumor cells. Combining tumor cell and stroma-targeting therapies thus have a potential to improve patient outcome. The neuroblastoma stroma contains cancer-associated fibroblasts expressing microsomal prostaglandin E synthase-1 (mPGES-1). mPGES-1-derived prostaglandin E2 (PGE2 ) is known to promote tumor growth through increased proliferation and survival of tumor cells, immune suppression, angiogenesis, and therapy resistance, and we, therefore, hypothesize that mPGES-1 constitutes an interesting stromal target. Here, we aimed to develop a relevant in vitro model to study combination therapies. Co-culturing of neuroblastoma and fibroblast cells in 3D tumor spheroids mimic neuroblastoma tumors with regard to the cyclooxygenase/mPGES-1/PGE2 pathway. Using the spheroid model, we show that the inhibition of fibroblast-derived mPGES-1 enhanced the cytotoxic effect of doxorubicin and vincristine and significantly reduced tumor cell viability and spheroid growth. Cyclic treatment with vincristine in combination with an mPGES-1 inhibitor abrogated cell repopulation. Moreover, inhibition of mPGES-1 potentiated the cytotoxic effect of vincristine on established neuroblastoma allografts in mice. In conclusion, we established a 3D neuroblastoma model, highlighting the potential of combining stromal targeting of mPGES-1 with tumor cell targeting drugs like vincristine.

BACKGROUND Preclinical studies have implicated excess release of catecholamines and prostaglandins in the mediation of prometastatic processes during surgical treatment of cancer. In this study, we tested the combined perioperative blockade of these pathways in patients with colorectal cancer (CRC). METHODS In a randomized, double-blind, placebo-controlled biomarker trial involving 34 patients, the β-blocker propranolol and the COX2-inhibitor etodolac were administered for 20 perioperative days, starting 5 days before surgery. Excised tumors were subjected to whole genome messenger RNA profiling and transcriptional control pathway analyses. RESULTS Drugs were well-tolerated, with minor complications in both the treatment group and the placebo group. Treatment resulted in a significant improvement (P

Background Brazilian berry is a fruit popularly known as "Jaboticaba," rich in bioactive compounds with antioxidant and anti-inflammatory properties. Senescence and overweight are increasing worldwide and are considered risk factors to prostatic pathogenesis mainly due to oxidative and inflammatory processes induction. Thus, this study aimed to evaluate the effect of two increasing doses of the patented jaboticaba peel extract (PJE) on oxidative-stress and inflammation in the prostate of aging or high-fat-fed aging mice. Methods PJE and/or high-fat diet (HFD) treatments started with 11-month-old mice and lasted 60 days. The levels or the immunoexpression of different inflammatory (nuclear factor κB [NFκB], CD3+, cyclooxygenase 2 [COX-2], toll-like receptor 4 [TLR4], phosphorylated signal transducers and activators of transcription 3 [pSTAT-3], tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and IL-1β) and oxidative-stress (catalase, superoxide dismutase 2 [SOD2], glutathione reductase [GSR], reduced glutathione, and glutathione peroxidase 3 [GPx3]) related molecules were analyzed by western-blotting, immunohistochemistry, and enzyme-linked immunosorbent assays. Results Both PJE doses reduced the levels of oxidative-stress-related molecules (GPx3, GSR, catalase), lipid peroxidation (4-hydroxynonenal), inflammatory mediators (COX-2, TNF-α, and pSTAT-3) and CD3+ T cells number, which were associated with the maintenance of the glandular morphological integrity in aging and HFD-fed-aging mice. Nevertheless, only the high PJE dose reduced the NFκB and TLR4 levels in aging mice; and SOD2, IL-6, and IL-1β levels in HFD-aging mice. Aging itself promoted an oxidative inflammation in the prostate, interfering in the levels of the different oxidative-stress, lipid peroxidation, and inflammatory mediators evaluated, in association with high incidence of prostate epithelial and stromal damages. The HFD intake intensified aging alterations, showing an unfavorable prostatic microenvironment prone to oxidative and inflammatory damages. Conclusions PJE exerted a dose-dependent effect controlling inflammation and oxidative-stress in aging and HFD-fed aging mice prostate. This fact contributed to prostate microenvironment balance recovery, preserving the tissue architecture of this gland. Thus, the PJE emerges as a potential therapy to prevent inflammation and oxidative stress in the prostate.

Background Worldwide, endometrial carcinoma is one of the most frequently diagnosed cancers among women and a considerable cause of death. The aims of this study were to determine the expression of cyclooxygenase-2 (COX-2) in endometrial adenocarcinoma in imprint smears as an alternative technique and to correlate the results with clinicopathologic parameters of primary untreated endometrial cancer patients. Methods One hundred twenty-six patients with endometrial carcinoma were evaluated with samples freshly resected after a total abdominal hysterectomy during a 29-month period. The cytologic imprint smears were obtained by touching the cut surface of cancer tissues and the expression of COX-2 was assessed by immunocytochemistry. Results The positive expression of COX-2 in malignant cells, was accompanied by morphologic features of more aggressiveness (pathogenetic type II, advanced clinical stage, mainly high grade, deep myometrial involvement >1/2) tumors and the affected from the disease lymph nodes cases showed higher positivity (41.2%) than the non-affected (13.4%). Conclusion Immunocytochemical findings from COX-2 stain in cancer cells could be a predictor of prognosis in most cases in endometrial cytology with imprint smears. Furthermore, positive expression of COX-2 in cancer cells was related to morphologic features of more aggressiveness tumors.

In China, Camellia oleifera oil (COO) is not only a common edible oil but also a traditional remedy widely applied to ameliorate a variety of illnesses associated with inflammation, such as mouth ulcers, thrush, eczema, etc. However, there has been a lack of relevant biological research on the anti-inflammatory capacity of COO, and the specific bioactive lipid phytochemicals contributing to the anti-inflammatory effect need further research. In this study, the RAW 264.7 macrophages model was used to investigate the anti-inflammatory capacity of COO. Our data showed that 33-200 μg/mL COO markedly inhibited the lipopolysaccharide lipopolysaccharide (LPS)-stimulated nitric oxide (NO.) secretion via the suppression of Nos2 and Cox-2 expression. The enzyme immunoassay confirmed that COO also exhibited a strong suppressive effect on the expression of proinflammatory cytokines such as Tnf-α and Il-6. To further explore the correlation between the anti-inflammatory effects and the lipid phytochemicals in COO, 10 samples were collected and screened for their chemical compositions. It was interestingly demonstrated that the polyphenol extracts of COO play a vital role in its anti-inflammatory properties. In addition, an oil-in-water (O/W) emulsion-based system was also developed to deliver the liposoluble COO into the cells, and the feasibility of this system was confirmed. Our research confirms the anti-inflammatory potential of COO and highlights that the main functional ingredient is polyphenol extracts. This may provide a scientific basis for the comprehensive utilization and development of COO and related functional foods.

An efficient and refined method for the separation of six aconitine‐type alkaloids from the alkaline prepared “Kusnezoff monkshood root” was established. It is the first study that two new lipo‐alkaloids were successfully isolated from refined sample by pH‐zone‐refining counter‐current chromatography rather than synthetic method. It was of interest that a great deal of lipo‐alkaloids was produced in crude extract from the alkalization of “Kusnezoff monkshood root.” A refined sample method was proposed to enrich two types of alkaloids by liquid–liquid extraction, i.e. lipo‐alkaloids and monoester‐diterpenoid alkaloids. The pH‐zone‐refining counter‐current chromatography was performed with an optimized two‐phase solvent system composed of n‐hexane‐ethyl acetate–methanol–water (3:5:4:5, v/v), where upper organic phase was added to 3 mmol/L triethylamine as a retainer and lower aqueous mobile phase was added to 3 mmol/L hydrochloric acid as an eluter. As a result, six aconitum alkaloids, including two lipo‐alkaloids (8‐lino‐14‐benzoylaconine, 8‐pal‐14‐benzoylaconine), three monoester‐diterpenoid alkaloids (14‐benzoylmesaconine, 14‐benzoylaconine, beyzoyldeoxyaconine), and one aconine alkaloid (neoline) were acquired from the plant at the same time. The anti‐inflammatory activities of the two new lipo‐alkaloids were compared to the six alkaloids in vitro, in cyclo‐oxygen‐ase‐2 inhibition assays. The separation mechanism of six alkaloids by pH‐zone‐refining counter‐current chromatography was illustrated.

Some novel non-ulcerogenic N-substitutedphenyl-6-oxo-3-phenylpyridazines as COX-2 inhibitors have been developed (Supplementary material Appendix 1). The novel aldehyde 3 was prepared by reacting 6-phenylpyridazin-3(2H)-one with 4-fluorobenzaldehyde. The aldehyde 3 was reacted with different hydrazines and thiazolidin-4-ones to obtain the novel N-substitutedphenyl-6-oxo-3-phenylpyridazine derivatives. These were assessed for their anti-inflammatory potential and gastric ulcerogenic effects. The molecular docking investigations were also undertaken. The spectroscopic data were coherent with the allocated structures of the compounds. The compounds 4a (IC50 = 17.45 nm; p

Aims Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease. Prostaglandins E2 (PGE2), the product of the cyclo-oxygenase 2 (COX-2) enzyme, has critical roles in the etiology of autoimmune diseases. PGE2 level is controlled by a balance between its synthesis mediator (COX-2 enzyme) and its catabolic key enzyme (15-hydroxyprostaglandin dehydrogenase [15-PGDH] enzyme). In the present study, the associations of genotypic polymorphisms in COX-2 and 15-PGDH with SLE were investigated. Methods One hundred and sixty SLE patients and 160 healthy controls participated in the study. The polymerase chain reaction - restriction fragments length polymorphism method was used for genotyping. The COX-2 rs2745557 G/A and 15-PGDH rs8752 G/A polymorphisms were investigated. Results Regarding the COX-2 rs2745557 single nucleotide polymorphism, there was no significant association between COX-2 rs2745557 polymorphism and SLE. However, the dominant models showed a marginally significant relation (P = .048, odds ratio = 0.63, 95% CI = 0.4-1.0). Regarding GA genotype of 15-PGDH rd8752 polymorphism, there was a significant difference between two groups with a 4.5-fold increase in SLE development (P = .0001). The frequency of the A allele was higher in SLE patients than that in controls, showing a 1.4-fold increase in SLE development (P = .018). Conclusion All results showed the protective effects of the dominant model of COX-2 rs2745557 polymorphism and risk factor of 15-PGDH rs8752 polymorphism on SLE development.

Tumour-associated macrophages (TAMs) play an important role in promoting the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to study the epigenetic mechanisms in regulating pro-tumour M2-polarised TAMs in the PDAC tumour microenvironment.This study was conducted based on ex vivo TAMs isolated from PDAC tissues and in vitro THP1-derived TAM model. RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing and chromatin immunoprecipitation sequencing were performed to investigate gene expression, chromatin accessibility, transcription factor binding sites and histone modifications. Gene knockdown in THP1-derived TAMs was performed with lentivirus, and the impact of THP1-derived TAMs on invasion and metastasis ability of PDAC cells were investigated with in vitro and in vivo functional assays. RNA-chromatin interaction was analysed by chromatin isolation through RNA purification with sequencing. RNA-protein interaction was studied by RNA immunoprecipitation and RNA pull-down.Our data showed that the transcription factor CTCF (CCCTC-binding factor) was highly expressed in TAMs and predicted to be significantly enriched in hyper-accessible chromatin regions when compared to monocytes. High infiltration of CTCFOur study demonstrated a novel epigenetic regulation mechanism of promoting pro-tumour M2-polarised TAMs in the PDAC tumour microenvironment.