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  1. Artikel ; Online: Lipid-laden foam cells in the pathology of atherosclerosis: shedding light on new therapeutic targets.

    Galindo, Cristi L / Khan, Saifur / Zhang, Xiangyu / Yeh, Yu-Sheng / Liu, Ziyang / Razani, Babak

    Expert opinion on therapeutic targets

    2023  Band 27, Heft 12, Seite(n) 1231–1245

    Abstract: Introduction: Lipid-laden foam cells within atherosclerotic plaques are key players in all phases of lesion development including its progression, necrotic core formation, fibrous cap thinning, and eventually plaque rupture. Manipulating foam cell ... ...

    Abstract Introduction: Lipid-laden foam cells within atherosclerotic plaques are key players in all phases of lesion development including its progression, necrotic core formation, fibrous cap thinning, and eventually plaque rupture. Manipulating foam cell biology is thus an attractive therapeutic strategy at early, middle, and even late stages of atherosclerosis. Traditional therapies have focused on prevention, especially lowering plasma lipid levels. Despite these interventions, atherosclerosis remains a major cause of cardiovascular disease, responsible for the largest numbers of death worldwide.
    Areas covered: Foam cells within atherosclerotic plaques are comprised of macrophages, vascular smooth muscle cells, and other cell types which are exposed to high concentrations of lipoproteins accumulating within the subendothelial intimal layer. Macrophage-derived foam cells are particularly well studied and have provided important insights into lipid metabolism and atherogenesis. The contributions of foam cell-based processes are discussed with an emphasis on areas of therapeutic potential and directions for drug development.
    Exert opinion: As key players in atherosclerosis, foam cells are attractive targets for developing more specific, targeted therapies aimed at resolving atherosclerotic plaques. Recent advances in our understanding of lipid handling within these cells provide insights into how they might be manipulated and clinically translated to better treat atherosclerosis.
    Mesh-Begriff(e) Humans ; Foam Cells/metabolism ; Foam Cells/pathology ; Plaque, Atherosclerotic/drug therapy ; Plaque, Atherosclerotic/pathology ; Atherosclerosis/drug therapy ; Macrophages/metabolism ; Lipoproteins
    Chemische Substanzen Lipoproteins
    Sprache Englisch
    Erscheinungsdatum 2023-12-30
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2055208-7
    ISSN 1744-7631 ; 1472-8222
    ISSN (online) 1744-7631
    ISSN 1472-8222
    DOI 10.1080/14728222.2023.2288272
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: metGWAS 1.0: an R workflow for network-driven over-representation analysis between independent metabolomic and meta-genome-wide association studies.

    Khan, Saifur R / Obersterescu, Andreea / Gunderson, Erica P / Razani, Babak / Wheeler, Michael B / Cox, Brian J

    Bioinformatics (Oxford, England)

    2023  Band 39, Heft 9

    Abstract: Motivation: The method of genome-wide association studies (GWAS) and metabolomics combined provide an quantitative approach to pinpoint metabolic pathways and genes linked to specific diseases; however, such analyses require both genomics and ... ...

    Abstract Motivation: The method of genome-wide association studies (GWAS) and metabolomics combined provide an quantitative approach to pinpoint metabolic pathways and genes linked to specific diseases; however, such analyses require both genomics and metabolomics datasets from the same individuals/samples. In most cases, this approach is not feasible due to high costs, lack of technical infrastructure, unavailability of samples, and other factors. Therefore, an unmet need exists for a bioinformatics tool that can identify gene loci-associated polymorphic variants for metabolite alterations seen in disease states using standalone metabolomics.
    Results: Here, we developed a bioinformatics tool, metGWAS 1.0, that integrates independent GWAS data from the GWAS database and standalone metabolomics data using a network-based systems biology approach to identify novel disease/trait-specific metabolite-gene associations. The tool was evaluated using standalone metabolomics datasets extracted from two metabolomics-GWAS case studies. It discovered both the observed and novel gene loci with known single nucleotide polymorphisms when compared to the original studies.
    Availability and implementation: The developed metGWAS 1.0 framework is implemented in an R pipeline and available at: https://github.com/saifurbd28/metGWAS-1.0.
    Mesh-Begriff(e) Humans ; Genome-Wide Association Study ; Workflow ; Metabolomics ; Computational Biology ; Databases, Factual
    Sprache Englisch
    Erscheinungsdatum 2023-08-23
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1422668-6
    ISSN 1367-4811 ; 1367-4803
    ISSN (online) 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btad523
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: Epigenetically active chromatin in neonatal iWAT reveals GABPα as a potential regulator of beige adipogenesis.

    Mooli, Raja Gopal Reddy / Zhu, Bokai / Khan, Saifur R / Nagati, Veerababu / Michealraj, Kulandaimanuvel Antony / Jurczak, Michael J / Ramakrishnan, Sadeesh K

    Frontiers in endocrinology

    2024  Band 15, Seite(n) 1385811

    Abstract: Background: Thermogenic beige adipocytes, which dissipate energy as heat, are found in neonates and adults. Recent studies show that neonatal beige adipocytes are highly plastic and contribute to >50% of beige adipocytes in adults. Neonatal beige ... ...

    Abstract Background: Thermogenic beige adipocytes, which dissipate energy as heat, are found in neonates and adults. Recent studies show that neonatal beige adipocytes are highly plastic and contribute to >50% of beige adipocytes in adults. Neonatal beige adipocytes are distinct from recruited beige adipocytes in that they develop independently of temperature and sympathetic innervation through poorly defined mechanisms.
    Methods: We characterized the neonatal beige adipocytes in the inguinal white adipose tissue (iWAT) of C57BL6 postnatal day 3 and 20 mice (P3 and P20) by imaging, genome-wide RNA-seq analysis, ChIP-seq analysis, qRT-PCR validation, and biochemical assays.
    Results: We found an increase in acetylated histone 3 lysine 27 (H3K27ac) on the promoter and enhancer regions of beige-specific gene UCP1 in iWAT of P20 mice. Furthermore, H3K27ac ChIP-seq analysis in the iWAT of P3 and P20 mice revealed strong H3K27ac signals at beige adipocyte-associated genes in the iWAT of P20 mice. The integration of H3K27ac ChIP-seq and RNA-seq analysis in the iWAT of P20 mice reveal epigenetically active signatures of beige adipocytes, including oxidative phosphorylation and mitochondrial metabolism. We identify the enrichment of GA-binding protein alpha (GABPα) binding regions in the epigenetically active chromatin regions of the P20 iWAT, particularly on beige genes, and demonstrate that GABPα is required for beige adipocyte differentiation. Moreover, transcriptomic analysis and glucose oxidation assays revealed increased glycolytic activity in the neonatal iWAT from P20.
    Conclusions: Our findings demonstrate that epigenetic mechanisms regulate the development of peri-weaning beige adipocytes via GABPα. Further studies to better understand the upstream mechanisms that regulate epigenetic activation of GABPα and characterization of the metabolic identity of neonatal beige adipocytes will help us harness their therapeutic potential in metabolic diseases.
    Mesh-Begriff(e) Animals ; Mice ; Epigenesis, Genetic ; Mice, Inbred C57BL ; Adipocytes, Beige/metabolism ; Animals, Newborn ; Chromatin/metabolism ; Chromatin/genetics ; Adipogenesis/genetics ; Adipose Tissue, White/metabolism ; GA-Binding Protein Transcription Factor/metabolism ; GA-Binding Protein Transcription Factor/genetics ; Male ; Thermogenesis/genetics ; Histones/metabolism ; Histones/genetics
    Sprache Englisch
    Erscheinungsdatum 2024-05-03
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2024.1385811
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Integration of AI and traditional medicine in drug discovery.

    Khan, Saifur R / Al Rijjal, Dana / Piro, Anthony / Wheeler, Michael B

    Drug discovery today

    2021  Band 26, Heft 4, Seite(n) 982–992

    Abstract: AI integration in plant-based traditional medicine could be used to overcome drug discovery challenges. ...

    Abstract AI integration in plant-based traditional medicine could be used to overcome drug discovery challenges.
    Mesh-Begriff(e) Artificial Intelligence ; Drug Discovery/methods ; Drug Discovery/trends ; Humans ; Medicine, Traditional/methods ; Phytotherapy/methods
    Sprache Englisch
    Erscheinungsdatum 2021-01-18
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/j.drudis.2021.01.008
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  5. Artikel: Heterogeneity in Early Postpartum Metabolic Profiles Among Women with GDM Who Progressed to Type 2 Diabetes During 10-Year Follow-Up: The SWIFT Study.

    Khan, Saifur R / Rost, Hannes / Cox, Brian / Razani, Babak / Alexeeff, Stacey / Wheeler, Michael B / Gunderson, Erica P

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: GDM is a strong risk factor for progression to T2D after pregnancy. Although both GDM and T2D exhibit heterogeneity, the link between the distinct heterogeneity of GDM and incident T2D has not been established. Herein, we evaluate early postpartum ... ...

    Abstract GDM is a strong risk factor for progression to T2D after pregnancy. Although both GDM and T2D exhibit heterogeneity, the link between the distinct heterogeneity of GDM and incident T2D has not been established. Herein, we evaluate early postpartum profiles of women with recent GDM who later developed incident T2D using a soft clustering method, followed by the integration of both clinical phenotypic variables and metabolomics to characterize these heterogeneous clusters/groups clinically and their molecular mechanisms. We identified three clusters based on two indices of glucose homeostasis at 6-9 weeks postpartum - HOMA-IR and HOMA-B among women who developed incident T2D during the 12-year follow-up. The clusters were classified as follows: pancreatic beta-cell dysfunction group (cluster-1), insulin resistant group (cluster-3), and a combination of both phenomena (cluster-2) comprising the majority of T2D. We also identified postnatal blood test parameters to distinguish the three clusters for clinical testing. Moreover, we compared these three clusters in their metabolomics profiles at the early stage of the disease to identify the mechanistic insights. A significantly higher concentration of a metabolite at the early stage of a T2D cluster than other clusters indicates its essentiality for the particular disease character. As such, the early-stage characters of T2D cluster-1 pathology include a higher concentration of sphingolipids, acyl-alkyl phosphatidylcholines, lysophosphatidylcholines, and glycine, indicating their essentiality for pancreatic beta-cell function. In contrast, the early-stage characteristics of T2D cluster-3 pathology include a higher concentration of diacyl phosphatidylcholines, acyl-carnitines, isoleucine, and glutamate, indicating their essentiality for insulin actions. Notably, all these biomolecules are found in the T2D cluster-2 with mediocre concentrations, indicating a true nature of a mixed group. In conclusion, we have deconstructed incident T2D heterogeneity and identified three clusters with their clinical testing procedures and molecular mechanisms. This information will aid in adopting proper interventions using a precision medicine approach.
    Sprache Englisch
    Erscheinungsdatum 2023-06-16
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.06.13.23291346
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Isoniazid and host immune system interactions: A proposal for a novel comprehensive mode of action.

    Khan, Saifur R / Manialawy, Yousef / Siraki, Arno G

    British journal of pharmacology

    2019  Band 176, Heft 24, Seite(n) 4599–4608

    Abstract: The known mode of action of isoniazid (INH) is to inhibit bacterial cell wall synthesis following activation by the bacterial catalase-peroxidase enzyme KatG in Mycobacterium tuberculosis (Mtb). This simplistic model fails to explain (a) how isoniazid ... ...

    Abstract The known mode of action of isoniazid (INH) is to inhibit bacterial cell wall synthesis following activation by the bacterial catalase-peroxidase enzyme KatG in Mycobacterium tuberculosis (Mtb). This simplistic model fails to explain (a) how isoniazid penetrates waxy granulomas with its very low lipophilicity, (b) how isoniazid kills latent Mtb lacking a typical cell wall, and (c) why isoniazid treatment time is remarkably long in contrast to most other antibiotics. To address these questions, a novel comprehensive mode of action of isoniazid has been proposed here. Briefly, isoniazid eradicates latent tuberculosis (TB) by prompting slow differentiation of pro-inflammatory monocytes and providing protection against reactive species-induced "self-necrosis" of phagocytes. In the case of active TB, different immune cells form INH-NAD
    Mesh-Begriff(e) Antitubercular Agents/pharmacology ; Bacterial Proteins/genetics ; Catalase/genetics ; Host Microbial Interactions/drug effects ; Host Microbial Interactions/immunology ; Humans ; Isoniazid/pharmacology ; Monocytes/drug effects ; Monocytes/immunology ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Oxidative Stress/drug effects ; Oxidative Stress/immunology ; Tuberculosis/blood ; Tuberculosis/drug therapy ; Tuberculosis/immunology
    Chemische Substanzen Antitubercular Agents ; Bacterial Proteins ; Catalase (EC 1.11.1.6) ; katG protein, Mycobacterium tuberculosis (EC 1.11.1.6) ; Isoniazid (V83O1VOZ8L)
    Sprache Englisch
    Erscheinungsdatum 2019-11-12
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1111/bph.14867
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: The magnesium transporter NIPAL1 is a pancreatic islet-expressed protein that conditionally impacts insulin secretion.

    Manialawy, Yousef / Khan, Saifur R / Bhattacharjee, Alpana / Wheeler, Michael B

    The Journal of biological chemistry

    2020  Band 295, Heft 29, Seite(n) 9879–9892

    Abstract: Type 2 diabetes is a chronic metabolic disease characterized by pancreatic β-cell dysfunction and peripheral insulin resistance. Among individuals with type 2 diabetes, ∼30% exhibit hypomagnesemia. Hypomagnesemia has been linked to insulin resistance ... ...

    Abstract Type 2 diabetes is a chronic metabolic disease characterized by pancreatic β-cell dysfunction and peripheral insulin resistance. Among individuals with type 2 diabetes, ∼30% exhibit hypomagnesemia. Hypomagnesemia has been linked to insulin resistance through reduced tyrosine kinase activity of the insulin receptor; however, its impact on pancreatic β-cell function is unknown. In this study, through analysis of several single-cell RNA-sequencing data sets in tandem with quantitative PCR validation in both murine and human islets, we identified
    Mesh-Begriff(e) Animals ; Cation Transport Proteins/biosynthesis ; Cation Transport Proteins/genetics ; Cell Line, Tumor ; Gene Expression Regulation ; Glucagon-Secreting Cells/cytology ; Glucagon-Secreting Cells/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/cytology ; Insulin-Secreting Cells/metabolism ; Magnesium/metabolism ; Male ; Mice
    Chemische Substanzen Cation Transport Proteins ; Magnesium (I38ZP9992A)
    Sprache Englisch
    Erscheinungsdatum 2020-05-21
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA120.013277
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: Unbiased data analytic strategies to improve biomarker discovery in precision medicine.

    Khan, Saifur R / Manialawy, Yousef / Wheeler, Michael B / Cox, Brian J

    Drug discovery today

    2019  Band 24, Heft 9, Seite(n) 1735–1748

    Abstract: Omics technologies promised improved biomarker discovery for precision medicine. The foremost problem of discovered biomarkers is irreproducibility between patient cohorts. From a data analytics perspective, the main reason for these failures is bias in ... ...

    Abstract Omics technologies promised improved biomarker discovery for precision medicine. The foremost problem of discovered biomarkers is irreproducibility between patient cohorts. From a data analytics perspective, the main reason for these failures is bias in statistical approaches and overfitting resulting from batch effects and confounding factors. The keys to reproducible biomarker discovery are: proper study design, unbiased data preprocessing and quality control analyses, and a knowledgeable application of statistics and machine learning algorithms. In this review, we discuss study design and analysis considerations and suggest standards from an expert point-of-view to promote unbiased decision-making in biomarker discovery in precision medicine.
    Mesh-Begriff(e) Biomarkers ; Computational Biology/methods ; Data Science/trends ; Electronic Data Processing/methods ; Humans ; Precision Medicine/trends ; Research Design/standards ; Research Design/trends
    Chemische Substanzen Biomarkers
    Sprache Englisch
    Erscheinungsdatum 2019-05-31
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/j.drudis.2019.05.018
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  9. Artikel ; Online: Diminished Sphingolipid Metabolism, a Hallmark of Future Type 2 Diabetes Pathogenesis, Is Linked to Pancreatic β Cell Dysfunction.

    Khan, Saifur R / Manialawy, Yousef / Obersterescu, Andreea / Cox, Brian J / Gunderson, Erica P / Wheeler, Michael B

    iScience

    2020  Band 23, Heft 10, Seite(n) 101566

    Abstract: Gestational diabetes mellitus (GDM) is the top risk factor for future type 2 diabetes (T2D) development. Ethnicity profoundly influences who will transition from GDM to T2D, with high risk observed in Hispanic women. To better understand this risk, a ... ...

    Abstract Gestational diabetes mellitus (GDM) is the top risk factor for future type 2 diabetes (T2D) development. Ethnicity profoundly influences who will transition from GDM to T2D, with high risk observed in Hispanic women. To better understand this risk, a nested 1:1 pair-matched, Hispanic-specific, case-control design was applied to a prospective cohort with GDM history. Women who were non-diabetic 6-9 weeks postpartum (baseline) were monitored for the development of T2D. Metabolomics were performed on baseline plasma to identify metabolic pathways associated with T2D risk. Notably, diminished sphingolipid metabolism was highly associated with future T2D. Defects in sphingolipid metabolism were further implicated by integrating metabolomics and genome-wide association data, which identified two significantly enriched T2D-linked genes,
    Sprache Englisch
    Erscheinungsdatum 2020-09-15
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2020.101566
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  10. Artikel: Global protein expression dataset acquired during isoniazid-induced cytoprotection against H2O2 challenge in HL-60 cells.

    Khan, Saifur R / Baghdasarian, Argishti / Fahlman, Richard P / Siraki, Arno G

    Data in brief

    2016  Band 6, Seite(n) 823–828

    Abstract: Isoniazid (INH) is one of the first-line anti-tuberculosis drugs. Its effect on oxidative stress, however, is unknown. Here we used a model of oxidative stress by employing glucose/glucose oxidase (GOx), which (based on the availability of glucose and ... ...

    Abstract Isoniazid (INH) is one of the first-line anti-tuberculosis drugs. Its effect on oxidative stress, however, is unknown. Here we used a model of oxidative stress by employing glucose/glucose oxidase (GOx), which (based on the availability of glucose and oxygen) is known to produce H2O2. This reaction induces oxidative stress culminating in necrotic cell death in HL-60 cells (a human promyelocytic leukemia cell line). The changes in protein levels have been quantified using global proteome expression changes through stable isotope labeling by amino acids in cell culture (SILAC) followed by LC-MS/MS analysis. A total of 1459 and 1712 proteins were identified in forward and reverse experiments, respectively. However, only 390 proteins were reproducibly identified in both samples. These 390 proteins were taken into account for further analysis which has been described in "Cytoprotective effect of isoniazid against H2O2 derived injury in HL-60 cells" [1].
    Sprache Englisch
    Erscheinungsdatum 2016-01-29
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article
    ZDB-ID 2786545-9
    ISSN 2352-3409
    ISSN 2352-3409
    DOI 10.1016/j.dib.2016.01.035
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