Metabolomics identifies novel blood biomarkers of pulmonary function and copd in the general population
Creator:
Suhre, K., Gieger, C., Kastenmüller, G., Schulz, H., Boerwinkle, E., London, S.J., Wyss, A., Karrasch, S., McGarrah, R.W., III, Peters, A., Morrison, A.C., Mohney, R.P., North, K.E., Flexeder, C., Michelotti, G.A., Wagner, G.R., and Yu, B.
Date of publication:
2019
Abstract Tesim:
Determination of metabolomic signatures of pulmonary function and chronic obstructive pulmonary disease (COPD) in the general population could aid in identification and understanding of early disease processes. Metabolome measurements were performed on serum from 4742 individuals (2354 African-Americans and 1529 European-Americans from the Atherosclerosis Risk in Communities study and 859 Europeans from the Cooperative Health Research in the Region of Augsburg study). We examined 368 metabolites in relation to cross-sectional measures of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), their ratio (FEV1/FVC) and COPD using multivariable regression followed by meta-analysis. At a false discovery rate of 0.05, 95 metabolites were associated with FEV1 and 100 with FVC (73 overlapping), including inverse associations with branched-chain amino acids and positive associations with glutamine. Ten metabolites were associated with FEV1/FVC and seventeen with COPD (393 cases). Enriched pathways of amino acid metabolism were identified. Associations with FEV1 and FVC were not driven by individuals with COPD. We identified novel metabolic signatures of pulmonary function and COPD in African and European ancestry populations. These may allow development of biomarkers in the general population of early disease pathogenesis, before pulmonary function has decreased to levels diagnostic for COPD.
Resource type:
Article
Affiliation Label Tesim:
Department of Epidemiology
DOI:
https://doi.org/10.17615/b2as-w526
Edition:
Publisher
Identifier:
https://doi.org/10.3390/metabo9040061
ISSN:
2218-1989
Journal Issue:
4
Journal Title:
Metabolites
Journal Volume:
9
Keyword:
Metabolomics, Forced expiratory volume, Chronic obstructive pulmonary disease, Metabolome, and Respiratory function tests
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
Weill Cornell Medicine-Qatar, Helmholtz Zentrum München—German Research Center for Environmental Health, The University of Texas Health Science Center at Houston, National Institutes of Health, Ludwig-Maximilians-Universität, Duke University, Metabolon, Inc., and
Person:
Suhre, K., Gieger, C., Kastenmüller, G., Schulz, H., Boerwinkle, E., London, S.J., Wyss, A., Karrasch, S., McGarrah, R.W., III, Peters, A., Morrison, A.C., Mohney, R.P., North, K.E., Flexeder, C., Michelotti, G.A., Wagner, G.R., and Yu, B.
Discrimination and leukocyte telomere length by depressive symptomatology: The jackson heart study
Creator:
Sims, M., Glover, L.M., North, K.E., Cené, C.W., Reiner, A., Gebreab, S., and Williams, D.R.
Date of publication:
2021
Abstract Tesim:
Background: Psychosocial stressors, such as perceived discrimination and depressive symptoms, may shorten telomeres and exacerbate aging-related illnesses. Methods: Participants from the Jackson Heart Study at visit 1 (2000–2004) with LTL data and Center for Epidemiological Studies-Depression (CES-D) scores (n = 580 men, n = 910 women) were utilized. The dimensions of discrimination scores (everyday, lifetime, burden of lifetime, and stress from lifetime discrimination) were standardized and categorized as low, moderate, and high. Coping responses to everyday and lifetime discrimination were categorized as passive and active coping. Multivariable linear regression analyses were performed to estimate the mean difference (standard errors-SEs) in LTL by dimensions of discrimination and coping responses stratified by CES-D scores < 16 (low) and ≥ 16 (high) and sex. Covariates were age, education, waist circumference, smoking and CVD status. Results: Neither everyday nor lifetime discrimination was associated with mean differences in LTL for men or women by levels of depressive symptoms. Burden of lifetime discrimination was marginally associated with LTL among women who reported low depressive symptoms after full adjustment (b = 0.11, SE = 0.06, p = 0.08). Passive coping with lifetime discrimination was associated with longer LTL among men who reported low depressive symptoms after full adjustment (b = 0.18, SE = 0.09, p < 0.05); and active coping with lifetime discrimination was associated with longer LTL among men who reported high depressive symptoms after full adjustment (b = 1.18, SE = 0.35, p < 0.05). Conclusions: The intersection of perceived discrimination and depressive symptomatology may be related to LTL, and the effects may vary by sex.
Resource type:
Article
Affiliation Label Tesim:
Department of Epidemiology and Department of Medicine
DOI:
https://doi.org/10.17615/g8b2-tz59
Edition:
Publisher
Identifier:
https://doi.org/10.3390/healthcare9060639
ISSN:
2227-9032
Journal Issue:
6
Journal Title:
Healthcare (Switzerland)
Journal Volume:
9
Keyword:
Leukocyte telomere length, Discrimination, African American adults, and Depressive symptoms
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
University of Mississippi Medical Center, , University of Washington, National Institutes of Health, and Harvard University
Person:
Sims, M., Glover, L.M., North, K.E., Cené, C.W., Reiner, A., Gebreab, S., and Williams, D.R.
Synthesis of 5-Benzylamino and 5-Alkylamino-Substituted Pyrimido[4,5-c]quinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity
Creator:
Asressu, Kesatebrhan Haile, Moorman, Nathaniel J., Wellnitz, James, Smith, Jeffery L., Dickmander, Rebekah J., Axtman, Alison D., Popov, Konstantin I., and Willson, Timothy M.
Date of publication:
2024
Abstract Tesim:
A series of 5-benzylamine-substituted pyrimido[4,5-c]quinoline derivatives of the CSNK2A chemical probe SGC-CK2-2 were synthesized with the goal of improving kinase inhibitor cellular potency and antiviral phenotypic activity while maintaining aqueous solubility. Among the range of analogs, those bearing electron-withdrawing (4c and 4g) or donating (4f) substituents on the benzyl ring as well as introduction of non-aromatic groups such as the cyclohexylmethyl (4t) were shown to maintain CSNK2A activity. The CSNK2A activity was also retained with N-methylation of SGC-CK2-2, but α-methyl substitution of the benzyl substituent led to a 10-fold reduction in potency. CSNK2A inhibition potency was restored with indene-based compound 4af, with activity residing in the S-enantiomer (4ag). Analogs with the highest CSNK2A potency showed good activity for inhibition of Mouse Hepatitis Virus (MHV) replication. Conformational analysis indicated that analogs with the best CSNK2A inhibition (4t, 4ac, and 4af) exhibited smaller differences between their ground state conformation and their predicted binding pose. Analogs with reduced activity (4ad, 4ae, and 4ai) required more substantial conformational changes from their ground state within the CSNK2A protein pocket.
Resource type:
Article
Affiliation Label Tesim:
Eshelman School of Pharmacy, Department of Microbiology and Immunology, and Division of Chemical Biology and Medicinal Chemistry
DOI:
https://doi.org/10.17615/jj3d-d958
Edition:
Publisher
Identifier:
https://doi.org/10.3390/ph17030306
ISSN:
1424-8247
Journal Issue:
3
Journal Title:
Pharmaceuticals
Journal Volume:
17
Keyword:
conformational analysis, antiviral, structure–activity study, CSNK2A, and kinase inhibitor
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
Page Start:
306
Person:
Asressu, Kesatebrhan Haile, Moorman, Nathaniel J., Wellnitz, James, Smith, Jeffery L., Dickmander, Rebekah J., Axtman, Alison D., Popov, Konstantin I., and Willson, Timothy M.
Impact of Hypoxia on Radiation-Based Therapies for Liver Cancer
Creator:
Lee, Jean, Westergaard, Sarah A., Kokabi, Nima, and Villalobos, Alexander
Date of publication:
2024
Abstract Tesim:
Background: Hypoxia, a state of low oxygen level within a tissue, is often present in primary and secondary liver tumors. At the molecular level, the tumor cells’ response to hypoxic stress induces proteomic and genomic changes which are largely regulated by proteins called hypoxia-induced factors (HIF). These proteins have been found to drive tumor progression and cause resistance to drug- and radiation-based therapies, ultimately contributing to a tumor’s poor prognosis. Several imaging modalities have been developed to visualize tissue hypoxia, providing insight into a tumor’s microbiology. Methods: A systematic literature search was conducted in PubMed, EMBASE, Cochrane, and Google Scholar for all reports related to hypoxia on liver tumors. All relevant studies were summarized. Results: This review will focus on the impact of hypoxia on liver tumors and review PET-, MRI-, and SPECT-based imaging modalities that have been developed to predict and assess a tumor’s response to radiation therapy, with a focus on liver cancers. Conclusion: While there are numerous studies that have evaluated the impact of hypoxia on tumor outcomes, there remains a relative paucity of data evaluating and quantifying hypoxia within the liver. Novel and developing non-invasive imaging techniques able to provide functional and physiological information on tumor hypoxia within the liver may be able to assist in the treatment planning of primary and metastatic liver lesions.
First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma
Creator:
Backman, Charles, Sohal, Davendra P. S., Yeh, Jen Jen, Lewis, Clayton S., Xie, Changchun, Ahsan, Sabahat, Cliff, Ashley, Hariharan, Arthi, Bogdanov, Vladimir Y., and Zhang, Xiang
Date of publication:
2024
Abstract Tesim:
Alternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating β1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Following in vivo screening of three asTF-proficient human PDAC cell lines, we chose to make use of KRAS G12V-mutant human PDAC cell line PaCa-44, which yields aggressive primary orthotopic tumors with spontaneous spread to PDAC-relevant anatomical sites, along with concomitant severe leukocytosis. The experimental design featured orthotopic tumors formed by luciferase labeled PaCa-44 cells; administration of hRabMab1 alone or in combination with gemcitabine/paclitaxel (gem/PTX); and the assessment of the treatment outcomes on the primary tumor tissue as well as systemic spread. When administered alone, hRabMab1 exhibited poor penetration of tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX, which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNA-seq analysis of primary tumors showed that the addition of hRabMab1 to gem/PTX enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. We here demonstrate for the first time that hRabMab1 may help suppress metastasis in PDAC. hRabMab1’s ability to improve the efficacy of chemotherapy is significant and warrants further investigation.
Evaluating Fatty Acid Amide Hydrolase as a Suitable Target for Sleep Promotion in a Transgenic TauP301S Mouse Model of Neurodegeneration
Creator:
Cohen, Todd J., Moy, Sheryl S., Diering, Graham H., Joyce, Kathryn K., Martin, Shenée C., Harper, Kathryn M., and Harp, Samuel J.
Date of publication:
2024
Abstract Tesim:
Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer’s disease (AD). Sleep disruption has been demonstrated as a driver of AD pathology and cognitive decline. Therefore, treatments designed to maintain sleep may be effective in slowing or halting AD progression. However, commonly used sleep aid medications are associated with an increased risk of AD, highlighting the need for sleep aids with novel mechanisms of action. The endocannabinoid system holds promise as a potentially effective and novel sleep-enhancing target. By using pharmacology and genetic knockout strategies, we evaluated fatty acid amide hydrolase (FAAH) as a therapeutic target to improve sleep and halt disease progression in a transgenic Tau P301S (PS19) model of Tauopathy and AD. We have recently shown that PS19 mice exhibit sleep disruption in the form of dark phase hyperarousal as an early symptom that precedes robust Tau pathology and cognitive decline. Acute FAAH inhibition with PF3845 resulted in immediate improvements in sleep behaviors in male and female PS19 mice, supporting FAAH as a potentially suitable sleep-promoting target. Moreover, sustained drug dosing for 5–10 days resulted in maintained improvements in sleep. To evaluate the effect of chronic FAAH inhibition as a possible therapeutic strategy, we generated FAAH−/− PS19 mice models. Counter to our expectations, FAAH knockout did not protect PS19 mice from progressive sleep loss, neuroinflammation, or cognitive decline. Our results provide support for FAAH as a novel target for sleep-promoting therapies but further indicate that the complete loss of FAAH activity may be detrimental.
Resource type:
Article
Affiliation Label Tesim:
Department of Neurology, Department of Psychiatry, and Department of Cell Biology and Physiology
DOI:
https://doi.org/10.17615/xrb7-f576
Edition:
Publisher
Identifier:
https://doi.org/10.3390/ph17030319
ISSN:
1424-8247
Journal Issue:
3
Journal Title:
Pharmaceuticals
Journal Volume:
17
Keyword:
FAAH, endocannabinoids, Alzheimer’s disease, sleep, tau, and anandamide
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
Page Start:
319
Person:
Cohen, Todd J., Moy, Sheryl S., Diering, Graham H., Joyce, Kathryn K., Martin, Shenée C., Harper, Kathryn M., and Harp, Samuel J.
Carbon Nanodots Inhibit Tumor Necrosis Factor-α-Induced Endothelial Inflammation through Scavenging Hydrogen Peroxide and Upregulating Antioxidant Gene Expression in EA.hy926 Endothelial Cells
Creator:
Jia, Zhenquan, Watson, Kenna R., Yi, Xianwen, Khan, Safeera, Khan, Ajmal, Koher, Grant, Deng, Alexandra Y., Anike, Mmesoma S., Si, Yaru, and Chavez, Jessica
Date of publication:
2024
Abstract Tesim:
Carbon nanodots (CNDs) are a new type of nanomaterial with a size of less than 10 nanometers and excellent biocompatibility, widely used in fields such as biological imaging, transmission, diagnosis, and drug delivery. However, its potential and mechanism to mediate endothelial inflammation have yet to be explored. Here, we report that the uptake of CNDs by EA.hy926 endothelial cells is both time and dose dependent. The concentration of CNDs used in this experiment was found to not affect cell viability. TNF-α is a known biomarker of vascular inflammation. Cells treated with CNDs for 24 h significantly inhibited TNF-α (0.5 ng/mL)-induced expression of intracellular adhesion molecule 1 (ICAM-1) and interleukin 8 (IL-8). ICAM-1 and IL-8 are two key molecules responsible for the activation and the firm adhesion of monocytes to activated endothelial cells for the initiation of atherosclerosis. ROS, such as hydrogen peroxide, play an important role in TNF-α-induced inflammation. Interestingly, we found that CNDs effectively scavenged H2O2 in a dose-dependent manner. CNDs treatment also increased the activity of the antioxidant enzyme NQO1 in EA.hy926 endothelial cells indicating the antioxidant properties of CNDs. These results suggest that the anti-inflammatory effects of CNDs may be due to the direct H2O2 scavenging properties of CNDs and the indirect upregulation of antioxidant enzyme NQO1 activity in endothelial cells. In conclusion, CND can inhibit TNF-α-induced endothelial inflammation, possibly due to its direct scavenging of H2O2 and the indirect upregulation of antioxidant enzyme NQO1 activity in endothelial cells.
Resource type:
Article
Affiliation Label Tesim:
Department of Biology and Department of Surgery
DOI:
https://doi.org/10.17615/hdyr-j044
Edition:
Publisher
Identifier:
https://doi.org/10.3390/antiox13020224
ISSN:
2076-3921
Journal Issue:
2
Journal Title:
Antioxidants
Journal Volume:
13
Keyword:
vascular inflammation, ROS, carbon nanodots, and tumor necrosis factor-alpha
Language Label:
English
License Label:
Attribution 4.0 International
Other Affiliation:
, Department of Biology, and Chapel Hill High School
Page Start:
224
Person:
Jia, Zhenquan, Watson, Kenna R., Yi, Xianwen, Khan, Safeera, Khan, Ajmal, Koher, Grant, Deng, Alexandra Y., Anike, Mmesoma S., Si, Yaru, and Chavez, Jessica
Validation of the Intermolecular Disulfide Bond in Caspase-2
Creator:
Harvest, Carissa K., Amason, Megan E., Lacey, Carolyn A., Li, Lupeng, and Miao, Edward A.
Date of publication:
2024
Abstract Tesim:
Caspases are a family of proteins involved in cell death. Although several caspase members have been well characterized, caspase-2 remains enigmatic. Caspase-2 has been implicated in several phenotypes, but there has been no consensus in the field about its upstream activating signals or its downstream protein targets. In addition, the unique ability of caspase-2 to form a disulfide-bonded dimer has not been studied in depth. Herein, we investigate the disulfide bond in the context of inducible dimerization, showing that disulfide bond formation is dimerization dependent. We also explore and review several stimuli published in the caspase-2 field, test ferroptosis-inducing stimuli, and study in vivo infection models. We hypothesize that the disulfide bond will ultimately prove to be essential for the evolved function of caspase-2. Proving this will require the discovery of cell death phenotypes where caspase-2 is definitively essential.
Resource type:
Article
Affiliation Label Tesim:
Department of Microbiology and Immunology
DOI:
https://doi.org/10.17615/c0sa-g692
Edition:
Publisher
Identifier:
https://doi.org/10.3390/biology13010049
ISSN:
2079-7737
Journal Issue:
1
Journal Title:
Biology
Journal Volume:
13
Keyword:
ferroptosis, disulfide bonds, oxidative damage, apoptosis, and caspase-2
Language Label:
English
License Label:
Attribution 4.0 International
ORCID:
Other Affiliation:
and Duke University School of Medicine
Page Start:
49
Person:
Harvest, Carissa K., Amason, Megan E., Lacey, Carolyn A., Li, Lupeng, and Miao, Edward A.
Unusual Vilasinin-Class Limonoids from Trichilia rubescens
Creator:
Nakagawa-Goto, Kyoko, Newman, David J., O’Keefe, Barry R., Amuti, Saidanxia, Miyake, Katsunori, Fukuyoshi, Shuichi, Lee, Kuo-Hsiung, and Saito, Yohei
Date of publication:
2024
Abstract Tesim:
Eight vilasinin-class limonoids, including the unusually chlorinated rubescins K–M (1–3), the 2,3-epoxylated rubescin N (4), and rubescins O–R (5–8), were newly isolated from Trichilia rubescens. The structures of the isolated compounds were determined through spectroscopic and spectrometric analyses, as well as ECD calculations. The natural occurrence of chlorinated limonoids 1–3 was confirmed by chemical methods and HPLC analysis of a roughly fractionated portion of the plant extract. Eight selected limonoids, including previously known and new compounds, were evaluated for antiproliferative activity against five human tumor cell lines. All tested limonoids, except 8, exhibited significant potency, with IC50 values of <10 μM; in particular, limonoid 14 strongly inhibited tumor cell growth, with IC50 values of 0.54–2.06 μM against all tumor cell lines, including multi-drug-resistant cells.
Resource type:
Article
Affiliation Label Tesim:
Eshelman School of Pharmacy
DOI:
https://doi.org/10.17615/az6w-sz73
Edition:
Publisher
Identifier:
https://doi.org/10.3390/molecules29030651
ISSN:
1420-3049
Journal Issue:
3
Journal Title:
Molecules
Journal Volume:
29
Keyword:
Trichilia rubescens, antiproliferative activity, chlorinated, rubescins K–R, and vilasinin-class limonoid
Language Label:
English
License Label:
Attribution 4.0 International
ORCID:
Other Affiliation:
, National Cancer Institute, Kanazawa University, and Tokyo University of Pharmacy and Life Sciences
Page Start:
651
Person:
Nakagawa-Goto, Kyoko, Newman, David J., O’Keefe, Barry R., Amuti, Saidanxia, Miyake, Katsunori, Fukuyoshi, Shuichi, Lee, Kuo-Hsiung, and Saito, Yohei
Synthesis and PET Imaging Biodistribution Studies of Radiolabeled Iododiflunisal, a Transthyretin Tetramer Stabilizer, Candidate Drug for Alzheimer’s Disease
Creator:
Joshi, Sameer M., Li, Zibo, Llop, Jordi, Arsequell, Gemma, Preshlock, Sean, Gouverneur, Véronique, Wilson, Thomas C., and Gómez-Vallejo, Vanessa
Date of publication:
2024
Abstract Tesim:
The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of IDIF improves Alzheimer’s Disease (AD)-like pathology in mice, although the mechanism of action and pharmacokinetics remain unknown. Radiolabeling IDIF with positron or gamma emitters may aid in the in vivo evaluation of IDIF using non-invasive nuclear imaging techniques. In this work, we report an isotopic exchange reaction to obtain IDIF radiolabeled with 18F. [19F/18F]exchange reaction over IDIF in dimethyl sulfoxide at 160 °C resulted in the formation of [18F]IDIF in 7 ± 3% radiochemical yield in a 20 min reaction time, with a final radiochemical purity of >99%. Biodistribution studies after intravenous administration of [18F]IDIF in wild-type mice using positron emission tomography (PET) imaging showed capacity to cross the blood-brain barrier (ca. 1% of injected dose per gram of tissue in the brain at t > 10 min post administration), rapid accumulation in the liver, long circulation time, and progressive elimination via urine. Our results open opportunities for future studies in larger animal species or human subjects.
Resource type:
Article
Affiliation Label Tesim:
UNC Lineberger Comprehensive Cancer Center
DOI:
https://doi.org/10.17615/5ee6-2w63
Edition:
Publisher
Identifier:
https://doi.org/10.3390/molecules29020488
ISSN:
1420-3049
Journal Issue:
2
Journal Title:
Molecules
Journal Volume:
29
Keyword:
in vivo imaging, transthyretin tetramer stabilizer, iododiflunisal, 18F, small-molecule chaperone, positron emission tomography (PET), and amyloid beta
Language Label:
English
License Label:
Attribution 4.0 International
ORCID:
Other Affiliation:
Basque Research and Technology Alliance, , Institut de Química Avançada de Catalunya, and Oxford University
Page Start:
488
Person:
Joshi, Sameer M., Li, Zibo, Llop, Jordi, Arsequell, Gemma, Preshlock, Sean, Gouverneur, Véronique, Wilson, Thomas C., and Gómez-Vallejo, Vanessa