bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthesis of potential antioxidants by microwave‐assisted solid phase diazotations and Friedel‐Crafts reactions of hydroquinone
Authors: Metras Breanna Nichole , Torok Bela , Elstrom Clifford 
Published: June 2021

Oxidative stress, a harmful condition, is due to an excess accumulation of free radicals in the body, leading to cellular damage and potentially pathological conditions. The damage caused by free radicals was connected to the aging process and numerous diseases such as cancer, cardiovascular diseases, neurodegenerative diseases (e.g. Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS)) or macular degeneration. Antioxidants can scavenge reactive oxygen species and effectively reduce oxidative stress. Quinone/hydroquinone easily undergoes redox changes and is perceived as potential antioxidants. In this work we explored the synthesis of hydroquinone derivatives using a new microwave‐assisted heterogeneous catalytic diazotization and subsequent coupling of the diazonium salts with hydroquinone as well as by applying traditional solid acid catalyzed Friedel‐Crafts alkylation and diazotation reactions.Support or Funding InformationFunding for this research was provided in part by the Sanofi Genzyme and Oracle Education Foundation grants to the College of Science and MathematicsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Carbamate Derivatives of Colchicine Show Potent Activity toward Primary Acute Lymphoblastic Leukemia and Primary Breast Cancer Cells: In Vitro and Ex Vivo Study
Authors: Urbaniak Alicja , Jousheghany Fariba , Yuan Youzhong , Pina‐Oviedo Segio , Delgado Magdalena , Majcher Urszula , Klejborowska Greta , Huczyński Adam , Monzavi‐Karbassi Behjatolah , Kieber‐Emmons Thomas , Chambers Timothy C. 
Published: June 2021

Colchicine (COL) is the major alkaloid isolated from the plant Colchicum autumnale. It shows strong therapeutic effects towards various types of cancer. Its biological activity is related to its ability to bind to tubulin causing microtubule depolymerization, mitotic arrest, and cell death. The colchicine binding site is an attractive target for potential tubulin polymerization destabilizers. Indeed, a large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. The identification of new therapeutics based on COL structure is warranted due to the toxicity of COL towards normal cells. In order to increase potency and reduce toxicity against normal cells, while retaining the activities in the nanomolar range, a library of novel COL analogs, namely N‐carbamates of N‐deacetyl‐4‐(bromo/chloro/iodo)thiocolchicine, has been synthesized (Fig. 1).COL and several of the derivatives arrested MCF‐7 cells in mitosis, and caused microtubule depolymerization. Compounds were then tested against two types of primary cancer cells; adult acute lymphoblastic leukemia (ALL) cells, and human breast cancer (BC) cells derived from newly excised human tumor tissue. These represent more clinically relevant drug screening models compared to established cell lines. Four novel colchicine derivatives showed higher activity towards primary ALL cells (IC50 = 1.1 ± 0.5 to 6.4 ± 1.4 nM) and nine were more potent towards primary BC cells (IC50 = 2.3 ± 0.0 to 10.3 ± 4.6 nM) compared to COL (IC50 = 8.6 ± 0.2 nM and 11.7 ± 3.1 nM, respectively) in cell viability assays. COL and two of the most active derivatives were also shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants derived from residual invasive ductal carcinoma and invasive mucinous carcinoma. The present findings indicate that the COL derivatives described here constitute promising lead compounds for targeting acute lymphoblastic leukemia and different subtypes of breast cancer.Support or Funding InformationThe present study was funded by a grant (to TCC) from the Arkansas Breast Cancer Research Program. Financial support by grant (to AH. UM, GK) of the Polish National Science Centre (NCN) – No. 2016/21/B/ST5/00111 is gratefully acknowledged.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Polyphenol‐Rich Fraction of Parquetina nigrescens Quenches Dichlorvos‐Induced Cardiorenal Dysfunction through Reduction in Nitrotyrosine/ p38 MAPK pathways
Authors: Ogunpolu Blessing Seun , Ochigbo Grace , Oyagbemi Ademola Adetokunbo , Omobowale Temidayo Olutayo , Falayi Olufunke Olubunmi , Saba Adebowale Benard , Adedapo Adeolu Alex , Yakubu Momoh Audu 
Published: June 2021

Parquetina nigrescens is commonly used to treat diseases in humans and animals in developing countries, including Nigeria. This study evaluates the effects of its polyphenol‐rich fraction (prf) on dichlorvos‐induced cardio‐ and renal toxicity. There were several factors assessed during this study, including cardiac and renal markers, serum myeloperoxidase and xanthine oxidase, and electrocardiograph (ECG) changes. The changes in electrocardiograph (ECG) were recorded. Immunohistochemistry of cardiac and renal p38 and nitrotyrosine was determined. Dichlorvos exposure caused a significant decrease in L‐glutathione (reduced glutathione) and other antioxidant enzymes with increases in malondialdehyde, myeloperoxidase, advanced oxidation protein products, and protein carbonyl levels. It also brought about alterations in microanatomy of the heart and kidneys accompanied by increases in serum creatinine and urea levels. Exposure to dichlorvos induced prolonged QRS interval and shortened QT durations in rats. Immunohistochemistry revealed lower expressions of cardiac nitrotyrosine and renal p38 (mitogen‐activated protein kinase; MAPK) in rats treated with prf of P. nigrescens. Combining all, prf of P. nigrescens demonstrated antioxidant as well as protective properties in the heart and kidneys of rats exposed to dichlorvos. It ameliorated dichlorvos‐induced cardio‐ and nephrotoxicity giving credence to its use in ethnomedicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Establishment of Optimum Conditions for Antioxidant Components Containing Curcuma L Longa (Turmeric) Leaf Extraction using Response Surface Methodology
Authors: Kim Sera , Ko Seok‐Chun , Kim Yoon‐Sook , Ha Sang‐Keun , Park Ho‐Young , Park Yong‐Gon , Lee Sang‐Hoon 
Published: June 2021

Curcuma L longa (turmeric) is a functional material but its leaves are wasted as byproduct. This study focused on the possibility of turmeric leaves as a functional food material by establishing its extraction condition using a reflux condenser with water and different concentrations of ethanol. According to the results, water extraction was efficient for extracting its total phenolic compounds (2.741±0.099 μg/ml), flavonoids (4.776±0.010 μg/ml) within various temperature and time conditions. DPPH (486.78±12.73 μg/ml), ABTS (123.19±2.42 μg/ml), and H2O2 (849.06±23.07 μg/ml) radical scavenging activities were also high in water extraction. We used response surface methodology (RSM) to optimize extraction conditions for Curcuma L longa leaves. After establishing the extraction ratio, we applied a central composite design to identify the effects of independent variables, temperature (X1), time (X2) to dependent variables, yield (Y1). From these results, the optimal conditions were established as 150 minutes with a 1:25 ratio at 85°C, giving a 15.57% extraction yield. Using the leaf extract, we measured cell viability and cytokine production using Raw 264.7 cell line to confirm its anti‐inflammatory effects. We confirmed there is no cytotoxicity in Curcuma L longa leaf extract treat groups compared to lipopolysaccharide treat (control) group. Also, production of cytokines such as TNF‐α, MCP‐1 and IL‐1β in Curcuma L longa leaf extract treat groups, decreased comparing with control group. In this study, we confirmed the optimum extract conditions of turmeric leaves as fundamental data for its application in the industry. Furthermore, we provide a new insight on turmeric leaf extract as a health‐beneficial natural product by identifying its antioxidant and anti‐inflammatory properties.Support or Funding InformationThis work was supported by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry (IPET) through High Value‐added Food Technology Development Program, funded by Korea Institute of Planning and Evaluation for Technology in Food, Agriculture and Forestry (IPET) (117078‐03).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Structure‐Toxicity Relationships of Trans‐Cinnamic Aldehyde and Its Substituted Analogs
Authors: True Heather , Debusman Chris , Harrelson John , Stamper Brendan 
Published: June 2021

ObjectiveTrans‐cinnamic aldehyde (CA) is a compound found in cinnamon and has promising potential as an agent for smoking cessation therapy. Current pharmaceutical options to treat nicotine addiction are only moderately effective and new approaches are needed. In this study, we aim to explore the hepatotoxicity profiles of CA and its structurally‐related analogs as one step in a more‐extensive evaluation of these agents to treat nicotine addiction.MethodsMouse hepatocytes were exposed to varying concentrations of CA or its structurally‐related analogs and toxicity was measured by determining median lethal dose (LC50) values. Stock solutions for all compounds were prepared in DMSO and proper vehicle controls were performed for all experiments. Cells were treated with either CA or one of eight analogs: α‐bromocinnamaldehyde (Br‐CA), α‐chlorocinnamaldehyde (Cl‐CA), 3‐phenylpropionaldehyde (sat‐CA), α‐methylcinnamaldehyde (Me‐CA), 2‐nitrocinnamaldehyde (N‐CA), 2‐trifluoromethylcinnamadehyde (CF3‐CA), 2,6‐difluorocinnamaldehyde (F‐CA), and 2‐methylcinnamaldehyde (2‐Me‐CA). After the LC50 determinations were completed, two different luminescence‐based assays were performed to assess reactive oxygen species production and glutathione (GSH) depletion during exposure to CA and its analogs. A cutoff of p < 0.05 was used to determine significance by means of one‐way analysis of variance (ANOVA) with post‐hoc Least Significant Difference (LSD) tests.ResultsSignificant differences in LC50 values were observed across the tested compounds indicating minor structural changes to the structure of CA can have profound toxicologic effects. CA analogs modified to contain electron‐withdrawing groups, as well as CA itself, were generally more toxic (lower LC50 values) than those that did not contain electron‐withdrawing groups. Furthermore, this toxicity was associated with significantly greater reactive oxygen species production and GSH depletion compared to the other CA analogs at equi‐toxic doses.ConclusionThese results indicate analogs that contain electron‐withdrawing groups share a similar or inferior toxicity profile compared to CA significantly impacting the generation of reactive oxygen species and GSH depletion. However, this toxicity profile is unique for other CA analogs that do not contain electron‐withdrawing groups, which appear to propagate toxicity through alternative cell death mechanisms. Information generated from this study will help to inform future pharmacologic studies in animal and human models as these agents are further evaluated as potential aids for smoking cessation therapy.Support or Funding InformationThis work was supported by the Pacific University Research Incentive Grant ProgramThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The CXCR7/CXCR4 heterodimer induced histone demethylation: A new mechanism of colorectal tumorigenesis
Authors: Qu Xianjun , Cui Shu Xiang 
Published: June 2021

PurposeBoth chemokine receptors (CXCR) 7 and 4 are known to be involved in a vast array of pathological events in the development cancer. However, it is not yet known whether the CXCR7/CXCR4 heterodimer can form in vivo, and if it does, the functional difference between CXCR7 monomer and the CXCR7/CXCR4 heterodimer.Experimental DesignThe expression of two CXCRs, CXCR7/CXCR4 heterodimer and histone demethylase JMJD2A in human colorectal rectal cancer (CRC) tissue was detected by western blot and immunohistochemistry. We then studied the role of the CXCR7/CXCR4 heterodimer in CRC tumorigenesis in Villin‐CXCR7‐CXCR4 transgenic mice and APCMin/+/villin‐CXCR7‐CXCR4 mice.ResultsCXCR 7 and 4 can form heterodimers in vivo and promote colorectal tumorigenesis through histone demethylation. Compared with adjacent non‐neoplastic tissue, human colorectal rectal cancer (CRC) tissue showed a significantly higher expression of CXCR4 and CXCR7, which was co‐localized in the cancer cell epithelium. CXCR/CXCR4 heterodimerization was associated with increased histone demethylase JMJD2A. Villin‐CXCR7‐CXCR4 transgenic mice presented a greater degree of exacerbated colitis and tumorigenesis than villin‐CXCR7 and villin‐CXCR4 mice. The CXCR7/CXCR4 heterodimer also increased APC mutation‐driven colorectal tumorigenesis in APCMin/+/villin‐CXCR7‐CXCR4 mice. Further analysis showed that the CXCR7/CXCR4 heterodimer induced nuclear β‐arrestin 1 recruitment and histone demethylase JMJD2A, leading to histone demethylation and increased transcription of inflammatory factors and oncogenes.ConclusionOur data reveal a novel mechanism of colorectal tumorigenesis through CXCR7/CXCR4 heterodimer‐induced histone demethylation. Inhibition of CXCR7/CXCR4 heterodimer‐induced histone demethylation could be an effective strategy for cancer treatment.Support or Funding InformationThis work was supported by Natural Science Foundation of China (91629303)
The graphical abstractimageThe graphical abstractThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
TAK1 inhibitor as a potential sensitizer for chemotherapy in glioblastoma
Authors: Campolo Michela , Lanza Marika , Casili Giovanna , Paterniti Irene , Filippone Alessia , Caffo Maria , cardali Salvatore M , Cuzzocrea Salvatore , Esposito Emanuela 
Published: June 2021

Glioblastoma (GBM) is the most deadly brain tumor, characterized by extremely poor therapeutic response and overall survival. Despite relevant progress in conventional treatments, mainly represented by the clinical use of Temozolomide (TMZ) as standard chemotherapy, the prognosis of such tumors remains almost invariably dismal. Transforming growth factor beta‐activated kinase 1 (TAK1) is an essential component in genotoxic stresses‐ induced NF‐κB activation and MAPK pathways; however, the role of TAK1 in the development of chemoresistance in GBM remains unknown. The aim of the study was to verify, in GBM human cell lines, the effect of TAK1 inhibition on the sensitivity of GBM cells to chemotherapy treatments. Moreover, we used GBM samples of TMZ‐treated patients to validate our its role. The human GBM cell lines U138, A172, U87 MG and L229 cultures were treated for 24h with 5Z‐7 ox and TMZ at a concentration of 5μM and 100μM respectively and then lysate for western blot analysis and comet assay. Moreover, glioblastoma tissues from patients treated with TMZ were processed for western blot analysis. Using GBM cell lines, we found that 5Z‐7‐oxozeaenol significantly augmented the cytotoxic effects of TMZ, blocking TMZ‐induced NF‐κB activation, reducing DNA damage and enhancing TMZ‐induced apoptosis in GMB cell lines. Moreover, our result showed a significant up‐regulation in TAK1, p‐p38, p‐JNK and NF‐κB in glioblastoma TMZ‐treated patients denoting the continuous involvement of TAK1/MAPKs in tumorigenesis following chemotherapy. Together, our results suggested the role of 5Z‐7‐oxozeaenol to increase the sensitivity of GBM cells to chemotherapy and to be an effective coadjuvant to current chemotherapeutic regimens, offering TAK1 inhibitors as a novel strategy into the cultivated fields of cancer research.Support or Funding InformationNo fundingThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Novel inhibitors of ABC transporters increase accumulation of transport substrates in multidrug resistant cancer cells and blood brain barrier cells
Authors: Nanayakkara Amila K. , Holcomb‐Webb Kasi L. , Bequeaith Beau A. , Aljowni Maha , Ammerman Lauren E. , Lippert Alexander R. , Vogel Pia D. , Wise John G. 
Published: June 2021

Multidrug resistance (MDR) is a major cause of chemotherapy failure. Overexpression of ATP‐binding cassette (ABC) transporters, P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) are two well‐studied drug transporters which are associated with MDR. These two transporters also act as a major functional unit of the blood brain barrier to protect the brain from xenobiotics and toxins. Lack of clinically approved P‐gp and BCRP inhibitors renders chemotherapy treatments of many MDR cancers ineffective and obstructs drug uptake into the brain. Using computational methods, we previously identified a novel class of P‐gp inhibitors that were not transport substrates of the pump. Here we describe the effects of chemical variants of the previously identified P‐gp inhibitor, SMU‐29. The variants were generated using computational approaches or by structure‐based design to improve protein binding interactions. All variants showed improved efficacy in reversing paclitaxel resistance in the P‐gp over‐expressing DU145 TXR prostate cancer cell line and their ability of increasing P‐gp substrate calcein in these cells. Five of these variants were not transported by P‐gp and three of them were substrates of the pump. Four variants only affected P‐gp, but not BCRP function, making them more selective than the parental compound, SMU 29. The three variants that affected BCRP reversed MDR in a BCRP over‐expressing breast cancer cell line, MCF‐7 M100, and increased accumulation of BCRP substrates such as Hoechst 33342, mitoxantrone and daunorubicin in these cells, indicating the potential to be used as BCRP inhibitors. The variants that affected both P‐gp and BCRP also showed higher accumulation of P‐gp and BCRP substrates in a blood brain barrier model cell line, hCMEC/D3, showing the potential to open the blood brain barrier for increased drug uptake into the brain.Support or Funding InformationThis work was supported by NIH NIGMS [R15GM094771‐02] to PVD and JGW, SMU University Research Council, the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, and a private gift from Ms. Suzy Ruff of Dallas, Texas.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Epigenetic Regulation of OCTN1‐mediated Cytarabine Transport in Acute Myeloid Leukemia
Authors: Anderson Jason T. , Buelow Daelynn R. , Guttke Christina D. , Hu Shuiying , Gibson Alice A. , Sparreboom Alex , Baker Sharyn D. 
Published: June 2021

BACKGROUNDCytarabine is used as first‐line therapy in acute myeloid leukemia (AML) and is reported to be transported into leukemic cells via OCTN1[i]. One hallmark of AML is dysregulation at the genetic and epigenetic level. Currently, clinical trials are underway using methyltransferase inhibitors such as 5‐azacytidine or decitabine to “epigenetically prime” AML patients and reverse these epigenetic dysregulations (NCT03164057). These clinical trials would benefit from a stronger understanding of the mechanism underlying improved patient outcomes. Here, we tested our hypothesis that these improved patient outcomes are due to epigenetic modifications impacting OCTN1 expression, intracellular accumulation of cytarabine and subsequent antileukemic effects in AML cells.METHODSUptake and cytotoxicity studies were performed in AML cell lines with prior 3‐day treatment with hypomethylating agents, 5‐azacytidine or decitabine. Uptake was conducted by using radioactive substrates and quantified by scintillation counts. OCTN1 expression levels were compared between treated and untreated AML cells with normalization to GAPDH. Methylation profiles were determined using bisulfite modification and pyrosequencing (BS‐Seq). Cytarabine cytotoxicity was determined via MTT and developed after 72 hours of treatment.RESULTSCytarabine uptake (1 μM; 15 min) and cytotoxicity (72 hours) varied among the 10 AML cell lines studied and were used to categorize “high” and “low” uptake. AML cell lines that showed low uptake had consistently higher methylation patterns in CpG islands upstream of SLC22A4 (OCTN1) as determined by BS‐Seq. Exposure to 500 nM of hypomethylating agent decitabine for 72 hours increased OCTN1 expression (5.0 fold), uptake of cytarabine (2.9 fold), and subsequent cytotoxicity (7.3 fold) in CHRF cells with low OCTN1 expression. In contrast, lower methylated cell line OCI‐AML3 showed modest to no increases in OCTN1 (1.0 fold), uptake of cytarabine (1.5 fold) and cytotoxicity (2.8 fold) following decitabine treatment. These findings are consistent with the notion that methylation of OCTN1 was inversely related to cytarabine uptake.CONCLUSIONSThese results identify SLC22A4 (OCTN1) methylation status as a contributor to the expression of OCTN1, cellular uptake and the efficacy of cytarabine; these results have broad implications for the future design of combination chemotherapy regimens.Support or Funding Information5R01CA138744‐09This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Connexin43 dephosphorylation at serine 282 is associated with connexin43‐mediated cardiomyocyte apoptosis
Authors: Luo Dali , Yang Yutong , Xue Jingyi 
Published: June 2021

Gap junction protein connexin 43 (Cx43), beyond electrical coordination regulation, plays an important role in the regulation of cardiomyocyte survival, and Cx43 dephosphorylation found in severe cardiac pathologies is proposed to be involved in myocardium injury. However, the mechanisms remain unknown. Here, we found that transfection of adenovirus carrying Cx43 mutant gene at serine 282 substituted with alanine (S282A) into neonatal rat ventricular cardiomyocytes (NRVMs) induced cell apoptosis and Ca2+ transient desynchronization, whereas gap junction inhibitor and knocking down Cx43 expression by Cx43‐miRNA caused uncoupled Ca2+ signalling but no cell death. Similarly, while Cx43‐S282A+/+ failed in generation, Cx43‐S282A+/− mice exhibited cardiomyocyte apoptosis and ventricular arrhythmia in a phosphorylated S282 deficiency‐dependent fashion. Further we found via physical interaction with p38 mitogen‐activated protein kinase (p38 MAPK), S282 dephosphorylation in Cx43 activates p38, factor‐associated suicide and caspase 8 apoptotic pathway. Finally, we found that Cx43 dephosphorylation at S282 participates in ischemia‐reperfusion (IR) induced cardiomyocyte death by activation of p38 MAPK/Fas/FADD/caspase 8. These findings uncover a specific phosphorylation residue of Cx43 in the regulation of cardiomyocyte homeostasis. Deficiency in S282 phosphorylation acts as a trigger inducing cardiomyocyte apoptosis and cardiac arrhythmia, contributing to IR‐induced myocardium apoptosis. Thus, this study provides a potential mechanism for Cx43‐mediated myocardium injury during severe cardiac diseases.Support or Funding InformationThis work was supported by the National Natural Science Foundation (81370339, 81570206) and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ201710025023).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.