Elevated Cyclooxygenase-2 Expression Research Articles

Oleuropein ameliorates hyperlipidemia, oxidative stress, inflammatory and liver dysfunction biomarkers, in streptozotocin-induced diabetic rats

Diabetes mellitus (DM) is a serious threat factor for chronic liver disorders and the development of nonalcoholic steatohepatitis into cirrhosis. However, numerous pharmacological actions of olive polyphenol have been discovered, with oleuropein being a primary phenolic substance found in olive leaves, olive oil, and olive fruit (Olea europaea). Our goal is to identify the impacts of oleuropein on lipid measurements, oxidative stress, serum leptin, adiponectin levels, inflammatory status, and hepatic dysfunctions in a male rat model with streptozotocin (STZ)-induced DM. Oleuropein was orally administered to diabetic rats at a 5 mg/kg bw/day dose for 15 days. Diabetic rats treated with oleuropein demonstrated improved hepatic function test results (ALT, AST, alkaline phosphatase, and bilirubin), while activity of the low liver glucose-6-phosphate dehydrogenase (G6PDH) increased. Moreover, serum triacylglycerol, very low-density lipoprotein, low-density lipoprotein, and total cholesterol (TC) were considerably reduced, while high-density lipoprotein increased markedly. In addition, serum antioxidative enzymes such as glutathione peroxidase, catalase, glutathione-S-transferase, and superoxide dismutase increased, as well as glutathione levels. Lipid peroxidation levels were lower than those in the STZ control group. Treating diabetic rats with oleuropein not only resulted in decreased serum leptin and increased adiponectin levels but also had a substantial inhibitory effect on the elevated COX-2 and TNF-α mRNA expression levels in the livers of the STZ group. In conclusion, oleuropein has shown promising results in mitigating hyperlipidemia, oxidative stress, inflammation, and hepatic dysfunction biomarkers in diabetic rats.

Deletion of Elovl5 leads to dyslipidemia and atherosclerosis in LDLR-deficient mice

Atherosclerosis is a chronic inflammatory disease for which hepatic steatosis and atherogenic dyslipidemia are significant risk factors. We investigated the effects of endogenously generated very-long-chain polyunsaturated fatty acids (VL-PUFAs) on dyslipidemia and atherosclerosis development using mice that lack ELOVL5, a PUFA elongase that is required for the synthesis of arachidonic acid, EPA, and DHA from the essential fatty acids linoleic and linolenic acids, and the LDL receptor (LDLR). Elovl5−/−;Ldlr−/− mice manifest increased liver triglyceride and cholesterol concentrations due to the activation of sterol regulatory element binding protein-1, a transcription factor that activates enzymes required for de novo lipogenesis. Plasma levels of triglycerides and cholesterol in VLDL, IDL, and LDL were markedly elevated in Elovl5−/−;Ldlr−/− mice fed a chow and the mice exhibited marked aortic atherosclerotic plaques. Bone marrow-derived monocytes from wild-type (WT) and Elovl5−/− mice were polarized to M1 and M2 macrophages, and the effects of ELOVL5 on inflammatory activity were determined. There were no differences in most of the markers tested for M1 and M2 polarized cells between WT and Elovl5−/− cells, except for a slight increase in PGE2 secretion in Elovl5−/− cells, likely due to elevated Cox-2 expression. These results suggest that the deletion of Elovl5 leads to hepatic steatosis and dyslipidemia, which are the major factors in severe atherosclerosis in Elovl5−/−;Ldlr−/− mice.

Activation of the JNK/COX-2/HIF-1α axis promotes M1 macrophage via glycolytic shift in HIV-1 infection.

Chronic inflammation is recognized as a major risk factor for the severity of HIV infection. Whether metabolism reprogramming of macrophages caused by HIV-1 is related to chronic inflammatory activation, especially M1 polarization of macrophages, is inconclusive. Here, we show that HIV-1 infection induces M1 polarization and enhanced glycolysis in macrophages. Blockade of glycolysis inhibits M1 polarization of macrophages, indicating that HIV-1-induced M1 polarization is supported by enhanced glycolysis. Moreover, we find that this immunometabolic adaptation is dependent on hypoxia-inducible factor 1α (HIF-1α), a strong inducer of glycolysis. HIF-1α-target genes, including HK2, PDK1, and LDHA, are also involved in this process. Further research discovers that COX-2 regulates HIF-1α-dependent glycolysis. However, the elevated expression of COX-2, enhanced glycolysis, and M1 polarization of macrophages could be reversed by inactivation of JNK in the context of HIV-1 infection. Our study mechanistically elucidates that the JNK/COX-2/HIF-1α axis is activated to strengthen glycolysis, thereby promoting M1 polarization in macrophages in HIV-1 infection, providing a new idea for resolving chronic inflammation in clinical AIDS patients.

Rosmarinic acid in combination with ginsenoside Rg1 suppresses colon cancer metastasis via co-inhition of COX-2 and PD1/PD-L1 signaling axis.

Metastasis of colorectal cancer (CRC) is a leading cause of mortality among CRC patients. Elevated COX-2 and PD-L1 expression in colon cancer tissue has been linked to distant metastasis of tumor cells. Although COX-2 inhibitors and immune checkpoint inhibitors demonstrate improved anti-tumor efficacy, their toxicity and variable therapeutic effects in individual patients raise concerns. To address this challenge, it is vital to identify traditional Chinese medicine components that modulate COX-2 and PD-1/PD-L1: rosmarinic acid (RA) exerts striking inhibitory effect on COX-2, while ginsenoside Rg1 (GR) possesses the potential to suppress the binding of PD-1/PD-L1. In this study we investigated whether the combination of RA and GR could exert anti-metastatic effects against CRC. MC38 tumor xenograft mouse model with lung metastasis was established. The mice were administered RA (100 mg·kg-1·d-1, i.g.) alone or in combination with GR (100 mg·kg-1·d-1, i.p.). We showed that RA (50, 100, 150 μM) or a COX-2 inhibitor Celecoxib (1, 3, 9 μM) concentration-dependently inhibited the migration and invasion of MC38 cells in vitro. We further demonstrated that RA and Celecoxib inhibited the metastasis of MC38 tumors in vitro and in vivo via interfering with the COX-2-MYO10 signaling axis and inhibiting the generation of filopodia. In the MC38 tumor xenograft mice, RA administration significantly decreased the number of metastatic foci in the lungs detected by Micro CT scanning; RA in combination with GR that had inhibitory effect on the binding of PD-1 and PD-L1 further suppressed the lung metastasis of colon cancer. Compared to COX-2 inhibitors and immune checkpoint inhibitors, RA and GR displayed better safety profiles without disrupting the tissue structures of the liver, stomach and colon, offering insights into the lower toxic effects of clinical traditional Chinese medicine against tumors while retaining its efficacy.

Protective Effects of Long-Term Usage of Cyclo-Oxygenase-2 Inhibitors on Colorectal Cancer in Genetically Predisposed Individuals and Their Overall Effect on Prognosis: A Systematic Review.

Colorectal cancer (CRC) is a major global health concern, accounting for significant cancer-related morbidity and mortality worldwide. Despite advancements in early detection and treatment modalities, the prevention of CRC remains a critical goal. Cyclo-oxygenase-2 (COX-2) is an inducible enzyme involved in the production of pro-inflammatory prostaglandins, which play a crucial role in various cellular processes, including inflammation, cell proliferation, apoptosis, and angiogenesis. Elevated COX-2 expression has been consistently observed in colorectal tumors, indicating their role in the pathogenesis of cancer. COX-2 inhibitors, such as celecoxib and rofecoxib, have been studied as potentiallyeffective treatment modalities due to their ability to decrease prostaglandin levels, which are generally higher in cancer patients.Aberrant prostaglandin production is linked to the adenoma-carcinoma sequence, during which adenomas turn dysplastic and accumulate enough damage to become malignant. COX-2 inhibitors have also been shown to modulate various signaling pathways involved in CRC development, such as wingless-related integration site/β-catenin (Wnt/β-catenin), mitogen-activated protein kinase (MAPK), and phosphoinositide-3-kinase-protein kinase B/Akt (PI3K/Akt) pathways. This systematic review aimed to evaluate the protective effects of long-term usage of COX-2 inhibitors on CRC in genetically predisposed individuals and their overall effect on the prognosis of the disease. The researchers conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and collected data from several databases, including PubMed, PubMed Central, Cochrane Library, and Web of Science. The search strategy combined keywords related to CRC, COX-2 inhibitors, protective effects, and prognosis. They identified 1189 articles and shortlisted 26 full-text articles that met the eligibility criteria. Quality assessment tools, such as the Assessment of Multiple Systematic Review (AMSTAR) for systematic reviews, the Cochrane bias assessment tool for randomized control trials, the scale for the assessment of narrative review articles(SANRA) checklist for narrative reviews, and the Joanna Briggs Institute (JBI) tool for cross-sectional studies and case reports, are used. This review's conclusions will assist in determining the effectiveness of COX-2 inhibitors to prevent CRC. This review may also contribute to developing guidelines for clinicians to manage genetically predisposed individuals with CRC. Furthermore, the results of this review will shed light on the potential of COX-2 inhibitors as a preventive measure against CRC in genetically predisposed individuals.

Alpha-enolase 1 knockdown facilitates the proliferation and invasion of villous trophoblasts by upregulating COX-2.

Enolase 1 (ENO1) is a metabolic enzyme which participates in pyruvate synthesis and ATP production in cells. Previously, differential expression of ENO1 was discovered in villous tissues between recurrent miscarriage and induced abortion. This study was designed to explore whether ENO1 influences the proliferation and invasion of villous trophoblasts and the related molecular mechanisms. First, ENO1 expression in placental villus tissues collected from recurrent miscarriage (RM) patients and women for induced abortion as well as in trophoblast-derived cell lines was detected by RT-qPCR and western blotting. ENO1 localization and expression in villus tissues were further confirmed through immunohistochemistry staining. Then, the effects of ENO1 downregulation on trophoblast Bewo cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process were evaluated by CCK-8 assay, transwell assay, and western blotting. As for the regulatory mechanism of ENO1, the expression of COX-2, c-Myc and cyclin D1 in Bewo cells after ENO1 knockdown was finally evaluated by RT-qPCR and western blotting. ENO1 was mainly localized in the cytoplasm, with very small amounts in the nucleus of trophoblast cells. ENO1 expression in the villi tissues of RM patients was significantly increased, when compared with the villous tissues of healthy controls. Furthermore, Bewo cells, a trophoblast cell line with relatively higher expression of ENO1, was used to downregulate the ENO1 expression by ENO1-siRNA transfection. ENO1 knockdown significantly facilitated Bewo cell growth, EMT process, migration, and invasion. ENO1 silencing markedly elevated COX-2, c-Myc, and cyclin D1 expression. ENO1 may participate in the development of RM via suppressing the growth and invasion of villous trophoblasts via reducing the expression of COX-2, c-Myc, and cyclin D1.

Extracellular stimulation of lung fibroblasts with arachidonic acid increases interleukin 11 expression through p38 and ERK signaling.

Interleukin-11 (IL-11) is a pleiotropic cytokine that regulates proliferation and motility of cancer cells. Fibroblasts reside in the cancer microenvironment and are the primary source of IL-11. Activated fibroblasts, including cancer-associated fibroblasts that produce IL-11, contribute to the development and progression ofcancer, and inducefibrosis associated with cancer. Changes in fatty acid composition or its metabolites, and an increase in free fatty acids have been observed in cancer. The effect of deregulated fatty acids on the development and progression of cancer isnot fully understood yet. In the present study, we investigated the effects of fatty acids on mRNA expression and secretion of IL-11 in lung fibroblasts. Among the eight fatty acids added exogenously, arachidonic acid (AA) increased mRNA expression and secretion of IL-11 in lung fibroblasts in a dose-dependent manner. AA-induced upregulation of IL-11 was dependent on the activation of the p38or ERK MAPK signaling pathways. Furthermore, prostaglandin E2, associated with elevated cyclooxygenase-2 expression, participated in the upregulation of IL-11 via its specific receptor in an autocrine/paracrine manner. These results suggest that AA may mediate IL-11 upregulation in lung fibroblasts in thecancer microenvironment, accompanied by unbalanced fatty acid composition.

A Novel Herbal Extract Blend Product Prevents Particulate Matters-Induced Inflammation by Improving Gut Microbiota and Maintaining the Integrity of the Intestinal Barrier

Air pollutants of PM2.5 can alter the composition of gut microbiota and lead to inflammation in the lung and gastrointestinal tract. The aim of this study was to evaluate the protective effect of a novel herbal extract blend, FC, composed of Lonicera japonica extract, Momordica grosvenori extract, and broccoli seed extract, on PM2.5-induced inflammation in the respiratory and intestinal tract. A549 cells and THP-1 cells, as well as C57BL/6 mice, were stimulated with PM2.5 to establish in vitro and in vivo exposure models. The models were treated with or without FC. The expression of inflammatory cytokines and tight junction proteins were studied. Proteomic analysis was performed to elucidate mechanisms. Mouse feces were collected for gut microbiota analysis. FC was shown to modulate the upregulation of pro-inflammatory cytokines mRNA expression in A549 and THP-1 cells and downregulated tight junction proteins mRNA expression in A549 cells due to PM2.5 stimulation. In animal models, the decreased expression of the anti-inflammatory factor il-10, tight junction protein ZO-1, and the elevated expression of COX-2 induced by PM2.5 were improved by FC intervention, which may be associated with zo-1 and cox-2 signaling pathways. In addition, FC was shown to improve the gut microbiota by increasing the abundance of beneficial bacteria.

Host‐directed anti‐mycobacterial activity of colchicine, an anti‐gout drug, via strengthened host innate resistance reinforced by the IL‐1β/PGE2 axis

To diversify and expand possible tuberculosis (TB) drug candidates and maximize limited global resources, we investigated the effect of colchicine, an FDA-approved anti-gout drug, against Mycobacterium tuberculosis (Mtb) infection because of its immune-modulating effects. We evaluated the intracellular anti-Mtb activity of different concentrations of colchicine in murine bone marrow-derived macrophages (BMDMs). To elucidate the underlying mechanism, RNA sequencing, biological and chemical inhibition assays, and Western blot, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemical analyses were employed. Finally, type I interferon-dependent highly TB-susceptible A/J mice were challenged with virulent Mtb H37Rv, and the host-directed therapeutic effect of oral colchicine administration on bacterial burdens and lung inflammation was assessed 30 days post-infection (2.5mg·kg-1 every 2days). Colchicine reinforced the anti-Mtb activity of BMDMs without affecting cell viability, indicating that colchicine facilitated macrophage immune activation upon Mtb infection. The results from RNA sequencing, NLRP3 knockout BMDM, IL-1 receptor blockade, and immunohistochemistry analyses revealed that this unexpected intracellular anti-Mtb activity of colchicine was mediated through NLRP3-dependent IL-1β signalling and Cox-2-regulated PGE2 production in macrophages. Consequently, the TB-susceptible A/J mouse model showed remarkable protection, with decreased bacterial loads in both the lungs and spleens of oral colchicine-treated mice, with significantly elevated Cox-2 expression at infection sites. The repurposing of colchicine against Mtb infection in this study highlights its unique function in macrophages upon Mtb infection and its novel potential use in treating TB as host-directed or adjunctive therapy.

The stability of the metabolic turnover of arachidonic acid in human unruptured intracranial aneurysmal walls is sustained

ObjectiveIntracranial aneurysm (IA) is considered a chronic inflammatory condition that affects intracranial arteries. Cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) are considered potential targets of specific medical treatment for IAs. Previous studies have reported the elevated COX2 expression in the IA wall. However, not much has been studied about the upstream regulation of COX2 and PGE2, and the metabolism of arachidonic acid (AA) in human IAs. In this study, we aimed to elucidate the distribution of fatty acids in human IA walls for the first time. MethodsSamples from 6 ruptured and 5 unruptured human IAs were surgically resected after the aneurysmal clipping and analyzed using desorption electrospray ionization imaging mass spectrometry. ResultsAA and AA-containing phospholipids were not detected in the unruptured IA walls. On the contrast, significantly larger amounts of AA and AA-containing phospholipids were detected in the ruptured IA walls compared to unruptured IA walls. ConclusionsThis study showed for the first time that AA was not detected in unruptured human IA walls. Our findings suggest that the stability of the turnover of AA in human unruptured IA walls is sustained. In contrast, this study showed that larger amounts of AA and AA-containing phospholipids were detected in the ruptured IA walls. More cases and further analysis are necessary to interpret our present results.

Abstract LB259: Circulating immune cells of patients with cervical dysplasia and cancer do not show elevated baseline expression of COX2

Abstract Background and objective: COX2, an enzyme that metabolizes arachidonic acid to prostaglandin E2 (PGE2), contributes to the development of cervical dysplasia and cancer by inhibiting the immune response in the tumor micro-environment, as well as promoting cell proliferation, angiogenesis and invasiveness. Little is known about the changes induced by the tumor and its micro-environment on circulating immune cells. We evaluated the relative baseline expression of COX2 by circulating immune cell types and whether it is different in patients with cervical dysplasia and cervical cancer compared to normal controls. Methods: Forty three patients were included: controls (n = 9), low grade dysplasia (CIN I, n = 13), high grade dysplasia (CIN II-III, n = 14), and invasive cervical cancer (n = 7) based on histopathology. Granulocytes, monocytes, and B and T lymphocytes were isolated by Ficoll-Paque density centrifugation (GE Healthcare, (Uppsala, Sweden)) followed by negative selection with MACS Miltenyi Biotec (Auburn, CA) anti-biotinylated microbeads, total RNA isolated (QIAGEN RNeasy (Germantown, MD)) and COX2 mRNA expression evaluated with reverse transcription quantitative PCR (RT-qPCR) normalized to GAPDH levels. Serum and plasma PGE2 levels were quantified by enzyme linked immunoassay (ELISA) (R&D Systems (Mineappolis, MN)). Results: There were marked differences in COX2 expression between the various cell types (p <0.0001, Kruskal-Wallis) with granulocytes producing the highest levels, comparable to GAPDH (1.56 ± 1.46), monocytes an intermediate amount (0.083 ± 0.086), and B and T cells very small amounts (0.033 ± 0.108 and 0.017 ± 0.079 respectively). There was no significant difference in COX2 expression by disease state. B and T cells trended toward significance (p 0.055 and p 0.08 respectively) with the relative expression of COX2 increasing with disease severity. The importance of this is not clear given the very low levels of expression. Plasma PGE2 levels differed significantly by disease state (p 0.0014) with mean levels of controls: 1083 ± 722 pg/mL, low grade: 1208 ± 576 pg/mL, and high grade: 1415 ± 2127 pg/mL. Surprisingly, levels in patients with invasive cancer were low, 464 ± 182 pg/mL. Discussion: This is the first exhaustive study of baseline COX2 expression in circulating immune cell types in any HPV-associated disease to the authors' knowledge. We have previously reported that circulating monocytes from patients with HPV-induced premalignant upper airway lesions show altered immune functions in response to stimuli compared to monocytes from normal controls. Future studies are necessary to determine whether circulating immune cells from patients with cervical dysplasia and cancer show pro-tumorigenic or immune down-regulating activity in response to stimuli. Citation Format: Bethany Bustamante, James A. DeVoti, Chris J. Papayannakos, Mohd Israr, Fung Lam, Bettie Steinberg, Vincent Bonagura, Gary L. Goldberg. Circulating immune cells of patients with cervical dysplasia and cancer do not show elevated baseline expression of COX2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB259.

The pro-inflammatory and anti-inflammatory role of hyaluronic acid in endometriosis

ObjectiveEndometriosis is a bothersome disease affected women worldwide, the mechanism of disease development is still under investigation. Several inflammatory responses after clinical hyaluronic acid (HA) use were reported. Cyclooxygenase (COX)-2 mediated inflammation pathway is involved in the pathogenesis of endometriosis. Thus, we tried to investigate the inflammatory role of hyaluronic acid in endometriosis. Materials and methodsPeritoneal fluid was collected in endometriosis and disease-free patients for the measurement of HA. Endometriotic stromal cells were treated with IL-1β and HA and expression of COX-2 was evaluated. Mice model of endometriosis was established and treated with fluid or gel form of HA. Endometriotic lesion size and weight were recorded and level of COX-2 was evaluated by immunohistochemistry staining. ResultsThe level of HA in the peritoneal fluid had no statistically significant difference between normal, early and advanced stage endometriosis patients. The overexpression of COX-2 protein was detected when treating endometriotic stromal cell with HA in the presence of IL-1β (P < 0.001). The endometriotic lesion size was reduced in mice model when treated with higher concentration gel form HA. It further showed less proportion of strong COX-2 expression compare of gel form HA to fluid form treatment in COX-2 expression score of endometriosis lesion. ConclusionBoth proinflammatory evidence, elevated COX-2 expression, and anti-inflammatory result, reduced endometriosis lesion size and COX-2 expression score, were noted in our study after treating HA in in vivo and in vitro models. We hypothesized it is possible that HA may induce an acute proinflammatory response followed by chronic anti-inflammatory reaction in the formation of endometriosis.

Elevated levels of TNF-\u03b1, IL-1\u03b2 and IL-6 in the synovial tissue of patients with labral tear: a comparative study with hip osteoarthritis

BackgroundLabral tear can be the initiating factor in the onset of hip osteoarthritis (HOA). However, the physiopathology of labral tear is not fully understood. Our aim was to compare synovial tissue inflammatory cytokine levels between patients with labral tear and late-stage HOA.MethodsSynovial tissue from sites showing the greatest inflammation was harvested from 106 hips from 100 subjects during hip surgery. RNA was extracted, and levels of TNFA, IL1B, IL6 and COX2 mRNA were compared among all patients using real-time PCR. Additionally, we examined whether femoroacetabular impingement (FAI) was associated with elevated levels of inflammatory cytokines in patients with labral tear. To analyze the effects of TNF-α on inflammatory mediators in hip synovial tissue, synovial fibroblasts were extracted from hip synovial tissue of patients with labral tear and late-stage HOA (n = 5 each). Mononuclear cells were extracted from synovial tissue, cultured for 7 days, and stimulated with control or 10 ng/mL human recombinant TNF-α for 1 day. mRNA was extracted from stimulated cells and IL1B, IL6, and COX2 levels were determined using real-time PCR.ResultsTNFA, IL1B, and COX2 expression in synovial tissue were significantly higher in patients with labral tear than late-stage HOA (TNFA, p < 0.001; IL1B, p < 0.001; COX2, p = 0.001). There were no differences in expression between patients with labral tear with and without FAI (TNFA, p = 0.546; IL1B, p = 0.559; IL6, p = 0.599; COX2, p = 0.124). Compared to vehicle control, TNF-α stimulation significantly elevated IL1B, IL6, and COX2 expression in synovial fibroblasts collected from patients with labral tear and late-stage HOA (IL1B, p = 0.043 and p = 0.043; IL6, p = 0.043 and 0.043; COX2, p = 0.043 and p = 0.080, respectively).ConclusionsTNFA, IL1B, and COX2 expression were elevated in the synovial tissue of patients with labral tear. Further investigations are needed to reveal the relationship between inflammatory cytokine levels and various aspects of labral tear pathology, including pain and the onset and progression of OA.

Effect of environmental tobacco smoke on COX-2 and SHP-2 expression in a periodontitis rat model.

ObjectivesTo investigate the effects of environmental tobacco smoke (ETS) on the inflammatory process of periodontitis by evaluating bone loss and the expression of cyclooxygenase‐2 (COX‐2) and Src homology phosphotyrosine phosphatase 2 (SHP‐2).Materials and MethodsEighty 6‐month‐old male SD rats were randomized into four groups (10 rats/group/per time point): (a) normal group, (b) ETS group, (c) ligature‐induced periodontitis group, and (d) ligature‐induced periodontitis + ETS group. After treatment with ligature and/or ETS for 8 and 12 weeks, the levels of alveolar bone resorption and the expressions of COX‐2 and SHP‐2 in periodontal tissue were analyzed using histology and immunohistochemistry.ResultsThe ligature‐induced periodontitis group displayed increased bone resorption and elevated expression of COX‐2 and SHP‐2 in periodontal tissues compared to the normal and ETS groups at 8 and 12 weeks. Furthermore, bone resorption and COX‐2 and SHP‐2 levels in the ligature‐induced periodontitis + ETS group were significantly increased compared to those in the normal and ligature‐induced periodontitis groups at both 8 and 12 weeks.ConclusionEnvironmental tobacco smoke increased alveolar bone loss in periodontitis with enhanced expression of COX‐2 and SHP‐2 in periodontal tissues. Further investigation is needed to explore the role of COX‐2 and SHP‐2 in ETS‐associated periodontitis.

Expression of Cyclooxygenase-2 in Human Epithelial Skin Lesions: A Systematic Review of Immunohistochemical Studies.

Permanent, elevated expression of cyclooxygenase-2 (COX-2) in keratinocytes of epidermis can stimulate its hyperplasia and constitute a factor promoting cancer development, as demonstrated in animal models. Intratumoral level and localization of COX-2 in epithelial lesions of human skin was examined immunohistochemically in 26 studies. In squamous cell carcinomas (SCCs), strong staining was observed with great compatibility. High COX-2 detectability throughout the entire tumor mass could be helpful in the finding of SCC cells. However, in basal cell carcinomas, and precancerous lesions, frequency and detection level of this protein, as well as the type and/or localization of stained cells within the tumor, varied among different research groups. The discrepancies may be due to the heterogeneity of each of these 2 groups of lesions. However, differences in COX-2 staining in normal skin indicate also possible methodological reasons. In general, COX-2 levels were significantly decreased in basal cell carcinomas compared with SCCs, which could be used in the differential diagnosis of these cancers. Reduced, although heterogenous, COX-2 expression in precancerous lesions may suggest its association with SCC development. These observations are consistent with data on the efficacy of preventive and therapeutic effects of nonsteroidal anti-inflammatory drugs that are COX-2 inhibitors.

Cadmium exposure activates Akt/ERK Signaling and pro-inflammatory COX-2 expression in human gallbladder epithelial cells via a ROS dependent mechanism

Gallbladder cancer (GBC) is the commonest biliary tract cancer with an ill-defined etiology. We examined the role of Cd+2 exposures in a primary human gallbladder (GB) cell line model in this study. Cd+2 exposures induced decreased cell viability, reactive oxygen species (ROS) generation, altered Akt/ERK signaling pathway activation, PGE2 and COX-2 expression in a human primary gallbladder epithelial cell model. Pharmacological inhibitors were used to determine the key drivers of elevated COX-2 expression due to Cd+2 exposure. Our results show Cd+2 causes a dose-dependent reduction in GB cell viability (EC50 value – 18.6 μM). Dose-dependent activation of phospho-Akt and phospho-ERK signaling pathways via increased phosphoprotein expression was observed due to Cd+2. Signaling activation of Akt and ERK was prevented by 5 mM N-Acetyl Cysteine (NAC), establishing the role of ROS as a key driver in the activation process. Importantly, we observed Cd+2 also caused a dose dependent change in the COX-2 and PGE2 expression levels. PI3K-Akt and NF-kB signaling pathways play a key role in Cd+2 exposure induced COX-2 activation in the gallbladder epithelial cells. In conclusion, our study measures the toxicological effects of Cd+2 exposures on human GB epithelial cells for the first time and establishes the role of Cd+2 as a possible driver of the Akt/ERK pathway overactivity and chronic inflammation in gallbladder carcinogenesis.

Metabolic syndrome exacerbates amyloid pathology in a comorbid Alzheimer's mouse model

Alzheimer's disease (AD) often coexists with other aging-associated diseases including obesity, diabetes, hypertension, and cardiovascular diseases. The early stage of these comorbidities is known as metabolic syndrome (MetS) which is highly prevalent in mid-life. An important cause of MetS is the deficiency of SIRT3, a mitochondrial deacetylase which enhances the functions of critical mitochondrial proteins, including metabolic enzymes, by deacetylation. Deletion of Sirt3 gene has been reported to result in the acceleration of MetS. In a recently published study, we demonstrated in the brain of Sirt3−/− mice, downregulation of metabolic enzymes, insulin resistance and elevation of inflammatory markers including microglial proliferation. These findings suggested a novel pathway that could link SIRT3 deficiency to neuroinflammation, an important cause of Alzheimer's pathogenesis. Therefore, we hypothesized that MetS and amyloid pathology may interact through converging pathways of insulin resistance and neuroinflammation in comorbid AD. To investigate these interactions, we crossed Sirt3−/− mice with APP/PS1 mice and successfully generated APP/PS1/Sirt3−/− mice with amyloid pathology and MetS. In these comorbid AD mice, we observed exacerbation of insulin resistance, glucose intolerance, amyloid plaque deposition, markers of neuroinflammation, including elevated expression of IL-1β, TNF-α and Cox-2 at 8 months of age. There was also increased microglial proliferation and activation. Our observations suggest a novel mechanism by which MetS may interact with amyloid pathology during the cellular phase of AD. Therapeutic targeting of SIRT3 in AD with comorbidities may produce beneficial effects.

Exposure to growth hormone is associated with hepatic up-regulation of cPLA2α and COX

Continuously elevated levels of growth hormone (GH) during life in mice are associated with hepatomegaly due to hepatocytes hypertrophy and hyperplasia, chronic liver inflammation, elevated levels of arachidonic acid (AA) at young ages and liver tumors development at old ages. In this work, the hepatic expression of enzymes involved in AA metabolism, cPLA2α, COX1 and COX2 enzymes, was evaluated in young and old GH-transgenic mice. Mice overexpressing GH exhibited higher hepatic expression of cPLA2α, COX1 and COX2 in comparison to controls at young and old ages and in both sexes. In old mice, when tumoral and non-tumoral tissue were compared, elevated expression of COX2 was observed in tumors. In contrast, exposure to continuous lower levels of hormone for a short period affected COX1 expression only in males. Considering the role of inflammation during liver tumorigenesis, these findings support a role of alterations in AA metabolism in GH-driven liver tumorigenesis.

Mutant GTF2I induces cell transformation and metabolic alterations in thymic epithelial cells.

The pathogenesis of thymic epithelial tumors (TETs) is poorly understood. Recently we reported the frequent occurrence of a missense mutation in the GTF2I gene in TETs and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of normal thymic epithelial cells and upregulated several oncogenic genes. Gtf2i L424H knockin cells exhibited cell transformation, aneuploidy, and increase tumor growth and survival under glucose deprivation or DNA damage. Gtf2i mutation also increased the expression of several glycolytic enzymes, cyclooxygenase-2, and caused modifications of lipid metabolism. Elevated cyclooxygenase-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver that is responsible for transformation of thymic epithelial cells.

Does tumour necrosis factor alpha-induced cyclooxygenase-2 expression lead to spontaneous abortion in Chlamydia trachomatis-infected women

Cytokines might be involved in spontaneous abortion by triggering inflammatory mediators (Cyclooxygenases (Cox)) leading to spontaneous abortion in Chlamydia trachomatis (Ct)-infected women. Study aimed to quantitate the expression of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-8) and Cox-2 in endometrial curettage tissue (ECT) of Spontaneous Aborters (SA). SA (n = 135) and 120 age-matched controls were enrolled from SJH, New Delhi, India. PCR was performed for detection of Ct MOMP gene (537 bp) in ECT. mRNA expression of pro-inflammatory cytokines and Cox-2 was assessed by real-time qPCR. Data was statistically evaluated. 14.8% SA were diagnosed as Ct-positive. Elevated expression of TNF-α, IFN-γ, IL-8 and Cox-2 was observed in Ct-infected SA. Ct-positive recurrent aborters showed significantly higher cytokine expression. Significant positive correlation was found between expression of Cox-2 and TNF-α in infected SA. Data suggested an increased expression of Th-1 cytokines, particularly TNF-α that induced Cox-2 expression in ECT, leading to spontaneous abortion in Ct-infected pregnant women.