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1
Visnes, Torkild, Carlos Benítez-Buelga, Armando Cázares-Körner, Kumar Sanjiv, Bishoy M. F. Hanna, Oliver Mortusewicz, Varshni Rajagopal, et al. "Targeting OGG1 arrests cancer cell proliferation by inducing replication stress." Nucleic Acids Research 48, no. 21 (November 19, 2020): 12234–51. http://dx.doi.org/10.1093/nar/gkaa1048.
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Abstract Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.
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Kim, Ki Cheon, In Kyung Lee, Kyoung Ah Kang, Ji Won Cha, Suk Ju Cho, Soo Young Na, Sungwook Chae, Hye Sun Kim, Suhkmann Kim, and Jin Won Hyun. "7,8-Dihydroxyflavone Suppresses Oxidative Stress-Induced Base Modification in DNA via Induction of the Repair Enzyme 8-Oxoguanine DNA Glycosylase-1." BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/863720.
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The modified guanine base 8-oxoguanine (8-oxoG) is abundantly produced by oxidative stress, can contribute to carcinogenesis, and can be removed from DNA by 8-oxoguanine DNA glycosylase-1 (OGG1), which acts as an 8-oxoG glycosylase and endonuclease. This study investigated the mechanism by which 7,8-dihydroxyflavone (DHF) inhibits oxidative stress-induced 8-oxoG formation in hamster lung fibroblasts (V79-4). DHF significantly reduced the amount of 8-oxoG induced by hydrogen peroxide (H2O2) and elevated the levels of OGG1 mRNA and protein. DHF increased the binding of nuclear factor erythroid 2-related factor 2 (Nrf2) to antioxidant response element sequences in the upstream promoter region of OGG1. Moreover, DHF increased the nuclear levels of Nrf2, small Maf proteins, and the Nrf2/small Maf complex, all of which are decreased by H2O2treatment. Likewise, the level of phosphorylated Akt, which activates Nrf2, was decreased by H2O2treatment but restored by DHF treatment. The levels of OGG1 and nuclear translocation of Nrf2 protein were decreased upon treatment with PI3K inhibitor or Akt inhibitor, and DHF treatment did not restore OGG1 and nuclear Nrf2 levels in these inhibitor-treated cells. Furthermore, PI3K and Akt inhibitors abolished the protective effects of DHF in cells undergoing oxidative stress. These data indicate that DHF induces OGG1 expression via the PI3K-Akt pathway and protects cells against oxidative DNA base damage by activating DNA repair systems.
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Behrouzi, Adib, Hanyu Xia, Eric L. Thompson, Mark R. Kelley, and Jill C. Fehrenbacher. "Oxidative DNA Damage and Cisplatin Neurotoxicity Is Exacerbated by Inhibition of OGG1 Glycosylase Activity and APE1 Endonuclease Activity in Sensory Neurons." International Journal of Molecular Sciences 23, no. 3 (February 8, 2022): 1909. http://dx.doi.org/10.3390/ijms23031909.
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Cisplatin can induce peripheral neuropathy, which is a common complication of anti-cancer treatment and negatively impacts cancer survivors during and after completion of treatment; therefore, the mechanisms by which cisplatin alters sensory neuronal function to elicit neuropathy are the subject of much investigation. Our previous work suggests that the DNA repair activity of APE1/Ref-1, the rate-limiting enzyme of the base excision repair (BER) pathway, is critical for neuroprotection against cisplatin. A specific role for 8-oxoguanine DNA glycosylase-1 (OGG1), the glycosylase that removes the most common oxidative DNA lesion, and putative coordination of OGG1 with APE1/Ref-1 in sensory neurons, has not been investigated. We investigated whether inhibiting OGG1 glycosylase activity with the small molecule inhibitor, TH5487, and/or APE1/Ref-1 endonuclease activity with APE Repair Inhibitor III would alter the neurotoxic effects of cisplatin in sensory neuronal cultures. Sensory neuron function was assessed by calcitonin gene-related peptide (CGRP) release, as a marker of sensitivity and by neurite outgrowth. Cisplatin altered neuropeptide release in an inverse U-shaped fashion, with low concentrations enhancing and higher concentrations diminishing CGRP release. Pretreatment with BER inhibitors exacerbated the functional effects of cisplatin and enhanced 8oxo-dG and adduct lesions in the presence of cisplatin. Our studies demonstrate that inhibition of OGG1 and APE1 endonuclease activity enhances oxidative DNA damage and exacerbates neurotoxicity, thus limiting oxidative DNA damage in sensory neurons that might alleviate cisplatin-induced neuropathy.
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Aguilera-Aguirre, Leopoldo, Wenging Hao, Lang Pan, Xiaoxue Li, Alfredo Saavedra-Molina, Attila Bacsi, Zsolt Radak, et al. "Pollen-induced oxidative DNA damage response regulates miRNAs controlling allergic inflammation." American Journal of Physiology-Lung Cellular and Molecular Physiology 313, no. 6 (December 1, 2017): L1058—L1068. http://dx.doi.org/10.1152/ajplung.00141.2017.
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A mucosal oxidative burst is a hallmark response to pollen exposure that promotes allergic inflammatory responses. Reactive species constituents of oxidative stress signal via the modification of cellular molecules including nucleic acids. One of the most abundant forms of oxidative genomic base damage is 8-oxo-7,8-dihydroguanine (8-oxoG), which is removed from DNA by 8-oxoguanine DNA glycosylase 1 (OGG1). OGG1 in complex with 8-oxoG acts as a GDP-GTP exchange factor and induces acute inflammation; however, the mechanism(s) by which OGG1 signaling regulates allergic airway inflammation is not known. Here, we postulate that the OGG1 signaling pathway differentially altered the levels of small regulatory RNAs and increased the expression of T helper 2 (Th2) cytokines in ragweed pollen extract (RWPE)-challenged lungs. To determine this, the lungs of sensitized mice expressing or lacking OGG1 were challenged with RWPE and/or with OGG1’s excision product 8-oxoG. The responses in lungs were assessed by next-generation sequencing, as well as various molecular and histological approaches. The results showed that RWPE challenge induced oxidative burst and damage to DNA and activated OGG1 signaling, resulting in the differential expression of 84 micro-RNAs (miRNAs), which then exacerbated antigen-driven allergic inflammation and histological changes in the lungs. The exogenous administration of the downregulated let-7b-p3 mimetic or inhibitors of upregulated miR-23a or miR-27a decreased eosinophil recruitment and mucus and collagen production via controlling the expression of IL-4, IL-5, and IL-13. Together, these data demonstrate the roles of OGG1 signaling in the regulation of antigen-driven allergic immune responses via differential expression of miRNAs upstream of Th2 cytokines and eosinophils.
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Donley, Nathan, Pawel Jaruga, Erdem Coskun, Miral Dizdaroglu, Amanda K. McCullough, and R. Stephen Lloyd. "Small Molecule Inhibitors of 8-Oxoguanine DNA Glycosylase-1 (OGG1)." ACS Chemical Biology 10, no. 10 (August 7, 2015): 2334–43. http://dx.doi.org/10.1021/acschembio.5b00452.
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Tahara, Yu-ki, Anna M. Kietrys, Marian Hebenbrock, Yujeong Lee, David L. Wilson, and Eric T. Kool. "Dual Inhibitors of 8-Oxoguanine Surveillance by OGG1 and NUDT1." ACS Chemical Biology 14, no. 12 (October 17, 2019): 2606–15. http://dx.doi.org/10.1021/acschembio.9b00490.
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Wang, Jiayu, Noemi Nagy, and Maria G. Masucci. "The Epstein–Barr virus nuclear antigen-1 upregulates the cellular antioxidant defense to enable B-cell growth transformation and immortalization." Oncogene 39, no. 3 (September 11, 2019): 603–16. http://dx.doi.org/10.1038/s41388-019-1003-3.
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Abstract Epstein–Barr virus (EBV) immortalizes human B-lymphocytes and is implicated in the pathogenesis of lymphoid and epithelial cell malignancies. The EBV nuclear antigen (EBNA)-1 induces the accumulation of reactive oxygen species (ROS), which enables B-cell immortalization but causes oxidative DNA damage and triggers antiproliferative DNA damage responses. By comparing pairs of EBV-negative and -positive tumor cell lines we found that, while associated with the accumulation of oxidized nucleotides, EBV carriage promotes the concomitant activation of oxo-dNTP sanitization and purging pathways, including upregulation of the nucleoside triphosphatase mut-T homolog 1 (MTH1) and the DNA glycosylases 8-oxoguanine-glycosylase-1 (OGG1) and mut-Y homolog (MUTYH). Expression of EBNA1 was reversibly associated with transcriptional activation of this cellular response. DNA damage and apoptosis were preferentially induced in EBNA1-positive cell lines by treatment with MTH1 inhibitors, suggesting that virus carriage is linked to enhanced vulnerability to oxidative stress. MTH1, OGG1, and MUTYH were upregulated upon EBV infection in primary B-cells and treatment with MTH1 inhibitors prevented B-cell immortalization. These findings highlight an important role of the cellular antioxidant response in sustaining EBV infection, and suggests that targeting this cellular defense may offer a novel approach to antiviral therapy and could reduce the burden of EBV associated cancer.
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Ahmadimanesh, Mahnaz, Mohammad Reza Abbaszadegan, Dorsa Morshedi Rad, Seyed Adel Moallem, Amir Hooshang Mohammadpour, Mohammad Hossein Ghahremani, Farhad Farid Hosseini, et al. "Effects of selective serotonin reuptake inhibitors on DNA damage in patients with depression." Journal of Psychopharmacology 33, no. 11 (September 26, 2019): 1364–76. http://dx.doi.org/10.1177/0269881119874461.
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Background: The relationship between depression and increased oxidative stress is well known. DNA damage by oxidation factors is an important cause of the aging process in psychiatric disorders. Aims: Owing to the scarcity of human studies and high inconsistencies in studies of the effects of antidepressants on DNA damage, the current study was undertaken to investigate the effects of depression and its treatment on DNA damage. Methods: In a 15-week open-label study of citalopram ( n = 25) and sertraline ( n = 20), levels of DNA damage were measured by comet assay, proinflammatory (Interlukin-6 (IL-6)) and oxidative DNA damage (8-hydroxy-2’-deoxyguanosine (8-OHdG)) markers by ELISA, and gene expression of base excision repair enzymes (8-oxoguanine glycosylase (OGG1) and poly (ADP)-ribose polymerase-1 (PARP1)) by quantitative real-time polymerase chain reaction in healthy control patients ( n = 14), with depression at the baseline and the same patients after week 15. Results: DNA damage, 8-OHdG, IL-6 and expression of PARP1 were elevated in patients with depression compared with the healthy controls ( p < 0.001). Selective serotonin reuptake inhibitor (SSRI) therapy could significantly reduce the depression score ( p < 0.01), DNA damage ( p < 0.001), as well as 8-OHdG and IL-6 ( p < 0.0001). Nevertheless, the expression of PARP1 and OGG1 showed no significant changes after treatment. Conclusions: This is the first study on the effect of SSRIs on the DNA damage and some of the repair enzymes in depression. Based on the results, depression can cause increased DNA damage. This damage is followed by activation of compensatory mechanisms whereby the expression of DNA damage repair enzymes is elevated. Finally, the treatment of psychiatric disorder by antidepressants can lower the level of oxidative DNA damage.
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Slupianek, Artur, Rafal Falinski, Pawel Znojek, Tomasz Stoklosa, Sylwia Flis, Valentina Doneddu, Ewelina Synowiec, Janusz Blasiak, Alfonso Bellacosa, and Tomasz Skorski. "BCR-ABL1 Kinase Inhibits DNA Glycosylases to Enhance Oxidative DNA Damage and Stimulate Genomic Instability." Blood 120, no. 21 (November 16, 2012): 520. http://dx.doi.org/10.1182/blood.v120.21.520.520.
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Abstract Abstract 520 Tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib and nilotinib revolutionized the treatment of BCR-ABL1 kinase-positive chronic myeloid leukemia in chronic phase (CML-CP). Unfortunately, 15–25% of patients initially responding favorably to imatinib will develop acquired drug resistance, which in 40–90% of cases is caused by genomic instability resulting in the appearance of clones expressing TKI resistant BCR-ABL1 kinase mutants. We reported that CML-CP leukemia stem and progenitor cell populations accumulate high amounts of reactive oxygen species (ROS) resulting in excessive oxidative DNA damage such as oxidized DNA bases (8-oxoguanine and 5-hydroxycytosine→uracil) (Nieborowska-Skorska et al., Blood, 2012). Unfaithful and/or inefficient repair of these lesions generates TKI resistant point mutations in BCR-ABL1 kinase. Oxidative DNA lesions may be removed by base excision repair (BER) or, if not removed, will create mismatches, which are repaired by mismatch repair (MMR). Since we found that MMR is inhibited in CML-CP (Stoklosa et al., Cancer Res., 2008), the activity of BER is critical to prevent the accumulation of point mutations. Using an array of specific substrates and inhibitors/blocking antibodies we found that two major glycosylases, uracil-DNA glycosylase UNG2 and 8-oxoguanine glycosylase (OGG1) responsible for the excision of uracil (product of oxidation of cytosine) and 8-oxoguanine (8-oxoG) from DNA, respectively, were inhibited in BCR-ABL1 –transformed cell lines and CD34+ CML cells. The inhibitory effect was even more pronounced in CML blast phase (CML-BP) in comparison to CML-CP, it depended on BCR-ABL1 kinase activity and was not accompanied by deregulation of nuclear expression and/or chromatin association of these glycosylases. The effect was BCR-ABL1 kinase-specific because several other fusion tyrosine kinases such as TEL-ABL1, TEL-PDGFbetaR and NPM-ALK did not reduce UNG2 activity. Using UNG2-specific inhibitor UGI we found that UNG2 activity diminished the number of oxidized DNA bases detected by modified comet assay and prevented accumulation of point mutations in reporter gene Na+/K+ATPase, which encode resistance to ouabain. In conclusion, we hypothesize that inhibition of UNG2 and OGG1, accompanied by reduced MMR activity is responsible for accumulation of TKI-resistant BCR-ABL1 kinase point mutations and perhaps also other point mutations facilitating malignant progression of CML. Disclosures: No relevant conflicts of interest to declare.
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Giovannini, Sara, Marie-Christine Weller, Simone Repmann, Holger Moch, and Josef Jiricny. "Synthetic lethality between BRCA1 deficiency and poly(ADP-ribose) polymerase inhibition is modulated by processing of endogenous oxidative DNA damage." Nucleic Acids Research 47, no. 17 (July 22, 2019): 9132–43. http://dx.doi.org/10.1093/nar/gkz624.
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Abstract Poly(ADP-ribose) polymerases (PARPs) facilitate the repair of DNA single-strand breaks (SSBs). When PARPs are inhibited, unrepaired SSBs colliding with replication forks give rise to cytotoxic double-strand breaks. These are normally rescued by homologous recombination (HR), but, in cells with suboptimal HR, PARP inhibition leads to genomic instability and cell death, a phenomenon currently exploited in the therapy of ovarian cancers in BRCA1/2 mutation carriers. In spite of their promise, resistance to PARP inhibitors (PARPis) has already emerged. In order to identify the possible underlying causes of the resistance, we set out to identify the endogenous source of DNA damage that activates PARPs. We argued that if the toxicity of PARPis is indeed caused by unrepaired SSBs, these breaks must arise spontaneously, because PARPis are used as single agents. We now show that a significant contributor to PARPi toxicity is oxygen metabolism. While BRCA1-depleted or -mutated cells were hypersensitive to the clinically approved PARPi olaparib, its toxicity was significantly attenuated by depletion of OGG1 or MYH DNA glycosylases, as well as by treatment with reactive oxygen species scavengers, growth under hypoxic conditions or chemical OGG1 inhibition. Thus, clinical resistance to PARPi therapy may emerge simply through reduced efficiency of oxidative damage repair.
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Mahajan, Tushar, Mari Ytre-Arne, Pernille Strøm-Andersen, Bjørn Dalhus, and Lise-Lotte Gundersen. "Synthetic Routes to N-9 Alkylated 8-Oxoguanines; Weak Inhibitors of the Human DNA Glycosylase OGG1." Molecules 20, no. 9 (September 2, 2015): 15944–65. http://dx.doi.org/10.3390/molecules200915944.
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Li, Chunshuang, Yaoyao Xue, Xueqing Ba, and Ruoxi Wang. "The Role of 8-oxoG Repair Systems in Tumorigenesis and Cancer Therapy." Cells 11, no. 23 (November 27, 2022): 3798. http://dx.doi.org/10.3390/cells11233798.
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Tumorigenesis is highly correlated with the accumulation of mutations. The abundant and extensive DNA oxidation product, 8-Oxoguanine (8-oxoG), can cause mutations if it is not repaired by 8-oxoG repair systems. Therefore, the accumulation of 8-oxoG plays an essential role in tumorigenesis. To avoid the accumulation of 8-oxoG in the genome, base excision repair (BER), initiated by 8-oxoguanine DNA glycosylase1 (OGG1), is responsible for the removal of genomic 8-oxoG. It has been proven that 8-oxoG levels are significantly elevated in cancer cells compared with cells of normal tissues, and the induction of DNA damage by some antitumor drugs involves direct or indirect interference with BER, especially through inducing the production and accumulation of reactive oxygen species (ROS), which can lead to tumor cell death. In addition, the absence of the core components of BER can result in embryonic or early post-natal lethality in mice. Therefore, targeting 8-oxoG repair systems with inhibitors is a promising avenue for tumor therapy. In this study, we summarize the impact of 8-oxoG accumulation on tumorigenesis and the current status of cancer therapy approaches exploiting 8-oxoG repair enzyme targeting, as well as possible synergistic lethality strategies involving exogenous ROS-inducing agents.
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Tempka, Dominika, Paulina Tokarz, Kinga Chmielewska, Magdalena Kluska, Julita Pietrzak, Żaneta Rygielska, László Virág, and Agnieszka Robaszkiewicz. "Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes human lung cancer cells to anticancer drug-induced death by impairing OGG1-dependent base excision repair." Redox Biology 15 (May 2018): 316–26. http://dx.doi.org/10.1016/j.redox.2017.12.017.
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Hajnády, Zoltán, Máté Nagy-Pénzes, Máté A. Demény, Katalin Kovács, Tarek El-Hamoly, József Maléth, Péter Hegyi, Zsuzsanna Polgár, Csaba Hegedűs, and László Virág. "OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis." Biomedicines 10, no. 10 (October 12, 2022): 2543. http://dx.doi.org/10.3390/biomedicines10102543.
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Acute pancreatitis (AP) is a potentially life-threatening gastrointestinal disease with a complex pathology including oxidative stress. Oxidative stress triggers oxidative DNA lesions such as formation of 7,8-dihydro-8-oxo-2′-oxoguanine (8-oxoG) and also causes DNA strand breaks. DNA breaks can activate the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) which contributes to AP pathology. 8-oxoG is recognized by 8-oxoG glycosylase 1 (OGG1) resulting in the removal of 8-oxoG from DNA as an initial step of base excision repair. Since OGG1 also possesses a DNA nicking activity, OGG1 activation may also trigger PARP1 activation. In the present study we investigated the role played by OGG1 in AP. We found that the OGG1 inhibitor compound TH5487 reduced edema formation, inflammatory cell migration and necrosis in a cerulein-induced AP model in mice. Moreover, TH5487 caused 8-oxoG accumulation and reduced tissue poly(ADP-ribose) levels. Consistent with the indirect PARP inhibitory effect, TH5487 shifted necrotic cell death (LDH release and Sytox green uptake) towards apoptosis (caspase activity) in isolated pancreatic acinar cells. In the in vivo AP model, TH5487 treatment suppressed the expression of various cytokine and chemokine mRNAs such as those of TNF, IL-1β, IL1ra, IL6, IL16, IL23, CSF, CCL2, CCL4, CCL12, IL10 and TREM as measured with a cytokine array and verified by RT-qPCR. As a potential mechanism underlying the transcriptional inhibitory effect of the OGG1 inhibitor we showed that while 8-oxoG accumulation in the DNA facilitates NF-κB binding to its consensus sequence, when OGG1 is inhibited, target site occupancy of NF-κB is impaired. In summary, OGG1 inhibition provides protection from tissue injury in AP and these effects are likely due to interference with the PARP1 and NF-κB activation pathways.
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Hanna, Bishoy M. F., Thomas Helleday, and Oliver Mortusewicz. "OGG1 Inhibitor TH5487 Alters OGG1 Chromatin Dynamics and Prevents Incisions." Biomolecules 10, no. 11 (October 26, 2020): 1483. http://dx.doi.org/10.3390/biom10111483.
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8-oxoguanine DNA glycosylase (OGG1) is the main DNA glycosylase responsible for the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from duplex DNA to initiate base excision repair. This glycosylase activity is relevant in many pathological conditions including cancer, inflammation, and neurodegenerative diseases. To have a better understanding of the role of OGG1, we previously reported TH5487, a potent active site inhibitor of OGG1. Here, we further investigate the consequences of inhibiting OGG1 with TH5487. TH5487 treatment induces accumulation of genomic 8-oxoG lesions. Furthermore, it impairs the chromatin binding of OGG1 and results in lower recruitment of OGG1 to regions of DNA damage. Inhibiting OGG1 with TH5487 interferes with OGG1′s incision activity, resulting in fewer DNA double-strand breaks in cells exposed to oxidative stress. This study validates TH5487 as a potent OGG1 inhibitor that prevents the repair of 8-oxoG and alters OGG1–chromatin dynamics and OGG1′s recruitment kinetics.
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Makhdoumi, Pouran, Hooshyar Hossini, Ghulam Md Ashraf, and Mojtaba Limoee. "Molecular Mechanism of Aniline Induced Spleen Toxicity and Neuron Toxicity in Experimental Rat Exposure: A Review." Current Neuropharmacology 17, no. 3 (February 14, 2019): 201–13. http://dx.doi.org/10.2174/1570159x16666180803164238.
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Aniline exposure leads to neuron and spleen toxicity specifically and makes diverse neurological effects and sarcoma that is defined by splenomegaly, hyperplasia, and fibrosis and tumors formation at the end. However, the molecular mechanism(s) of aniline-induced spleen toxicity is not understood well, previous studies have represented that aniline exposure results in iron overload and initiation of oxidative/nitrosative disorder stress and oxidative damage to proteins, lipids and DNA subsequently, in the spleen. Elevated expression of cyclins, cyclin-dependent kinases (CDKs) and phosphorylation of pRB protein along with increases in A, B and CDK1 as a cell cycle regulatory proteins cyclins, and reduce in CDK inhibitors (p21 and p27) could be critical in cell cycle regulation, which contributes to tumorigenic response after aniline exposure. Aniline-induced splenic toxicity is correlated to oxidative DNA damage and initiation of DNA glycosylases expression (OGG1, NEIL1/2, NTH1, APE1 and PNK) for removal of oxidative DNA lesions in rat. Oxidative stress causes transcriptional up-regulation of fibrogenic/inflammatory factors (cytokines, IL- 1, IL-6 and TNF-α) via induction of nuclear factor-kappa B, AP-1 and redox-sensitive transcription factors, in aniline treated-rats. The upstream signalling events as phosphorylation of IκB kinases (IKKα and IKKβ) and mitogen-activated protein kinases (MAPKs) could potentially be the causes of activation of NF-κB and AP-1. All of these events could initiate a fibrogenic and/or tumorigenic response in the spleen. The spleen toxicity of aniline is studied more and the different mechanisms are suggested. This review summarizes those events following aniline exposure that induce spleen toxicity and neurotoxicity.
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Lin, Po-Han. "Association of DNA repair gene-mutation, mutation burden and, neoantigen load in breast cancer." Journal of Clinical Oncology 36, no. 5_suppl (February 10, 2018): 9. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.9.
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9 Background: Anti-cancer therapy with immune checkpoint inhibitors demonstrated high efficacy in hypermutated tumors; Food and Drug Administration recently proved PD1/PDL-1 blockade therapy in solid tumors characterized with deficiency of mismatch repair (MMR). However, several malignancies contain less feature of MMR deficiency. Except MMR, it remains uncertain whether mutations of other DNA repair genes are associated with hypermutated status. We aim to analyze the relationship between DNA repair gene-mutation statuses, mutation burden and neoantigen load in breast cancer. Methods: Whole exome sequencing was performed on germline and tumor DNA in 82 patients with early-onset breast cancer (≤ 40 year-old). Calculation of mutation burden includes tumor-specific insertion/deletion (Indel) and single nucleotide variants. Missense mutations, frameshift mutations and uncorrected splicing were considered to generate new peptides (neopeptides). Binding affinity of neopeptide-major histocompatibility complex class I and their immunogenicity were predicted by NetMHC 4.0 and POPI 2.0. Results: A total of 18 pathogenic mutations were found, 4 in ATM (2 germline and 2 somatic), 3 in BRCA1 (germline), 4 in BRCA2 (germline), 1 in BRIP1 (germline), 1 in CHK2 (germline), 1 in ERCC8 (germline), 2 in MSH2 (1 germline and 1 somatic), 1 in RAD51C (somatic) and 1 in OGG1 (germline). The median number of exomic mutations (missense mutations and Indels) were 744 (min. 355; max. 3587) variants per sample. Tumors with mutations of homologous recombination (HR) and MMR genes contained a higher trend of exomic mutations than those without mutation. However, tumors with mutations of HR and MMR genes contained significantly higher numbers of neopeptides with high binding affinity and immunogenicity than those without mutation (p = 0.04). Conclusions: Tumors with mutations of HR and MMR genes contained higher numbers of neoantigens. This study showed that HR and MMR mutation may be a biomarker predicted clinical benefit of immune checkpoint blockade therapy in breast cancer.
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Visnes, Torkild, Armando Cázares-Körner, Wenjing Hao, Olov Wallner, Geoffrey Masuyer, Olga Loseva, Oliver Mortusewicz, et al. "Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation." Science 362, no. 6416 (November 15, 2018): 834–39. http://dx.doi.org/10.1126/science.aar8048.
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The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor–α–induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.
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Le, Kang, Zenaide Quezado, Sayuri Kamimura, Meghann L. Smith, Yuki Tahara, Yujeong Lee, Laxminath Tumburu, Anna Conrey, Eric T. Kool, and Swee Lay Thein. "8-Oxoguanine DNA Glycosylase 1 Inhibition Suppresses Inflammatory Responses in Sickle Cell Disease." Blood 142, Supplement 1 (November 28, 2023): 2482. http://dx.doi.org/10.1182/blood-2023-182157.
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Background: The continuous production of reactive oxygen species (ROS) and oxidative stress contribute to ongoing inflammation and the pathology of sickle cell disease (SCD). ROS are known to mediate DNA damage through oxidation of nucleotide bases with guanine being the primary target. Although guanine base lesions vary according to the nature of the oxidants, 7,8-dihydro-8-oxoguanine (8-oxoG) is the most frequent oxidation product of DNA, which is repaired by 8-Oxoguanine-DNA glycosylase-1 (OGG1) via the DNA base excision repair pathway (OGG1-BER). The release of the 8-oxoG base from the genome by OGG1-BER is a prerequisite for increasing expression of pro-inflammatory cytokines and immune response. OGG1 inhibition has been shown to attenuate proinflammatory responses via the mitochondrial DNA-cGAS-STING axis in mice (Qin et al, 2020), a pathway also involved in the activation of neutrophils in SCD (Tumburu et al, 2021). Here, we evaluate the effect of OGG1 inhibition on expression of pro-inflammatory cytokines and immune response in SCD. Methods: Blood samples were obtained from ethnic-matched healthy controls (HbAA) and patients with SCD (HbSS) enrolled under protocols NCT03049475 and NCT00047996. CD14+ monocytes were isolated from PBMC of HbAA and HbSS subjects using EasySep™ Human Monocyte Isolation Kit (STEMCELL Technologies). 8-oxoG was measured by staining CD14+ monocytes with anti-8-oxoG antibody; OGG1 and pro-inflammatory cytokine levels were evaluated by qRT-PCR and western blotting. After differentiation, macrophages derived from CD14+ monocytes were treated with or without 10 µM SU0268 (OGG1 inhibitor) for 1 hour and then incubated with plasma from healthy controls or HbSS patients in steady or crisis status, followed by qRT-PCR quantitation of IL-1ꞵ, IL-6, TNF-α, and OGG1 mRNA levels. These measurements were repeated after OGG1 knockdown using OGG1 siRNA in macrophages derived from CD14+ monocytes. We repeated the study on peritoneal macrophages (PMs) from Townes HbAA and HbSS mice that were collected 4 days after a 3% Brewer's thioglycolate medium intraperitoneal injection. The level of 8-oxoG was measured by staining PMs with anti-8-oxoG antibody. The mRNA and protein level of OGG1 and pro-inflammatory cytokines were evaluated by qRT-PCR and western blotting. PMs from HbAA mice were treated with 10 µM SU0268 (OGG1 inhibitor) or vehicle for 1 hour, before incubation with plasma from HbAA or HbSS mice, the mRNA levels of IL-1ꞵ, IL-6, TNF-α, and OGG1 were measured by qRT-PCR. Results: CD14+ monocytes isolated from human HbSS PBMC showed increased levels of 8-oxoG nuclear staining when compared with human HbAA CD14+ monocytes, consistent with an increased oxidative burden in SCD patients (Fig 1A). The mRNA and protein levels of OGG1 were also increased in HbSS monocytes, suggestive of a potential therapeutic target of OGG1. Consistent with previous studies, mRNA levels of pro-inflammatory cytokines IL-1ꞵ, IL-6, and TNF-α were increased in SS compared with AA monocytes. To investigate the role of OGG1 in regulating cytokine expression, we treated the macrophages derived from CD14+ monocytes with SU0268, a selective OGG1 inhibitor (Tahara et al, 2018). Macrophages treated with plasma from HbSS patients (steady and crisis status) showed increased expression of OGG1, IL-1ꞵ, IL-6, and TNF-α compared with cells treated with normal plasma, and the increase was largely blocked by SU0268 pretreatment (Fig1B). Further, siRNA knockdown of OGG1 decreased the expression of IL-1ꞵ and TNF-α, confirming the role of OGG1 in regulating pro-inflammatory cytokine expression. We then evaluated the effect of OGG1 in regulating cytokines expression in cells form SCD mice. The levels of 8-oxoG and OGG1, as well as cytokines (IL-1ꞵ, IL-6, and TNF-α), were increased in PMs obtained from HbSS mice compared with macrophages obtained from HbAA mice. Similar to the results obtained from human macrophages, murine cells treated with plasma from SS mice showed increased expression of IL-1ꞵ, IL-6, TNF-α and OGG1 compared with cells treated with plasma from HbAA mice, and pretreatment with SU0268 largely blocked their increased expression. Conclusion: OGG1 has a regulatory role in the expression of pro-inflammatory cytokines in SCD. OGG1 inhibition could be a potential therapeutic approach to control sickle cell inflammation.
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Hanna, Bishoy M. F., Maurice Michel, Thomas Helleday, and Oliver Mortusewicz. "NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487." International Journal of Molecular Sciences 22, no. 9 (April 27, 2021): 4542. http://dx.doi.org/10.3390/ijms22094542.
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DNA damage caused by reactive oxygen species may result in genetic mutations or cell death. Base excision repair (BER) is the major pathway that repairs DNA oxidative damage in order to maintain genomic integrity. In mammals, eleven DNA glycosylases have been reported to initiate BER, where each recognizes a few related DNA substrate lesions with some degree of overlapping specificity. 7,8-dihydro-8-oxoguanine (8-oxoG), one of the most abundant DNA oxidative lesions, is recognized and excised mainly by 8-oxoguanine DNA glycosylase 1 (OGG1). Further oxidation of 8-oxoG generates hydantoin lesions, which are recognized by NEIL glycosylases. Here, we demonstrate that NEIL1, and to a lesser extent NEIL2, can potentially function as backup BER enzymes for OGG1 upon pharmacological inhibition or depletion of OGG1. NEIL1 recruitment kinetics and chromatin binding after DNA damage induction increase in cells treated with OGG1 inhibitor TH5487 in a dose-dependent manner, whereas NEIL2 accumulation at DNA damage sites is prolonged following OGG1 inhibition. Furthermore, depletion of OGG1 results in increased retention of NEIL1 and NEIL2 at damaged chromatin. Importantly, oxidatively stressed NEIL1- or NEIL2-depleted cells show excessive genomic 8-oxoG lesions accumulation upon OGG1 inhibition, suggesting a prospective compensatory role for NEIL1 and NEIL2. Our study thus exemplifies possible backup mechanisms within the base excision repair pathway.
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Huang, Hai-Li, Ya-Peng Shi, Hui-Juan He, Ya-Hong Wang, Ting Chen, La-Wei Yang, Teng Yang, et al. "MiR-4673 Modulates Paclitaxel-Induced Oxidative Stress and Loss of Mitochondrial Membrane Potential by Targeting 8-Oxoguanine-DNA Glycosylase-1." Cellular Physiology and Biochemistry 42, no. 3 (2017): 889–900. http://dx.doi.org/10.1159/000478644.
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Background: Our previous study identified a novel microRNA, miR-4673, which is upregulated in A549 cells exposed to paclitaxel (PTX). In this study, we investigated the role of miR-4673 in PTX-induced cytotoxicity. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, apoptosis assay, 5,5’,6,6’-Tetrachloro-1,1’,3,3’-tetraethyl-imidacarbocyanine iodide (JC-1) staining and 2’,7’-Dichlorofluorescein (DCFH) staining were used to evaluate cell viability, apoptosis, mitochondrial membrane potential (MMP) loss and reactive oxygen species (ROS) generation in A549 and H1299 cells. Bioinformatics analysis and Luciferase reporter assay were used to explore whether 8-oxoguanine-DNA glycosylase-1 (OGG1) is a target gene of miR-4673. Results: Enforced expression of miR-4673 decreased cell viability and increased PTX-induced apoptosis, MMP loss and reactive oxygen species (ROS) generation in A549 and H1299 cells. Bioinformatics analysis, which was used to identify potential target of miR-4673, revealed a binding site of miR-4673 in 3’UTR of OGG1. Luciferase reporters assays showed that miR-4673 specifically binds to ‘CUGUUGA’ in 3’UTR of OGG1. Enforced expression of miR-4673 decreased accumulation of OGG1. In addition, silencing OGG1 enhanced inhibitory effects of PTX on apoptosis, MMP loss and ROS generation, which is similar to effects of miR-4673. Moreover, enforced expression of OGG1 compromised promoting effects of miR-4673 on PTX-induced apoptosis, MMP loss and ROS generation. Conclusion: miR-4673 modulates PTX-induced apoptosis, MMP loss and ROS generation by targeting OGG1.
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Liu, Jin-Peng, Mayumi Komachi, Hideaki Tomura, Chihiro Mogi, Alatangaole Damirin, Masayuki Tobo, Mutsumi Takano, et al. "Ovarian cancer G protein-coupled receptor 1-dependent and -independent vascular actions to acidic pH in human aortic smooth muscle cells." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 3 (September 2010): H731—H742. http://dx.doi.org/10.1152/ajpheart.00977.2009.
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Atherosclerosis is a chronic inflammation disease characterized by acidic micromilieu and the accumulation of numerous bioactive lipid mediators, such as lysophosphatidic acid (LPA) and prostaglandins, in the atherosclerotic lesion. Chronic acidification induced various effects on vascular smooth muscle cells, but the molecular mechanisms underlying these effects remain unknown. In this study, we examine the role of proton-sensing ovarian cancer G protein-coupled receptor 1 (OGR1) in extracellular acidification-induced regulation of cyclooxygenase (COX)-2 induction, PGI2 production, MAPK phosphatase (MKP)-1 expression, and plasminogen activator inhibitor (PAI)-1 expression and proliferation in human aortic smooth muscle cells (AoSMCs). Experiments with knockdown with small interfering RNA specific to OGR1 and specific inhibitors for G proteins showed that acidification-induced COX-2 expression, PGI2 production, and MKP-1 expression, but not PAI-1 expression and inhibition of proliferation, were dependent on OGR1 and mainly mediated by Gq/11 protein. LPA remarkably enhanced, through the LPA1 receptor/Gi protein, the OGR1-mediated vascular actions to acidic pH. In conclusion, acidic pH-induced vascular actions of AoSMCs can be dissected to OGR1-dependent and -independent pathways: COX-2 expression, PGI2 production, and MKP-1 expression are mediated by OGR1, but PAI-1 expression and inhibition of proliferation are not. LPA, which is usually thought to be a proatherogenic lipid mediator, may exert antiatherogenic actions under acidic micromilieu through cross-talk between LPA1/Gi protein and OGR1/Gq/11 protein.
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Le, Kang, Zenaide Quezado, Haiou Li, Sayuri Kamimura, Meghann L. Smith, Yuki Tahara, Yujeong Lee, et al. "8-Oxoguanine DNA Glycosylase 1 Recruits Transcription Factor STAT1 to Promote the Inflammatory Responses in Sickle Cell Disease." Blood 144, Supplement 1 (November 5, 2024): 2490. https://doi.org/10.1182/blood-2024-201619.
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A key intermediate in the inflammatory pathway is 7,8-dihydro-8-oxoguanine (8-oxoG), the most frequent oxidation DNA product of reactive oxygen species (ROS). In the process of repair and release of 8-oxoG from the genome, 8-Oxoguanine-DNA glycosylase-1 (OGG1) has been reported to increase expression of pro-inflammatory cytokines. In our previous study, we showed that 8-oxoG and OGG1 were highly expressed in peripheral CD14+ monocytes from patients with sickle cell disease (SCD) and peritoneal macrophages from Townes HbSS mice. Macrophages incubated with plasma from SCD-HbSS patients showed increased expression of pro-inflammatory cytokines IL-1ꞵ, IL-6, TNF-α, which was largely blocked by pretreatment with SU0268, a selective OGG1 inhibitor, further confirmed using OGG1-unique siRNAs. Objective: To investigate the mechanism of how OGG1 regulates expression of the pro-inflammatory cytokines utilizing mass-spectrometry analysis. Methods: Blood samples were obtained from ethnic-matched healthy controls (HbAA) and patients with SCD-HbSS enrolled under protocols NCT03049475 and NCT00047996). CD14+ monocytes were isolated from PBMCs of HbAA and HbSS subjects using EasySep™ Human Monocyte Isolation Kit (STEMCELL Technologies). Human THP-1 monocytic cells were grown in RPMI 1640 medium supplemented with 10% FBS and 1% penicillin-streptomycin. To acquire macrophages from monocytes, THP1 cells were incubated with 50 ng/ml PMA (Sigma-Aldrich, MO USA) for 24h. One transfection reagent and two siRNAs from an evaluation of four different transfection reagents and four OGG1-unique siRNAs were chosen for the study. After differentiation, macrophages derived from THP1 cells were transfected with OGG1 siRNA for 48h and then incubated with HbAA or HbSS steady state or crisis plasma, followed by qRT-PCR quantitation of IL-1ꞵ, IL-6, and TNF-α mRNA. To identify the binding partner of OGG1, a mass-spectrometry method was employed to analyze the product immunoprecipitated by OGG1. The identified proteins were further filtered based on the Human Transcription Factor database. Differential expressed proteins were selected based on t-test and fold change along with volcano plot. Null expression PSM was adjusted by adding negligible value. All analyses were conducted with R (v4.3.2). The interaction between OGG1 and STAT1 was confirmed by co-immunoprecipitation, and the level of tyrosine phosphorylation of STAT1 (Tyr-p-STAT1) measured by Western blotting. To confirm the effect of STAT1 on immune response, THP1 derived macrophages were treated with fludarabine (STAT1 inhibitor) or transfected with two STAT1-unique siRNAs, and then incubated with plasma from HbSS patients, followed by qRT-PCR quantitation of IL-1ꞵ, IL-6, TNF-α, and OGG1 mRNA. The putative binding sites of STAT1 on IL-1ꞵ, IL-6, and TNF-α promoters were predicted by JASPAR database. Results: We first confirmed that siRNA knockdown of OGG1 blocked the increased expression of IL-1ꞵ, IL-6, and TNF-α in macrophages treated with plasma from HbSS patients (steady and crisis status). We next sought to identify the binding partners of OGG1 in the initiation of expression of these inflammatory cytokines. Mass-spectrometry analysis of OGG1 immunoprecipitation product identified more than one thousand proteins, of which 81 were transcription factors. Signal transducer and activator of transcription 1 (STAT1) ranked as the second highest occurrence. We confirmed the interaction between OGG1 and STAT1 via co-immunoprecipitation. Interestingly, the activity of STAT1 (Tyr-p-STAT1) in HbSS CD14+ monocytes is higher than that in HbAA CD14+ monocytes, suggesting STAT1 as a potential therapeutic target of inflammation in SCD. To investigate the role of STAT1 in regulating cytokine expression, we treated THP1 derived macrophages with fludarabine or STAT1 siRNA. Plasma from HbSS patients increased the expression of OGG1, IL-1ꞵ, IL-6, and TNF-α, and the increase was largely blocked by fludarabine or STAT1 siRNA. A search of JASPAR database revealed three, three, and one putative binding sites of STAT1 on the promoters of IL-1ꞵ, TNF-α, and IL-6, respectively, which suggests a direct regulatory role of STAT1 on these pro-inflammatory cytokines. Conclusion: OGG1 recruits STAT1 to regulate the expression of pro-inflammatory cytokines in SCD. OGG1 inhibition could be a potential therapeutic approach to control sickle cell inflammation.
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Xu, Xiaofang, Dianhua Qiao, Lang Pan, Istvan Boldogh, Yingxin Zhao, and Allan R. Brasier. "RELA∙8-Oxoguanine DNA Glycosylase1 Is an Epigenetic Regulatory Complex Coordinating the Hexosamine Biosynthetic Pathway in RSV Infection." Cells 11, no. 14 (July 15, 2022): 2210. http://dx.doi.org/10.3390/cells11142210.
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Respiratory syncytial virus (RSV), or human orthopneumovirus, is a negative-sense RNA virus that is the causative agent of severe lower respiratory tract infections in children and is associated with exacerbations of adult lung disease. The mechanisms how severe and/or repetitive virus infections cause declines in pulmonary capacity are not fully understood. We have recently discovered that viral replication triggers epithelial plasticity and metabolic reprogramming involving the hexosamine biosynthetic pathway (HBP). In this study, we examine the relationship between viral induced innate inflammation and the activation of hexosamine biosynthesis in small airway epithelial cells. We observe that RSV induces ~2-fold accumulation of intracellular UDP-GlcNAc, the end-product of the HBP and the obligate substrate of N glycosylation. Using two different silencing approaches, we observe that RSV replication activates the HBP pathway in a manner dependent on the RELA proto-oncogene (65 kDa subunit). To better understand the effect of RSV on the cellular N glycoproteome, and its RELA dependence, we conduct affinity enriched LC-MS profiling in wild-type and RELA-silenced cells. We find that RSV induces the accumulation of 171 N glycosylated peptides in a RELA-dependent manner; these proteins are functionally enriched in integrins and basal lamina formation. To elaborate this mechanism of HBP expression, we demonstrate that RSV infection coordinately induces the HBP pathway enzymes in a manner requiring RELA; these genes include Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT)-1/2, Glucosamine-Phosphate N-Acetyltransferase (GNPNAT)-1, phosphoglucomutase (PGM)-3 and UDP-N-Acetylglucosamine Pyrophosphorylase (UAP)-1. Using small-molecule inhibitor(s) of 8-oxoguanine DNA glycosylase1 (OGG1), we observe that OGG1 is also required for the expression of HBP pathway. In proximity ligation assays, RSV induces the formation of a nuclear and mitochondrial RELA∙OGG1 complex. In co-immunoprecipitaton (IP) experiments, we discover that RSV induces Ser 536-phosphorylated RELA to complex with OGG1. Chromatin IP experiments demonstrate a major role of OGG1 in supporting the recruitment of RELA and phosphorylated RNA Pol II to the HBP pathway genes. We conclude that the RELA∙OGG1 complex is an epigenetic regulator mediating metabolic reprogramming and N glycoprotein modifications of integrins in response to RSV. These findings have implications for viral-induced adaptive epithelial responses.
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Chen, Yuwei, and Jun Wang. "1-Deoxynojirimycin Attenuates High-Glucose-Induced Oxidative DNA Damage via Activating NRF2/OGG1 Signaling." Applied Sciences 14, no. 8 (April 10, 2024): 3186. http://dx.doi.org/10.3390/app14083186.
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1-Deoxynojirimycin (DNJ) is a type of alkaloid that mainly exists in mulberry fruit and leaves. DNJ inhibits α-glucosidase, reduces the absorption of sugar, and suppresses after-meal hyperglycemia. It was reported that DNJ functions in attenuating cellular oxidative stress. However, the mechanisms remain largely unknown. In this study, we firstly confirmed that 5 µmol/L DNJ treatment mitigated the oxidative DNA damage and cell senescence in human umbilical vein endothelial cells (HUVEC) cultured in medium containing 50 mmol/L glucose. Next, we found that DNJ treatment stimulates the expression of anti-oxidative response regulator, Nuclear factor (erythroid-derived 2)-like 2 (NRF2) by around 50% in cells cultured with high glucose. In addition, 8-oxoguanine DNA glycosylase (OGG1) was upregulated by over 15% after DNJ treatment to mitigate high-glucose-induced oxidative DNA damage, and it was identified as a downstream target of NRF2. Further, DNJ treatment promoted the phosphorylation and activation of AKT (ser473) by around 50% in cells cultured with high glucose, and AKT inhibitor treatment abrogated DNJ-induced upregulation of NRF2 and OGG1. Taken together, our results indicate that DNJ is an effective natural antioxidant in mitigating high-glucose-induced oxidative stress in HUVEC via activating the AKT-NRF2-OGG1 anti-oxidative response.
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Muhseen, Ziyad Tariq, Mustafa Hussein Ali, Nawar Rushdi Jaber, Dheyaa Shakir Mashrea, Ali Mamoon Alfalki, and Guanglin Li. "Determination of Novel Anti-Cancer Agents by Targeting OGG1 Enzyme Using Integrated Bioinformatics Methods." International Journal of Environmental Research and Public Health 18, no. 24 (December 16, 2021): 13290. http://dx.doi.org/10.3390/ijerph182413290.
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The 8-oxoguanine DNA glycosylase (OGG1) enzyme is a key DNA glycosylase mediating the excision of 7,8-dihydro-8-oxoguanine (8-oxoG) from DNA molecule to the start base excision repair pathway. The OGG1 glycosylase function depletion has been seen to obstruct pathological conditions such as inflammation, A3 T-cell lymphoblastic acute leukemia growth, and neurodegenerative diseases, thus warranting OGG1 as an attractive anti-cancer enzyme. Herein, we employed several drug libraries intending to screen non-toxic inhibitory molecules against the active pocket of the enzyme that achieved stable binding mode in dynamics. Two anti-cancer compounds ([O-]C1=C(CC2=CC=CC=C2)SC(=[N+]1CC(=O)NC3=NC=C(CC4=CC=CC=C4)S3)S and CCCN(CCC)[S]-(=O)(=O)C1=CC=C(C=C1)C(=O)NNC2=NC3=CC=C(Br)C=C3C(=N2)C4=CC=CC=C4) from Selleckchem.com were identified to occupy the active pocket of OGG1 and bind with greater affinity than Control TH5487. The binding affinity of Top-1 is −11.6 kcal/mol while that of Top-2 is −10.7 kcal/mol in contrast to TH5487 Control (−9 kcal/mol). During molecular dynamic simulations versus time, the said compounds are tightly held by the enzyme with no minor structural deviations reported except flexible loops in particular those present at the N and C-terminal. Both the compounds produced extensive hydrophobic interactions with the enzyme along with stable hydrogen bonding. The docking and molecular dynamics simulations predictions were further validated by molecular mechanics with generalized Born and surface area solvation (MM/GBSA) and Poisson Boltzmann surface area (MM/PBSA), and WaterSwap binding energies that validated strong binding of the compounds to the enzyme. The MM/GBSA binding free energy for Top-1 complex is −28.10 kcal/mol, Top-2 complex is −50.14 kcal/mol) and Control is −46.91 kcal/mol while MM/PBSA value for Top-1, Top-2 and Control is −23.38 kcal/mol, −35.29 kcal/mol and −38.20 kcal/mol, respectively. Computational pharmacokinetics support good druglike candidacy of the compounds with acceptable profile of pharmacokinetics and very little toxicity. All these findings support the notion that the compounds can be used in experiments to test their anti-cancer activities.
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Ramirez, Jessica, Elizabeth Paris, Sanjib Basu, and Animesh Barua. "Abstract A015: Age-associated molecular changes may predispose the ovary to malignant transformation leading to ovarian cancer (OVCA)." Cancer Research 83, no. 2_Supplement_1 (January 15, 2023): A015. http://dx.doi.org/10.1158/1538-7445.agca22-a015.
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Abstract Background: Ovarian cancer (OVCA) is a fatal malignancy of women which in most cases is a disease of postmenopausal women. Thus, age-associated changes in women may predispose them to malignancy. Persistent high levels of follicle stimulating hormone (FSH) is a feature of aging and we have shown that aging was associated with increased expression of inflammatory cytokine interleukin 16 (IL-16) and glucose regulatory protein (GRP78), a marker of cellular stress. It is possible that age-associated increased expression of IL-16 and GRP78 might be involved in production of mutagenic 8-OXO-2dG or its cognate enzyme OGG1 and malondialdehyde (MDA) as well as markers of DNA repair mechanisms. The goal of this study was to determine the mechanism of age-associated malignant transformation in the ovary. Materials and Methods: Exploratory study: Archived tissue specimens were selected for immunohistochemical, immunoblotting, genomic studies and immunoassays based on the review of their hematoxylin and eosin staining and final Pathological reports. Specimens were grouped as normal premenopausal women (30-50 years old), normal postmenopausal women (55-85 years old) and ovarian high grade serous carcinoma (HGSC). In vitro study: human ovarian surface epithelium (HOSE) cells were treated with or without FSH for 24 hours, and their cytoplasmic and nuclear fractionations together with that of OVCAR3 (HGSC cell line) cells were extracted. Expression of markers of inflammation (IL-16), oxidative stress (SOD2, GRP78), DNA adducts (8-OXO-2dG/OGG1, MDA) and epigenetics (HDAC1, gH2AX) and were examined. Significant differences in expression of different markers among different age groups and ovarian HGSC, and treated or control OVCAR3 cells were determined by ANOVA and t-tests. Results: Compared with premenopausal women, expression of markers of inflammation and oxidative stress including IL-16, GRP78, SOD2, 8-OXO-2dG/OGG1, MDA as well as markers of epigenetic changes including HDAC1 and gH2AX was significantly higher (<0.0001) in a subset of postmenopausal women. Similar patterns of expression were also observed in patients with ovarian HGSC. Nuclear expression of mutagenic DNA adducts (OGG1, MDA) and inhibitor of DNA damage repair mechanism (GRP78) enhanced during aging. Thus, age-associated inflammation and oxidative stress are predispositions to malignant transformation. This assumption is based on the observation from the treatment of HOSE cells with FSH which showed increased expression of the above markers as also observed in OVCAR3 cells. Conclusion: Expression of IL-16, GRP78, SOD2, 8-OXO-2dG/OGG1, MDA and HDAC1 increased in ovary during aging. These results suggest that aging is associated with persistent inflammation and oxidative stress in ovarian tissues, which predisposes these tissues to malignant transformation leading to OVCA development. Support: NIH/NCI: CA210370 Citation Format: Jessica Ramirez, Elizabeth Paris, Sanjib Basu, Animesh Barua. Age-associated molecular changes may predispose the ovary to malignant transformation leading to ovarian cancer (OVCA) [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A015.
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Bhatia, Shama, Yongran Yan, Mina Ly, and Peter G. Wells. "Sex- and OGG1-dependent reversal of in utero ethanol-initiated changes in postnatal behaviour by neonatal treatment with the histone deacetylase inhibitor trichostatin A (TSA) in oxoguanine glycosylase 1 (Ogg1) knockout mice." Toxicology Letters 356 (March 2022): 121–31. http://dx.doi.org/10.1016/j.toxlet.2021.12.010.
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Kuck, Jamie L., Boniface O. Obiako, Olena M. Gorodnya, Viktor M. Pastukh, Justin Kua, Jon D. Simmons, and Mark N. Gillespie. "Mitochondrial DNA damage-associated molecular patterns mediate a feed-forward cycle of bacteria-induced vascular injury in perfused rat lungs." American Journal of Physiology-Lung Cellular and Molecular Physiology 308, no. 10 (May 15, 2015): L1078—L1085. http://dx.doi.org/10.1152/ajplung.00015.2015.
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Fragments of the mitochondrial genome released into the systemic circulation after mechanical trauma, termed mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs), are thought to mediate the systemic inflammatory response syndrome. The close association between circulating mtDNA DAMP levels and outcome in sepsis suggests that bacteria also might be a stimulus for mtDNA DAMP release. To test this hypothesis, we measured mtDNA DAMP abundance in medium perfusing isolated rat lungs challenged with an intratracheal instillation of 5 × 107 colony-forming units of Pseudomonas aeruginosa (strain 103; PA103). Intratracheal PA103 caused rapid accumulation of selected 200-bp sequences of the mitochondrial genome in rat lung perfusate accompanied by marked increases in both lung tissue oxidative mtDNA damage and in the vascular filtration coefficient ( Kf). Increases in lung tissue mtDNA damage, perfusate mtDNA DAMP abundance, and Kf were blocked by addition to the perfusion medium of a fusion protein targeting the DNA repair enzyme Ogg1 to mitochondria. Intra-arterial injection of mtDNA DAMPs prepared from rat liver mimicked the effect of PA103 on both Kf and lung mtDNA integrity. Effects of mtDNA and PA103 on Kf were also attenuated by an oligodeoxynucleotide inhibitor of Toll-like receptor 9 (TLR-9) by mitochondria-targeted Ogg1 and by addition of DNase1 to the perfusion medium. Collectively, these findings are consistent with a model wherein PA103 causes oxidative mtDNA damage leading to a feed-forward cycle of mtDNA DAMP formation and TLR-9-dependent mtDNA damage that culminates in acute lung injury.
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Ichimonji, Isao, Hideaki Tomura, Chihiro Mogi, Koichi Sato, Haruka Aoki, Takeshi Hisada, Kunio Dobashi, Tamotsu Ishizuka, Masatomo Mori, and Fumikazu Okajima. "Extracellular acidification stimulates IL-6 production and Ca2+ mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 299, no. 4 (October 2010): L567—L577. http://dx.doi.org/10.1152/ajplung.00415.2009.
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The asthmatic airway has been shown to be an acidic environment that may be involved in the pathophysiological features of asthma. However, the mechanism by which an acidic pH modulates the cellular activities involved in the asthmatic airway remains elusive. Here, we characterized acidic pH-induced actions in human airway smooth muscle cells (ASMCs). Extracellular acidification stimulates the mRNA expression and protein production of IL-6, a proinflammatory cytokine, in association with the phosphorylation of extracellular signal-regulated kinase (ERK) and p38MAPK, reflecting the activation of the enzymes. Acidification-induced cytokine production was inhibited by inhibitors of ERK and p38MAPK. Acidification also increased intracellular Ca2+ concentration, which was accompanied by cell rounding, most likely reflecting contraction. In ASMCs, OGR1 is expressed at by far the highest levels among proton-sensing G protein-coupled receptors. The knockdown of OGR1 and Gq/11 protein with their specific small interfering RNAs and an inhibition of Gq/11 protein with YM-254890 attenuated the acidification-induced actions. We conclude that extracellular acidification stimulates IL-6 production and Ca2+ mobilization through proton-sensing OGR1 receptors/Gq/11 proteins in human ASMCs.
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Baebler, K., C. Maeyashiki, P. Busenhart, M. Schwarzfischer, K. Atrott, S. Lang, M. Spalinger, M. Scharl, G. Rogler, and C. de Vallière. "P087 A novel OGR1 (GPR68) inhibitor attenuates inflammation in a murine model of Acute Colitis." Journal of Crohn's and Colitis 12, supplement_1 (January 16, 2018): S137. http://dx.doi.org/10.1093/ecco-jcc/jjx180.214.
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Baebler, Katharina, Cheryl de Valliere, Chiaki Maeyashiki, Philipp Busenhart, Marlene Schwarzfischer, Kirstin Atrott, Silvia Lang, Marianne Spalinger, Michael M. Scharl, and Gerhard Rogler. "Tu1775 - A Novel Ogr1 (GPR68) Inhibitor Attenuates Inflammation in a Murine Model of Acute Colitis." Gastroenterology 154, no. 6 (May 2018): S—1016. http://dx.doi.org/10.1016/s0016-5085(18)33401-2.
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Ding, Shenglong, Ji Xu, Qichen Zhang, Fangyi Chen, Jihong Zhang, Keke Gui, Min Xiong, Bing Li, Zhiyong Ruan, and Mingdong Zhao. "OGR1 mediates the inhibitory effects of acidic environment on proliferation and angiogenesis of endothelial progenitor cells." Cell Biology International 43, no. 11 (July 16, 2019): 1307–16. http://dx.doi.org/10.1002/cbin.11179.
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Wang, Ju-Qiang, Junko Kon, Chihiro Mogi, Masayuki Tobo, Alatangaole Damirin, Koichi Sato, Mayumi Komachi, et al. "TDAG8 Is a Proton-sensing and Psychosine-sensitive G-protein-coupled Receptor." Journal of Biological Chemistry 279, no. 44 (August 23, 2004): 45626–33. http://dx.doi.org/10.1074/jbc.m406966200.
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T cell death-associated gene 8 (TDAG8) has been reported to be a receptor for psychosine. Ovarian cancer G-protein-coupled receptor 1 (OGR1) and GPR4, G-protein-coupled receptors (GPCRs) closely related to TDAG8, however, have recently been identified as proton-sensing or extracellular pH-responsive GPCRs that stimulate inositol phosphate and cAMP production, respectively. In the present study, we examined whether TDAG8 senses extracellular pH change. In the several cell types that were transfected with TDAG8 cDNA, cAMP was markedly accumulated in response to neutral to acidic extracellular pH, with a peak response at approximately pH 7.0–6.5. The pH effect was inhibited by copper ions and was reduced or lost in cells expressing mutated TDAG8 in which histidine residues were changed to phenylalanine. In the membrane fractions prepared from TDAG8-transfected cells, guanosine 5′-O-(3-thiotriphosphate) binding activity and adenylyl cyclase activity were remarkably stimulated in response to neutral and acidic pH. The concentration-dependent effect of extracellular protons on cAMP accumulation was shifted to the right in the presence of psychosine. The inhibitory psychosine effect was also observed for pH-dependent actions in OGR1- and GPR4-expressing cells but not for prostaglandin E2- and sphingosine 1-phosphate-induced actions in any pH in native and sphingosine 1-phosphate receptor-expressing cells. Glucosylsphingosine and sphingosylphosphorylcholine similarly inhibited the pH-dependent action, although to a lesser extent. Psychosine-sensitive and pH-dependent cAMP accumulation was also observed in mouse thymocytes. We concluded that TDAG8 is one of the proton-sensing GPCRs coupling to adenylyl cyclase and psychosine, and its related lysosphingolipids behave as if they were antagonists against protein-sensing receptors, including TDAG8, GPR4, and OGR1.
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Nwokwu, Chukwumaobim Daniel, Adam Y. Xiao, Lynn Harrison, and Gergana G. Nestorova. "Identification of microRNA-mRNA regulatory network associated with oxidative DNA damage in human astrocytes." ASN Neuro 14 (January 2022): 175909142211017. http://dx.doi.org/10.1177/17590914221101704.
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The high lipid content of the brain, coupled with its heavy oxygen dependence and relatively weak antioxidant system, makes it highly susceptible to oxidative DNA damage that contributes to neurodegeneration. This study is aimed at identifying specific ROS-responsive miRNAs that modulate the expression and activity of the DNA repair proteins in human astrocytes, which could serve as potential biomarkers and lead to the development of targeted therapeutic strategies for neurological diseases. Oxidative DNA damage was established after treatment of human astrocytes with 10μM sodium dichromate for 16 h. Comet assay analysis indicated a significant increase in oxidized guanine lesions. RT-qPCR and ELISA assays confirmed that sodium dichromate reduced the mRNA and protein expression levels of the human base-excision repair enzyme, 8-deoxyguanosine DNA glycosylase 1 (hOGG1). Small RNAseq data were generated on an Ion Torrent™ system and the differentially expressed miRNAs were identified using Partek Flow® software. The biologically significant miRNAs were selected using miRNet 2.0. Oxidative-stress-induced DNA damage was associated with a significant decrease in miRNA expression: 231 downregulated miRNAs and 2 upregulated miRNAs (p < 0.05; >2-fold). In addition to identifying multiple miRNA-mRNA pairs involved in DNA repair processes, this study uncovered a novel miRNA-mRNA pair interaction: miR-1248:OGG1. Inhibition of miR-1248 via the transfection of its inhibitor restored the expression levels of hOGG1. Therefore, targeting the identified microRNA candidates could ameliorate the nuclear DNA damage caused by the brain’s exposure to mutagens, reduce the incidence and improve the treatment of cancer and neurodegenerative disorders.
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Lin, Yunfu, and John H. Wilson. "Transcription-Induced CAG Repeat Contraction in Human Cells Is Mediated in Part by Transcription-Coupled Nucleotide Excision Repair." Molecular and Cellular Biology 27, no. 17 (June 25, 2007): 6209–17. http://dx.doi.org/10.1128/mcb.00739-07.
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ABSTRACT Expansions of CAG repeat tracts in the germ line underlie several neurological diseases. In human patients and mouse models, CAG repeat tracts display an ongoing instability in neurons, which may exacerbate disease symptoms. It is unclear how repeats are destabilized in nondividing cells, but it cannot involve DNA replication. We showed previously that transcription through CAG repeats induces their instability (Y. Lin, V. Dion, and J. H. Wilson, Nat. Struct. Mol. Biol. 13:179-180). Here, we present a genetic analysis of the link between transcription-induced repeat instability and nucleotide excision repair (NER) in human cells. We show that short interfering RNA-mediated knockdown of CSB, a component specifically required for transcription-coupled NER (TC-NER), and knockdowns of ERCC1 and XPG, which incise DNA adjacent to damage, stabilize CAG repeat tracts. These results suggest that TC-NER is involved in the pathway for transcription-induced CAG repeat instability. In contrast, knockdowns of OGG1 and APEX1, key components involved in base excision repair, did not affect repeat instability. In addition, repeats are stabilized by knockdown of transcription factor IIS, consistent with a requirement for RNA polymerase II (RNAPII) to backtrack from a transcription block. Repeats also are stabilized by knockdown of either BRCA1 or BARD1, which together function as an E3 ligase that can ubiquitinate arrested RNAPII. Treatment with the proteasome inhibitor MG132, which stabilizes repeats, confirms proteasome involvement. We integrate these observations into a tentative pathway for transcription-induced CAG repeat instability that can account for the contractions observed here and potentially for the contractions and expansions seen with human diseases.
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He, Xiaofei, Mark Wunderlich, Benjamin Mizukawa, James C. Mulloy, Saran Feng, Lauren Lawley, Caleb Hawkins, et al. "Proton Sensor GPR68 Is Essential to Maintain Myeloid Malignancies." Blood 132, Supplement 1 (November 29, 2018): 1353. http://dx.doi.org/10.1182/blood-2018-99-110399.
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Abstract Despite the improvement of chemotherapy and targeted therapy, drug resistance still remains a challenge for long term disease free survival in aggressive leukemia patients. Recently, enhanced glycolysis is observed in acute myeloid leukemia (AML), and in association with poor clinical outcomes and chemoresistance. The byproducts of glycolysis include lactate and protons (H+), which contribute to intracellular acidosis. The extrusion of protons further results in extracellular acidosis. A group of G protein-coupled receptors (GPCRs), including GPR4, GPR65 (TDAG8), GPR68 (OGR1) and GPR132 (G2A), have been demonstrated to respond to extracellular acidosis, resulting in activation of downstream signaling pathways that regulate pleotropic cellular processes. However, it remains unclear whether these proton-sensing GPCRs contribute to the etiology of AML. Here, we performed genomic examination of leukemia (via cBioPortal). Among 660 leukemia patients, only one patient exhibited deletion of GPR132. Other than this single case, we found no genetic mutations or cytogenetic abnormalities pertaining to proton-sensing GPCRs. Examination of transcripts of these proton-sensing GPCRs revealed that GPR68 was upregulated in both pediatric and adult AML. AML patients with higher levels of GPR68 were associated with shorter overall survival. To understand the function of GPR68 in AML, we knocked down GPR68 in AML cell lines with shRNA targeting GPR68 (shGPR68). GPR68 knockdown markedly induced apoptosis, and reduced colony formation and proliferation in AML cells. This result indicates that myeloid malignancies acquire a dependency on GPR68 function. In response to extracellular H+ or overexpression, GPR68 activates Ca2+ pathway. To determine the molecular mechanism by which GPR68 overexpression supports leukemia cell growth and survival, we examined the intracellular Ca2+ levels (i.e. [Ca2+]i) in primary AML samples. Compared with CD34+ normal hematopoietic cells, all primary AML specimens tested exhibited increased [Ca2+]i, consistent with GPR68 overexpression in AML cells. Meanwhile, shGPR68 reduced [Ca2+]i in all AML cell lines tested, indicating that overexpressed GPR68 activates the Ca2+ pathway in AML. Given that enhanced glycolysis leads to extracellular acidosis, we tested whether glycolysis-mediated local acidosis could also explain enhanced GPR68 activation in AML. Indeed, inhibition of glycolysis by 2-deoxyglucose (2-DG) reduced [Ca2+]i in most of the AML cell lines tested, indicating that glycolysis is likely responsible for enhanced GPR68 activation in AML as well. Next, we attempted to identify the Ca2+-dependent molecular mechanism that mediates the prosurvival effects due to GPR68 activation. We screened a series of pharmacological inhibitors for their efficacy in reducing cell growth and inducing apoptosis. Among the inhibitors tested, only a calcineurin (CaN) inhibitor, Cyclosporine, dramatically reduced cell growth and induced apoptosis in AML cells. This finding raises the possibility that GPR68 promotes AML cell survival through activating the Gq/11/Ca2+/CaN pathway. In summary, we find that the myeloid malignancies acquire a dependency on GPR68 signaling pathway, and inhibition of GPR68 might provide a novel therapeutic strategy for AML, especially in those developing chemoresistance. Disclosures No relevant conflicts of interest to declare.
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Das, Rickta Rani, Md Atiar Rahman, Salahuddin Qader Al-Araby, Md Shahidul Islam, Md Mamunur Rashid, Nouf Abubakr Babteen, Afnan M. Alnajeebi, et al. "The Antioxidative Role of Natural Compounds from a Green Coconut Mesocarp Undeniably Contributes to Control Diabetic Complications as Evidenced by the Associated Genes and Biochemical Indexes." Oxidative Medicine and Cellular Longevity 2021 (July 27, 2021): 1–22. http://dx.doi.org/10.1155/2021/9711176.
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The purpose of this study was to look into the effects of green coconut mesocarp juice extract (CMJE) on diabetes-related problems in streptozotocin- (STZ-) induced type 2 diabetes, as well as the antioxidative functions of its natural compounds in regulating the associated genes and biochemical markers. CMJE’s antioxidative properties were evaluated by the standard antioxidant assays of 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide radical, nitric oxide, and ferrous ions along with the total phenolic and flavonoids content. The α-amylase inhibitory effect was measured by an established method. The antidiabetic effect of CMJE was assayed by fructose-fed STZ-induced diabetic models in albino rats. The obtained results were verified by bioinformatics-based network pharmacological tools: STITCH, STRING, GSEA, and Cytoscape plugin cytoHubba bioinformatics tools. The results showed that GC-MS-characterized compounds from CMJE displayed a very promising antioxidative potential. In an animal model study, CMJE significantly ( P < 0.05 ) decreased blood glucose, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, uric acid, and lipid levels and increased glucose tolerance as well as glucose homeostasis (HOMA-IR and HOMA-b scores). The animal’s body weights and relative organ weights were found to be partially restored. Tissue architectures of the pancreas and the kidney were remarkably improved by low doses of CMJE. Compound-protein interactions showed that thymine, catechol, and 5-hydroxymethylfurfural of CMJE interacted with 84 target proteins. Of the top 15 proteins found by Cytoscape 3.6.1, 8, CAT and OGG1 (downregulated) and CASP3, COMT, CYP1B1, DPYD, NQO1, and PTGS1 (upregulated), were dysregulated in diabetes-related kidney disease. The data demonstrate the highly prospective use of CMJE in the regulation of tubulointerstitial tissues of patients with diabetic nephropathy.
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Hoell, Jessica I., Sebastian Ginzel, Cornelia Eckert, Michael Gombert, Ute Fischer, Martin Stanulla, Martin Schrappe, et al. "Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia Relapsing after Allogeneic Stem Cell Transplantation." Blood 128, no. 22 (December 2, 2016): 601. http://dx.doi.org/10.1182/blood.v128.22.601.601.
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Abstract The prognosis of children with acute lymphoblastic leukemia (ALL) relapsing following allogeneic hematopoietic stem cell transplantation (allo-SCT) is still dismal. Within the framework of the ALL-REZ BFM 2002/ALL-SZT BFM 2003 trials, we performed whole-exome sequencing (WES) of ten patients relapsing after allo-SCT with the aim to thoroughly characterize the spectrum of acquired mutations and to identify potentially druggable targets, thus laying the ground for future personalized treatment strategies. Patients' age at initial diagnosis ranged from <12 months to 10 years. Two patients were diagnosed with T-ALL and 8 with pre-B-ALL. Time from initial disease to relapse ranged from 13 to 40 months. Patients underwent allo-SCT 3 to 6 months after diagnosis of relapse, donors were either HLA-matched unrelated volunteers (n=6), HLA-identical siblings (n=1) or HLA-haploidentical family donors (n=1). Time from SCT to relapse ranged from 3 to 21 months. Treatment following the post allo-SCT relapse varied considerably (from palliative care to a second allo-SCT). Only 2/10 patients are still alive, with one recently having been diagnosed with subsequent relapse following a second SCT. To investigate the mutational landscape of relapsed ALL following high-dose chemotherapeutic and immunologic attack both provided by an allo-SCT, five samples per patient were analyzed: initial leukemia (INIT), remission (REMI) after front-line chemotherapy representing patient germline, first relapse (RLPS), full donor-chimeric remission post allo-SCT (TREMI) representing donor germline, and relapse post allo-SCT (TRLPS). For comparative analyses, we defined the following three "oncogenomes" (OGs): OG1 (initial leukemia, SNVs in INIT minus REMI)), OG2 (first relapse, SNVs in RLPS minus REMI), OG3 (post allo-SCT relapse, SNVs in TRPLS minus REMI or TREMI). Median numbers of leukemia-specific SNVs in OG1-3 were 8.5, 34 and 37.5. We detected a median of 0.18 mutations per megabase (MB) in OG1, 0.67 mutations/MB in OG2 and 0.74 mutations/MB in OG3 (p= 0.005 for OG2/3 vs. OG1 [Wilcoxon test]). Although the mutational spectrum was highly diverse between individual patients and within the oncogenomes, we also identified several recurrent alterations: in OG1, five genes had recurrent SNVs (IGSF3, TTN, NOTCH1, CTBP2, NRAS). Seven genes were recurrently affected in three OG2s, including IKZF1, NOTCH1, NRAS, NT5C2. In OG3 we detected eleven recurrently mutated genes in three patients, among which were NRAS, FLT4, and TP53. Notably, TP53 was mutated in 5/10 patients. One patient carried a TP53 germline mutation, one patient had one unique SNV each in OG2 as well as OG3 and three patients had TP53 mutations only present in their OG3s. All but one SNV (resulting in a premature stop codon) were non-synonymously coding and were predicted to be deleterious for protein function. Of particular note, leukemic blasts showed profound plasticity concerning the mutational status of the nucleoside exporter NT5C2, mutations of which were previously shown to drive chemotherapy resistance in relapsed childhood ALL. While NT5C2 alterations were completely absent in OG1, 4 SNVs were detected in the OG2s of 3/10 patients. However, these NT5C2 mutations disappeared again in the OG3s once selection pressure of maintenance chemotherapy employing nucleoside analogues had been withdrawn. To identify novel treatment options in the desperate clinical scenario of post allo-SCT relapse, we searched OG3 for genetic lesions in genes known to be either targeted directly (a certain gene) or indirectly (a certain pathway) by currently approved therapeutic agents. To our surprise, nine out of ten patients exhibited such SNVs, for which additional targeted therapies are already available. Those therapeutic agents comprise small molecules inhibitors as well as antibodies such as Dasatinib, Erlotinib, Ibrutinib, Pazopanib, Tocilizumab, and Trastuzumab. Conclusion: Our comprehensive genetic analysis of ten children with ALL relapsing post allo-SCT revealed profound leukemic cell plasticity (e.g. loss of acquired NT5C2 mutations) as well as identified several recurrent genetic alterations (e.g. NOTCH1, NRAS, IKZF1) including TP53 (5/10 patients). Most importantly, we identified alterations in genes amenable to targeted treatment approaches in 9/10 patients thus potentially opening new therapeutic avenues. Disclosures Bader: Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Neovii Biotech: Research Funding; Riemser: Research Funding; Medac: Consultancy, Research Funding. Peters:Novartis: Consultancy; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy; Medac: Consultancy.
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Krieger, Nancy S., and David A. Bushinsky. "Pharmacological inhibition of intracellular calcium release blocks acid-induced bone resorption." American Journal of Physiology-Renal Physiology 300, no. 1 (January 2011): F91—F97. http://dx.doi.org/10.1152/ajprenal.00276.2010.
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In vivo chronic metabolic acidosis induces net Ca2+ efflux from bone, and incubation of neonatal mouse calvariae in medium simulating physiological metabolic acidosis induces bone resorption. It appears that activation of the proton (H+) receptor OGR1 in the osteoblast leads to an increase in intracellular Ca2+, which is associated with an increase in cyclooxygenase 2 (COX2) and PGE2-induced receptor activator of NF-κB ligand (RANKL) and H+-induced osteoclastic bone resorption. To support this hypothesis, we tested whether intracellular Ca2+ signaling was integral to H+-induced bone resorption by determining whether 8-( N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) and 2-aminoethoxydiphenyl borate (2-APB), inhibitors of inositol trisphosphate-mediated Ca2+ signaling, would block H+-induced bone resorption in cultured neonatal calvariae and, if so, would do so by inhibiting H+-induced stimulation of COX2 and RANKL in osteoblastic cells. We found that H+-induced bone resorption is significantly inhibited by TMB-8 and 2-APB. Both compounds also inhibit H+-induced stimulation of COX2 protein in calvariae and COX2 mRNA and protein levels in primary osteoblasts. H+-induced stimulation of RANKL in calvarial cultures, as well as primary cells, is also completely inhibited by TMB-8 and 2-APB. These results support the hypothesis that H+ stimulation of net Ca2+ efflux from bone, mediated by COX2- and subsequent PGE2-induced RANKL production, is initiated in the osteoblast via activation of Ca2+ signaling.
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Bahl, Martin Iain, Søren J. Sørensen, Lars Hestbjerg Hansen, and Tine Rask Licht. "Effect of Tetracycline on Transfer and Establishment of the Tetracycline-Inducible Conjugative Transposon Tn916 in the Guts of Gnotobiotic Rats." Applied and Environmental Microbiology 70, no. 2 (February 2004): 758–64. http://dx.doi.org/10.1128/aem.70.2.758-764.2004.
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ABSTRACT We have investigated the transfer of Tn916 among strains of Enterococcus faecalis OG1 colonizing in the intestines of gnotobiotic rats. This animal model allows a low limit of detection and efficient colonization of the chosen bacteria. The animals continuously received tetracycline in drinking water. A tetracycline-sensitive recipient strain was allowed to colonize the animals before the resistant donor was introduced. The numbers of donors, recipients, and transconjugants in fecal samples and intestinal segments were estimated. The bioavailable amounts of tetracycline in fecal samples and intestinal segments were monitored by using bacterial biosensors carrying a transcriptional fusion of a tetracycline-regulated promoter and a lacZ reporter gene. Chromosomal locations of Tn916 in transconjugants isolated either from the same animal or from different animals were compared by Southern blot analysis. Our results indicated that selection for the resistant phenotype was the major factor causing higher numbers of transconjugants in the presence of tetracycline. Tetracycline-sensitive E. faecalis cells colonized the intestine even when the concentrations of tetracycline in feces and intestinal luminal contents exceeded growth-inhibitory concentrations. This suggests the existence of tetracycline-depleted microhabitats in the intestinal environment.
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Fang, Jing, Xiaona Liu, Lyndsey Bolanos, Brenden Barker, Carmela Rigolino, Agostino Cortelezzi, Esther Natalie Oliva, Kyle J. MacBeth, Kakajan Komurov, and Daniel T. Starczynowski. "A Calcium-Dependent Pathway Determines Response to Lenalidomide in Del(5q) Myelodysplastic Syndromes." Blood 124, no. 21 (December 6, 2014): 1898. http://dx.doi.org/10.1182/blood.v124.21.1898.1898.
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Abstract Deletions of the long arm of chromosome 5 (del(5q)) are common cytogenetic alterations in myelodysplastic syndrome (MDS), a disease characterized by refractory anemia, megakaryocyte dysplasia, and thrombocytosis. The thalidomide analogue lenalidomide (LEN) produces durable erythroid responses in ~60% of del(5q) MDS patients, including a majority of cytogenetic responses in which the del(5q) clone becomes undetectable in the bone marrow. Despite high response rates, clinical and cytogenetic relapse occur within 2-3 years. Mechanisms of clinical response, resistance and relapse with LEN therapy remain to be elucidated. The target of LEN has recently been identified as the cereblon (CRBN) component of the cullin 4 RING E3 ubiquitin ligase complex (CRL4-CRBN). Upon LEN binding, the substrate-specificity of the CRL4-CRBN complex is altered, and LEN-regulated substrates are beginning to be identified. An RNA interference screen was performed to identify genes/pathways that mediate LEN sensitivity and resistance in del(5q) MDS. The LEN-sensitive del(5q) MDS patient-derived cell line MDSL was screened with a genome-wide shRNA library (SBI GeneNet Human 50K Library) in the presence and absence of LEN treatment (0 and 10 μM) for 7 days. Three independent shRNAs targeting the proton-sensing G protein-coupled receptor 1 (GPR68 or OGR1) were among the most enriched shRNAs in LEN-treated cells, suggesting that loss of GPR68 expression conferred resistance to LEN. This finding was validated in MDSL cells, using an independent set of shRNAs. Conversely, a GPR68 agonist (N-cyclopropoyl-5-[thiophen-2-yl]-isoxazole-3-carboxamid) enhanced LEN-induced cytotoxicity to MDSL cells. GPR68 is a proton-sensing G-protein coupled receptor that stimulates inositol phosphate production and/or intracellular calcium (Ca2+) mobilization. Curiously, CRBN was originally identified as a binding protein of calcium-activated potassium channels. These data led us to hypothesize that Ca2+ signaling may be responsible for LEN-mediated cytotoxic effect in MDS cells. Reducing intracellular Ca2+ level with chelators reversed LEN’s cytotoxic effects, while increasing intracellular Ca2+ level with ionomycin enhanced LEN’s cytotoxic effect, indicating that intracellular Ca2+ levels determine cellular responsiveness to LEN. Although LEN did not induce an instant burst of Ca2+ influx, a gradual increase of basal intracellular free Ca2+ was observed following LEN treatment in LEN-sensitive cell lines and primary MDS marrow cells, but not in LEN-resistant cells, suggesting that LEN cytotoxicity was dependent on the cell’s ability to release Ca2+ from intracellular stores. GPR68 and CRBN were both necessary for the LEN-induced increase in Ca2+, as knockdown of GPR68 or CRBN in LEN-sensitive cells prevented the Ca2+increase. To identify the Ca2+-dependent signaling pathway responsible for mediating the cytotoxic effect of LEN, a panel of seven inhibitors that blocked mitochondrial/caspase-, calpain-, autophagy-, or lysosomal-dependent cell death pathways was tested in combination with LEN on MDSL cells. Only the inhibitor of calpains (PD150606) prevented LEN-induced cytotoxic effects in MDSL cells, indicating that calpain activation was necessary for mediating cell death in LEN-treated cells. Calpains are Ca2+-dependent cysteine proteases that can induce apoptotic and necrotic cell death by proteolytic cleavage of protein substrates. Calpastatin, the only endogenous calpain inhibitor, is localized to 5q15 and its expression is haploinsufficient in del(5q) MDS as compared to normal karyotype MDS. Taken together, our results show that LEN increased intracellular Ca2+ levels by a CRBN- and GPR68-dependent mechanism, leading to calpain-mediated cytotoxicity in del(5q) MDS cells. We propose a model in which haploinsufficient expression of calpastatin in del(5q) MDS sensitizes cells to cytotoxic effects of LEN. Further studies are required to identify the direct LEN-modulated substrates of CRBN that mediate this effect. Disclosures Oliva: Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria. MacBeth:Celgene: Employment, Equity Ownership. Starczynowski:Celgene: Research Funding.
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Zhu, Liqian, Xiaotian Fu, Chen Yuan, Xinyi Jiang, and Gaiping Zhang. "Induction of Oxidative DNA Damage in Bovine Herpesvirus 1 Infected Bovine Kidney Cells (MDBK Cells) and Human Tumor Cells (A549 Cells and U2OS Cells)." Viruses 10, no. 8 (July 26, 2018): 393. http://dx.doi.org/10.3390/v10080393.
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Bovine herpesvirus 1 (BoHV-1) is an important pathogen of cattle that causes lesions in mucosal surfaces, genital tracts and nervous systems. As a novel oncolytic virus, BoHV-1 infects and kills numerous human tumor cells. However, the mechanisms underlying the virus-induced cell damages are not fully understood. In this study, we demonstrated that virus infection of MDBK cells induced high levels of DNA damage, because the percentage of comet tail DNA (tailDNA%) determined by comet assay, a direct indicator of DNA damage, and the levels of 8-hydroxyguanine (8-oxoG) production, an oxidative DNA damage marker, consistently increased following the virus infection. The expression of 8-oxoguanine DNA glycosylase (OGG-1), an enzyme responsible for the excision of 8-oxoG, was significantly decreased due to the virus infection, which corroborated with the finding that BoHV-1 infection stimulated 8-oxoG production. Furthermore, the virus replication in human tumor cells such as in A549 cells and U2OS cells also induced DNA damage. Chemical inhibition of reactive oxidative species (ROS) production by either ROS scavenger N-Acetyl-l-cysteine or NOX inhibitor diphenylene iodonium (DPI) significantly decreased the levels of tailDNA%, suggesting the involvement of ROS in the virus induced DNA lesions. Collectively, these results indicated that BoHV-1 infection of these cells elicits oxidative DNA damages, providing a perspective in understanding the mechanisms by which the virus induces cell death in both native host cells and human tumor cells.
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Tanushi, Xhaferr, Guillaume Pinna, Marie Vandamme, Capucine Siberchicot, Ostiane D’Augustin, Anne-Marie Di Guilmi, J. Pablo Radicella, et al. "OGG1 competitive inhibitors show important off-target effects by directly inhibiting efflux pumps and disturbing mitotic progression." Frontiers in Cell and Developmental Biology 11 (February 3, 2023). http://dx.doi.org/10.3389/fcell.2023.1124960.
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One of the most abundant DNA lesions induced by Reactive oxygen species (ROS) is 8-oxoG, a highly mutagenic lesion that compromises genetic instability when not efficiently repaired. 8-oxoG is specifically recognized by the DNA-glycosylase OGG1 that excises the base and initiates the Base Excision Repair pathway (BER). Furthermore, OGG1 has not only a major role in DNA repair but it is also involved in transcriptional regulation. Cancer cells are particularly exposed to ROS, thus challenging their capacity to process oxidative DNA damage has been proposed as a promising therapeutic strategy for cancer treatment. Two competitive inhibitors of OGG1 (OGG1i) have been identified, TH5487 and SU0268, which bind to the OGG1 catalytic pocket preventing its fixation to the DNA. Early studies with these inhibitors show an enhanced cellular sensitivity to cytotoxic drugs and a reduction in the inflammatory response. Our study uncovers two unreported off-targets effects of these OGG1i that are independent of OGG1. In vitro and in cellulo approaches have unveiled that OGG1i TH5487 and SU0268, despite an unrelated molecular structure, are able to inhibit some members of the ABC family transporters, in particular ABC B1 (MDR1) and ABC G2 (BCRP). The inhibition of these efflux pumps by OGG1 inhibitors results in a higher intra-cellular accumulation of various fluorescent probes and drugs, and largely contributes to the enhanced cytotoxicity observed when the inhibitors are combined with cytotoxic agents. Furthermore, we found that SU0268 has an OGG1-independent anti-mitotic activity—by interfering with metaphase completion—resulting in a high cellular toxicity. These two off-target activities are observed at concentrations of OGG1i that are normally used for in vivo studies. It is thus critical to consider these previously unreported non-specific effects when interpreting studies using TH5487 and SU0268 in the context of OGG1 inhibition. Additionally, our work highlights the persistent need for new specific inhibitors of the enzymatic activity of OGG1.
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Samaila, Abdullahi, Rusliza Basir, Nur Aimi Liyana Abdul Aziz, Abdusalam Abdullah Alarabei, Mukhtar Lawal Gambo, Maizaton Atmadini Abdullah, Mohd Khairi Hussain, Norshariza Nordin, and Roslaini Abd Majid. "Modulation of 8-Oxoguanine DNA Glycosylase 1 (OGG1) Alleviated Anemia Severity and Excessive Cytokines Release during Plasmodium berghei Malaria in Mice." Iranian Journal of Parasitology, December 8, 2024. https://doi.org/10.18502/ijpa.v19i4.17163.
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Background: The interplay of OGG1, 8-Oxoguanine, and oxidative stress triggers the exaggerated release of cytokines during malaria, which worsens the outcome of the disease. We aimed to investigate the involvement of OGG1 in malaria and assess the effect of modulating its activity on the cytokine environment and anemia during P. berghei malaria in mice. Methods: Plasmodium berghei ANKA infection in ICR mice was used as a malaria model. OGG1 concentration and oxidative stress levels in P. berghei-infected mice and their control counterparts were assessed during malaria using enzyme-linked immunosorbent assay. OGG1 activity in malaria mice was modulated using treatment with TH5487 and O8-OGG1 inhibitors. The effects of modulating OGG1 activity using OGG1 inhibitors on cytokine release and anemia during P. berghei malaria infection were assessed by cytometric bead array and measurement of total normal red blood cell count respectively. Results: The plasma OGG1 level was significantly upregulated and positively correlated with parasitemia during P. berghei malaria in mice. Modulation of OGG1 ameliorated malaria severity by improving the total normal RBC count in TH5487 and O8-treated mice. Modulation of OGG1 with TH5487 caused significant reductions in serum levels of TNF-α, IFN-γ, IL-6, and IL-10. Similarly, OGG1 modulation activity using an O8-OGG1 inhibitor caused a significant reduction in serum levels of TNF-α, IL-2, IL-6, and IL-10. Conclusion: The findings indicate the involvement of OGG1 in the P. berghei malaria infection. OGG1 inhibition by TH5487 and O8-OGG1 inhibitors suppressed excessive cytokine release, and this may represent a novel therapeutic strategy for ameliorating the severity of malaria infection.
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Baquero, Juan Miguel, Erik Marchena-Perea, Rocío Mirabet, Raúl Torres-Ruiz, Carmen Blanco-Aparicio, Sandra Rodríguez-Perales, Thomas Helleday, Carlos Benítez-Buelga, Javier Benítez, and Ana Osorio. "OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells." Frontiers in Oncology 12 (May 10, 2022). http://dx.doi.org/10.3389/fonc.2022.888810.
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BackgroundPARP1 plays a critical role in the base excision repair (BER) pathway, and PARP1 inhibition leads to specific cell death, through a synthetic lethal interaction, in the context of BRCA1/2 deficiency. To date, up to five different PARP inhibitors (PARPi), have been approved, nevertheless, the acquisition of resistance to PARPi is common and there is increasing interest in enhancing responses and expand their use to other tumour types.MethodsWe hypothesized that other BER members could be additional synthetic lethal partners with mutated BRCA genes. To test this, we decided to evaluate the glycosylase OGG1 as a potential candidate, by treating BRCA1 proficient and deficient breast cancer cells with PARPi olaparib and the OGG1 inhibitor TH5478.ResultsKnocking out BRCA1 in triple-negative breast cancer cell lines causes hypersensitivity to the OGG1 inhibitor TH5487. Besides, TH5487 enhances the sensitivity to the PARP inhibitor olaparib, especially in the context of BRCA1 deficiency, reflecting an additive interaction.DiscussionThese results provide the first evidence that OGG1 inhibition is a promising new synthetic lethality strategy in BRCA1-deficient cells, and could lead to a new framework for the treatment of hereditary breast and ovarian cancer.
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Baquero, Juan Miguel, Carlos Benítez-Buelga, Varshni Rajagopal, Zhao Zhenjun, Raúl Torres-Ruiz, Sarah Müller, Bishoy M. F. Hanna, et al. "Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects." Scientific Reports 11, no. 1 (February 10, 2021). http://dx.doi.org/10.1038/s41598-021-82917-7.
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AbstractThe most common oxidative DNA lesion is 8-oxoguanine which is mainly recognized and excised by the 8-oxoG DNA glycosylase 1 (OGG1), initiating the base excision repair (BER) pathway. Telomeres are particularly sensitive to oxidative stress (OS) which disrupts telomere homeostasis triggering genome instability. In the present study, we have investigated the effects of inactivating BER in OS conditions, by using a specific inhibitor of OGG1 (TH5487). We have found that in OS conditions, TH5487 blocks BER initiation at telomeres causing an accumulation of oxidized bases, that is correlated with telomere losses, micronuclei formation and mild proliferation defects. Moreover, the antimetabolite methotrexate synergizes with TH5487 through induction of intracellular reactive oxygen species (ROS) formation, which potentiates TH5487-mediated telomere and genome instability. Our findings demonstrate that OGG1 is required to protect telomeres from OS and present OGG1 inhibitors as a tool to induce oxidative DNA damage at telomeres, with the potential for developing new combination therapies for cancer treatment.
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Zhong, Yunxiao, Xinya Zhang, Ruibing Feng, Yu Fan, Zhang Zhang, Qing‐Wen Zhang, Jian‐Bo Wan, Yitao Wang, Hua Yu, and Guodong Li. "OGG1: An emerging multifunctional therapeutic target for the treatment of diseases caused by oxidative DNA damage." Medicinal Research Reviews, August 9, 2024. http://dx.doi.org/10.1002/med.22068.
Full textAbstract:
AbstractOxidative DNA damage‐related diseases, such as incurable inflammation, malignant tumors, and age‐related disorders, present significant challenges in modern medicine due to their complex molecular mechanisms and limitations in identifying effective treatment targets. Recently, 8‐oxoguanine DNA glycosylase 1 (OGG1) has emerged as a promising multifunctional therapeutic target for the treatment of these challenging diseases. In this review, we systematically summarize the multiple functions and mechanisms of OGG1, including pro‐inflammatory, tumorigenic, and aging regulatory mechanisms. We also highlight the potential of OGG1 inhibitors and activators as potent therapeutic agents for the aforementioned life‐limiting diseases. We conclude that OGG1 serves as a multifunctional hub; the inhibition of OGG1 may provide a novel approach for preventing and treating inflammation and cancer, and the activation of OGG1 could be a strategy for preventing age‐related disorders. Furthermore, we provide an extensive overview of successful applications of OGG1 regulation in treating inflammatory, cancerous, and aging‐related diseases. Finally, we discuss the current challenges and future directions of OGG1 as an emerging multifunctional therapeutic marker for the aforementioned challenging diseases. The aim of this review is to provide a robust reference for scientific researchers and clinical drug developers in the development of novel clinical targeted drugs for life‐limiting diseases, especially for incurable inflammation, malignant tumors, and age‐related disorders.
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"Dual Inhibitors of OGG1/NUDT1 for Probing Disease States." Synfacts 16, no. 02 (January 21, 2020): 0223. http://dx.doi.org/10.1055/s-0039-1691638.
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Savino, Luca, Maria Carmela Di Marcantonio, Carmelo Moscatello, Roberto Cotellese, Lucia Centurione, Raffaella Muraro, Gitana Maria Aceto, and Gabriella Mincione. "Effects of H2O2 Treatment Combined With PI3K Inhibitor and MEK Inhibitor in AGS Cells: Oxidative Stress Outcomes in a Model of Gastric Cancer." Frontiers in Oncology 12 (March 16, 2022). http://dx.doi.org/10.3389/fonc.2022.860760.
Full textAbstract:
Gastric cancer is worldwide the fifth and third cancer for incidence and mortality, respectively. Stomach wall is daily exposed to oxidative stress and BER system has a key role in the defense from oxidation-induced DNA damage, whilst ErbB receptors have important roles in the pathogenesis of cancer. We used AGS cells as an aggressive gastric carcinoma cell model, treated with H2O2 alone or combined with ErbB signaling pathway inhibitors, to evaluate the effects of oxidative stress in gastric cancer, focusing on the modulation of ErbB signaling pathways and their eventual cross-talk with BER system. We showed that treatment with H2O2 combined with PI3K/AKT and MEK inhibitors influenced cell morphology and resulted in a reduction of cancer cell viability. Migration ability was reduced after H2O2 treatment alone or combined with MEK inhibitor and after PI3K/AKT inhibitor alone. Western blotting analysis showed that oxidative stress stimulated EGFR pathway favoring the MAPKs activation at the expense of PI3K/AKT pathway. Gene expression analysis by RT-qPCR showed ErbB2 and OGG1 increase under oxidative stress conditions. Therefore, we suggest that in AGS cells a pro-oxidant treatment can reduce gastric cancer cell growth and migration via a different modulation of PI3K and MAPKs pathways. Moreover, the observed ErbB2 and OGG1 induction is a cellular response to protect the cells from H2O2-induced cell death. In conclusion, to tailor specific combinations of therapies and to decide which strategy to use, administration of a chemotherapy that increases intracellular ROS to toxic levels, might not only be dependent on the tumor type, but also on the molecular targeting therapy used.