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Article ; Online: Characterization of antibody-dependent cellular phagocytosis in patients infected with hepatitis C virus with different clinical outcomes.

Adhikari, Anurag / Abayasingam, Arunasingam / Brasher, Nicholas A / Kim, Ha Na / Lord, Megan / Agapiou, David / Maher, Lisa / Rodrigo, Chaturaka / Lloyd, Andrew R / Bull, Rowena A / Tedla, Nicodemus

Journal of medical virology

2024 Volume 96, Issue 1, Page(s) e29381

Abstract: Early neutralizing antibodies against hepatitis C virus (HCV) and CD8 + T cell effector responses ...

Abstract	Early neutralizing antibodies against hepatitis C virus (HCV) and CD8 + T cell effector responses can lead to viral clearance. However, these functions alone are not sufficient to protect patients against HCV infection, thus undefined additional antiviral immune mechanisms are required. In recent years, Fc-receptor-dependent antibody effector functions, particularly, antibody-dependent cellular phagocytosis (ADCP) were shown to offer immune protection against several RNA viruses. However, its development and clinical role in patients with HCV infection remain unknown. In this study, we found that patients with chronic GT1a or GT3a HCV infection had significantly higher concentrations of anti-envelope 2 (E2) antibodies, predominantly IgG1 subclass, than patients that cleared the viruses while the latter had antibodies with higher affinities. 97% of the patients with HCV had measurable ADCP of whom patients with chronic disease showed significantly higher ADCP than those who naturally cleared the virus. Epitope mapping studies showed that patients with antibodies that target antigenic domains on the HCV E2 protein that are known to associate with neutralization function are also strongly associated with ADCP, suggesting antibodies with overlapping/dual functions. Correlation studies showed that ADCP significantly correlated with plasma anti-E2 antibody levels and neutralization function regardless of clinical outcome and genotype of infecting virus, while a significant correlation between ADCP and affinity was only evident in patients that cleared the virus. These results suggest ADCP was mostly driven by antibody titer in patients with chronic disease while maintained in clearers due to the quality (affinity) of their anti-E2 antibodies despite having lower antibody titers.
MeSH term(s)	Humans ; Hepacivirus ; Hepatitis C Antibodies ; Hepatitis C ; Antibodies, Neutralizing ; Viral Envelope Proteins ; Phagocytosis ; Chronic Disease
Chemical Substances	Hepatitis C Antibodies ; Antibodies, Neutralizing ; Viral Envelope Proteins
Language	English
Publishing date	2024-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	752392-0
ISSN	1096-9071 ; 0146-6615
ISSN (online)	1096-9071
ISSN	0146-6615
DOI	10.1002/jmv.29381
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Zs.A 1320: Show issues

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Article ; Online: Regioselective Direct C-H Bond Heteroarylation of Thiazoles Enabled by an Iminopyridine-Based α-Diimine Nickel(II) Complex Evaluated by DFT Studies.

Arche, Phillip Damien E / Chatterjee, Shubham / Talukder, Md Muktadir / Miller, Justin T / Cue, John Michael O / Udamulle Gedara, Chinthaka M / Lord, Richard L / Biewer, Michael C / Cisneros, G Andrés / Stefan, Mihaela C

The Journal of organic chemistry

2023 Volume 88, Issue 17, Page(s) 12319–12328

Abstract: Direct C-H bond arylation is a highly effective method for synthesizing arylated heteroaromatics ... experiments and density functional theory calculations revealed that the mechanism of C-H activation in 4 ... °C) under aerobic conditions, we produced mono- and diarylated thiazole units. Competition ...

Abstract	Direct C-H bond arylation is a highly effective method for synthesizing arylated heteroaromatics. This method reduces the number of synthetic steps and minimizes the formation of impurities. We report an air- and moisture-stable iminopyridine-based α-diimine nickel(II) complex for direct C5-H bond arylation of thiazole derivatives. Under a low catalyst loading and performing the reactions at lower temperatures (80 °C) under aerobic conditions, we produced mono- and diarylated thiazole units. Competition experiments and density functional theory calculations revealed that the mechanism of C-H activation in 4-methylthiazole involves an electrophilic aromatic substitution.
Language	English
Publishing date	2023-08-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	123490-0
ISSN	1520-6904 ; 0022-3263
ISSN (online)	1520-6904
ISSN	0022-3263
DOI	10.1021/acs.joc.3c01021
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Zs.A 4473: Show issues

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Article ; Online: Markers of Systemic Inflammation in Acute Attacks of Ulcerative Colitis: What Level of C-reactive Protein Constitutes Severe Colitis?

Croft, Anthony / Lord, Anton / Radford-Smith, Graham

Journal of Crohn's & colitis

2022 Volume 16, Issue 7, Page(s) 1089–1096

Abstract: ... of ulcerative colitis [UC] activity. However, the C-reactive protein [CRP] is preferentially used in contemporary ...

Abstract	Background and aims: The erythrocyte sedimentation rate [ESR] as a component of the Truelove and Witts Criteria [TWC] is the traditional inflammatory marker used for the assessment of ulcerative colitis [UC] activity. However, the C-reactive protein [CRP] is preferentially used in contemporary clinical practice. We aimed to determine the equivalent CRP cut-off for an ESR of >30 mm/h in patients presenting with acute severe UC. Methods: Clinical and pathological data were prospectively collected from 163 presentations of severe UC. A CRP cut-off corresponding to an ESR of >30 mm/h was determined using confusion matrices. A validation cohort of 128 presentations was prospectively collected and analysed. Results: A CRP cut-off of ≥12 mg/L generated an 85% positive predictive value [PPV] with a sensitivity of 95% and an accuracy of 82% for having a paired ESR of >30 mm/h. There were no statistically significant differences between groups determined by the traditional ESR versus the new CRP-based criterion in the presenting faecal calprotectin, Mayo endoscopic subscore, or the rates of intravenous corticosteroid therapy failure and colectomy-by-discharge. Applying the CRP ≥12 mg/L criterion to a validation cohort of 128 presentations generated a PPV of 83% and a sensitivity of 94%. Conclusions: The proposed CRP ≥12 mg/L cut-off is an inclusive, sensitive, and very practical alternative to ESR as part of the TWC for defining UC presentation severity. It demonstrated similar performance characteristics to the classical ESR criterion when used for the assessment of acute UC disease activity. These findings were confirmed in a validation cohort.
MeSH term(s)	Biomarkers/metabolism ; Blood Sedimentation ; C-Reactive Protein/metabolism ; Colitis, Ulcerative/pathology ; Feces/chemistry ; Humans ; Inflammation ; Leukocyte L1 Antigen Complex/analysis ; Severity of Illness Index
Chemical Substances	Biomarkers ; Leukocyte L1 Antigen Complex ; C-Reactive Protein (9007-41-4)
Language	English
Publishing date	2022-02-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2390120-2
ISSN	1876-4479 ; 1873-9946
ISSN (online)	1876-4479
ISSN	1873-9946
DOI	10.1093/ecco-jcc/jjac014
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Zs.A 6634: Show issues

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Article ; Online: Chemical Permeation Enhancers for Topically-Applied Vitamin C and Its Derivatives

Lord Sam Liston / Precious Lorraine Rivas / Pajaree Sakdiset / Gerard Lee See / Florencio Arce

Cosmetics, Vol 9, Iss 4, p

A Systematic Review

2022 Volume 85

Abstract: ... enhancers (CPEs) on the topical delivery of vitamin C (VC) and its derivatives. A literature search using ...

Abstract	This paper reports the permeation-enhancing properties and safety of different chemical permeation enhancers (CPEs) on the topical delivery of vitamin C (VC) and its derivatives. A literature search using search keywords or phrases was done in PubMed ® , ScienceDirect, and MEDLINE databases. The calculated Log P (cLog P ) values were referenced from PubChem and the dermal LD 50 values were referenced from safety data sheets. Thirteen studies described the permeation-enhancing activity of 18 identified CPEs in the topical delivery of VC. Correlation analysis between ER and cLog P values for porcine ( r = 0.114) and rabbit ( r = 0.471) showed weak and moderate positive correlation, while mouse ( r = −0.135), and reconstructed human epidermis ( r = −0.438) had a negative correlation. The majority ( n = 17) of the CPEs belonged to Category 5 of the Globally Harmonized System of Classification or low toxicity hazard. CPEs alone or in combination enhanced permeation (ER = 0.198–106.57) of VC in topical formulations. The combination of isopropyl myristate, sorbitan monolaurate, and polyoxyethylene 80 as CPEs for VC resulted in the highest permeation enhancement ratio.
Keywords	chemical permeation enhancer ; skin permeation ; ascorbic acid ; vitamin C ; cosmetics ; systematic review ; Chemistry ; QD1-999
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Mortality risk prediction of high-sensitivity C-reactive protein in suspected acute coronary syndrome: A cohort study.

Kaura, Amit / Hartley, Adam / Panoulas, Vasileios / Glampson, Ben / Shah, Anoop S V / Davies, Jim / Mulla, Abdulrahim / Woods, Kerrie / Omigie, Joe / Shah, Anoop D / Thursz, Mark R / Elliott, Paul / Hemmingway, Harry / Williams, Bryan / Asselbergs, Folkert W / O'Sullivan, Michael / Lord, Graham M / Trickey, Adam / Sterne, Jonathan Ac /

Haskard, Dorian O / Melikian, Narbeh / Francis, Darrel P / Koenig, Wolfgang / Shah, Ajay M / Kharbanda, Rajesh / Perera, Divaka / Patel, Riyaz S / Channon, Keith M / Mayet, Jamil / Khamis, Ramzi

PLoS medicine

2022 Volume 19, Issue 2, Page(s) e1003911

Abstract: Background: There is limited evidence on the use of high-sensitivity C-reactive protein (hsCRP ...

Abstract	Background: There is limited evidence on the use of high-sensitivity C-reactive protein (hsCRP) as a biomarker for selecting patients for advanced cardiovascular (CV) therapies in the modern era. The prognostic value of mildly elevated hsCRP beyond troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndrome (ACS) is unknown. We evaluated whether a mildly elevated hsCRP (up to 15 mg/L) was associated with mortality risk, beyond troponin level, in patients with suspected ACS. Methods and findings: We conducted a retrospective cohort study based on the National Institute for Health Research Health Informatics Collaborative data of 257,948 patients with suspected ACS who had a troponin measured at 5 cardiac centres in the United Kingdom between 2010 and 2017. Patients were divided into 4 hsCRP groups (<2, 2 to 4.9, 5 to 9.9, and 10 to 15 mg/L). The main outcome measure was mortality within 3 years of index presentation. The association between hsCRP levels and all-cause mortality was assessed using multivariable Cox regression analysis adjusted for age, sex, haemoglobin, white cell count (WCC), platelet count, creatinine, and troponin. Following the exclusion criteria, there were 102,337 patients included in the analysis (hsCRP <2 mg/L (n = 38,390), 2 to 4.9 mg/L (n = 27,397), 5 to 9.9 mg/L (n = 26,957), and 10 to 15 mg/L (n = 9,593)). On multivariable Cox regression analysis, there was a positive and graded relationship between hsCRP level and mortality at baseline, which remained at 3 years (hazard ratio (HR) (95% CI) of 1.32 (1.18 to 1.48) for those with hsCRP 2.0 to 4.9 mg/L and 1.40 (1.26 to 1.57) and 2.00 (1.75 to 2.28) for those with hsCRP 5 to 9.9 mg/L and 10 to 15 mg/L, respectively. This relationship was independent of troponin in all suspected ACS patients and was further verified in those who were confirmed to have an ACS diagnosis by clinical coding. The main limitation of our study is that we did not have data on underlying cause of death; however, the exclusion of those with abnormal WCC or hsCRP levels >15 mg/L makes it unlikely that sepsis was a major contributor. Conclusions: These multicentre, real-world data from a large cohort of patients with suspected ACS suggest that mildly elevated hsCRP (up to 15 mg/L) may be a clinically meaningful prognostic marker beyond troponin and point to its potential utility in selecting patients for novel treatments targeting inflammation. Trial registration: ClinicalTrials.gov - NCT03507309.
MeSH term(s)	Acute Coronary Syndrome/blood ; Acute Coronary Syndrome/diagnosis ; Acute Coronary Syndrome/mortality ; Aged ; Aged, 80 and over ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Cohort Studies ; Female ; Follow-Up Studies ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Mortality/trends ; Predictive Value of Tests ; Retrospective Studies ; Risk Factors ; United Kingdom/epidemiology
Chemical Substances	Biomarkers ; C-Reactive Protein (9007-41-4)
Language	English
Publishing date	2022-02-22
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Multicenter Study ; Pragmatic Clinical Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2185925-5
ISSN	1549-1676 ; 1549-1277
ISSN (online)	1549-1676
ISSN	1549-1277
DOI	10.1371/journal.pmed.1003911
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Zs.A 6042: Show issues

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Article ; Online: Investigation into the presence and functional significance of proinsulin C-peptide in the female germline†.

Martin, Jacinta H / Aitken, R John / Bromfield, Elizabeth G / Cafe, Shenae L / Sutherland, Jessie M / Frost, Emily R / Nixon, Brett / Lord, Tessa

Biology of reproduction

2019 Volume 100, Issue 5, Page(s) 1275–1289

Abstract: ... reproduction. What remains less certain is whether proinsulin C-peptide, which has recently been implicated ... we examined the expression of insulin, C-peptide, and its purported receptor; GPR146, within the mouse ovary ... and oocyte. Our data establish the presence of abundant C-peptide within follicular fluid and raise ...

Abstract	Diabetes is associated with poor oocyte quality and the dysregulation of ovarian function and is thus a leading contributor to the increasing prevalence of female reproductive pathologies. Accordingly, it is well-established that insulin fulfills a key role in the regulation of several facets of female reproduction. What remains less certain is whether proinsulin C-peptide, which has recently been implicated in cellular signaling cascades, holds a functional role in the female germline. In the present study, we examined the expression of insulin, C-peptide, and its purported receptor; GPR146, within the mouse ovary and oocyte. Our data establish the presence of abundant C-peptide within follicular fluid and raise the prospect that this bioactive peptide is internalized by oocytes in a G-protein coupled receptor-dependent manner. Further, our data reveal that internalized C-peptide undergoes pronounced subcellular relocalization from the ooplasm to the pronuclei postfertilization. The application of immunoprecipitation analysis and mass spectrometry identified breast cancer type 2 susceptibility protein (BRCA2), the meiotic resumption/DNA repair protein, as a primary binding partner for C-peptide within the oocyte. Collectively, these findings establish a novel accumulation profile for C-peptide in the female germline and provide the first evidence for an interaction between C-peptide and BRCA2. This interaction is particularly intriguing when considering the propensity for oocytes from diabetic women to experience aberrant meiotic resumption and perturbation of traditional DNA repair processes. This therefore provides a clear imperative for further investigation of the implications of dysregulated C-peptide production in these individuals.
MeSH term(s)	Animals ; BRCA2 Protein/genetics ; BRCA2 Protein/metabolism ; Blastocyst/cytology ; Blastocyst/drug effects ; C-Peptide/genetics ; C-Peptide/metabolism ; C-Peptide/pharmacology ; Cells, Cultured ; Cumulus Cells/cytology ; Cumulus Cells/drug effects ; Cumulus Cells/metabolism ; Embryonic Development/drug effects ; Embryonic Development/genetics ; Female ; Fertilization in Vitro/veterinary ; Germ Cells/cytology ; Germ Cells/drug effects ; Germ Cells/metabolism ; In Vitro Oocyte Maturation Techniques/methods ; In Vitro Oocyte Maturation Techniques/veterinary ; Male ; Meiosis/drug effects ; Meiosis/genetics ; Meiosis/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Oocytes/cytology ; Oocytes/drug effects ; Oocytes/metabolism ; Oogenesis/drug effects ; Oogenesis/genetics
Chemical Substances	BRCA2 Protein ; BRCA2 protein, mouse ; C-Peptide
Language	English
Publishing date	2019-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1118-6
ISSN	1529-7268 ; 0006-3363
ISSN (online)	1529-7268
ISSN	0006-3363
DOI	10.1093/biolre/ioz008
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Zs.A 551: Show issues

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Article ; Online: Comprehensive database of Manufactured Gas Plant tars. Part C. Heterocyclic and hydroxylated polycyclic aromatic hydrocarbons.

Gallacher, Christopher / Thomas, Russell / Lord, Richard / Kalin, Robert M / Taylor, Chris

Rapid communications in mass spectrometry : RCM

2017 Volume 31, Issue 15, Page(s) 1250–1260

Abstract: Rationale: Coal tars are a mixture of organic and inorganic compounds that were by-products from the manufactured gas and coke making industries. The tar compositions varied depending on many factors such as the temperature of production and the type of ...

Abstract	Rationale: Coal tars are a mixture of organic and inorganic compounds that were by-products from the manufactured gas and coke making industries. The tar compositions varied depending on many factors such as the temperature of production and the type of retort used. For this reason a comprehensive database of the compounds found in different tar types is of value to understand both how their compositions differ and what potential chemical hazards are present. This study focuses on the heterocyclic and hydroxylated compounds present in a database produced from 16 different tars from five different production processes. Methods: Samples of coal tar were extracted using accelerated solvent extraction (ASE) and derivatized post-extraction using N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane (TMCS). The derivatized samples were analysed using two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GCxGC/TOFMS). Results: A total of 865 heterocyclic compounds and 359 hydroxylated polycyclic aromatic hydrocarbons (PAHs) were detected in 16 tar samples produced by five different processes. The contents of both heterocyclic and hydroxylated PAHs varied greatly with the production process used, with the heterocyclic compounds giving information about the feedstock used. Of the 359 hydroxylated PAHs detected the majority would not have been be detected without the use of derivatization. Conclusions: Coal tars produced using different production processes and feedstocks yielded tars with significantly different heterocyclic and hydroxylated contents. The concentrations of the individual heterocyclic compounds varied greatly even within the different production processes and provided information about the feedstock used to produce the tars. The hydroxylated PAH content of the samples provided important analytical information that would otherwise not have been obtained without the use of derivatization and GCxGC/TOFMS.
Language	English
Publishing date	2017-08-15
Publishing country	England
Document type	Journal Article
ZDB-ID	58731-x
ISSN	1097-0231 ; 0951-4198
ISSN (online)	1097-0231
ISSN	0951-4198
DOI	10.1002/rcm.7904
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Zs.A 3461: Show issues

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Article ; Online: Phenylanthraquinones and flavone-C-glucosides from the disjunct Bulbinella in New Zealand.

Richardson, Alistair T B / Lord, Janice M / Perry, Nigel B

Phytochemistry

2017 Volume 134, Page(s) 64–70

Abstract: ... to the stele and peel was observed in roots. Two flavone-C-glucosides were found in leaves of Bulbinella. ...

Abstract	The genera Bulbine, Bulbinella and Kniphofia produce phenylanthraquinones and are mostly found in southern Africa, although a disjunct group of Bulbinella species endemic to New Zealand also contain phenylanthraquinones as reported herein. The sub-Antarctic megaherb B. rossii yielded sulphated phenylanthraquinones, including a phenylanthraquinone found to carry a sulphated glycoside substituent, 4'-O-demethylknipholone-4'-β-D-xylopyranosyl-3″-sulphate. A sensitive HPLC method was used to analyse 5 of the 6 New Zealand Bulbinella species, all of which contained phenylanthraquinones. Leaves and roots had different profiles, but species were not distinct. Roots were rich in sulphated and free phenylanthraquinones (0.27 ± 0.09% dry wt), whereas leaves typically only contained free knipholone (0.14 ± 0.01%). Localisation of phenylanthraquinones to the stele and peel was observed in roots. Two flavone-C-glucosides were found in leaves of Bulbinella.
MeSH term(s)	Africa, Southern ; Anthraquinones/chemistry ; Anthraquinones/isolation & purification ; Antimalarials/chemistry ; Antimalarials/isolation & purification ; Antimalarials/pharmacology ; Chromatography, High Pressure Liquid ; Flavones/chemistry ; Flavones/isolation & purification ; Glucosides/chemistry ; Glucosides/isolation & purification ; Glycosides/chemistry ; Glycosides/isolation & purification ; Liliaceae/chemistry ; Magnoliopsida/chemistry ; Molecular Structure ; New Zealand ; Plant Leaves/chemistry ; Plant Roots/chemistry
Chemical Substances	4'-O-demethylknipholone-4'-beta-D-xylopyranosyl-3'-sulfate ; Anthraquinones ; Antimalarials ; Flavones ; Glucosides ; Glycosides ; knipholone ; chrysophanic acid (N1ST8V8RR2)
Language	English
Publishing date	2017-02
Publishing country	England
Document type	Journal Article
ZDB-ID	208884-8
ISSN	1873-3700 ; 0031-9422
ISSN (online)	1873-3700
ISSN	0031-9422
DOI	10.1016/j.phytochem.2016.11.014
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Article ; Online: Mortality risk prediction of high-sensitivity C-reactive protein in suspected acute coronary syndrome

Amit Kaura / Adam Hartley / Vasileios Panoulas / Ben Glampson / Anoop S V Shah / Jim Davies / Abdulrahim Mulla / Kerrie Woods / Joe Omigie / Anoop D Shah / Mark R Thursz / Paul Elliott / Harry Hemmingway / Bryan Williams / Folkert W Asselbergs / Michael O'Sullivan / Graham M Lord / Adam Trickey / Jonathan Ac Sterne /

Dorian O Haskard / Narbeh Melikian / Darrel P Francis / Wolfgang Koenig / Ajay M Shah / Rajesh Kharbanda / Divaka Perera / Riyaz S Patel / Keith M Channon / Jamil Mayet / Ramzi Khamis

PLoS Medicine, Vol 19, Iss 2, p e

A cohort study.

2022 Volume 1003911

Abstract: Background There is limited evidence on the use of high-sensitivity C-reactive protein (hsCRP ...

Abstract	Background There is limited evidence on the use of high-sensitivity C-reactive protein (hsCRP) as a biomarker for selecting patients for advanced cardiovascular (CV) therapies in the modern era. The prognostic value of mildly elevated hsCRP beyond troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndrome (ACS) is unknown. We evaluated whether a mildly elevated hsCRP (up to 15 mg/L) was associated with mortality risk, beyond troponin level, in patients with suspected ACS. Methods and findings We conducted a retrospective cohort study based on the National Institute for Health Research Health Informatics Collaborative data of 257,948 patients with suspected ACS who had a troponin measured at 5 cardiac centres in the United Kingdom between 2010 and 2017. Patients were divided into 4 hsCRP groups (<2, 2 to 4.9, 5 to 9.9, and 10 to 15 mg/L). The main outcome measure was mortality within 3 years of index presentation. The association between hsCRP levels and all-cause mortality was assessed using multivariable Cox regression analysis adjusted for age, sex, haemoglobin, white cell count (WCC), platelet count, creatinine, and troponin. Following the exclusion criteria, there were 102,337 patients included in the analysis (hsCRP <2 mg/L (n = 38,390), 2 to 4.9 mg/L (n = 27,397), 5 to 9.9 mg/L (n = 26,957), and 10 to 15 mg/L (n = 9,593)). On multivariable Cox regression analysis, there was a positive and graded relationship between hsCRP level and mortality at baseline, which remained at 3 years (hazard ratio (HR) (95% CI) of 1.32 (1.18 to 1.48) for those with hsCRP 2.0 to 4.9 mg/L and 1.40 (1.26 to 1.57) and 2.00 (1.75 to 2.28) for those with hsCRP 5 to 9.9 mg/L and 10 to 15 mg/L, respectively. This relationship was independent of troponin in all suspected ACS patients and was further verified in those who were confirmed to have an ACS diagnosis by clinical coding. The main limitation of our study is that we did not have data on underlying cause of death; however, ...
Keywords	Medicine ; R
Subject code	610 ; 616
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: ATGL-1 mediates the effect of dietary restriction and the insulin/IGF-1 signaling pathway on longevity in C. elegans.

Zaarur, Nava / Desevin, Kathleen / Mackenzie, James / Lord, Avery / Grishok, Alla / Kandror, Konstantin V

Molecular metabolism

2019 Volume 27, Page(s) 75–82

Abstract: ... increases basal and maximal oxygen consumption rate and extends lifespan in C. elegans. Reduction of ATGL-1 ...

Abstract	Objective: Animal lifespan is controlled through genetic pathways that are conserved from nematodes to humans. Lifespan-promoting conditions in nematodes include fasting and a reduction of insulin/IGF signaling. Here we aimed to investigate the input of the Caenorhabditis elegans homologue of the mammalian rate-limiting lipolytic enzyme Adipose Triglyceride Lipase, ATGL-1, in longevity control. Methods: We used a combination of genetic and biochemical approaches to determine the role of ATGL-1 in accumulation of triglycerides and regulation of longevity. Results: We found that expression of ATGL is increased in the insulin receptor homologue mutant daf-2 in a FoxO/DAF-16-dependent manner. ATGL-1 is also up-regulated by fasting and in the eat-2 loss-of-function mutant strain. Overexpression of ATGL-1 increases basal and maximal oxygen consumption rate and extends lifespan in C. elegans. Reduction of ATGL-1 function suppresses longevity of the long-lived mutants eat-2 and daf-2. Conclusion: Our results demonstrate that ATGL is required for extended lifespan downstream of both dietary restriction and reduced insulin/IGF signaling.
MeSH term(s)	Animals ; Caenorhabditis elegans/physiology ; Caenorhabditis elegans Proteins/metabolism ; Fasting ; Insulin/metabolism ; Insulin-Like Growth Factor I/metabolism ; Lipase/metabolism ; Longevity ; Signal Transduction
Chemical Substances	Caenorhabditis elegans Proteins ; Insulin ; Insulin-Like Growth Factor I (67763-96-6) ; ATGL-1 protein, C elegans (EC 3.1.1.3) ; Lipase (EC 3.1.1.3)
Language	English
Publishing date	2019-07-05
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2212-8778
ISSN (online)	2212-8778
DOI	10.1016/j.molmet.2019.07.001
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