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  1. Article ; Online: Flavipin from fungi as a potential inhibitor of rheumatoid arthritis signaling molecules.

    Ahmed, Emad A / Alzahrani, Abdulaah M / Abdelsalam, Salah A / Ibrahim, Hairul-Islam M

    Inflammopharmacology

    2024  Volume 32, Issue 2, Page(s) 1171–1186

    Abstract: Flavipin, a fungal lower molecular weight biomolecule (MW 196.16 g/mol), has not been yet extensively studied for beneficial preclinical and clinical applications. In recent years, various preclinical mouse models including adjuvant-induced arthritis ( ... ...

    Abstract Flavipin, a fungal lower molecular weight biomolecule (MW 196.16 g/mol), has not been yet extensively studied for beneficial preclinical and clinical applications. In recent years, various preclinical mouse models including adjuvant-induced arthritis (AIA) were employed to understand mechanisms associated with Rheumatoid arthritis (RA) and to develop new therapeutic drugs. In the current study, we studied the inhibitory effect of Flavipin on major signaling molecules involved in the inflammatory response during RA using both in-silico virtual interaction and in vivo mouse model of AIA. Our in-silico results clarified that Flavipin interacts with the tumor necrosis factor alpha (TNF-α) through conventional hydrogen binding (H-H) at one of TNF-α critical amino acids tyrosine residues, Tyr119, with binding energy (b.e.) -5.9. In addition, Flavipin binds to ATP-binging sites of the Jesus kinases, JAK1, JAK2 and JAK3, through H-H (b. e. between -5.8 and -6.1) and then it may inhibit JAKs, regulators of RA signaling molecules. Moreover, our molecular dynamics stimulation for the docked TNF-α/Flavipin complex confirmed the specificity and the stability of the interaction. In vitro, Flavipin is not toxic to normal cells at doses below 50 µM (its IC50 in normal fibroblast cell line was above 100 µM). However, in vivo, the arthritis score and hind paw oedema parameters were modulated in Flavipin treated mice. Consistent with the in-silico results the levels of the TNF-α, the nuclear transcription factor kappaB (NF-κB) and the signal transduction and activator of transcription (STAT3, downstream of JAKs) were modulated at joint tissues of the hind-paw of Flavipin/AIA treated mice. Our data suggest Flavipin as a potential therapeutic agent for arthritis can inhibit RA major signaling molecules.
    MeSH term(s) Mice ; Animals ; Tumor Necrosis Factor-alpha/pharmacology ; Signal Transduction ; Arthritis, Rheumatoid/metabolism ; NF-kappa B/metabolism ; Fungi/metabolism ; Arthritis, Experimental/metabolism ; o-Phthalaldehyde/analogs & derivatives
    Chemical Substances Tumor Necrosis Factor-alpha ; flavipin ; NF-kappa B ; o-Phthalaldehyde (643-79-8)
    Language English
    Publishing date 2024-02-13
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1080058-x
    ISSN 1568-5608 ; 0925-4692
    ISSN (online) 1568-5608
    ISSN 0925-4692
    DOI 10.1007/s10787-024-01429-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Carboxymethyl Cellulose/Zn-Organic Framework Down-Regulates Proliferation and Up-Regulates Apoptosis and DNA Damage in Colon and Lung Cancer Cell Lines.

    Negm, Amr / Gouda, Mohamed / Ibrahim, Hairul-Islam M

    Polymers

    2022  Volume 14, Issue 10

    Abstract: A solvothermal technique was used to prepare a Zn-benzenetricarboxylic acid (Zn@BTC) organic framework covered with a carboxymethyl cellulose (CMC/Zn@BTC). Fourier transform infrared spectroscopy (FTIR), field emission scanning electron microscope (FESEM) ...

    Abstract A solvothermal technique was used to prepare a Zn-benzenetricarboxylic acid (Zn@BTC) organic framework covered with a carboxymethyl cellulose (CMC/Zn@BTC). Fourier transform infrared spectroscopy (FTIR), field emission scanning electron microscope (FESEM), and Brunauer, Emmett, and Teller (BET) surface area were applied to characterize CMC/Zn@BTC. Moreover, the anticancer, anti-migrative, anti-invasive, and anti-proliferative action of CMC/Zn@BTC nanoparticles were assessed on cancer cell lines. Apoptotic markers and DNA damage were assessed to explore the cellular and biological changes induced by CMC/Zn@BTC nanoparticles. The microscopic observation revealed that CMC controls the surface morphology and surface characteristics of the Zn@BTC. The obtained BET data revealed that the Zn@BTC nanocomposite surface area lowers from 1061 m
    Language English
    Publishing date 2022-05-15
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527146-5
    ISSN 2073-4360 ; 2073-4360
    ISSN (online) 2073-4360
    ISSN 2073-4360
    DOI 10.3390/polym14102015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Atropine Is a Suppressor of Epithelial-Mesenchymal Transition (EMT) That Reduces Stemness in Drug-Resistant Breast Cancer Cells.

    Ahmed, Emad A / Alkuwayti, Mayyadah A / Ibrahim, Hairul-Islam M

    International journal of molecular sciences

    2022  Volume 23, Issue 17

    Abstract: Atropine (ATR) is extracted from a belladonna plant that belongs to a class of anticholinergic drugs and is therefore involved in the treatment of the overdose of cholinergic drugs or mushroom poisoning. It is a well-known blocker of muscarinic ... ...

    Abstract Atropine (ATR) is extracted from a belladonna plant that belongs to a class of anticholinergic drugs and is therefore involved in the treatment of the overdose of cholinergic drugs or mushroom poisoning. It is a well-known blocker of muscarinic acetylcholine receptors (mAChRs) that are expressed in various tumor cells, including breast tumors from animal and human origin, but it has yet to be recommended as an anticancer drug. Our in silico docking analysis indicates that atropine has a roust virtual binding, with a stable binding energy, to two major signaling molecules involved in EMT regulation: E-cad and ZEB-2. For both, the gene and the protein expression level results show that atropine is an effective molecule in reducing epithelial-mesenchymal transition (EMT) and colony formation induced by TGF-B or carboplatin in both the mesenchymal-like cell line MDA-MB-231 and the epithelial-like cell line T47D. We conclude that atropine as a potential suppressor of EMT could be co-administrated with other chemotherapeutic drugs to reduce stemness in drug-resistant breast tumor cells.
    MeSH term(s) Animals ; Atropine/pharmacology ; Breast/pathology ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Movement ; Epithelial-Mesenchymal Transition/genetics ; Female ; Humans
    Chemical Substances Atropine (7C0697DR9I)
    Language English
    Publishing date 2022-08-30
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms23179849
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Aryl Hydrocarbon Receptor as an Anticancer Target: An Overview of Ten Years Odyssey.

    Hanieh, Hamza / Bani Ismail, Mohammad / Alfwuaires, Manal A / Ibrahim, Hairul-Islam M / Farhan, Mahdi

    Molecules (Basel, Switzerland)

    2023  Volume 28, Issue 10

    Abstract: Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor belonging to the basic helix-loop-helix (bHLH)/per-Arnt-sim (PAS) superfamily, is traditionally known to mediate xenobiotic metabolism. It is activated by structurally diverse ... ...

    Abstract Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor belonging to the basic helix-loop-helix (bHLH)/per-Arnt-sim (PAS) superfamily, is traditionally known to mediate xenobiotic metabolism. It is activated by structurally diverse agonistic ligands and regulates complicated transcriptional processes through its canonical and non-canonical pathways in normal and malignant cells. Different classes of AhR ligands have been evaluated as anticancer agents in different cancer cells and exhibit efficiency, which has thrust AhR into the limelight as a promising molecular target. There is strong evidence demonstrating the anticancer potential of exogenous AhR agonists including synthetic, pharmaceutical, and natural compounds. In contrast, several reports have indicated inhibition of AhR activity by antagonistic ligands as a potential therapeutic strategy. Interestingly, similar AhR ligands exert variable anticancer or cancer-promoting potential in a cell- and tissue-specific mode of action. Recently, ligand-mediated modulation of AhR signaling pathways and the associated tumor microenvironment is emerging as a potential approach for developing cancer immunotherapeutic drugs. This article reviews advances of AhR in cancer research covering publication from 2012 to early 2023. It summarizes the therapeutic potential of various AhR ligands with an emphasis on exogenous ligands. It also sheds light on recent immunotherapeutic strategies involving AhR.
    MeSH term(s) Receptors, Aryl Hydrocarbon/metabolism ; Ligands ; Signal Transduction
    Chemical Substances Receptors, Aryl Hydrocarbon ; Ligands
    Language English
    Publishing date 2023-05-09
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules28103978
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Beta-Caryophyllene Enhances the Anti-Tumor Activity of Cisplatin in Lung Cancer Cell Lines through Regulating Cell Cycle and Apoptosis Signaling Molecules.

    Ahmed, Emad A / Abu Zahra, Hamad / Ammar, Rebai Ben / Mohamed, Maged Elsayed / Ibrahim, Hairul-Islam M

    Molecules (Basel, Switzerland)

    2022  Volume 27, Issue 23

    Abstract: Beta-Caryophyllene (BCP), a natural bicyclic sesquiterpenes, is an abundant biomolecule in red pepper and other plants. Recently, it was reported to reduce the growth and the proliferation as well as enhance the apoptosis in numerous cancer cells, ... ...

    Abstract Beta-Caryophyllene (BCP), a natural bicyclic sesquiterpenes, is an abundant biomolecule in red pepper and other plants. Recently, it was reported to reduce the growth and the proliferation as well as enhance the apoptosis in numerous cancer cells, including colorectal, ovarian, bladder cancer and lung cancer. On the other hand, the combination therapy of cisplatin (CDDP) with other phytochemical compounds has synergistically enhanced the killing effect of CDDP on several types of cancer. In the current model, we have tested the role of BCP in enhancing the anti-tumor activity of CDDP on lung cancer cell lines. The results showed that BCP is not toxic at moderate doses and it can prevent lung cancer progression in doses above 75 µM. However, when being combined with CDDP, BCP improved the former chemotherapeutic function through regulating cell cycle, apoptosis and EMT signaling molecules. Gene and protein expression analysis showed that the combined treatment of CDDP and BCP significantly upregulated the level of the cyclin-dependent kinase inhibitor, CDKN1A, and the inhibitor of the apoptosis, BCL-xl2. In addition, the combination treatment reduced the protein level of the apoptosis regulator, BCL-2. Moreover, BCP appears to prohibit the EMT process that is associated with CDDP chemotherapy since the combination treatment induced a significant increase in the level of the epithelial cell marker E-cad that was reduced in CDDP-treated cells. In agreement with that, the combined treatment managed to modulate the effect of CDDP on the mesenchymal transcription factor ZEB-2. Additionally, molecular docking has been conducted to check the virtual interaction of BCP with these and other signaling molecules, but only cyclin-dependent kinase CDK6 was found to virtually bind with BCP, and at four sites with higher and stable biding energy (-7.8). Together, these data indicate that BCP enhances CDDP chemotherapeutic function through regulating the cell cycle, the apoptosis and EMT signaling molecules.
    Language English
    Publishing date 2022-11-30
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules27238354
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: The Halotolerant Probiotic Bacterium

    Alsaud, Najla / Almajed, Amjad / Lwusaybie, Allujayn / Alsubaie, Aljawharah / Alobaidan, Hela / Alessa, Jihad / Almousa, Abeer / Ibrahim, Hairul Islam M / Khalifa, Ashraf

    Microorganisms

    2023  Volume 11, Issue 10

    Abstract: Inflammation-related diseases are major causes of mortality and disability worldwide. This study aimed to identify and investigate probiotic bacteria that could be present in Al-Asfar Lake in Al-Ahsa City, Saudi Arabia to prevent the inflammatory ... ...

    Abstract Inflammation-related diseases are major causes of mortality and disability worldwide. This study aimed to identify and investigate probiotic bacteria that could be present in Al-Asfar Lake in Al-Ahsa City, Saudi Arabia to prevent the inflammatory responses of carrageenan-induced paw edema. In total, seven active strains were isolated, and three isolates (ASF-1, ASF-2, and ASF-3) exhibited a positive Gram stain and viable growth at 20% NaCl salinity; they also lacked catalase and hemolytic activities and had high levels of cell surface hydrophobicity (CSH). They also demonstrated potent antibacterial activity against
    Language English
    Publishing date 2023-09-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2720891-6
    ISSN 2076-2607
    ISSN 2076-2607
    DOI 10.3390/microorganisms11102415
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Activation of aryl hydrocarbon receptor signaling by gallic acid suppresses progression of human breast cancer in vitro and in vivo

    Hanieh, Hamza / Ibrahim, Hairul-Islam M. / Mohammed, Maged / Alwassil, Osama I. / Abukhalil, Mohammad H. / Farhan, Mahdi

    Phytomedicine. 2022 Feb., v. 96 p.153817-

    2022  

    Abstract: Despite the significant advances in diagnosis and treatment, breast cancer remains the most common malignancy and the second cause of death in women. Increasingly, preclinical evidence has suggested aryl hydrocarbon receptor (Ahr), a ligand activated ... ...

    Abstract Despite the significant advances in diagnosis and treatment, breast cancer remains the most common malignancy and the second cause of death in women. Increasingly, preclinical evidence has suggested aryl hydrocarbon receptor (Ahr), a ligand activated transcription factor, a promising therapeutic target in breast cancer.This study aims at screening a number of phenolic compounds to identify an Ahr ligand with suppressive effects on human breast cancer.Potential interactions between Ahr and phenolic compounds were predicted in silico, and physical interaction was examined by ligand competitive binding in vitro. The MDA-MB-231 and T47D breast cancer cell lines were used to examine the expression of Ahr downstream genes and progression of breast cancer cells in vitro. Binding of Ahr/Ahr nuclear transporter (Arnt) complex to the xenobiotic-responsive element (XRE)-box was examined by DNA-protein interaction (DPI)-ELISA, promoter activity was assessed using luciferase reporter system, and RNA interreference was carried out using electroporation. The real-time PCR and/or immunoblotting were used to quantify gene expressions. Tumor growth in vivo was assessed using a murine orthotopic model.A combined computational modeling and in vitro approaches identified gallic acid (GA) as an Ahr ligand with agonistic properties. It induced binding of Ahr/Arnt to the XRE-box, enhanced the promoter activity and expression of Ahr downstream genes including cytochrome P450 1A1 (CYP1A1), and SRY-related HMG-box4 (SOX4)-targeting miR-212/132 cluster and miR-335 in both MDA-MB-231 and T47D cells. GA increased apoptosis while decreased proliferation, migration and invasion capacities of breast cancer cells in an Ahr-dependent fashion. Furthermore, it reduced the levels of B-cell lymphoma 2 (BCL-2), cyclooxygenase-2 (COX-2) and SOX4, while selectively increased that of tumor protein 53 (P53), in an Ahr-dependent and -independent fashions. In an in vivo orthotopic model, GA activated Ahr signaling and reduced the growth of breast cancer cells.We identified GA as an Ahr phenolic ligand, and provided evidence on the role of Ahr in mediating its anti-breast cancer effects, indicating that GA, and possibly other phenolic compounds, have important therapeutic implications in human breast cancer through activation of Ahr signaling.
    Keywords B-cell lymphoma ; antineoplastic activity ; apoptosis ; aryl hydrocarbon receptors ; breast neoplasms ; cytochrome P-450 ; gallic acid ; gene expression ; gene expression regulation ; human cell lines ; in vitro studies ; in vivo studies ; ligands ; neoplasm cells ; neoplasm progression ; promoter regions ; prostaglandin synthase ; signal transduction ; tumor suppressor protein p53 ; women ; Aryl hydrocarbon receptor ; Ligand ; Phenolic compounds ; Breast cancer ; Ahr ; Arnt ; AO ; BCL-2 ; bHLH-PAS ; CCL2 ; COX-2 ; CXCR4 ; CYP1A1 ; DMEM ; EB ; ER ; GA ; HAP ; HIF-2α ; MCDF ; miR ; MMP ; PAS ; PDLIM4 ; SOX4 ; TCDD ; TCDF ; TGF-β ; TP53 ; XRE
    Language English
    Dates of publication 2022-02
    Publishing place Elsevier GmbH
    Document type Article ; Online
    ZDB-ID 1205240-1
    ISSN 1618-095X ; 0944-7113
    ISSN (online) 1618-095X
    ISSN 0944-7113
    DOI 10.1016/j.phymed.2021.153817
    Database NAL-Catalogue (AGRICOLA)

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  8. Article ; Online: Activation of aryl hydrocarbon receptor signaling by gallic acid suppresses progression of human breast cancer in vitro and in vivo.

    Hanieh, Hamza / Ibrahim, Hairul-Islam M / Mohammed, Maged / Alwassil, Osama I / Abukhalil, Mohammad H / Farhan, Mahdi

    Phytomedicine : international journal of phytotherapy and phytopharmacology

    2021  Volume 96, Page(s) 153817

    Abstract: Background: Despite the significant advances in diagnosis and treatment, breast cancer remains the most common malignancy and the second cause of death in women. Increasingly, preclinical evidence has suggested aryl hydrocarbon receptor (Ahr), a ligand ... ...

    Abstract Background: Despite the significant advances in diagnosis and treatment, breast cancer remains the most common malignancy and the second cause of death in women. Increasingly, preclinical evidence has suggested aryl hydrocarbon receptor (Ahr), a ligand activated transcription factor, a promising therapeutic target in breast cancer.
    Purpose: This study aims at screening a number of phenolic compounds to identify an Ahr ligand with suppressive effects on human breast cancer.
    Methods: Potential interactions between Ahr and phenolic compounds were predicted in silico, and physical interaction was examined by ligand competitive binding in vitro. The MDA-MB-231 and T47D breast cancer cell lines were used to examine the expression of Ahr downstream genes and progression of breast cancer cells in vitro. Binding of Ahr/Ahr nuclear transporter (Arnt) complex to the xenobiotic-responsive element (XRE)-box was examined by DNA-protein interaction (DPI)-ELISA, promoter activity was assessed using luciferase reporter system, and RNA interreference was carried out using electroporation. The real-time PCR and/or immunoblotting were used to quantify gene expressions. Tumor growth in vivo was assessed using a murine orthotopic model.
    Results: A combined computational modeling and in vitro approaches identified gallic acid (GA) as an Ahr ligand with agonistic properties. It induced binding of Ahr/Arnt to the XRE-box, enhanced the promoter activity and expression of Ahr downstream genes including cytochrome P450 1A1 (CYP1A1), and SRY-related HMG-box4 (SOX4)-targeting miR-212/132 cluster and miR-335 in both MDA-MB-231 and T47D cells. GA increased apoptosis while decreased proliferation, migration and invasion capacities of breast cancer cells in an Ahr-dependent fashion. Furthermore, it reduced the levels of B-cell lymphoma 2 (BCL-2), cyclooxygenase-2 (COX-2) and SOX4, while selectively increased that of tumor protein 53 (P53), in an Ahr-dependent and -independent fashions. In an in vivo orthotopic model, GA activated Ahr signaling and reduced the growth of breast cancer cells.
    Conclusion: We identified GA as an Ahr phenolic ligand, and provided evidence on the role of Ahr in mediating its anti-breast cancer effects, indicating that GA, and possibly other phenolic compounds, have important therapeutic implications in human breast cancer through activation of Ahr signaling.
    MeSH term(s) Animals ; Apoptosis ; Breast Neoplasms/drug therapy ; Cytochrome P-450 CYP1A1/genetics ; Cytochrome P-450 CYP1A1/metabolism ; Female ; Gallic Acid/pharmacology ; Humans ; Mice ; MicroRNAs ; Receptors, Aryl Hydrocarbon/metabolism ; SOXC Transcription Factors ; Signal Transduction
    Chemical Substances MIRN212 microRNA, human ; MicroRNAs ; Receptors, Aryl Hydrocarbon ; SOX4 protein, human ; SOXC Transcription Factors ; Gallic Acid (632XD903SP) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1)
    Language English
    Publishing date 2021-10-19
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1205240-1
    ISSN 1618-095X ; 0944-7113
    ISSN (online) 1618-095X
    ISSN 0944-7113
    DOI 10.1016/j.phymed.2021.153817
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Anti-Allergic Potential of Cinnamaldehyde via the Inhibitory Effect of Histidine Decarboxylase (HDC) Producing

    Badger-Emeka, Lorina I / Emeka, Promise Madu / Thirugnanasambantham, Krishnaraj / Ibrahim, Hairul Islam M

    Molecules (Basel, Switzerland)

    2020  Volume 25, Issue 23

    Abstract: Allergy is an immunological disorder that develops in response to exposure to an allergen, and histamines mediate these effects via histidine decarboxylase (HDC) activity at the intracellular level. In the present study, we developed a 3D model ... ...

    Abstract Allergy is an immunological disorder that develops in response to exposure to an allergen, and histamines mediate these effects via histidine decarboxylase (HDC) activity at the intracellular level. In the present study, we developed a 3D model of
    MeSH term(s) Acrolein/analogs & derivatives ; Acrolein/pharmacology ; Anti-Allergic Agents/pharmacology ; Cell Proliferation ; Cytokines/metabolism ; Histamine/metabolism ; Histidine Decarboxylase/antagonists & inhibitors ; Humans ; Hypersensitivity/drug therapy ; Hypersensitivity/enzymology ; Hypersensitivity/immunology ; Hypersensitivity/pathology ; Klebsiella pneumoniae/enzymology ; Leukemia, Basophilic, Acute/drug therapy ; Leukemia, Basophilic, Acute/enzymology ; Leukemia, Basophilic, Acute/immunology ; Leukemia, Basophilic, Acute/pathology ; Mast Cells/drug effects ; Signal Transduction ; Tumor Cells, Cultured
    Chemical Substances Anti-Allergic Agents ; Cytokines ; Acrolein (7864XYD3JJ) ; Histamine (820484N8I3) ; Histidine Decarboxylase (EC 4.1.1.22) ; cinnamaldehyde (SR60A3XG0F)
    Language English
    Publishing date 2020-11-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules25235580
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Activation of aryl hydrocarbon receptor signaling by a novel agonist ameliorates autoimmune encephalomyelitis.

    Alzahrani Abdullah / Mohammed Maged / Ibrahim Hairul-Islam M / Alwassil Osama I / Habash Maha / Alfuwaires Manal / Hanieh Hamza

    PLoS ONE, Vol 14, Iss 4, p e

    2019  Volume 0215981

    Abstract: Background Multiple sclerosis (MS) is a widespread neurological autoimmune disease that includes episodes of demyelination in the central nervous system (CNS). The accumulated evidence has suggested that aryl hydrocarbon receptor (Ahr), a ligand- ... ...

    Abstract Background Multiple sclerosis (MS) is a widespread neurological autoimmune disease that includes episodes of demyelination in the central nervous system (CNS). The accumulated evidence has suggested that aryl hydrocarbon receptor (Ahr), a ligand-activated transcription factor, is a promising treatment target for MS. Thus, the current study aimed to identify a novel Ahr ligand with anti-inflammatory potential in experimental autoimmune encephalomyelitis (EAE). Methods An in silico analysis was carried out to predict interactions between Ahr and potential natural ligands. The effects of a predicted interaction were examined in vitro using CD4+ T cells under T helper17 (Th17) cell-polarizing conditions and lipopolysaccharide (LPS)-stimulated macrophages. Silencing Ahr and microRNA (miR)-132 was achieved by electroporation. Myelin oligodendrocyte glycoprotein (MOG)35-55 and the adoptive transfer of encephalitogenic CD4+ T cells were used to induce EAE. Results Molecular docking analysis and in vitro data identified gallic acid (GA) as a novel Ahr ligand with potent activation potential. GA induced the expression of Ahr downstream genes, including cytochrome P450 family 1 subfamily A member 1 (Cyp1a1) and the miR-212/132 cluster, and promoted the formation of the Ahr/Ahr nuclear translocator (Arnt) complex. In vivo, GA-treated mice were resistant to EAE and exhibited reduced levels of proinflammatory cytokines and increased levels of transforming growth factor-β (TGF-β). Furthermore, GA reduced infiltration of CD4+CD45+ T cells and monocytes into the CNS. The anti-inflammatory effects of GA were concomitant with miR-132-potentiated cholinergic anti-inflammation and the regulation of the pathogenic potential of astrocytes and microglia. Inducing EAE by adoptive transfer revealed that CD4+ T cells were not entirely responsible for the ameliorative effects of GA. Conclusion Our findings identify GA as a novel Ahr ligand and provide molecular mechanisms elucidating the ameliorative effects of GA on EAE, suggesting that ...
    Keywords Medicine ; R ; Science ; Q
    Subject code 500 ; 570
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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