Статті в журналах: "PTGS2 / Cox-2 expression"

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Ayiomamitis, Georgios D., George Notas, Thivi Vasilakaki, Aikaterini Tsavari, Styliani Vederaki, Theodosis Theodosopoulos, Elias Kouroumalis, and Apostolos Zaravinos. "Understanding the Interplay between COX-2 and hTERT in Colorectal Cancer Using a Multi-Omics Analysis." Cancers 11, no. 10 (October 11, 2019): 1536. http://dx.doi.org/10.3390/cancers11101536.

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Background: Cyclooxygenase 2 (COX-2) is involved in the initial steps of colorectal cancer (CRC) formation, playing a key role in the catalysis of arachidonic acid to prostaglandin E2 (PGE2). The human telomerase reverse transcriptase (hTERT or TERT) also plays an important role in colorectal cancer growth, conferring sustained cell proliferation and survival. Although hTERT induces COX-2 expression in gastric and cervical cancer, their interaction has not been investigated in the context of CRC. Methods: COX-2, PGE2 levels, and telomerase activity were evaluated by immunohistochemistry, ELISA, and TRAP assay in 49 colorectal cancer samples. PTGS1, PTGS2, PTGES3, TERT mRNA, and protein levels were investigated using RNA-seq and antibody-based protein profiling data from the TCGA and HPA projects. A multi-omics comparison was performed between PTGS2 and TERT, using RNAseq, DNA methylation, copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and insertions/deletions (Indels) data. Results: COX-2 expression was positive in 40/49 CRCs, bearing cytoplasmic and heterogeneous staining, from moderate to high intensity. COX-2 staining was mainly detected in the stroma of the tumor cells and the adjacent normal tissues. PGE2 expression was lower in CRC compared to the adjacent normal tissue, and inversely correlated to telomerase activity in right colon cancers. COX-1 and COX-2 were anticorrelated with TERT. Isoform structural analysis revealed the most prevalent transcripts driving the differential expression of PTGS1, PTGS2, PTGES3, and TERT in CRC. COX-2 expression was significantly higher among B-Raf proto-oncogene, serine/threonine kinase, mutant (BRAFmut) tumors. Kirsten ras oncogene (KRAS) mutations did not affect COX-2 or TERT expression. The promoter regions of COX-2 and TERT were reversely methylated. Conclusions: Our data support that COX-2 is involved in the early stages of colorectal cancer development, initially affecting the tumor’s stromal microenvironment, and, subsequently, the epithelial cells. They also highlight an inverse correlation between COX-2 expression and telomerase activity in CRC, as well as differentially methylated patterns within the promoter regions of COX-2 and TERT.

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Zhang, S., S. P. Barros, M. D. Niculescu, A. J. Moretti, J. S. Preisser, and S. Offenbacher. "Alteration of PTGS2 Promoter Methylation in Chronic Periodontitis." Journal of Dental Research 89, no. 2 (December 30, 2009): 133–37. http://dx.doi.org/10.1177/0022034509356512.

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Levels of prostaglandin E2 and the prostaglandin-endoperoxide synthase-2 ( PTGS2, or COX-2) increase in actively progressing periodontal lesions, but decrease in chronic disease. We hypothesized that chronic inflammation is associated with altered DNA methylation levels within the PTGS2 promoter, with effects on COX-2 mRNA expression. PTGS2 promoter methylation levels from periodontally inflamed gingival biopsies showed a 5.06-fold increase as compared with non-inflamed samples (p = 0.03), and the odds of methylation in a CpG site in the inflamed gingival group is 4.46 times higher than in the same site in the non-inflamed group (p = 0.016). The level of methylation at −458 bp was inversely associated with transcriptional levels of PTGS2 (RT-PCR) (p = 0.01). Analysis of the data suggests that, in chronically inflamed tissues, there is a hypermethylation pattern of the PTGS2 promoter in association with a lower level of PTGS2 transcription, consistent with a dampening of COX-2 expression in chronic periodontitis. These findings suggest that the chronic persistence of the biofilm and inflammation may be associated with epigenetic changes in local tissues at the biofilm-gingival interface.

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Seta, Francesca, Andrew D. Chung, Patricia V. Turner, Jeffrey D. Mewburn, Ying Yu, and Colin D. Funk. "Renal and cardiovascular characterization of COX-2 knockdown mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 296, no. 6 (June 2009): R1751—R1760. http://dx.doi.org/10.1152/ajpregu.90985.2008.

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Selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) increase the incidence of cardiovascular and cerebrovascular events. Complete disruption of the murine gene encoding COX-2 ( Ptgs2) leads to renal developmental problems, as well as female reproductive anomalies and patent ductus arteriosus of variable penetrance in newborns, thus rendering this genetic approach difficult to compare with coxib administration. Here, we created hypomorphic Ptgs2 (COX-2Neo/Neo) mice in which COX-2 expression is suppressed to an extent similar to that achieved with coxibs, but not eliminated, in an attempt to circumvent these difficulties. In LPS-challenged macrophages and cytokine-stimulated endothelial cells obtained from COX-2Neo/Neo mice, COX-2 expression was reduced 70–90%, and these mice developed a mild renal phenotype compared with COX-2 mice possessing an active site mutation (COX-2Y385F/Y385F), with minimal signs of renal dysfunction as measured by FITC-inulin clearance and blood urea nitrogen. These COX-2 knockdown mice displayed an increased propensity for thrombogenesis compared with their wild-type (COX-2+/+) littermates observed by intravital microscopy in cremaster muscle arterioles upon ferric chloride challenge. Measurement of urinary prostanoid metabolites indicated that COX-2Neo/Neo mice produced 50% less prostacyclin but similar levels of PGE2 and thromboxane compared with COX-2+/+ mice in the absence of any blood pressure and ex vivo platelet aggregation abnormalities. COX-2Neo/Neo mice, therefore, provide a genetic surrogate of coxib therapy with disrupted prostacyclin biosynthesis that predisposes to induced arterial thrombosis.

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Hamy, Anne-Sophie, Sandrine Tury, Xiaofei Wang, Junheng Gao, Jean-Yves Pierga, Sylvie Giacchetti, Etienne Brain, et al. "Celecoxib With Neoadjuvant Chemotherapy for Breast Cancer Might Worsen Outcomes Differentially by COX-2 Expression and ER Status: Exploratory Analysis of the REMAGUS02 Trial." Journal of Clinical Oncology 37, no. 8 (March 10, 2019): 624–35. http://dx.doi.org/10.1200/jco.18.00636.

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PURPOSE The overexpression of cyclooxygenase 2 (COX-2) gene, also known as prostaglandin-endoperoxide synthase 2 ( PTGS2), occurs in breast cancer, but whether it affects response to anticox drugs remains unclear. We investigated the relationships between PTGS2 expression, celecoxib use during neoadjuvant chemotherapy (NAC), and both event-free survival (EFS) and overall survival (OS). MATERIALS AND METHODS We analyzed a cohort of 156 patients with human epidermal growth factor receptor 2 –negative breast cancer from the REMAGUS02 (ISRCTN Registry No. 10059974) trial with pretreatment PTGS2 expression data. Patients were treated by sequential NAC (epirubicin plus cyclophosphamide followed by docetaxel with or without celecoxib). Experimental validation was performed on breast cancer cell lines. The Cancer and Leukemia Group B (CALGB) 30801 ( ClinicalTrials.gov identifier: NCT01041781) trial that tested chemotherapy with or without celecoxib in patients with lung cancer served as an independent validation cohort. RESULTS After 94.5 months of follow-up, EFS was significantly lower in the celecoxib group (hazard ratio [HR], 1.7; 95% CI, 1 to 2.88; P = .046). A significant interaction between PTGS2 expression and celecoxib use was detected ( Pinteraction = .01). In the PTGS2-low group (n = 100), EFS was lower in the celecoxib arm (HR, 3.01; 95% CI, 1.45 to 6.24; P = .002) than in the standard treatment arm. Celecoxib use was an independent predictor of poor EFS, distant relapse–free survival, and OS. Celecoxib in addition to docetaxel enhanced cell viability in PTGS2-low cell lines but not in PTGS2-high cell lines. In CALGB 30801, a trend toward poorer progression-free survival was observed in the patients with low urinary metabolite of prostaglandin E2 who received celecoxib (HR = 1.57; 95% CI, 0.87 to 2.84; P = .13). CONCLUSION Celecoxib use during chemotherapy adversely affected survival in patients with breast cancer, and the effect was more marked in PTGS2-low and/or estrogen receptor–negative tumors. COX-2 inhibitors should preferably be avoided during docetaxel use in patients with breast cancer who are undergoing NAC.

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Zając-Grabiec, Anna, Karoline Bartusek, Katarzyna Sroczyńska, Tadeusz Librowski та Joanna Gdula-Argasińska. "Effect of Eicosapentaenoic Acid Supplementation on Murine Preadipocytes 3T3-L1 Cells Activated with Lipopolysaccharide and/or Tumor Necrosis Factor-α". Life 11, № 9 (16 вересня 2021): 977. http://dx.doi.org/10.3390/life11090977.

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The beneficial effect of n-3 fatty acids can be related to anti-inflammatory properties. The aim of the study was to analyzed the effect of eicosapentaenoic acid (EPA) on 3T3-L1 cells (murine embryonic fibroblasts‒preadipocytes) activated with inflammatory factors (IF). Cells were incubated with 50 µmol of EPA for 48 h, and then activated with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α). The level of cycloxygenase-2 (Prostaglandin-Endoperoxide Synthase 2, PTGS2, COX-2), cytosolic prostaglandin synthase E2 (cPGES), fatty acid binding protein 4 (FABP4), toll-like receptor 4 (TLR4), glucose receptor type 4 (GLUT-4), and cannabinoid receptor 2 (CB2) was determined using Western blot analysis. The phospholipase A2 (Pla2g4a), and prostaglandin-Endoperoxide Synthase 2 (Ptgs2) gene expression was analyzed by real-time qPCR. After EPA and IF activation, a significant decrease in the COX-2, cPGES, and TRL4 protein levels was observed. Incubation of cells with EPA and IF resulted in a decrease in Ptgs2 and an increase in the Pla2g4a gene. A significant increase in the CB2 protein was observed in adipocytes co-treated with EPA and IF. The results indicated an anti-inflammatory properties of EPA. Interestingly, the activation of the GLUT4 receptor by EPA suggests an unique role of this FA in the regulation of the adipocyte metabolism and prevention of insulin resistance.

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Zahner, Gunther, Melanie Schaper, Ulf Panzer, Malte Kluger, Rolf A. K. Stahl, Friedrich Thaiss, and André Schneider. "Prostaglandin EP2 and EP4 receptors modulate expression of the chemokine CCL2 (MCP-1) in response to LPS-induced renal glomerular inflammation." Biochemical Journal 422, no. 3 (August 27, 2009): 563–70. http://dx.doi.org/10.1042/bj20090420.

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The pro-inflammatory chemokine CCL2 [chemokine (Cys-Cys motif) ligand 2; also known as MCP-1 (monocyte chemotactic protein-1)] is up-regulated in the glomerular compartment during the early phase of LPS (lipopolysaccharide)-induced nephritis. This up-regulation also occurs in cultured MCs (mesangial cells) and is more pronounced in MCs lacking the PGE2 (prostaglandin E2) receptor EP2 or in MCs treated with a prostaglandin EP4 receptor antagonist. To examine a possible feedback mechanism of EP receptor stimulation on CCL2 expression, we used an in vitro model of MCs with down-regulated EP receptor expression. Selectively overexpressing the various EP receptors in these cells then allows the effects on the LPS-induced CCL2 expression to be examined. Cells were stimulated with LPS and CCL2 gene expression was examined and compared with LPS-stimulated, mock-transfected PTGS2 [prostaglandin-endoperoxide synthase 2, also known as COX-2 (cyclo-oxygenase-2)]-positive cells. Overexpression of EP1, as well as EP3, had no effect on LPS-induced Ccl2 mRNA expression. In contrast, overexpression of EP2, as well as EP4, significantly decreased LPS-induced CCL2 expression. These results support the hypothesis that PTGS2-derived prostaglandins, when strongly induced, counter-balance inflammatory processes through the EP2 and EP4 receptors in MCs.

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Hermawan, Adam, Herwandhani Putri, Naufa Hanif, and Muthi Ikawati. "Integrative Bioinformatics Study of Tangeretin Potential Targets for Preventing Metastatic Breast Cancer." Evidence-Based Complementary and Alternative Medicine 2021 (July 13, 2021): 1–15. http://dx.doi.org/10.1155/2021/2234554.

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Agents that target metastasis are important to improve treatment efficacy in patients with breast cancer. Tangeretin, a citrus flavonoid, exhibits antimetastatic effects on breast cancer cells, but its molecular mechanism remains unclear. Tangeretin targets were retrieved from PubChem, whereas metastatic breast cancer regulatory genes were downloaded from PubMed. In total, 58 genes were identified as potential therapeutic target genes of tangeretin (PTs). GO and KEGG pathway enrichment analyses of PTs were performed using WebGestalt (WEB-based Gene SeT AnaLysis Toolkit). The PPI network was analyzed using STRING-DB v11.0 and visualized by Cytoscape software. Hub genes were selected on the basis of the highest degree score as calculated by the CytoHubba plugin. Genetic alterations of the PTs were analyzed using cBioPortal. The prognostic values of the PTs were evaluated with the Kaplan–Meier plot. The expression of PTs across breast cancer samples was confirmed using GEPIA. The reliability of the PTs in metastatic breast cancer cells was validated using ONCOMINE. Molecular docking was performed to foresee the binding sites of tangeretin with PIK3Cα, MMP9, PTGS2, COX-2, and IKK. GO analysis showed that PTs participate in the biological process of stimulus response, are the cellular components of the nucleus and the membrane, and play molecular roles in enzyme regulation. KEGG pathway enrichment analysis revealed that PTs regulate the PI3K/Akt pathway. Genetic alterations for each target gene were MTOR (3%), NOTCH1 (4%), TP53 (42%), MMP9 (4%), NFKB1 (3%), PIK3CA (32%), PTGS2 (15%), and RELA (5%). The Kaplan–Meier plot showed that patients with low mRNA expression levels of MTOR, TP53, MMP9, NFKB1, PTGS2, and RELA and high expression of PIK3CA had a significantly better prognosis than their counterparts. Further validation of gene expression by using GEPIA revealed that the mRNA expression of MMP9 was significantly higher in breast cancer tissues than in normal tissues, whereas the mRNA expression of PTGS2 showed the opposite. Analysis with ONCOMINE demonstrated that the mRNA expression levels of MMP9 and NFKB1 were significantly higher in metastatic breast cancer cells than in normal tissues. The results of molecular docking analyses revealed the advantage of tangeretin as an inhibitor of PIK3CA, MMP9, PTGS2, and IKK. Tangeretin inhibits metastasis in breast cancer cells by targeting TP53, PTGS2, MMP9, and PIK3CA and regulating the PI3K/Akt signaling pathway. Further investigation is needed to validate the results of this study.

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Hickman, Oliver J., Richard A. Smith, Prokar Dasgupta, Sudha Narayana Rao, Soumya Nayak, Shubha Sreenivasan, Annapurna Vyakarnam, and Christine Galustian. "Expression of two WFDC1/ps20 isoforms in prostate stromal cells induces paracrine apoptosis through regulation of PTGS2/COX-2." British Journal of Cancer 114, no. 11 (April 26, 2016): 1235–42. http://dx.doi.org/10.1038/bjc.2016.91.

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Nelson, Tracy, Heino Velazquez, Nancy Troiano, and Jackie A. Fretz. "Early B Cell Factor 1 (EBF1) Regulates Glomerular Development by Controlling Mesangial Maturation and Consequently COX-2 Expression." Journal of the American Society of Nephrology 30, no. 9 (August 12, 2019): 1559–72. http://dx.doi.org/10.1681/asn.2018070699.

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BackgroundWe recently showed the transcription factor Early B cell factor 1 (EBF1) is essential for the last stages of metanephric development, and that mice globally deficient in EBF1 display impaired maturation of peripheral glomeruli. EBF1 is present within multiple glomerular cell types, including the glomerular mesangium and podocytes.MethodsTo identify which cell type is driving the glomerular developmental defects in the global EBF1 knockout mice, we deleted EBF1 from the mesangium/pericytes (Foxd1-cre) or podocytes (Podocin-cre) in mice.ResultsDeletion of EBF1 from Foxd1 lineage cells resulted in hypoplastic kidneys, poorly differentiated peripheral glomeruli, and decreased proximal tubular mass in the outer cortex. Renal insufficiency was apparent at P21 when proteinuria presents, fibrosis of both the glomeruli and interstitium rapidly progresses, microthrombi appear, and hematuria develops. Approximately half of the Foxd1+, Ebf1fl/fl mice die before they are 3 months old. Mice with podocyte-targeted deletion of EBF1 exhibited no developmental abnormalities. Mice with Ebf1 deficiency in Foxd1 lineage cells shared characteristics with Ptgs2/COX-2–insufficient models, and mechanistic investigation revealed impaired calcineurin/NFATc1 activation and decreased COX-2 expression. Deletion of COX-2 from the interstitial/mesangial lineage displayed a less severe phenotype than EBF1 deficiency in mice. Overexpressing COX-2 in the EBF1-deficient mice, however, partially restored glomerular development.ConclusionsThe results suggest that EBF1 regulates metanephric development at the last stages of glomerular maturation through its actions in the stromal progenitor (Foxd1+) lineage where it mediates proper regulation of calcineurin/NFAT signaling and COX-2 expression.

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Nwakiban, Achille Parfait Atchan, Marco Fumagalli, Stefano Piazza, Andrea Magnavacca, Giulia Martinelli, Giangiacomo Beretta, Paolo Magni, et al. "Dietary Cameroonian Plants Exhibit Anti-Inflammatory Activity in Human Gastric Epithelial Cells." Nutrients 12, no. 12 (December 10, 2020): 3787. http://dx.doi.org/10.3390/nu12123787.

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In Cameroon, local plants are traditionally used as remedies for a variety of ailments. In this regard, several papers report health benefits of Cameroonian spices, which include antioxidant and anti-microbial properties, whereas gastric anti-inflammatory activities have never been previously considered. The present study investigates the antioxidant and anti-inflammatory activities of hydro-alcoholic extracts of eleven Cameroonian spices in gastric epithelial cells (AGS and GES-1 cells). The extracts showed antioxidant properties in a cell-free system and reduced H2O2-induced ROS generation in gastric epithelial cells. After preliminary screening on TNFα-induced NF-κB driven transcription, six extracts from Xylopia parviflora, Xylopia aethiopica, Tetrapleura tetraptera, Dichrostachys glomerata, Aframomum melegueta, and Aframomum citratum were selected for further studies focusing on the anti-inflammatory activity. The extracts reduced the expression of some NF-κB-dependent pro-inflammatory mediators strictly involved in the gastric inflammatory process, such as IL-8, IL-6, and enzymes such as PTGS2 (COX-2), without affecting PTGS1 (COX-1). In conclusion, the selected extracts decreased pro-inflammatory markers by inhibiting the NF-κB signaling in gastric cells, justifying, in part, the traditional use of these spices. Other molecular mechanisms cannot be excluded, and further studies are needed to better clarify their biological activities at the gastric level.

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Jamshed, Laiba, Genevieve A. Perono, Shanza Jamshed, Kim Ann Cheung, Philippe J. Thomas, and Alison Holloway. "The Effects of Naphthenic Acids on Tryptophan Metabolism and Peripheral Serotonin Signalling." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A493. http://dx.doi.org/10.1210/jendso/bvab048.1008.

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Abstract Introduction: Serotonin produced in the periphery has been shown to affect glucose and lipid homeostasis. The availability of the amino acid tryptophan, the precursor of serotonin, affects serotonin availability. In addition, the metabolism of tryptophan via the kynurenine pathway produces physiologically active metabolites which have been shown to be altered under conditions of increased adiposity and dysglycemia. There is now evidence demonstrating some environmental xenobiotics, known to affect glucose and lipid homeostasis, can also alter serotonin production and key components of the kynurenine pathway. Recent evidence suggests that exposure to compounds present in petroleum and wastewaters from oil and gas extraction sites can impact endocrine signaling and result in aberrant lipid accumulation and altered glycemic control. However, whether any of these changes can be causally ascribed to altered serotonin synthesis/signaling or tryptophan metabolism remains unknown. The goal of this study was to determine the effects of exposure to naphthenic acid (NA), a key toxicant found in wastewater from bitumen (thick crude oil present in oil sands deposits) extraction on the enzymes involved in tryptophan metabolism and serotonin production. Methods: McA-RH7777 rat hepatoma cells, were exposed to a technical NA mixture for 48 hours at concentrations within the reported range of NA found in wastewaters from oil extraction. We assessed mRNA expression for key rate-limiting enzymes involved in tryptophan metabolism that lead to either serotonin [Tph1] and/or kynurenine [Ido2 and Tdo2] production, as well as downstream enzymes in the kynurenine pathway [Afmid, Kyat1, Aadat, Kyat3, Kmo, Haao, Acmsd, Qprt]. We also examined the effects of NA on prostaglandin synthesis [Ptgs1, Ptgs2, Ptges] and signalling [Ptger2, Ptger4] as prostaglandins have been shown to be induced by serotonin and are linked to hepatic fat accumulation. Results: NA treatment significantly increased Tph1 and Ido2 expression; this occurred in association with a significant increase in the expression of the inducible prostaglandin synthase Ptgs2 (COX-2), prostaglandin E synthase Ptges, and prostaglandin receptors Ptger2 and Ptger4. Acmsd was the only downstream enzyme in the kynurenine pathway that was significantly altered by NA treatment. Conclusion: These results provide proof-of-concept that compounds associated with oil sands extraction have the potential to perturb key components of serotonin synthesis (Tph1) and tryptophan metabolism (Ido2, Acmsd). Furthermore, we found that the increase in Tph1 expression paralleled expression of Ptgs2. As increased prostaglandin production has been reported in association with nonalcoholic steatohepatitis, these data provide a potential mechanism by which exposure to NA and other petroleum-based compounds may increase the risk of metabolic disease.

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Ren, Xin-Lu, Peiyu Han, and Yiteng Meng. "Aflatoxin B1-Induced COX-2 Expression Promotes Mitophagy and Contributes to Lipid Accumulation in Hepatocytes In Vitro and In Vivo." International Journal of Toxicology 39, no. 6 (July 20, 2020): 594–604. http://dx.doi.org/10.1177/1091581820939081.

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Aim: Aflatoxin B1 (AFB1) is hepatotoxic. Numerous studies have shown that mitochondria play an essential role in AFB1-induced steatosis. However, the mechanisms of AFB1-induced steatosis via mitochondria are still obscure. The present study aimed to confirm that AFB1 causes hepatocyte steatosis regulated by cyclooxygenase-2 (COX-2)-induced mitophagy, both in vivo and in vitro. Methods: Adult male C57BL/6 mice were randomly divided into control group with the same volume of peanut oil and exposure group administered 0.6 mg/kg AFB1 once in 2 days for 1 month. HepG2 and Cas9-PTGS2 cells were treated with 5 μM AFB1 for 48 hours. Then, various indicators were evaluated. Results: Aflatoxin B1 causes liver injury and steatosis with increased alanine aminotransferase, aspartate aminotransferase, total cholesterol, total triglyceride levels in vivo and in vitro, and elevated lipid droplets in HepG2 cells. Cyclooxygenase-2 and mitophagy pathway were induced by AFB1 in both liver tissues and cultured HepG2 cells. Further studies have shown that knockout of COX-2 with the CRISPR/Cas9 system inhibited the AFB1-induced mitophagy and steatosis in HepG2 cells. Also, the inhibition of PTEN-induced putative kinase with RNA interference attenuated the AFB1-induced steatosis. Conclusions: The results of the current study suggested that AFB1 increases the expression of COX-2, which, in turn, elevates the level of mitophagy, thereby disrupting the normal mitochondrial lipid metabolism and causing steatosis. Thus, this study implies that COX-2 may be a potential target for therapy against AFB1-induced steatosis.

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Ansari, Mohammad Y., Nashrah Ahmad, Sriharsha Voleti, Saima J. Wase, Kimberly Novak, and Tariq M. Haqqi. "Mitochondrial dysfunction triggers a catabolic response in chondrocytes via ROS-mediated activation of the JNK/AP1 pathway." Journal of Cell Science 133, no. 22 (October 23, 2020): jcs247353. http://dx.doi.org/10.1242/jcs.247353.

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ABSTRACTMitochondrial function is impaired in osteoarthritis (OA) but its impact on cartilage catabolism is not fully understood. Here, we investigated the molecular mechanism of mitochondrial dysfunction-induced activation of the catabolic response in chondrocytes. Using cartilage slices from normal and OA cartilage, we showed that mitochondrial membrane potential was lower in OA cartilage, and that this was associated with increased production of mitochondrial superoxide and catabolic genes [interleukin 6 (IL-6), COX-2 (also known as PTGS2), MMP-3, -9, -13 and ADAMTS5]. Pharmacological induction of mitochondrial dysfunction in chondrocytes and cartilage explants using carbonyl cyanide 3-chlorophenylhydrazone increased mitochondrial superoxide production and the expression of IL-6, COX-2, MMP-3, -9, -13 and ADAMTS5, and cartilage matrix degradation. Mitochondrial dysfunction-induced expression of catabolic genes was dependent on the JNK (herein referring to the JNK family)/activator protein 1 (AP1) pathway but not the NFκB pathway. Scavenging of mitochondrial superoxide with MitoTEMPO, or pharmacological inhibition of JNK or cFos and cJun, blocked the mitochondrial dysfunction-induced expression of the catabolic genes in chondrocytes. We demonstrate here that mitochondrial dysfunction contributes to OA pathogenesis via JNK/AP1-mediated expression of catabolic genes. Our data shows that AP1 could be used as a therapeutic target for OA management.This article has an associated First Person interview with the first author of the paper.

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Hamada, Tsuyoshi, Yin Cao, Zhi Rong Qian, Yohei Masugi, Jonathan A. Nowak, Juhong Yang, Mingyang Song, et al. "Aspirin Use and Colorectal Cancer Survival According to Tumor CD274 (Programmed Cell Death 1 Ligand 1) Expression Status." Journal of Clinical Oncology 35, no. 16 (June 1, 2017): 1836–44. http://dx.doi.org/10.1200/jco.2016.70.7547.

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Purpose Blockade of the programmed cell death 1 (PDCD1, PD-1) immune checkpoint pathway can improve clinical outcomes in various malignancies. Evidence suggests that aspirin (a widely used nonsteroidal anti-inflammatory drug) not only prolongs colorectal cancer survival, but can also activate T cell–mediated antitumor immunity and synergize with immunotherapy through inhibition of prostaglandin E2 production. We hypothesized that the survival benefit associated with aspirin might be stronger in colorectal carcinoma with a lower CD274 (PDCD1 ligand 1, PD-L1) expression level that resulted in lower signaling of the immune checkpoint pathway. Patients and Methods Using data from 617 patients with rectal and colon cancer in the Nurses’ Health Study and the Health Professionals Follow-Up Study, we examined the association of postdiagnosis aspirin use with patient survival in strata of tumor CD274 expression status measured by immunohistochemistry. We used multivariable Cox proportional hazards regression models to control for potential confounders, including disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, cyclooxygenase-2 (PTGS2), and CDX2 expression, and KRAS, BRAF, and PIK3CA mutations. Results The association of postdiagnosis aspirin use with colorectal cancer–specific survival differed by CD274 expression status ( Pinteraction < .001); compared with aspirin nonusers; multivariable-adjusted hazard ratios for regular aspirin users were 0.16 (95% CI, 0.06 to 0.41) in patients with low CD274 and 1.01 (95% CI, 0.61 to 1.67) in patients with high CD274. This differential association seemed consistent in patients with microsatellite-stable or PIK3CA wild-type disease and in strata of PTGS2 expression, CDX2 expression, tumor-infiltrating lymphocytes, or prediagnosis aspirin use status. Conclusion The association of aspirin use with colorectal cancer survival is stronger in patients with CD274-low tumors than CD274-high tumors. Our findings suggest a differential antitumor effect of aspirin according to immune checkpoint status.

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Elmes, M. J., D. S.-Y. Tan, Z. Cheng, D. C. Wathes, and S. McMullen. "The effects of a high-fat, high-cholesterol diet on markers of uterine contractility during parturition in the rat." REPRODUCTION 141, no. 2 (February 2011): 283–90. http://dx.doi.org/10.1530/rep-10-0378.

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Increasing levels of obesity within women of reproductive age is a major concern in the UK. Approximately, 13% of women aged <30 and 22% of 31- to 40-year-old women are obese. Obesity increases complications during pregnancy and the risk of caesarean section due to prolonged labour and poor uterine activity. The aim was to investigate whether a high-fat, high-cholesterol (HFHC) diet decreases markers of uterine contractility during parturition in the rat. Female Wistar rats were fed control (CON,n=10) or HFHC (n=10) diets for 6 weeks. Animals were mated and, once pregnant, maintained on their diet throughout gestation. On gestational day 19, rats were monitored continuously and killed at the onset of parturition. Body and fat depot weights were recorded. Myometrial tissue was analysed for cholesterol (CHOL), triglycerides (TAG), and expression of the contractile associated proteins gap junction protein alpha 1 (GJA1; also known as connexin-43, CX-43), prostaglandin-endoperoxide synthase 2 (PTGS2; also known as cyclo-oxygenase-2, COX-2) and caveolin-1 (CAV1) and maternal plasma for prostaglandin F2α(PGF2α) and progesterone. HFHC fed rats gained greater weight than CON (P<0.003) with significant increases in peri-renal fat (P<0.01). The HFHC diet increased plasma CHOL, TAG and progesterone, but decreased PGF2αversus CON (P<0.01,P<0.01,P=0.05 andP<0.02 respectively). Total CHOL and TAG levels of uterine tissue were similar. However, HFHC fed rats showed significant increases in PTGS2 (P<0.037), but decreases in GJA1 and CAV1 (P=0.059). In conclusion, a HFHC diet significantly increases body weight and alters lipid profiles that correlate with decreases in key markers of uterine contractility. Further work is required to ascertain whether these changes have adverse effects on uterine activity.

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Allen, David Z., Jihad Aljabban, Dustin Silverman, Sean McDermott, Ross A. Wanner, Michael Rohr, Dexter Hadley, and Maryam Panahiazar. "Meta-Analysis illustrates possible role of lipopolysaccharide (LPS)-induced tissue injury in nasopharyngeal carcinoma (NPC) pathogenesis." PLOS ONE 16, no. 10 (October 14, 2021): e0258187. http://dx.doi.org/10.1371/journal.pone.0258187.

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Background Nasopharyngeal carcinoma (NPC) is a cancer of epithelial origin with a high incidence in certain populations. While NPC has a high remission rate with concomitant chemoradiation, recurrences are frequent, and the downstream morbidity of treatment is significant. Thus, it is imperative to find alternative therapies. Methods We employed a Search Tag Analyze Resource (STARGEO) platform to conduct a meta-analysis using the National Center for Biotechnology’s (NCBI) Gene Expression Omnibus (GEO) to define NPC pathogenesis. We identified 111 tumor samples and 43 healthy nasopharyngeal epithelium samples from NPC public patient data. We analyzed associated signatures in Ingenuity Pathway Analysis (IPA), restricting genes that showed statistical significance (p<0.05) and an absolute experimental log ratio greater than 0.15 between disease and control samples. Results Our meta-analysis identified activation of lipopolysaccharide (LPS)-induced tissue injury in NPC tissue. Additionally, interleukin-1 (IL-1) and SB203580 were the top upstream regulators. Tumorigenesis-related genes such as homeobox A10 (HOXA10) and prostaglandin-endoperoxide synthase 2 (PTGS2 or COX-2) as well as those associated with extracellular matrix degradation, such as matrix metalloproteinases 1 and 3 (MMP-1, MMP-3) were also upregulated. Decreased expression of genes that encode proteins associated with maintaining healthy nasal respiratory epithelium structural integrity, including sentan-cilia apical structure protein (SNTN) and lactotransferrin (LTF) was documented. Importantly, we found that etanercept inhibits targets upregulated in NPC and LPS induction, such as MMP-1, PTGS2, and possibly MMP-3. Conclusions Our analysis illustrates that nasal epithelial barrier dysregulation and maladaptive immune responses are key components of NPC pathogenesis along with LPS-induced tissue damage.

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Allen, David Z., Jihad Aljabban, Dustin Silverman, Sean McDermott, Ross A. Wanner, Michael Rohr, Dexter Hadley, and Maryam Panahiazar. "Meta-Analysis illustrates possible role of lipopolysaccharide (LPS)-induced tissue injury in nasopharyngeal carcinoma (NPC) pathogenesis." PLOS ONE 16, no. 10 (October 14, 2021): e0258187. http://dx.doi.org/10.1371/journal.pone.0258187.

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Анотація:

Background Nasopharyngeal carcinoma (NPC) is a cancer of epithelial origin with a high incidence in certain populations. While NPC has a high remission rate with concomitant chemoradiation, recurrences are frequent, and the downstream morbidity of treatment is significant. Thus, it is imperative to find alternative therapies. Methods We employed a Search Tag Analyze Resource (STARGEO) platform to conduct a meta-analysis using the National Center for Biotechnology’s (NCBI) Gene Expression Omnibus (GEO) to define NPC pathogenesis. We identified 111 tumor samples and 43 healthy nasopharyngeal epithelium samples from NPC public patient data. We analyzed associated signatures in Ingenuity Pathway Analysis (IPA), restricting genes that showed statistical significance (p<0.05) and an absolute experimental log ratio greater than 0.15 between disease and control samples. Results Our meta-analysis identified activation of lipopolysaccharide (LPS)-induced tissue injury in NPC tissue. Additionally, interleukin-1 (IL-1) and SB203580 were the top upstream regulators. Tumorigenesis-related genes such as homeobox A10 (HOXA10) and prostaglandin-endoperoxide synthase 2 (PTGS2 or COX-2) as well as those associated with extracellular matrix degradation, such as matrix metalloproteinases 1 and 3 (MMP-1, MMP-3) were also upregulated. Decreased expression of genes that encode proteins associated with maintaining healthy nasal respiratory epithelium structural integrity, including sentan-cilia apical structure protein (SNTN) and lactotransferrin (LTF) was documented. Importantly, we found that etanercept inhibits targets upregulated in NPC and LPS induction, such as MMP-1, PTGS2, and possibly MMP-3. Conclusions Our analysis illustrates that nasal epithelial barrier dysregulation and maladaptive immune responses are key components of NPC pathogenesis along with LPS-induced tissue damage.

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Ferreira, Silvana R., Leandro M. Vélez, Maria F. Heber, Giselle A. Abruzzese, and Alicia B. Motta. "Prenatal androgen excess alters the uterine peroxisome proliferator-activated receptor (PPAR) system." Reproduction, Fertility and Development 31, no. 8 (2019): 1401. http://dx.doi.org/10.1071/rd18432.

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It is known that androgen excess induces changes in fetal programming that affect several physiological pathways. Peroxisome proliferator-activated receptors (PPARs) α, δ and γ are key mediators of female reproductive functions, in particular in uterine tissues. Thus, we aimed to study the effect of prenatal hyperandrogenisation on the uterine PPAR system. Rats were treated with 2mg testosterone from Day 16 to 19 of pregnancy. Female offspring (PH group) were followed until 90 days of life, when they were killed. The PH group exhibited an anovulatory phenotype. We quantified uterine mRNA levels of PPARα (Ppara), PPARδ (Ppard), PPARγ (Pparg), their regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a) and nuclear receptor co-repressor 1 (Ncor1) and cyclo-oxygenase (COX)-2 (Ptgs2), and assessed the lipid peroxidation (LP) index and levels of glutathione (GSH) and prostaglandin (PG) E2. The PH group showed decreased levels of all uterine PPAR isoforms compared with the control group. In addition, PGE2 and Ptgs2 levels were increased in the PH group, which led to a uterine proinflammatory environment, as was LP, which led to a pro-oxidant status that GSH was not able to compensate for. These results suggest that prenatal exposure to androgen excess has a fetal programming effect that affects the gene expression of PPAR isoforms, and creates a misbalanced oxidant–antioxidant state and a proinflammatory status.

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Balamurugan, Kuppusamy, Saadiya Sehareen, Savitri Krishnamurthy, Shikha Sharan, Wei Tang, Naoto Ueno, Stefan Ambs, Dipak Poria та Esta Sterneck. "Abstract P1-06-03: Promotion of E-cadherin-mediated tumor cell adhesion by COX-2/GSK3β signaling is a targetable mechanism of metastatic breast cancer". Cancer Research 82, № 4_Supplement (15 лютого 2022): P1–06–03—P1–06–03. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-06-03.

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Abstract Purpose: Metastatic progression and treatment resistance of breast cancer has been associated with epithelial-mesenchymal transition (EMT), including downregulation of E-cadherin (CDH1) gene expression, which can be initiated by inflammatory signaling such as by COX-2 (PTGS2). However, E-cadherin expression is maintained in many advanced breast cancers, including inflammatory BC (IBC), where it plays an essential role in forming tumor cell emboli within the cancer parenchyma and dermal lymph vasculature and which predict poor outcomes. Thus, the study of IBC offers an opportunity to understand the mechanisms of IBC and other aggressive BCs that lead to E-cadherin-associated cluster-based metastasis, which has recently received heightened recognition. Here, we have investigated the mechanisms that sustain E-cadherin expression in metastatic breast cancer to identify new targeted treatment options. Study Design and Methods: In vitro emboli formation assays and gene/protein expression studies with IBC (SUM149, IBC-3) and non-IBC (SUM159, MCF-7) cell lines along with gene silencing, overexpression, and pharmacological interventions. Analysis of experimental (SUM149) and spontaneous (orthotopic patient-derived xenograft, PDX) lung metastases and of circulating tumor cells (CTCs) in xenograft models treated with celecoxib (Cxb) and/or paclitaxel by imaging cytometry, immunohistochemistry, and/or Western analysis. Results: By analyzing the transcription factor C/EBPδ (CEBPD) and cells derived from inflammatory breast cancer (IBC), an aggressive breast cancer subtype that often presents with E-cadherin-dependent tumor cell emboli, we discovered that COX-2, unexpectedly, sustained E-cadherin protein expression without changing its mRNA levels. Using an in vitro tumor cell emboli culture paradigm (3D), we found that COX-2 or its metabolite PGE2 increased AKT activity and the inhibitory phosphorylation on GSK3β that prevents degradation of p120 catenin (CTNND1), a stabilizer of E-cadherin adhesion complexes. Conversely, the COX-2 inhibitor celecoxib downregulated E-cadherin specifically at the protein level and caused cell death in 3D. Co-expression of E-cadherin and COX-2 was seen in breast cancer patients with poor outcomes and, along with inhibitory GSK3β phosphorylation, in patient-derived xenografts (PDX) of metastatic triple-negative breast cancers (TNBC). Celecoxib alone decreased E-cadherin protein expression within xenograft primary tumors, reduced circulating tumor cells (CTCs) and clusters, and sensitized lung metastases to paclitaxel treatment. Conclusions: Our study uncovered a novel function of COX-2/PGE2 in promoting E-cadherin protein expression and cell-cell adhesions that are relevant for tumor cell cluster-based metastasis. Indeed, COX-2 inhibition reduced CTC clusters in a xenograft model, and sentized established metastases to chemotherapy. These results suggest that patients with COX-2+/E-cadherin+ metastastic BC, including IBC, may specifically benefit from targeting the PGE2 pathway in cobniation therapy approaches. Citation Format: Kuppusamy Balamurugan, Saadiya Sehareen, Savitri Krishnamurthy, Shikha Sharan, Wei Tang, Naoto Ueno, Stefan Ambs, Dipak Poria, Esta Sterneck. Promotion of E-cadherin-mediated tumor cell adhesion by COX-2/GSK3β signaling is a targetable mechanism of metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-06-03.

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Kosumi, Keisuke, Tsuyoshi Hamada, Sui Zhang, Li Liu, Annacarolina da Silva, Hideo Koh, Tyler S. Twombly, et al. "Prognostic association of PTGS2 (COX-2) over-expression according to BRAF mutation status in colorectal cancer: Results from two prospective cohorts and CALGB 89803 (Alliance) trial." European Journal of Cancer 111 (April 2019): 82–93. http://dx.doi.org/10.1016/j.ejca.2019.01.022.

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Wyatt, Garhett L., Lyndsey S. Crump, Traci R. Lyons, and Weston W. Porter. "Abstract P4-02-11: A SIM2s/SEMA7A switch drives therapeutic resistance in ER+ breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–02–11—P4–02–11. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-02-11.

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Abstract BACKGROUND: Estrogen Receptor (ER) + breast cancers (BC) comprise over 70% of BC cases and can be targeted via ER modulated therapies. Despite this, ER+BC patients can experience recurrence within 20 years and the majority of BC related deaths can be attributed to metastatic ER+BC. These distant metastases commonly become diagnosed as endocrine therapy resistant. Thus, there is an unmet need to identify novel biomarkers for treating ER+ patients with metastasis. We have identified a tumor suppressor, Singleminded 2s (SIM2s), expressed in breast epithelial cells that inhibits EMT and metastasis, and is downregulated in the progression of breast disease. Our previous studies found that loss of SIM2s expression results in downregulation of ESR1 and increased basal markers in the MCF7 (ER+BC) cell line. Likewise, Semaphorin 7a (SEMA7A) expression is associated with decreased overall survival in ER+BC patients. Patients with SEMA7Ahi tumors treated with Tamoxifen exhibit shortened relapse free survival. SEMA7A is a downstream target of both NFKB and PTGS2/COX-2; and our previously published results establish a cross-talk between NFKB and SIM2s to regulate PTGS2 via interactions with the AKT pathway. Moreover, COX-2 inhibition is associated with better prognosis for breast cancer patients. Therefore, we are investigating how SIM2s may repress AKT signaling in SEMA7A driven ER resistance and metastasis. Methods: We performed in silico analysis of the SEMA7A promoter using the ConTra web server. For in vitro assays, we examined estrogen dependent differences in SIM2s, ER, and SP1 binding utilizing luciferase reporter assays using intact promoter and SIM2s site deletion mutants (Invitrogen) in MCF7 cells. Using immunoblotting and qPCR analysis we also assessed expression of SEMA7A, ESR1, PI3K/AKT signaling genes and EMT associated genes in Crispr/Cas9 SIM2s knockout (SIM2KO) MCF7 cells. Treatment of MCF7 cells with exogenous SEMA7A was used to observe possible changes in SIM2s expression and SIM2s promoter activity. For in vivo assays, we used immunohistochemistry (IHC) to assess SIM2s in SEMA7A low and high expressing MCF7 xenografts. To examine the relationship between SIM2s and ER, SEMA7A-/- (KO) mice were crossed with C57/BL6 MMTV-PYMT mice. Results: In silico analysis of the SEMA7A promoter via ConTra revealed four potential SIM2 response elements containing the SIM2s central midline elements (CME) binding motif and highly conserved estrogen response element half-sites adjacent to two specificity protein 1 consensus bindings sites. Luciferase reporter assays in MCF7 cells confirmed SIM2s represses basal and estrogen induced-SEMA7A promoter activity. Moreover, SIM2s was unable to repress the SEMA7A promoter activity with CME mutation. MCF7 SIM2KO cells exhibit increased SEMA7A promoter activity, SEMA7A, AKT signaling, EMT signatures and decreased ESR1, CDH1, and PTEN protein and mRNA expression. Both SIM2s expression and SIM2s promoter activity are significantly decreased with the addition of exogenous SEMA7A. Moreover, MCF7 xenografts reveal reciprocal expression of SIM2s and SEMA7A. Additionally in MMTV-PyMT mice, SIM2s expression is lost as tumors transition from pre-malignant to invasive phenotypes, yet we observe maintenance of SIM2s and ER in SEMA7A-/-;PyMT mice. Conclusion: These findings establish a regulatory relationship between SIM2s and SEMA7A in ER+BC. SIM2s functions to downregulate SEMA7A mediated pro-tumor signaling and maintain ER expression, but can be turned off to allow for resistance in ER+BC. Given the observed reciprocal expression, our study suggests a SIM2s/SEMA7A switch which may confer resistance in ER+BC via AKT signaling through downregulation of PTEN. Thus, a SIM2s/SEMA7A switch may act as a prognostic indicator to provide therapeutic advantages in resistant ER+BC metastasis. Citation Format: Garhett L Wyatt, Lyndsey S Crump, Traci R Lyons, Weston W Porter. A SIM2s/SEMA7A switch drives therapeutic resistance in ER+ breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-02-11.

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Farrugia, Mark K., Mark D. Long, David M. Mattson, Leayn T. Flaherty, Bowen Dong, Eduardo Cortes Gomez, Lei Wei, et al. "Concurrent Aspirin Use Is Associated with Improved Outcome in Rectal Cancer Patients Who Undergo Chemoradiation Therapy." Cancers 13, no. 2 (January 8, 2021): 205. http://dx.doi.org/10.3390/cancers13020205.

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Background: The benefit of aspirin in rectal cancer during chemoradiation therapy (CRT) and the factors affecting its efficacy are not well characterized. We compared the outcomes of rectal patients undergoing neoadjuvant CRT based on aspirin use. Methods: Patients undergoing CRT for rectal cancer from 2010 to 2018 were evaluated. Aspirin use was determined by medication list prior to treatment. RNA sequencing and subsequent gene set enrichment analysis was performed on surgically resected specimens. Results: 147 patients underwent neoadjuvant CRT with a median follow-up of 38.2 months. Forty-two patients were taking aspirin prior to CRT. Aspirin users had significantly less local and distant progression, and improved progression-free and overall survival. On RNA-sequencing, neither PI3KCA nor KRAS mutational status were associated with the benefit of aspirin use or tumor downstaging. PTGS2/COX2 expression trended lower in aspirin users, but not with tumor response. Aspirin use was associated with increases of M1 macrophages, plasma cells, CD8+ T cells, and reduction of M2 macrophages in the resected tumor. Conclusions: Concurrent aspirin use during neoadjuvant CRT was associated with improved local and distant tumor control leading to significantly improved survival. Neither mutations in KRAS or PI3CKA, nor the levels of COX-2 expression at the time of resection of the residual tumor were predictive of these aspirin benefits.

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Farrugia, Mark K., Mark D. Long, David M. Mattson, Leayn T. Flaherty, Bowen Dong, Eduardo Cortes Gomez, Lei Wei, et al. "Concurrent Aspirin Use Is Associated with Improved Outcome in Rectal Cancer Patients Who Undergo Chemoradiation Therapy." Cancers 13, no. 2 (January 8, 2021): 205. http://dx.doi.org/10.3390/cancers13020205.

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Background: The benefit of aspirin in rectal cancer during chemoradiation therapy (CRT) and the factors affecting its efficacy are not well characterized. We compared the outcomes of rectal patients undergoing neoadjuvant CRT based on aspirin use. Methods: Patients undergoing CRT for rectal cancer from 2010 to 2018 were evaluated. Aspirin use was determined by medication list prior to treatment. RNA sequencing and subsequent gene set enrichment analysis was performed on surgically resected specimens. Results: 147 patients underwent neoadjuvant CRT with a median follow-up of 38.2 months. Forty-two patients were taking aspirin prior to CRT. Aspirin users had significantly less local and distant progression, and improved progression-free and overall survival. On RNA-sequencing, neither PI3KCA nor KRAS mutational status were associated with the benefit of aspirin use or tumor downstaging. PTGS2/COX2 expression trended lower in aspirin users, but not with tumor response. Aspirin use was associated with increases of M1 macrophages, plasma cells, CD8+ T cells, and reduction of M2 macrophages in the resected tumor. Conclusions: Concurrent aspirin use during neoadjuvant CRT was associated with improved local and distant tumor control leading to significantly improved survival. Neither mutations in KRAS or PI3CKA, nor the levels of COX-2 expression at the time of resection of the residual tumor were predictive of these aspirin benefits.

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Villapol, Sonia, Valerie Faivre, Pooja Joshi, Raffaella Moretti, Valerie C. Besson, and Christiane Charriaut-Marlangue. "Early Sex Differences in the Immune-Inflammatory Responses to Neonatal Ischemic Stroke." International Journal of Molecular Sciences 20, no. 15 (August 4, 2019): 3809. http://dx.doi.org/10.3390/ijms20153809.

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We recently reported that neonatal ischemia induces microglia/macrophage activation three days post-ischemia. We also found that female mice sustained smaller infarcts than males three months post-ischemia. The objective of our current study was to examine whether differential acute neuroinflammatory response and infiltrated immune cells occurs between male and females after three days post-ischemia. Permanent middle cerebral artery occlusion was induced in male and female postnatal 9-day-old (P9) mice, and mice were sacrificed three days after ischemia. Brains were analyzed for mRNA transcription after microglia magnetic cell sorting to evaluate M1 and M2 markers. FACS analysis was performed to assess myeloid infiltration and microglial expression of CX3 chemokine receptor 1 (CX3CR1). Inflammatory cytokine expression and microglia/macrophage activation were analyzed via in situ hybridization combined with immunofluorescence techniques. Lesion volume and cell death were measured. An increase in microglia/macrophages occurred in male versus female mice. The cells exhibited amoeboid morphology, and TNFα and ptgs2 (Cox-2) genes were more expressed in males. More myeloid cell infiltration was found in male versus female brains. However, we did not observe sex-dependent differences in the injured volume or cell death density. Our data show that sex differences in the acute microglial and immune responses to neonatal ischemia are likely both gene- and region-specific.

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Ghorbel, Mohamed T., Myriam Cherif, Amir Mokhtari, Vito Domenico Bruno, Massimo Caputo, and Gianni D. Angelini. "Off-pump coronary artery bypass surgery is associated with fewer gene expression changes in the human myocardium in comparison with on-pump surgery." Physiological Genomics 42, no. 1 (June 2010): 67–75. http://dx.doi.org/10.1152/physiolgenomics.00174.2009.

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Off-pump coronary artery bypass surgery reduces the myocardial injury associated with on pump surgery with cardiopulmonary bypass (CPB) and ischemic-cardioplegic arrest (CA). We sought to find a mechanistic explanation for this by comparing the transcriptomic changes in the myocardium of patients undergoing on- and off-pump surgery. Transcriptomic analyses were performed on left ventricular biopsies obtained from patients prior to (pre-op) and after completion of all coronary anastomoses (post-op). Microarray results were validated with real-time polymerase chain reaction. In on-pump group, 68 genes were upregulated in post-op vs. pre-op biopsies ( P < 0.01, ≥2-fold). They included inflammatory genes CCL3 and CCL4, apoptotic gene GADD45B and prostaglandin synthesis gene PTGS2 ( COX-2). In the off-pump group, 17 genes were upregulated in post-op vs. pre-op biopsies ( P < 0.01, ≥2-fold), all shared with on-pump patients. To uncover the genes implicated in CPB and ischemic-CA response, we compared the postoperative gene profiles of the two groups. Thirty-eight genes were upregulated in the on-pump vs. off-pump patients ( P < 0.01, ≥2-fold). On-pump surgery induces injury-related response, as demonstrated by the upregulation of apoptosis and remodeling markers, whereas off-pump surgery ameliorates that by mainly upregulating a cytoprotective genetic program. Blood levels of the identified cytokines and chemokines followed the same pattern obtained by transcriptomics, suggesting that the myocardium is a likely source for these proteomic changes. In conclusion, off-pump surgery is associated with fewer alterations in gene expression connected with inflammation, apoptosis, and remodeling seen after on-pump surgery with CPB and ischemic-CA.

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das Neves, Raquel Nascimento, Aparna Gorthi, Alexander James Roy Bishop, and Alfeu Zanotto Filho. "Abstract P5-10-03: Mutant p53 and ERK1/2 MAPK cooperate with the production of TNBC inflammatory secretome." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–10–03—P5–10–03. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-10-03.

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Abstract TP53 is the most frequently mutated gene in most types of human cancer, including breast cancer. The triple-negative breast cancer (TNBC) subtype in particular displays TP53 mutation in approximately 80% of patients. Unlike other breast cancer subtypes (e.g., ER/PR-positive or HER2-positive), TNBC patients currently lack an approved highly effective targeted therapy. Notably, most TNBC acquires TP53 mutations, which, in addition to the loss of canonical p53 functions, can result in gain-of-function, activating different cellular mechanisms involved in tumor phenotypes such as proliferation, metastasis, invasiveness, and angiogenesis. Here we evaluate the role of mutant p53 in cancer phenotypes of TNBC cell lines, in particular their inflammatory profile. As expected, loss of p53 protein by small interfering RNA depletion did not show a major impact on the cell viability of MDA-MB231 and Hs578t cells in MTT assay. However, depleting mutant p53 knockdown made MDA-MB231 cells more susceptible to treatment with methyl-methane sulfonate, a genotoxic alkylating agent. Interestingly, cell invasion as measured by the transwell assay demonstrated that depletion of mutant p53 depletion decreased the invasiveness potential of MDA-MB231 and Hs578t cells which was substantiated with decreased migration of MDA-MB231 cells in a scratch assay over 24 h. RNA sequencing of MDA-MB231 and Hs578t cells revealed that mutant p53 knockdown decreased the expression of several constitutively expressed pro-inflammatory cytokines such as IL8, IL6, CXCL2, and CXCL3, but not genes associated with survival to alkylating agents (NRF2 and Endoplasmic reticulum stress markers) or genes typically regulated by wild-type p53 when compared to control-silenced and MMS-treated cells as indicated by Pathway Enrichment Analysis using the Enrich R and DAVID tools. These results were confirmed by ELISA quantification of IL8, IL6, and CXCL2 in MDA-MB231 and Hs578t transfected with two sequences of siRNA targeting mutant p53. On the other hand, RNA sequencing revealed some constitutively expressed genes known to be involved in breast cancer cells malignancy, such as PTGS2 (COX-2 enzyme gene) and MMP1, which were not affected by p53 knockdown. We found that MMP1, and PGE2 (the product of PTGS2/COX-2 enzyme), are upregulated by the ERK1/2 MAPK signaling pathway as determined in MDA-MB231 cells treated with the MEK1/2 inhibitor UO126 and sorafenib. UO126 and sorafenib also decreased IL8 and IL6 production. Furthermore, combined mutant p53 knockdown with MEK/ERK1/2 pathway inhibition caused a more pronounced IL8 and IL6 inhibition when compared to either p53 knockdown or UO126/sorafenib alone, whereas MMP1 and PGE2 levels were only reduced by MEK/ERK1/2 inhibitor treatments. Interestingly, neither mutant p53 knockdown impacted ERK1/2 phosphorylation status nor did UO126/sorafenib alter mutant p53 immunocontent. Reporter assays showed that mutant p53 promotes NFkappaB reporter activation, and MEK/ERK1/2 controls both NFkappaB and AP-1 transcription factors, both associated with the expression of the secretome components evaluated herein. Functional cell assays showed that concomitant inhibition of mutant p53 and MEK/ERK1/2 pathways reduce cell proliferation, invasion, and migration, indicating that mutant p53 protein gain of function cooperates with ERK1/2 MAPK signaling pathway to promote secretome production and malignant phenotypes in TNBC cell models. Citation Format: Raquel Nascimento das Neves, Aparna Gorthi, Alexander James Roy Bishop, Alfeu Zanotto Filho. Mutant p53 and ERK1/2 MAPK cooperate with the production of TNBC inflammatory secretome [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-10-03.

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Gu, Xiao-Wei, Zi-Cong Chen, Zhen-Shan Yang, Yan Yang, Ya-Ping Yan, Yue-Fang Liu, Ji-Min Pan, Ren-Wei Su, and Zeng-Ming Yang. "Blastocyst-induced ATP release from luminal epithelial cells initiates decidualization through the P2Y2 receptor in mice." Science Signaling 13, no. 646 (August 25, 2020): eaba3396. http://dx.doi.org/10.1126/scisignal.aba3396.

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Embryo implantation involves a sterile inflammatory reaction that is required for the invasion of the blastocyst into the decidua. Adenosine triphosphate (ATP) released from stressed or injured cells acts as an important signaling molecule to regulate many key physiological events, including sterile inflammation. We found that the amount of ATP in the uterine luminal fluid of mice increased during the peri-implantation period, and this depended on the presence of an embryo. We further showed that the release of ATP from receptive epithelial cells was likely stimulated by lactate released from the blastocyst through connexin hemichannels. The ATP receptor P2y2 was present on uterine epithelial cells during the preimplantation period and increased in the stromal cells during the time at which decidualization began. Pharmacological inhibition of P2y2 compromised decidualization and implantation. ATP-P2y2 signaling stimulated the phosphorylation of Stat3 in uterine luminal epithelial cells and the expression of early growth response 1 (Egr1) and prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox-2), all of which are required for decidualization and/or implantation, in stromal cells. Short exposure to high concentrations of ATP promoted decidualization of primary stromal cells, but longer exposures or lower ATP concentrations did not. The expression of genes encoding ATP-degrading ectonucleotidases increased in the decidua during the peri-implantation period, suggesting that they may limit the duration of the ATP signal. Together, our results indicate that the blastocyst-induced release of ATP from uterine epithelial cells during the peri-implantation period may be important for the initiation of stromal cell decidualization.

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Qi, Li-Jie, Ren-Zhong Wang, Shang Gao, Xiang-Jing Chen, Xin Zhang, and Yi-Peng Zhang. "Molecular Mechanisms Underlying the Effects of Bimin Kang Mixture on Allergic Rhinitis: Network Pharmacology and RNA Sequencing Analysis." BioMed Research International 2022 (October 28, 2022): 1–23. http://dx.doi.org/10.1155/2022/7034078.

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Background. Allergic rhinitis (AR) is a highly prevalent chronic inflammatory disease of the respiratory tract. Previous studies have demonstrated that Bimin Kang Mixture (BMK) is effective in alleviating AR symptoms and reducing the secretion of inflammatory factors and mucin; however, the precise mechanisms underlying these effects remain unclear. Methods. We built target networks for each medication component using a network pharmacology technique and used RNA-seq transcriptome analysis to screen differentially expressed genes (DEGs) for AR patients and control groups. The overlapping targets in the two groups were assessed using PPI networks, GO, and KEGG enrichment analyses. The binding ability of essential components to dock with hub target genes was investigated using molecular docking. Finally, we demonstrate how BMK can treat AR by regulating the NF-κB signaling pathway through animal experiments. Results. Effective targets from network pharmacology were combined with DEGs from RNA-seq, with 20 intersections as key target genes. The construction of the PPI network finally identified 5 hub target genes, and all hub target genes were in the NF-κB signaling pathway. Molecular docking suggests that citric acid, deoxyandrographolide, quercetin, luteolin, and kaempferol are structurally stable and can spontaneously attach to IL-1β, CXCL2, CXCL8, CCL20, and PTGS2 receptors. Animal experiments have shown that BMK inhibits NF-κB transcription factor activation, reduces the expression of proinflammatory cytokines and chemokines IL-1β, CXCL2, IL-8, and COX-2, and exerts anti-inflammatory and anti-allergic effects. Conclusion. BMK by regulating the NF-κB signaling pathway improves inflammatory cell infiltration, regulates mucosal immune balance, and reduces airway hypersensitivity. These findings provide theoretical support for the clinical efficacy of BMK for AR treatment.

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Lv, Mi, Jinke Huang, Jiayan Hu, Wenxi Yu, Ping Liu, Kunli Zhang, and Fengyun Wang. "Pharmacological Mechanism of Zuojin Pill for Gastroesophageal Reflux Disease: A Network Pharmacology Study." Journal of Food Quality 2022 (August 27, 2022): 1–13. http://dx.doi.org/10.1155/2022/5933348.

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Background. Although Zuojin Pill (ZJP) is widely used in China as a traditional prescription to treat gastroesophageal reflux disease (GERD), its exact mechanism of action is still unknown. Therefore, we employed network pharmacology (NP), molecular docking (MD), and molecular dynamics simulation (MDS) to investigate the pharmacological mechanisms of ZJP against GERD. Methods. Active compounds and target genes corresponding to ZJP and target genes related to GERD were identified through analysis of publicly available datasets. Subsequently, the obtained data were subjected to further network pharmacological analysis to explore the potential key active compounds, core target genes, and biological processes (BPs) associated with the effect of ZJP against GERD. Finally, the prediction results of NP were validated by MD, and MDS of the optimal core protein-ligand for each component obtained by MD were performed using Gromacs 2020 software. Results. Twelve active components of ZJP were identified to act on 82 target genes associated with GERD, and ZJP might exert an anti-GERD effect through the regulation of BPs such as reactive oxygen species (ROS) metabolism, response to oxidative stress (OS), and ROS, as well as the activation of signaling pathways such as apoptosis, p53 signaling, chemical carcinogenesis-ROS, and HIF-1 signaling pathways. Furthermore, quercetin, kaempferol, and coptisine, the three key components of ZJP were shown to stably bond with the 14 core target genes, including AKT1, MMP2, TP53, EGFR, JUN, CASP3, CXCL8, HIF1α, IL-1β, MYC, PPARG, MMP9, PTGS2, and FOS. Results from MDS showed that PPARG-quercetin and MMP2-quercetin bound more stably. Conclusions. The findings suggest that ZJP alleviates the symptoms of GERD and improves the prognosis by regulating ROS metabolism, thereby reducing the secretion of proinflammatory cytokines like IL-1β, COX-2, CXCL8, and MMPs, regulating the expression of oncogenes such as JUN and FOS, and maintaining the normal expression of tumor suppressor genes such as TP53 and MYC. However, whether the effect of this modulation of ROS metabolism is positive or negative needs to be further verified by pharmacological experiments.

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Weisberg, Stuart Phillip, Boguslaw S. Wojczyk, Sheila Bandyopadhyay, Richard O. Francis, and Eldad A. Hod. "Transfusion of Stored Red Blood Cells Activates an Inflammatory Program in Mouse Spleen That Is Enhanced By Endotoxemia." Blood 124, no. 21 (December 6, 2014): 598. http://dx.doi.org/10.1182/blood.v124.21.598.598.

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Abstract BACKGROUND: Transfusion of stored red blood cells (RBCs) induces a variable amount of erythrophagocytosis depending on the extent of RBC damage suffered from the storage lesion. Both murine and canine studies show that transfusion of RBCs after prolonged refrigerated storage leads to inflammation, as evidenced by increased post-transfusion levels of circulating pro-inflammatory cytokines. An analogous cytokine response was not observed in healthy humans volunteers. However, underlying inflammation may synergize with the cytokine response to stored RBCs; thus, results with healthy human volunteers may not reflect those with ill patients. Finally, plasma cytokine profiles may not accurately reflect local tissue responses at sites of erythrophagocytosis, such as the liver and spleen. AIMS: A mouse model was used to identify splenic transcriptional programs underlying the inflammatory response to stored RBC transfusions. Furthermore, mice were pretreated with a sub-lethal dose of lipopolysaccharide (LPS) to test the effect of underlying inflammation on the response to transfusion. METHODS: RBCs from 8-12 week old wild-type C57BL/6 male mice donors were collected, leukoreduced, and stored in citrate-phosphate-dextrose-adenine (CPDA)-1. Cohorts of syngeneic mice (n=3 per group) were infused with saline or transfused with one human equivalent unit of fresh RBCs (<24 hours old) or stored RBCs (11 days old). In parallel, cohorts of mice were pretreated with 1 μg of LPS (E. coli 0111:B4) and similarly transfused. Two hours after transfusion, blood and organs were collected and plasma cytokine levels were measured by a multiplex assay. Total RNA from each spleen was processed for hybridization to Affymetrix WT Gene microarrays. Whole genome expression profiles were analyzed using publicly available NIA Array and Gene Set Enrichment Analysis (GSEA) software. RESULTS: The 2-hour post-transfusion RBC recovery averaged 75% for mice transfused older RBCs. Non-LPS treated mice transfused with stored RBCs showed no statistically significant change in any plasma cytokine post-transfusion, however several cytokines were increased by stored RBC transfusion in LPS pretreated mice. Principle Component Analysis revealed a distinct splenic gene expression program associated with stored RBC transfusion in both LPS treated and non-LPS treated mice. GSEA showed significant enrichment of macrophage activation gene sets in spleens from non-LPS treated mice transfused with stored RBCs (see Figure). LPS pre-treatment increased baseline expression of macrophage activation genes, and these genes were further increased by stored RBC transfusion. Specifically, transfusion of stored RBCs acted in synergy with LPS to induce the cytokine genes (Il6 and Il1a), chemokine genes (Ccl2, Ccl3, Cxcl1, Cxcl2), the immediate early gene Fos, and the gene encoding COX-2 (Ptgs2; see Figure). Finally, a set of genes activated by stored blood transfusion independent of inflammation was identified. These genes included oxidative stress inducible genes (Hmox1 and Osgin) as well as GDF-15, which has previously been associated with states of hemolysis or ineffective erythropoieisis such as sickle cell disease and thalassemia. CONCLUSIONS: Taken together, these results suggest that although transfusion of one unit of stored RBCs in mice does not lead to a significant difference in circulating cytokine levels at two-hours post-transfusion, it does lead to activation of a distinct inflammatory transcriptional program in spleen. Moreover, sublethal endotoxemia synergizes with stored RBC transfusions to enhance expression of a specific subset of these inflammatory genes. Thus, stored RBC transfusions may be well tolerated by healthy human volunteers, but have a more detrimental impact on hospitalized patients, particularly those with sepsis and low-grade endotoxinemia. Figure 1 Figure 1. Transfusion of stored RBCs activates gene expression in synergy with LPS. A) A macrophage activation gene set was analyzed for its enrichment in mouse spleen by stored RBC transfusion and LPS treatment. Shown is the output of GSEA with the enrichment score graphs on top. B) Transfusion of stored RBCs in the setting of low dose LPS treatment further increases expression of LPS response genes. Shown are microarray expression values for Ptgs2 in spleens of stored RBC transfused healthy and LPS-treated mice. (mean ± SEM, n = 3). ∗∗p < 0.01, ns not significant. Disclosures No relevant conflicts of interest to declare.

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Nuttinck, Fabienne, Brigitte Marquant-Le Guienne, Laetitia Clément, Pierrette Reinaud, Gilles Charpigny, and Bénédicte Grimard. "Expression of genes involved in prostaglandin E2 and progesterone production in bovine cumulus–oocyte complexes during in vitro maturation and fertilization." REPRODUCTION 135, no. 5 (May 2008): 593–603. http://dx.doi.org/10.1530/rep-07-0453.

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Prostaglandin E2(PGE2) and progesterone appear to be critical mediators of cumulus expansion and the resumption of oocyte meiosis. The aim of this study was to identify the types of prostaglandin E synthase (PTGES) expressed in the bovine cumulus–oocyte complex (COC), to characterize their temporal expression during the periconceptional interval using anin vitromodel of maturation (IVM) and fertilization (IVF), and to compare their expression with the level of steroidogenic gene expression. Real-time RT-PCR analysis revealed that enzymes related to the PGE2biosynthesis pathway were mainly expressed during IVM. Transcripts encoding PTGES1–3 were detected in bovine COCs. Only the expression of PTGES1 significantly increased during IVM whereas that of PTGES2 and PTGES3 remained unchanged. The induction of PTGES1 expression paralleled the induction of prostaglandin G/H synthase-2 (PTGS2) expression and the amounts of PGE2secreted by maturing COCs. Concomitantly, cholesterol side chain cleavage cytochrome P450 expression was significantly upregulated in maturing COCs and the high level of expression persisted in fertilized COCs. The expression of the StAR protein remained constant during IVM and then decreased significantly during IVF. Expression of the progesterone catabolic-related enzyme, 20α-hydroxysteroid dehydrogenase significantly decreased throughout the periconceptional interval. This was associated with a rising level of progesterone released by COCs in the culture media. In conclusion, our results suggest that the periconceptional differentiation of the bovine COC includes the transient induction of PGE2biosynthetic activity via the PTGS2/PTGES1 pathway during the maturation period and the increasing ability to produce progesterone from the immature to the fertilized stages.

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Kurusu, Shiro, Masako Jinno, Hirosato Ehara, Tomohiro Yonezawa, and Mitsumori Kawaminami. "Inhibition of ovulation by a lipoxygenase inhibitor involves reduced cyclooxygenase-2 expression and prostaglandin E2 production in gonadotropin-primed immature rats." REPRODUCTION 137, no. 1 (January 2009): 59–66. http://dx.doi.org/10.1530/rep-08-0257.

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Potential roles of cyclooxygenase (COX) pathway of arachidonic acid (AA) metabolism are established in a murine model of induced ovulation. Pharmacological inhibition of an alternative lipoxygenase (LOX) pathway has been shown to cause defective ovulation, but the mechanism is still undefined. This study investigated the effects of two LOX inhibitors and their time dependency on ovulation and COX activity in gonadotropins (eCG and human chorionic gonadotropin (hCG))-primed immature rats. Intra-ovarian bursal treatment with a general LOX inhibitor nordihydroguaiaretic acid (NDGA) at 0 h post-hCG (hCG0h) dose dependently inhibited ovulation rate. The drug was still but less effective when treated at hCG6h. A more specific inhibitor, 3,4-dihydroxyphenyl ethanol (DPE) was also inhibitory when treated at hCG0h but not at hCG6h. Interestingly, treatment with DPE at hCG0h resulted in attenuated expression of immunoreactive PTGS2 in granulosa layers and concomitant decrease in ovarian prostaglandin E2(PGE2) content at hCG8h. NDGA treatment reduced immunoreactive PTGS2. Ovulatory impairment by both inhibitors was prevented by systemic administration of PGE2at hCG6h. Immunohistochemistry revealed the expression of ALOX5 and ALOX12 in both thecal and granulosa layers of preovulatory follicles and, notably, the augmented immunoreactivities during 8 h after hCG treatment. Our results indicate the probable presence of multiple LOX isoforms and that specific inhibition of LOX at an early stage of hCG-signaling led to reduced PTGS2 activity and thus defective ovulation. They reveal a probable relationship between two pathways of AA metabolism and account at least partly for the mechanism by which the LOX inhibitor causes impaired ovulation.

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Ratovitski, Edward A. "LKB1/PEA3/ΔNp63 Pathway Regulates PTGS-2 (COX-2) Transcription in Lung Cancer Cells Upon Cigarette Smoke Exposure". Oxidative Medicine and Cellular Longevity 3, № 5 (2010): 317–24. http://dx.doi.org/10.4161/oxim.3.5.13108.

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This is the first study to show that cigarette smoking induced the LKB1/PEA 3/ΔNp63-dependent transcriptional regulation of inflammatory molecules, such as COX-2/PTGS-2. Using mainstream smoke extract (MSE) and sidestream smoke extract (SSE) as modeling tools for primary and secondhand smoking, we found that both MSE and SSE downregulated protein levels for LKB1, while upregulated protein levels for PEA 3 and COX-2 in a dose-dependent manner. Using the endogenous ChIP analysis, we further found that the C/EBPβ, NFκB, NF-Y (CHOP), PEA 3 (ETS) and ΔNp63 proteins bound to the specific area (-550 to -130) of the COX-2 promoter, while forming multiple protein complexes in lung cancer cells exposed to MSE and SSE. Our results define a novel link between various transcription factors occupying the COX-2 promoter and cellular response to cigarette smoke exposure bringing a new component, ΔNp63α, showing a critical role for cooperation between various chromatin components in regulation of COX-2 expression and, therefore strengthening the central role of inflammatory process in tumorigenesis of epithelial cells, especially after cigarette smoke exposure (both primary and secondhand).

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Park, Hyo-Jin, Bokyung Kim, Deog-Bon Koo, and Dong-Seok Lee. "Peroxiredoxin 1 Controls Ovulation and Ovulated Cumulus–Oocyte Complex Activity through TLR4-Derived ERK1/2 Signaling in Mice." International Journal of Molecular Sciences 22, no. 17 (August 30, 2021): 9437. http://dx.doi.org/10.3390/ijms22179437.

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Peroxiredoxins (PRDXs) are expressed in the ovary and during ovulation. PRDX1 activity related to the immuno-like response during ovulation is unknown. We investigated the roles of Prdx1 on TLR4 and ERK1/2 signaling from the ovulated cumulus–oocyte complex (COC) using Prdx1-knockout (K/O) and wild-type (WT) mice. Ovulated COCs were collected 12 and 16 h after pregnant mare serum gonadotropin/hCG injection. PRDX1 protein expression and COC secretion factors (Il-6, Tnfaip6, and Ptgs2) increased 16 h after ovulated COCs of the WT mice were obtained. We treated the ovulated COCs in mice with LPS (0.5 μg/mL) or hyaluronidase (Hya) (10 units/mL) to induce TLR4 activity. Intracellular reactive oxygen species (ROS), cumulus cell apoptosis, PRDX1, TLR4/P38/ERK1/2 protein expression, and COC secretion factors’ mRNA levels increased in LPS- and Hya-treated COCs. The ERK inhibitor (U0126) and Prdx1 siRNA affected TLR4/ERK1/2 expression. The number and cumulus expansion of ovulated COCs by ROS were impaired in Prdx1 K/O mice but not in WT ones. Prdx1 gene deletion induced TLR4/P38/ERK1/2 expression and cumulus expansion genes. These results show the controlling roles of PRDX1 for TLR4/P38/ERK1/2 signaling activity in ovulated mice and the interlink of COCs with ovulation.

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Morinelli, Thomas A., John R. Raymond, Aleksander Baldys, Qing Yang, Mi-hye Lee, Louis Luttrell, and Michael E. Ullian. "Identification of a putative nuclear localization sequence within ANG II AT1A receptor associated with nuclear activation." American Journal of Physiology-Cell Physiology 292, no. 4 (April 2007): C1398—C1408. http://dx.doi.org/10.1152/ajpcell.00337.2006.

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Angiotensin II (ANG II) type 1 (AT1) receptors, similar to other G protein-coupled receptors, undergo desensitization and internalization, and potentially nuclear localization, subsequent to agonist interaction. Evidence suggests that the carboxy-terminal tail may be involved in receptor nuclear localization. In the present study, we examined the carboxy-terminal tail of the receptor for specific regions responsible for the nuclear translocation phenomenon and resultant nuclear activation. Human embryonic kidney cells stably expressing either a wild-type AT1A receptor-green fluorescent protein (AT1AR/GFP) construct or a site-directed mutation of a putative nuclear localization sequence (NLS) [K307Q]AT1AR/GFP (KQ/AT1AR/GFP), were examined for differences in receptor nuclear trafficking and nuclear activation. Receptor expression, intracellular signaling, and ANG II-induced internalization of the wild-type/GFP construct and of the KQ/AT1AR/GFP mutant was similar. Laser scanning confocal microscopy showed that in cells expressing the AT1AR/GFP, trafficking of the receptor to the nuclear area and colocalization with lamin B occurred within 30 min of ANG II (100 nM) stimulation, whereas the KQ/AT1AR/GFP mutant failed to demonstrate nuclear localization. Immunoblotting of nuclear lysates with an anti-GFP antibody confirmed these observations. Nuclear localization of the wild-type receptor correlated with increase transcription for both EGR-1 and PTGS-2 genes while the nuclear-deficient KQ/AT1AR/GFP mutant demonstrated increases for only the EGR-1 gene. These results suggest that a NLS (KKFKKY; aa307–312) is located within the cytoplasmic tail of the AT1A receptor and that nuclear localization of the receptor corresponds with specific activation of transcription for the COX-2 gene PTGS-2.

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Ekwemalor, Kingsley, and Mulumebet Worku. "PSVI-3 The effect of oligodeoxynucleotides on Toll-like receptor pathway genes in goat blood." Journal of Animal Science 97, Supplement_3 (December 2019): 197. http://dx.doi.org/10.1093/jas/skz258.406.

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Abstract The objective of this study was to investigate the effect of two classes of oligodeoxynucleotides (ODNs) on the expression of genes involved in Toll-like receptor signaling in goat blood. Toll-like receptors play a critical role in initiating innate immune responses. Select synthetic oligodeoxynucleotides containing methylated CpG motifs (CpG ODN) have immunologic effects similar to those seen with bacterial DNA. These short synthetic single-stranded DNA molecules are being explored as adjuvants to enhance animal health. Blood samples were collected from the jugular vein of BoerXSpanish goats (n = 3) into tubes containing an anticoagulant. Blood was treated with the 10 µg/ml CpG ODN (2216, 2006) class A and B, or 200µl of PBS which served as control. Cells were incubated at 37°C with 5% CO2 and 85% humidity for 30 minutes. Total RNA was isolated using Trizol and then converted to cDNA using RETROscript kit (Qiagen). The expression of 84 genes in the human TLR signaling pathway RT2 PCR Array was evaluated using real-time PCR. Fold change in gene expression was calculated using the 2−ΔΔCt method. The housekeeping genes GAPDH, ACTB, HPRT1, TBP, and YWHAZ was used to normalize the data. Of 84 genes tested, 74 genes were expressed in the control group. Following treatment with ODN 2006, 50 genes were expressed, 29 were up-regulated while 17 genes were down-regulated. The genes HSPD1, IFNG, MAPK8, and PTGS2 were induced by ODN 2006 treatment. Following treatment with ODN 2216, 52 genes were expressed. Treatment with ODN 2216, upregulated 26 genes and down-regulated the expression of 19 genes. The genes CLEC4E, HSPD1, IFNG, IRF1, MAPK8, PTGS2, and UBE2V1 were induced by ODN 2216. Thus specific patterns of TLR signaling may be involved in response to the immunostimulatory effect of CpG ODN in goats with implicates for their use as adjuvants to enhance animal health.

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Veraguas, D., S. R. Cuevas, P. F. Gallegos, F. O. Castro, and L. Rodriguez-Alvarez. "189 EFFECT OF THE OVARIAN STIMULATION OF ANESTROUS CATS WITH eCG ON MORPHOLOGICAL QUALITY AND GENE EXPRESSION PROFILE OF CUMULUS-OOCYTE COMPLEXES." Reproduction, Fertility and Development 29, no. 1 (2017): 203. http://dx.doi.org/10.1071/rdv29n1ab189.

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The objective of this research was to evaluate the effect of eCG on morphological quality and gene expression profile of cumulus-oocyte complexes (COC) recovered from anestrous cats. For this purpose, 3 experimental groups were made. Group 1 consisted of 11 oestrous cats (oestrous); Group 2 had 13 anestrous cats (anestrous); and Group 3 was made up of 11 anestrous cats treated with a single subcutaneous dose of 200 IU of eCG. In oestrous and anestrous groups the ovaries were obtained directly by ovariohysterectomy, whereas in the eCG group this was achieved 4 days after the dose injection. In all groups, each cat corresponded to an individual biological replicate, whereby the COC recovered from each cat were classified and processed separately for the experiments of gene expression analysis and in vitro maturation (IVM). The COC were collected by slicing of the ovaries and classified morphologically as grade I (excellent), grade II (good), grade III (fair), and grade IV (poor) quality. For gene expression analysis, pools of 8 to 10 grade I and II immature COC were made, resulting in 7 pools for each group. Quantitative RT-PCR was performed for gonadotrophin receptor genes (FSHR and LHCGR), FSH-induced genes (EGFR, EGR1, ESR2, and PTGS2), and genes related to oocyte competence (GDF9, BMP15, and GATM). The gene SDHA was used as the internal control. The total remaining proportion of grade I and II COC were used for IVM, and maturation rate was measured by visualisation of the first polar body. Statistical analysis was performed using the Kruskal–Wallis test. No differences were found in the total number of COC (mean ± standard deviation) recovered per cat among the oestrous (56.8 ± 20.5), anestrous (80.2 ± 35.2), and eCG groups (96.5 ± 62.0; P > 0.05). With respect to morphological quality of COC, the eCG group had a higher proportion of grade I COC (33.6 ± 11.0%) than the oestrous and anestrous groups (16.5 ± 8.7 and 8.9 ± 6.0%, respectively; P < 0.05). However, the anestrous group had a higher proportion of grade II COC (26.8 ± 6.4%) than the eCG group (21.1 ± 6.6%; P < 0.05). On the other hand, the eCG group had a lower proportion of grade III and IV COC (45.3 ± 12.8%) than the anestrous group (64.3 ± 9.1%; P < 0.05), without differences from the oestrous group (57.1 ± 12.0%; P > 0.05). Concerning to gene expression analysis, COC from the eCG group had a higher relative expression of FSHR, LHCGR, and EGFR than COC from the oestrous and anestrous group (P < 0.05). Furthermore, the COC from the eCG group had a higher relative expression of EGR1 than COC from the anestrous group and a higher expression of ESR2 than COC from the oestrous group (P < 0.05). However, COC from the eCG group had a lower relative expression of GATM and PTGS2 than COC from the oestrous group and a lower expression of GDF9 and BMP15 than COC from the anestrous group (P < 0.05). Although a higher number of oocytes with a first polar body could be seen in the eCG group after IVM, no significant differences in the maturation rate were found among the eCG (55.3 ± 13.2), oestrous (43.7 ± 11.1), and anestrous groups (47.9 ± 13.6; P > 0.05). In conclusion, the treatment with eCG improved the morphological quality of COC recovered from anestrous cats, which agrees with an increased relative expression of FSHR, LHCGR, EGFR, EGR1, and ESR2 and might be related to an enhanced competence of COC.

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Nautiyal, Jaya, Jennifer H. Steel, Meritxell M. Rosell, Evanthia Nikolopoulou, Kevin Lee, Francesco J. DeMayo, Roger White, JoAnne S. Richards, and Malcolm G. Parker. "The Nuclear Receptor Cofactor Receptor-Interacting Protein 140 Is a Positive Regulator of Amphiregulin Expression and Cumulus Cell-Oocyte Complex Expansion in the Mouse Ovary." Endocrinology 151, no. 6 (March 22, 2010): 2923–32. http://dx.doi.org/10.1210/en.2010-0081.

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The nuclear receptor cofactor receptor-interacting protein 140 (RIP140) is essential for cumulus cell-oocyte complex (COC) expansion, follicular rupture, and oocyte release during ovulation. The expression of many genes necessary for COC expansion is impaired in the absence of RIP140, but the studies herein document that their expression can be restored and COC expansion rescued by treatment with the epidermal growth factor (EGF)-like factor amphiregulin (AREG) both in vitro and in vivo. We demonstrate by several approaches that RIP140 is required for the expression of the EGF-like factors in granulosa cells, but the dependence of genes involved in cumulus expansion, including Ptgs2 Has2, Tnfaip6, and Ptx3, is indirect because they are induced by AREG. Treatment of granulosa cells with forskolin to mimic the effects of LH increases AREG promoter activity in a RIP140-dependent manner that 1) requires an intact cAMP response element in the proximal promoter region of the Areg gene and 2) involves its actions as a coactivator for cAMP response element-binding protein/c-Jun transcription factors. Although human chorionic gonadotropin and AREG coadministration is sufficient to restore ovulation fully in RIP140 heterozygous mice in vivo, both follicular rupture and ovulation remain impaired in the RIP140 null mice. Thus, we conclude that although the level of RIP140 expression in the ovary is a crucial factor required for the transient expression of EGF-like factors necessary for cumulus expansion, it also plays a role in other signaling pathways that induce follicular rupture.

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Yamashita, Yasuhisa, Ikkou Kawashima, Yoshiari Yanai, Masahide Nishibori, JoAnne S. Richards та Masayuki Shimada. "Hormone-Induced Expression of Tumor Necrosis Factor α-Converting Enzyme/A Disintegrin and Metalloprotease-17 Impacts Porcine Cumulus Cell Oocyte Complex Expansion and Meiotic Maturation via Ligand Activation of the Epidermal Growth Factor Receptor". Endocrinology 148, № 12 (1 грудня 2007): 6164–75. http://dx.doi.org/10.1210/en.2007-0195.

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The epidermal growth factor (EGF)-like growth factors, amphiregulin (AREG) and epiregulin (EREG), are expressed in murine cumulus oocyte complexes (COCs) where they impact the function of cumulus cells and oocyte maturation during LH-mediated ovulation. Because TNFα-converting enzyme (TACE)/a disintegrin and metalloprotease-17 (ADAM17) is essential for ectodomain shedding of AREG and EREG from the surface of other cell types, the expression and function of TACE/ADAM17 was analyzed in a porcine COC culture system in which FSH- and LH-mediated expansion and oocyte meiotic maturation have been well characterized and shown to occur between 20 and 40 h. In this model, Areg, Ereg, and Tace/Adam17 mRNAs increased significantly with maximal levels observed between 5 and 20 h of culture with FSH plus LH. TACE/ADAM17 protein and protease activity were up-regulated markedly at 10 h and maintained to 40 h. Treatment of COCs with the TACE/ADAM17-selective inhibitor TNFα-processing inhibitor-2 (TAPI-2) significantly suppressed in a time-dependent manner downstream targets of EGF receptor activation such as ERK1/2 phosphorylation, Ptgs2, Has2, and Tnfaip6 mRNA expression, hormone-induced COC expansion, and meiotic maturation of the oocytes. Addition of EGF to COCs cultured in the presence of FSH/LH reversed the inhibitory effects of TAPI-2 on these ovulation-related processes. Gonadotropin-induced phosphorylation of ERK1/2 was also inhibited in rat granulosa cells treated with TAPI-2 or after transfection with Tace/Adam17 small interfering RNA. Induced expression of Tnfaip6 mRNA was also reduced by Tace/Adam17 small interfering RNA. Thus, TACE/ADAM17 is induced and the activity is involved in porcine COC expansion as well as oocyte meiotic maturation through the activation of EGF receptor in cumulus cells.

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Ormond, C. M., P. F. Lima, D. T. Jardina-Sartor, C. A. Price, and J. Buratini. "257 EFFECTS OF FIBROBLAST GROWTH FACTOR 8 ON CUMULUS EXPANSION AND NUCLEAR MATURATION IN BOVINE CUMULUS - OOCYTE COMPLEXES." Reproduction, Fertility and Development 25, no. 1 (2013): 276. http://dx.doi.org/10.1071/rdv25n1ab257.

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Recent data indicate that fibroblast growth factor (FGF) signalling regulates oocyte developmental competence. Fibroblast growth factor 10 enhanced nuclear maturation, cumulus expansion, and embryo development in cattle (Zhang et al. 2010 Reproduction 140, 815–826). Like FGF10, FGF8 is expressed in the bovine oocyte, but whereas FGF10 activates FGF receptors (FGFR) 1B and 2B with higher affinity, FGF8 preferentially activates FGF receptor (FGFR) 2C, FGFR3C, and FGFR4. The involvement of FGF8 in the regulation of bovine cumulus–oocyte complex (COC) maturation has remained unknown. This study aimed to assess the effects of FGF8 supplementation in the in vitro maturation medium on nuclear maturation, degree of cumulus expansion, and expression of the genes necessary for expansion in bovine COC. Groups of 20 immature COC (grades 1 and 2) aspirated from 3- to 8-mm follicles were cultured in 200-µL drops of TCM-199 supplemented with FSH (1 µg mL–1), LH (10 IU mL–1), pyruvate (22 µg mL–1), amikacin (75 µg mL–1), and graded doses of recombinant human FGF8 (Peprotech, Rocky Hill, NJ, USA; 0, 1, 10, and 100 ng mL–1) for 22 h at 38.5°C and 5% CO2. After culture, COC were visually classified according to the degree of cumulus expansion (grades 1 to 3, indicating absent, moderate, and full expansion, respectively). Oocytes were mechanically separated from cumulus cells and stained with Hoechst 33342 to assess meiosis progression. Total RNA was extracted from cumulus cells using RNeasy (Qiagen, Venlo, the Netherlands), and 100 ng of RNA was reverse-transcribed using Omniscript (Qiagen). Expression levels of messenger RNA encoding genes necessary for cumulus expansion [prostaglandin endoperoxide synthase 2 (PTGS2), hyaluronan synthase 2 (HAS2), pentraxin 3 (PTX3) and tumour necrosis factor-stimulated gene-6 protein (TSG6)] were assessed by real-time PCR, with cyclophilin (CYCA) as the housekeeping gene. Data were derived from 5 replicates. Maturation and expansion data were transformed to arcsine, and gene expression data were log transformed. Effects of treatments were tested by ANOVA, and means were compared with the Tukey-Kramer honestly significant difference test. The FGF8 at 10 and 100 ng mL–1 reduced the proportion of oocytes reaching metaphase II (70, 64.8, 52.8, and 36% for FGF8 at 0, 1, 10, and 100 ng mL–1, respectively; P = 0.005) and increased the proportion of oocytes in metaphase I at 22 h of culture (30, 35.2, 47.2, and 64% for FGF8 at 0, 1, 10, and 100 ng mL–1, respectively; P = 0.004). Fibroblast growth factor 8 did not affect the degree of cumulus expansion as visually assessed. However, FGF8 at 10 and 100 ng mL–1 increased the messenger RNA abundance of PTGS2 [P = 0.0002; relative values (±SEM) of 0.69 ± 0.10, 0.63 ± 0.11, 1.56 ± 0.44, and 1.67 ± 0.20 for FGF8 at 0, 1, 10, and 100 ng mL–1, respectively] and HAS2 [P = 0.0002; relative values (±SEM) of 1.38 ± 0.15, 1.37 ± 0.24, 3.58 ± 0.61, and 4.14 ± 0.27 for FGF8 at 0, 1, 10, and 100 ng mL–1, respectively] in cumulus cells. In conclusion, the present data suggest the involvement of FGF8 in the mechanisms regulating transcription of expansion-inducing genes in cattle. In contrast with previous findings with FGF10, FGF8 inhibited nuclear maturation, suggesting different actions for different FGF in the regulation of COC maturation. Further research is needed to clarify the roles of FGF8 in the bovine COC. Supported by FAPESP.

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Romagnolo, Donato, Micah Donovan, Tom Doetschman, and Ornella Selmin. "n-6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer." Nutrients 11, no. 1 (January 15, 2019): 171. http://dx.doi.org/10.3390/nu11010171.

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The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States, n-6 linoleic acid (LA) is the most commonly used dietary vegetable fat. Metabolism of n-6 fatty acids has been linked to a higher risk of intestinal cancer. The objectives of this study were to investigate in colonic mucosa the effects of a high-fat diet rich in LA (n-6HFD) on CpG methylation of Fxr and prostaglandin-endoperoxide synthase-2 (Ptsg-2) genes, and the impact on the expression of tumor suppressor adenomatous polyposis Coli (Apc) and proliferative cyclin D1 (Ccnd1) genes. Weaned C57BL/6J male mice were fed for 6 weeks either an n-6HFD containing 44% energy (44%E) from 22% safflower oil (SO, 76% LA by weight) or a 13% energy (13%E) control diet (Control) from SO (5% by weight). Mice fed the n-6HFD had reduced (60%) Fxr promoter CpG methylation and increased (~50%) Fxr mRNA. The expression of FXR-target ileal bile acid-binding protein (Ibabp), small heterodimer protein (Shp), and anti-inflammatory peroxisome proliferator-activated-γ1 genes was increased. The n-6HFD reduced Ptgs-2 CpG methylation, increased the expression of Cox-2, and increased Apc CpG methylation in colonic mucosa. Accordingly, reduced expression of Apc was coupled to accumulation of c-JUN and Ccnd1, respectively cofactor and gene targets for the β-catenin/Wnt signaling pathway. Finally, the n-6HFD reduced the expression of histone deacetylase-1 while favoring the accumulation of acetylated histone 3. We conclude that an n-6HFD epigenetically modifies Fxr, leading to the activation of downstream factors that participate in BA homeostasis. However, epigenetic activation of Ptsg-2 coupled with silencing of Apc and accumulation of C-JUN and Ccnd1 may increase the risk of inflammation and cancer of the colon.

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Jang, You-Jee, Jin-Seon Kim, Pu-Reum Yun, Young-Woo Seo, Tae-Hoon Lee, Jae-Il Park, and Sang-Young Chun. "Involvement of peroxiredoxin 2 in cumulus expansion and oocyte maturation in mice." Reproduction, Fertility and Development 32, no. 8 (2020): 783. http://dx.doi.org/10.1071/rd19310.

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Peroxiredoxin 2 (Prdx2), an antioxidant enzyme, is expressed in the ovary during the ovulatory process. The aim of the present study was to examine the physiological role of Prdx2 during ovulation using Prdx2-knockout mice and mouse cumulus–oocyte complex (COC) from WT mice. Two days of treatment of immature mice (21–23 days old) with equine chorionic gonadotrophin and followed by treatment with human chorionic gonadotrophin greatly impaired cumulus expansion and oocyte maturation in Prdx2-knockout but not wild-type mice. Treatment of COCs in culture with conoidin A (50µM), a 2-cys Prdx inhibitor, abolished epiregulin (EPI)-induced cumulus expansion. Conoidin A treatment also inhibited EPI-stimulated signal molecules, including signal transducer and activator of transcription-3, AKT and mitogen-activated protein kinase 1/2. Conoidin A treatment also reduced the gene expression of EPI-stimulated expansion-inducing factors (hyaluronan synthase 2 (Has2), pentraxin 3 (Ptx3), TNF-α induced protein 6 (Tnfaip6) and prostaglandin-endoperoxide synthase 2 (Ptgs2)) and oocyte-derived factors (growth differentiation factor 9 (Gdf9) and bone morphogenetic protein 15 (Bmp15)). Furthermore, conoidin A inhibited EPI-induced oocyte maturation and the activity of connexins 43 and 37. Together, these results demonstrate that Prdx2 plays a role in regulating cumulus expansion and oocyte maturation during the ovulatory process in mice, probably by modulating epidermal growth factor receptor signalling.

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Andreas, E., D. Salilew-Wondim, F. Rings, E. Held, M. Hoelker, C. Neuhoff, E. Tholen, K. Schellander, and D. Tesfaye. "176 REGULATORY ROLE OF miR-20a DURING BOVINE OOCYTE MATURATION." Reproduction, Fertility and Development 29, no. 1 (2017): 196. http://dx.doi.org/10.1071/rdv29n1ab176.

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The role of microRNA in oocyte maturation is mostly associated with optimal turnover of the accumulated maternal transcripts during their growth to allow maturation. MiR-20a is a member of the miR-17–92 cluster, which has been found to be differentially expressed in bovine granulosa cells derived from preovulatory dominant and subordinate follicles. Our recent study showed that miR-20a is involved in the regulation of granulosa cell proliferation, differentiation, and progesterone synthesis by targeting PTEN and BMPR2 genes. Here, we aimed to investigate the role of miR-20a in the bovine oocyte maturation processes. For this, cumulus-oocyte complexes (COC) were aspirated from small antral follicles (2–8 mm in diameter) and cultured in groups of 50 in 400 µL of maturation media (TCM-199 media supplemented with 12% oestrus cow serum and 10 µg/ml Follitropin®) at 39°C in a humidified atmosphere with 5% (vol/vol) CO2 in the air for 22 h. The cumulus cells and oocytes before (germinal vesicle) and after maturation (metaphase II) were mechanically separated in 0.1% hyaluronidase (in TCM-199 media). To study whether the presence of cumulus cells or oocyte has an impact on the miR-20a expression, we cultured oocytectomized cumulus cells and oocytes with and without their companion cells. Moreover, COC were co-cultured with miR-20a mimic, inhibitor, or corresponding controls to investigate the role of this miRNA in oocyte maturation. The total RNA from cumulus cells and oocytes was extracted using miRNeasy® mini kit (Qiagen GmbH, Hilden, Germany). Total RNA from respective samples was reverse transcribed for mRNA and microRNA expression analysis. Quantitative expression analysis was performed using StepOnePlus™ System (Applied Biosystems, Foster City, CA, USA) and subsequent data were analysed using a comparative cycle threshold method. The progesterone released in the spent media was measured using progesterone enzyme-linked immunosorbent assay kit (ENZO Life Sciences GmbH, Loerrach, Germany). Here, we found that miR-20a expression in cumulus cells increased (P < 0.05) during oocyte maturation. Conversely, miR-20a expression in metaphase II stage oocytes was significantly lower (P < 0.001) compared with the germinal vesicle stage. The absence of oocyte cytoplasm resulted in reduced miR-20a expression in cumulus cells. On the other hand, the absent of cumulus cells increased miR-20a expression in oocytes. The miR-20a expression revealed that the microRNA transduction is restricted in the cumulus cells. The overexpression of miR-20a increased oocyte maturation rate (P < 0.05) by 4.8% (as determined by extrusion of the polar body) and the expression of oocyte maturation-related genes (INHBA, MAPK1, PTGS2, PTX3, and EGFR). The progesterone released in spent media of COC co-cultured with miR-20a mimic and inhibitor showed increasing (P = 0.0936) and decreasing (P = 0.0993) trends, respectively. In this study, we also found that miR-20a modulation altered the expression of PTEN and BMPR2 in cumulus cells. In conclusion, the modulation of miR-20a expression in cumulus cells regulates the oocyte maturation and partially involved in the progesterone synthesis by fine-tuning the expression of PTEN and BMPR2 genes.

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Wang, Yingzi, Andrei V. Krivtsov, Amit U. Sinha, Trista North, Wolfram Goessling, Leonard I. Zon та Scott Armstrong. "β-Catenin Determines Developmental Stage Specific Transformation by Hox Genes." Blood 114, № 22 (20 листопада 2009): 385. http://dx.doi.org/10.1182/blood.v114.22.385.385.

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Abstract Abstract 385 Leukemia stem cells (LSC) possess extensive proliferative and self-renewal potential similar to normal hematopoietic stem cells (HSC). Therefore understanding the similarities and differences between HSC and LSC is critical if LSC specific therapies are to be developed. Hox genes represent a group of genes that can influence both normal HSC and LSC self-renewal, and are critical targets of leukemogenic MLL fusion proteins. Previous reports have described the ability of Hoxa9 and Meis1a (HoxA9/M) to induce leukemia when expressed in mouse bone marrow (BM). However, whether HoxA9/M can fully recapitulate the leukemogenic activity of MLL fusion proteins remains unclear. In this study, we show that HoxA9/M, unlike MLL-AF9, fails to induce leukemia from granulocyte-macrophage progenitors (GMP) but does so from HSC. Immunophenotypic analysis and in vivo limiting dilution transplantation of HSC-derived leukemias demonstrate heterogeneity with only a subset of cells possessing leukemia-propagating activity. The LSC in this model have an immunophenotype consistent with differentiating myeloid cells. Gene expression analysis of LSC induced by MLL-AF9 expression in GMP and HoxA9/M expression in HSC demonstrate an approximately 10-fold increase in prostaglandin-endoperoxide synthase 1 (PTGS1) (also known as Cycloxygenase-1 or Cox-1) and prostaglandin E receptor 1 (PTGER1) expression. As recent studies have highlighted a critical connection between prostaglandin synthesis and Wnt/ β-catenin signaling pathway, we hypothesized that β-catenin is aberrantly activated in LSC derived from either GMP expressing MLL-AF9 or HSC expressing HoxA9/M. Western blots and immunofluorescence using an antibody specific for dephosphorylated (activated) β-catenin identified active β-catenin in MLL-AF9-driven and HoxA9/M-driven LSC but not normal GMP. These data suggested that insufficient β-catenin activity might be a contributing factor to the inability of HoxA9/M to transform GMP and thus we sought to determine if activated β-catenin cooperated to induce leukemia from GMP. We found that co-expression of HoxA9/M and activated β-catenin efficiently induced leukemia from GMP whereas neither expressed alone had leukemogenic activity. Next, we assessed if β-catenin is required for HoxA9/M-mediated leukemogenesis initiated from HSC. Conditional β-catenin loss-of-function experiments demonstrated impaired in vivo expansion of cells derived from HoxA9/M transduced HSC, and β-cat-/- cells did not induce leukemia. This defect could be rescued by expression of a constitutively active form of β-catenin. Finally, we demonstrate that continued β-catenin activity is required for LSC maintenance by chemical suppression of the β-catenin pathway with indomethacin (a cox-1/cox-2 inhibitor), which shows remarkable selective elimination of the LSC fraction in mice transplanted with HoxA9/M transduced HSC. Our gain and loss-of-function studies demonstrate that β-catenin activity is required for leukemia initiation from HSC, and that constitutively active β-catenin can cooperate with HoxA9/M to efficiently transform GMP. Thus, Wnt/β-catenin activity makes cells permissive to transformation, which suggests that its restricted activation to stem cell populations in normal hematopoietic development limits the permissiveness of developmental cell types to transformation by specific oncogenes. These data have important implications for tumor development in other tissues/organs and for the development of β-catenin pathway antagonists in AML. Disclosures: No relevant conflicts of interest to declare.

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Kim, B., I. M. Saadeldin, B. Lee, and G. Jang. "130 THE SYNERGIC EFFECT OF NERVE GROWTH FACTOR AND VASCULAR ENDOTHELIAL GROWTH FACTOR ON IN VITRO MATURATION AND DEVELOPMENTAL COMPETENCE IN BOVINE OOCYTES." Reproduction, Fertility and Development 23, no. 1 (2011): 169. http://dx.doi.org/10.1071/rdv23n1ab130.

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Nerve growth factor (NGF) has been reported to increase the mRNA expression of vascular endothelial growth factor (VEGF) in granulose cells of human, rat via TrkA signaling; VEGF has been shown to exert beneficial effects during bovine in vitro maturation (IVM) as well as early embryonic development. The aims of this study were 1) to investigate not only the direct effect of NGF but also the collaborative effect of NGF and VEGF during bovine in vitro maturation (IVM), in vitro culture (IVC), or both; and 2) to validate the correlation among transcript abundance of 7 genes (VEGF164, VEGF120, Flt-1, Flk-1, TrkA, PTGS2, and CYP11A1) in bovine cumulus cells and the results of IVM or IVC among the differently treated groups. In Experiment 1, concentrations of 0, 10, and 100 ng mL–1 NGF were added to our established IVM medium without serum, and in Experiment 2, control and treatment groups (concentration of 0, 10, and 100 ng mL–1 NGF with VEGF 100 ng mL–1) were added into chemically defined media. The oocytes of each group in Experiments 1 and 2 were determined by the proportion of MII oocytes after 24 h, and embryos were assessed after parthenogenetic activation. Cumulus cells from the differently treated matured cumulus cell–oocyte complexes (COC) were separated and synthesised into cDNA for RT-PCR and real-time PCR in order to measure relative abundance of 7 genes in a dose-dependent manner or a time-dependent manner. In Experiment 1, the concentration of 10 ng mL–1 (57.40%) and 100 ng mL–1 (62.75%) NGF treatment groups did not significantly increase the proportion of MII oocytes compared with the control group (55.06%). In Experiment 2, both the NGF 10 ng mL–1 with VEGF 100 ng mL–1 treated group (67.69%; P ≤ 0.01) and the NGF 100 ng mL–1 with VEGF 100 ng mL–1 treated group (72.24%; P ≤ 0.001) had a significantly higher percentage of polar body extrusion than control group (51.77%) and the group which was treated with VEGF 100 ng mL–1 (56.39%). The NGF treatment group with VEGF increased transcriptional level of VEGF164 and VEGF120 compared with the control group and only NGF- or VEGF-treated groups. In addition, either the NGF-treated group or NGF plus VEGF showed significantly increased mRNA abundance in VEGF164, VEGF120, Flt-1, Flk-1, and TrkA genes, whereas the NGF plus VEGF-treated group indicated the up-regulation of VEGF164, VEGF120, CYP11A1, and PTGS2 genes. In conclusion, NGF and exogenous VEGF have a synergic effect during bovine IVM and the early stage of embryo development; the elevated VEGF mRNA abundance in cumulus cells might contribute to the viability of bovine oocytes and early embryonic development. This study was supported by grants from IPET (#109023-05-1-CG000), NRF (#M10625030005-10N250300510), MKE (#2009-67-10033839, #2009-67-10033805), and BK21 program.

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Mingoti, G., P. Dall'Acqua, G. Nunes, C. Silva, P. Fontes, and M. Nogueira. "168 The Effect of Prematuration Culture Using Epidermal Growth Factor Receptor Kinase Inhibitor on Nuclear Maturation of Bovine Oocytes and Cumulus Cell Gene Expression." Reproduction, Fertility and Development 30, no. 1 (2018): 223. http://dx.doi.org/10.1071/rdv30n1ab168.

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Epidermal growth factor receptor (EGFR) activation is an essential step in triggering LH-induced meiotic resumption. Here, we used an EGFR kinase inhibitor (AG1478) to assess the blockage and reversal of meiosis block in bovine oocytes, the competence of such oocytes for the embryonic development, and the gene expression of cumulus cells (CC). Cumulus-oocyte complexes (COC, n = 583) were pre-matured (PM) during 8 h in TCM-199 with 1 μM AG1478 (EGFR-group). Next, COC were washed from meiotic inhibitor and cultured for 22 h in in vitro maturation (IVM) medium (TCM-199 with bicarbonate, 0.5 mg mL−1 FSH, 100 IU mL−1 hCG, and 10% FCS). The control group was only cultured for 22 h in IVM medium. Meiosis progression in oocytes was evaluated after PM (blocked_GV) and after IVM of PM oocytes (blocked_MII) or immediately after follicle aspiration (immature control = control_GV) and IVM (matured control = control_MII); oocytes were classified as immature (germinal vesicle; GV) or mature (metaphase II; MII). Another sample of matured oocytes was fertilized and cultured to the blastocyst stage. Abundance of 81 transcripts was evaluated by qPCR using a microfluidic platform (BioMark HD System™, Fluidigm®, South San Francisco, CA, USA) in CC collected at the same time as oocyte evaluation. Relative mRNA abundance was calculated by ΔCt (target genes were normalized by 2 reference genes: PPIA and RPL15). Data were analysed by ANOVA followed by Tukey’s test (P ≤ 0.05). The GV rates after 8-h PM differed (P ≤ 0.05) between 0-h oocytes (96.4 ± 2.2%) and EGFR- (59.8 ± 2.2%). After 22-h IVM, meiosis block was fully reversed and there was no difference (P ≥ 0.05) in MII rates between treatments (84.8%, averaged). Blastocyst rates (38.2%, averaged) were unaffected by treatment (P ≥ 0.05). Abundance of several transcripts was modulated by PM culture (blocked_GV v. control_GV), including up-regulation of genes that control the expansion of CC/COC competence markers (GREM1 and VCAN), cell proliferation/survival control (IGF1R and EGFR) and maintenance of cellular structural integrity/prediction of embryo quality (KRT8 and GATM), and down-regulation of genes associated with failures in pregnancy establishment/glucose metabolism (AKR1B1), endoplasmic reticulum stress (ATF4), meiotic arrest (ADCY3 and NOS2) and cell survival(HSPA1A). After IVM (blocked_MII v. control_MII), it was found an up-regulation in the relative abundance of PTX3 and PTGS2 (expansion of CC), RGS2 (regulator of G-protein signalling), LUM (embryo quality) and FOXO3 (apoptosis and oxidative stress resistance), whereas relative abundance of PFKP (glucose metabolism) was down-regulated. Our results indicate that blockade of meiosis with the EGFR kinase inhibitor before IVM is reversible and does not affect subsequent embryonic development. The gene expression profile of CC indicates a possible improvement in the quality of COC; however, more studies will be necessary to evaluate whether these improvements will be maintained until the embryonic stage. Financial support provided by FAPESP (#2015/06733-5 and #2012/50533-2) and CNPq (#307416/2015-1).

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Moran, Nancy E., Jennifer M. Thomas-Ahner, Joshua W. Smith, Ceasar Silva, Noor A. Hason, John W. Erdman та Steven K. Clinton. "β-Carotene Oxygenase 2 Genotype Modulates the Impact of Dietary Lycopene on Gene Expression during Early TRAMP Prostate Carcinogenesis". Journal of Nutrition 152, № 4 (29 грудня 2021): 950–60. http://dx.doi.org/10.1093/jn/nxab445.

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ABSTRACT Background Epidemiologic studies suggest lycopene and tomato intake are inversely associated with human prostate cancer incidence. In the genetically driven murine prostate carcinogenesis model transgenic adenocarcinoma of the mouse prostate (TRAMP), prostate cancer is inhibited by feeding of lycopene or tomatoes, and these effects are modulated by the β-carotene oxygenase 2 (Bco2) genotype. Objective We sought insight into this interaction through evaluation of prostate gene expression patterns during early TRAMP carcinogenesis. Methods Three-week-old TRAMP/+ or TRAMP/– × Bco2+/+ or Bco2–/– mice were fed a control, lycopene beadlet, or 10% tomato powder–containing semipurified diet (providing 0, 384 and 462 mg lycopene/kg diet, respectively) for 5 wk. Gene expression patterns were evaluated by prostate cancer- and cholesterol and lipoprotein metabolism-focused arrays at age 8 wk. Results The TRAMP genotype profoundly alters gene expression patterns, specifically inducing pathways associated with cell survival [z-score = 2.09, –log(P value) = 29.2, p53 signaling (z-score 1.13, –log(P value) = 13.5], and phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) signaling [z-score = 0.302, –log(P value) = 12.1], while repressing phosphatase and tensin homolog (PTEN) signaling [(z-score = –0.905, –log(P value) = 12.3], cholesterol synthesis [z-score = –1.941, –log(P-value) = 26.2], and LXR/RXR pathway activation [z-score = –1.941, –log(P value) = 23.1]. In comparison, lycopene- and tomato-feeding modestly modulate strong procarcinogenic TRAMP signaling. Lycopene decreased gene expression related to carcinogenesis [ Nkx3-1(NK3 homeobox 1)], tomato feeding increased expression of a gene involved in circadian regulation [Arntl (aryl hydrocarbon receptor nuclear translocator like)], and tomato and/or lycopene increased expression of genes involved in lipid metabolism [Fasn (fatty acid synthase), Acaca(acetyl-CoA carboxylase alpha), Srebf1 (sterol regulatory element binding transcription factor 1), Hmgcr (3-hydroxy-3-methylglutaryl-coA reductase), and Ptgs1 (prostaglandin-endoperoxide synthase 1)] (all P < 0.05). The impact of Bco2 genotype was limited to a subset of lycopene-impacted genes [Apc (adenomatous polyposis coli), Mto1 (mitochondrial TRNA translation optimization 1), Nfkb1 (nuclear factor kappa B subunit 1), andRbm39 (RNA binding motif protein 39)]. Conclusions The TRAMP genotype strongly impacts procarcinogenic gene expression prior to emergence of histopathologic disease. Dietary tomato and lycopene modestly temper these processes, while Bco2 genotype has a limited impact at this early stage. These observed patterns provide insight into the complex interactions between a dietary variable, here tomatoes and lycopene, genes impacting nutrient metabolism, and their modulating influences on oncogene-driven prostate carcinogenesis. These findings provide further mechanistic support, consistent with cancer outcomes in rodents experiments and human epidemiologic studies.

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Wyatt, Garhett L., Lyndsey S. Crump, Chloe M. Young, Veronica M. Wessells, Cole M. McQueen, Steven W. Wall, Tanya L. Gustafson та ін. "Cross-talk between SIM2s and NFκB regulates cyclooxygenase 2 expression in breast cancer". Breast Cancer Research 21, № 1 (29 листопада 2019). http://dx.doi.org/10.1186/s13058-019-1224-y.

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Abstract Background Breast cancer is a leading cause of cancer-related death for women in the USA. Thus, there is an increasing need to investigate novel prognostic markers and therapeutic methods. Inflammation raises challenges in treating and preventing the spread of breast cancer. Specifically, the nuclear factor kappa b (NFκB) pathway contributes to cancer progression by stimulating proliferation and preventing apoptosis. One target gene of this pathway is PTGS2, which encodes for cyclooxygenase 2 (COX-2) and is upregulated in 40% of human breast carcinomas. COX-2 is an enzyme involved in the production of prostaglandins, which mediate inflammation. Here, we investigate the effect of Singleminded-2s (SIM2s), a transcriptional tumor suppressor that is implicated in inhibition of tumor growth and metastasis, in regulating NFκB signaling and COX-2. Methods For in vitro experiments, reporter luciferase assays were utilized in MCF7 cells to investigate promoter activity of NFκB and SIM2. Real-time PCR, immunoblotting, immunohistochemistry, and chromatin immunoprecipitation assays were performed in SUM159 and MCF7 cells. For in vivo experiments, MCF10DCIS.COM cells stably expressing SIM2s-FLAG or shPTGS2 were injected into SCID mice and subsequent tumors harvested for immunostaining and analysis. Results Our results reveal that SIM2 attenuates the activation of NFκB as measured using NFκB-luciferase reporter assay. Furthermore, immunostaining of lysates from breast cancer cells overexpressing SIM2s showed reduction in various NFκB signaling proteins, as well as pAkt, whereas knockdown of SIM2 revealed increases in NFκB signaling proteins and pAkt. Additionally, we show that NFκB signaling can act in a reciprocal manner to decrease expression of SIM2s. Likewise, suppressing NFκB translocation in DCIS.COM cells increased SIM2s expression. We also found that NFκB/p65 represses SIM2 in a dose-dependent manner, and when NFκB is suppressed, the effect on the SIM2 is negated. Additionally, our ChIP analysis confirms that NFκB/p65 binds directly to SIM2 promoter site and that the NFκB sites in the SIM2 promoter are required for NFκB-mediated suppression of SIM2s. Finally, overexpression of SIM2s decreases PTGS2 in vitro, and COX-2 staining in vivo while decreasing PTGS2 and/or COX-2 activity results in re-expression of SIM2. Conclusion Our findings identify a novel role for SIM2s in NFκB signaling and COX-2 expression.

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Tso, Michael K., Paul Turgeon, Bert Bosche, Charles K. Lee, Tian Nie, Josephine D’Abbondanza, Jinglu Ai, Philip A. Marsden, and R. Loch Macdonald. "Gene expression profiling of brain endothelial cells after experimental subarachnoid haemorrhage." Scientific Reports 11, no. 1 (April 9, 2021). http://dx.doi.org/10.1038/s41598-021-87301-z.

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AbstractSubarachnoid haemorrhage (SAH) is a type of hemorrhagic stroke that is associated with high morbidity and mortality. New effective treatments are needed to improve outcomes. The pathophysiology of SAH is complex and includes early brain injury and delayed cerebral ischemia, both of which are characterized by blood–brain barrier (BBB) impairment. We isolated brain endothelial cells (BECs) from mice subjected to SAH by injection of blood into the prechiasmatic cistern. We used gene expression profiling to identify 707 unique genes (2.8% of transcripts, 403 upregulated, 304 downregulated, 24,865 interrogated probe sets) that were significantly differentially expressed in mouse BECs after SAH. The pathway involving prostaglandin synthesis and regulation was significantly upregulated after SAH, including increased expression of the Ptgs2 gene and its corresponding COX-2 protein. Celecoxib, a selective COX-2 inhibitor, limited upregulation of Ptgs2 in BECs. In this study, we have defined the gene expression profiling of BECs after experimental SAH and provide further insight into BBB pathophysiology, which may be relevant to other neurological diseases such as traumatic brain injury, brain tumours, ischaemic stroke, multiple sclerosis, and neurodegenerative disorders.

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Nagata, Kazuki, Kazumi Kasakura, Ryosuke Miura, Takuya Yashiro та Chiharu Nishiyama. "Suppressive role of PPARγ in the IgE-dependent activation of mast cells". International Immunology, 21 жовтня 2019. http://dx.doi.org/10.1093/intimm/dxz069.

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Abstract Mast cells (MCs) play a central role in IgE-dependent immune responses. PPARγ is a nuclear receptor that is essential for adipocyte differentiation and insulin sensitivity. Although PPARγ is expressed in activated MCs, the effect of PPARγ suppression in IgE-mediated activation of MCs is largely unknown. In the current study, we evaluated the effect of PPARγ knockdown on the function of IgE plus antigen (Ag)-stimulated MCs using siRNA-transfected BMMCs. We found that the mRNA expression level of cytokines in IgE/Ag-stimulated BMMCs was significantly increased in PPARγ knockdown BMMCs, and IgE/Ag-mediated degranulation and the protein production level of TNF-α was moderately increased by PPARγ knockdown, whereas the cell surface expression level of FcεRI was not affected by PPARγ knockdown. Oral administration of pioglitazone (PPARγ agonist) significantly suppressed body temperature change of mice in passive systemic anaphylaxis, supporting the inhibitory functions of PPARγ in IgE/Ag-dependent activation of MCs in vivo. IgE-mediated upregulation of mRNA levels of Ptgs2 (encoding COX-2) was drastically enhanced in PPARγ knockdown BMMCs. Although several prostaglandin (PG) derivatives are known to be ligands for PPARγ, treatment with a COX inhibitor, acetyl salicylic acid, upregulated the IgE-mediated increase of Il13, Tnf, and Ptgs2 mRNA levels in a synergistic manner with PPARγ siRNA. Knockdown of COX-1 and/or COX-2 by siRNA showed that suppression of IgE/Ag-mediated activation was mainly dependent on COX-1. Taken together, these results indicate that PPARγ suppresses IgE/Ag-induced transactivation of cytokine genes and the Ptgs2 gene in MCs in a manner distinguishable from that of PGs.

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