Imperial College London

ProfessorJulianGriffin

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 3220julian.griffin

 
 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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378 results found

Burkhardt P, Palma-Duran SA, Tuck ARR, Norgren K, Li X, Nikiforova V, Griffin JL, Munic Kos Vet al., 2024, Environmental chemicals change extracellular lipidome of mature human white adipocytes., Chemosphere, Vol: 349

Certain environmental chemicals affect the body's energy balance and are known as metabolism disrupting chemicals (MDCs). MDCs have been implicated in the development of metabolic diseases, such as obesity and type 2 diabetes. In contrast to their well-known impact on developing adipocytes, MDC effects leading to altered energy balance and development of insulin resistance in mature white adipocytes, constituents of adult adipose tissue, are largely unclear. Here, we investigated the effects of six well-established environmental MDCs (bisphenol A (BPA), perfluorooctanoic acid (PFOA), triclosan (TCS), p,p-dichlorodiphenyl-dichloroethylene (ppDDE), tributyltin chloride (TBT) and triphenyl phosphate (TPP)) on mature human white adipocytes derived from mesenchymal stem cells in vitro. We aimed to identify biomarkers and sensitive endpoints of their metabolism disrupting effects. While most of the tested exposures had no effect on adipocyte glucose consumption, lipid storage and assessed gene expression endpoints, the highest concentration of triclosan affected the total lipid storage and adipocyte size, as well as glucose consumption and mRNA expression of the glucose transporter GLUT1, leptin and adiponectin. Additionally, an increased expression of adiponectin was observed with TPP and the positive control PPARγ agonist rosiglitazone. In contrast, the lipidomic analysis of the cell culture medium after a 3-day exposure was extremely sensitive and revealed concentration-dependent changes in the extracellular lipidome of adipocytes exposed to nearly all studied chemicals. While some of the extracellular lipidome changes were specific for the MDC used, some effects were found common to several tested chemicals and included increases in lysophosphatidylcholines, glycerophospholipids and ceramides and a decrease in fatty acids, with possible implications in inflammation, lipid and glucose uptake. This study points to early signs of metabolic disruption and likely sys

Journal article

Pereira M, Liang J, Edwards-Hicks J, Meadows AM, Hinz C, Liggi S, Hepprich M, Mudry J, Han K, Griffin JL, Fraser I, Sack MN, Hess C, Bryant CEet al., 2024, Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting., Cell Rep, Vol: 43

Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated. Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.

Journal article

Trichia E, Koulman A, Stewart ID, Brage S, Griffin SJ, Griffin JL, Khaw K-T, Langenberg C, Wareham NJ, Imamura F, Forouhi NGet al., 2024, Plasma Metabolites Related to the Consumption of Different Types of Dairy Products and Their Association with New-Onset Type 2 Diabetes: Analyses in the Fenland and EPIC-Norfolk Studies, United Kingdom., Mol Nutr Food Res, Vol: 68

SCOPE: To identify metabolites associated with habitual dairy consumption and investigate their associations with type 2 diabetes (T2D) risk. METHODS AND RESULTS: Metabolomics assays were conducted in the Fenland (n = 10,281) and EPIC-Norfolk (n = 1,440) studies. Using 82 metabolites assessed in both studies, we developed metabolite scores to classify self-reported consumption of milk, yogurt, cheese, butter, and total dairy (Fenland Study-discovery set; n = 6035). Internal and external validity of the scores was evaluated (Fenland-validation set, n = 4246; EPIC-Norfolk, n = 1440). The study assessed associations between each metabolite score and T2D incidence in EPIC-Norfolk (n = 641 cases; 16,350 person-years). The scores classified low and high consumers for all dairy types with internal validity, and milk, butter, and total dairy with external validity. The scores were further associated with lower incident T2D: hazard ratios (95% confidence interval) per standard deviation: milk 0.71 (0.65, 0.77); butter 0.62 (0.57, 0.68); total dairy 0.66 (0.60, 0.72). These associations persisted after adjustment for known dairy-fat biomarkers. CONCLUSION: Metabolite scores identified habitual consumers of milk, butter, and total dairy products, and were associated with lower T2D risk. These findings hold promise for identifying objective indicators of the physiological response to dairy consumption.

Journal article

Michael BD, Dunai C, Needham EJ, Tharmaratnam K, Williams R, Huang Y, Boardman SA, Clark JJ, Sharma P, Subramaniam K, Wood GK, Collie C, Digby R, Ren A, Norton E, Leibowitz M, Ebrahimi S, Fower A, Fox H, Tato E, Ellul MA, Sunderland G, Held M, Hetherington C, Egbe FN, Palmos A, Stirrups K, Grundmann A, Chiollaz A-C, Sanchez J-C, Stewart JP, Griffiths M, Solomon T, Breen G, Coles AJ, Kingston N, Bradley JR, Chinnery PF, Cavanagh J, Irani SR, Vincent A, Baillie JK, Openshaw PJ, Semple MG, ISARIC4C Investigators, COVID-CNS Consortium, Taams LS, Menon DKet al., 2023, Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses, Nature Communications, Vol: 14, ISSN: 2041-1723

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.

Journal article

Li K, Mocciaro G, Griffin JL, Zhang Net al., 2023, The Saccharomyces cerevisiae acetyltransferase Gcn5 exerts antagonistic pleiotropic effects on chronological ageing., Aging (Albany NY), Vol: 15, Pages: 10915-10937

Compared to replicative lifespan, epigenetic regulation of chronological lifespan (CLS) is less well understood in yeast. Here, by screening all the viable mutants of histone acetyltransferase (HAT) and histone deacetylase (HDAC), we demonstrate that Gcn5, functioning in the HAT module of the SAGA/SLIK complex, exhibits an epistatic relationship with the HDAC Hda1 to control the expression of starvation-induced stress response and respiratory cell growth. Surprisingly, the gcn5Δ mutants lose their colony-forming potential early in the stationary phase but display a longer maximum CLS than their WT counterparts, suggesting the contradictory roles of Gcn5 in lifespan regulation. Integrative analyses of the transcriptome, metabolome and ChIP assays reveal that Gcn5 is necessary for the activation of two regulons upon glucose starvation: the Msn2/4-/Gis1-dependent stress response and the Cat8-/Adr1-mediated metabolic reprogramming, to enable pro-longevity characteristics, including redox homeostasis, stress resistance and maximal storage of carbohydrates. The activation of Cat8-/Adr1-dependent regulon also promotes the pyruvate dehydrogenase (PDH) bypass, leading to acetyl-CoA synthesis, global and targeted H3K9 acetylation. Global H3K9 acetylation levels mediated by Gcn5 and Hda1 during the transition into stationary phase are positively correlated with senescent cell populations accumulated in the aged cell cultures. These data suggest that Gcn5 lies in the centre of a feed-forward loop between histone acetylation and starvation-induced gene expression, enabling stress resistance and homeostasis but also promoting chronological ageing concomitantly.

Journal article

Han K, Singh K, Meadows AM, Sharma R, Hassanzadeh S, Wu J, Goss-Holmes H, Huffstutler RD, Teague HL, Mehta NN, Griffin JL, Tian R, Traba J, Sack MNet al., 2023, Boosting NAD preferentially blunts Th17 inflammation via arginine biosynthesis and redox control in healthy and psoriasis subjects, CELL REPORTS MEDICINE, Vol: 4, ISSN: 2666-3791

Journal article

Kanai M, Andrews SJ, Cordioli M, Stevens C, Neale BM, Daly M, Ganna A, Pathak GA, Iwasaki A, Karjalainen J, Mehtonen J, Pirinen M, Chwialkowska K, Trankiem A, Balaconis MK, Veerapen K, Wolford BN, Ahmad HF, Andrews S, von Hohenstaufen Puoti KA, Boer C, Boua PR, Butler-Laporte G, Cadilla CL, Chwiałkowska K, Colombo F, Douillard V, Dueker N, Dutta AK, El-Sherbiny YM, Eltoukhy MM, Esmaeeli S, Faucon A, Fave M-J, Cadenas IF, Francescatto M, Francioli L, Franke L, Fuentes M, Durán RG, Cabrero DG, Harry EN, Jansen P, Szentpéteri JL, Kaja E, Kanai M, Kirk C, Kousathanas A, Krieger JE, Patel SK, Lemaçon A, Limou S, Lió P, Marouli E, Marttila MM, Medina-Gómez C, Michaeli Y, Migeotte I, Mondal S, Moreno-Estrada A, Moya L, Nakanishi T, Nasir J, Pasko D, Pearson NM, Pereira AC, Priest J, Prijatelj V, Prokić I, Teumer A, Várnai R, Romero-Gómez M, Roos C, Rosenfeld J, Ruolin L, Schulte EC, Schurmann C, Sedaghati-khayat B, Shaheen D, Shivanathan I, Sipeky C, Sirui Z, Striano P, Tanigawa Y, Remesal AU, Vadgama N, Vallerga CL, van der Laan S, Verdugo RA, Wang QS, Wei Z, Zainulabid UA, Zárate RN, Auton A, Shelton JF, Shastri AJ, Weldon CH, Filshtein-Sonmez T, Coker D, Symons A, Aslibekyan S, OConnell J, Ye C, Hatoum AS, Agrawal A, Bogdan R, Colbert SMC, Thompson WK, Fan CC, Johnson EC, Niazyan L, Davidyants M, Arakelyan A, Avetyan D, Bekbossynova M, Tauekelova A, Tuleutayev M, Sailybayeva A, Ramankulov Y, Zholdybayeva E, Dzharmukhanov J, Kassymbek K, Tsechoeva T, Turebayeva G, Smagulova Z, Muratov T, Khamitov S, Kwong ASF, Timpson NJ, Niemi MEK, Rahmouni S, Guntz J, Beguin Y, Cordioli M, Pigazzini S, Nkambule L, Georges M, Moutschen M, Misset B, Darcis G, Gofflot S, Bouysran Y, Busson A, Peyrassol X, Wilkin F, Pichon B, Smits G, Vandernoot I, Goffard J-C, Tiembe N, Morrison DR, Afilalo J, Mooser V, Richards JB, Rousseau S, Durand M, Butler-Laporte G, Forgetta V, Laurent L, Afrasiabi Z, Bouab M, Tselios C, Xue X, Afilalo M, Oliveira M, St-Cyr J, Boisclair A, Ragoussis J, Auld D, Kaufet al., 2023, A second update on mapping the human genetic architecture of COVID-19, Nature, Vol: 621, Pages: E7-E26, ISSN: 0028-0836

Journal article

Jones RE, Gruszczyk AV, Schmidt C, Hammersley DJ, Mach L, Lee M, Wong J, Yang M, Hatipoglu S, Lota AS, Barnett SN, Toscano-Rivalta R, Owen R, Raja S, De Robertis F, Smail H, De-Souza A, Stock U, Kellman P, Griffin J, Dumas M-E, Martin JL, Saeb-Parsy K, Vazir A, Cleland JGF, Pennell DJ, Bhudia SK, Halliday BP, Noseda M, Frezza C, Murphy MP, Prasad SKet al., 2023, Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease, Nature Cardiovascular Research, Vol: 2, Pages: 733-745, ISSN: 2731-0590

Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

Journal article

Mocciaro G, Allison M, Jenkins B, Azzu V, Huang-Doran I, Herrera-Marcos LV, Hall Z, Murgia A, Susan D, Frontini M, Vidal-Puig A, Koulman A, Griff JL, Vacca Met al., 2023, Non-alcoholic fatty liver disease is characterised by a reduced polyunsaturated fatty acid transport via free fatty acids and high-density lipoproteins (HDL), MOLECULAR METABOLISM, Vol: 73, ISSN: 2212-8778

Journal article

Hundertmark MJ, Adler A, Antoniades C, Coleman R, Griffin JL, Holman RR, Lamlum H, Lee J, Massey D, Miller JJJJ, Milton JE, Monga S, Mozes FE, Nazeer A, Raman B, Rider O, Rodgers CT, Valkovic L, Wicks E, Mahmod M, Neubauer Set al., 2023, Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking Empagliflozin: The Randomized, Controlled EMPA-VISION Trial, CIRCULATION, Vol: 147, Pages: 1654-1669, ISSN: 0009-7322

Journal article

Meadows AM, Han K, Singh K, Murgia A, McNally BD, West JA, Huffstutler RD, Powell-Wiley TM, Baumer Y, Griffin JL, Sack MNet al., 2023, N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4<SUP>+</SUP>T cell responsiveness, ISCIENCE, Vol: 26

Journal article

Sarmad S, Viant MR, Dunn WB, Goodacre R, Wilson ID, Chappell KE, Griffin JL, O'Donnell VB, Naicker B, Lewis MR, Suzuki Tet al., 2023, A proposed framework to evaluate the quality and reliability of targeted metabolomics assays from the UK Consortium on Metabolic Phenotyping (MAP/UK), NATURE PROTOCOLS, Vol: 18, Pages: 1017-1027, ISSN: 1754-2189

Journal article

Goldswain H, Dong X, Penrice-Randal R, Alruwaili M, Shawli GT, Prince T, Williamson MK, Raghwani J, Randle N, Jones B, Donovan-Banfield I, Salguero FJ, Tree JA, Hall Y, Hartley C, Erdmann M, Bazire J, Jearanaiwitayakul T, Semple MG, Openshaw PJM, Baillie JK, ISARIC4C Investigators, Emmett SR, Digard P, Matthews DA, Turtle L, Darby AC, Davidson AD, Carroll MW, Hiscox JAet al., 2023, The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection, Genome Biology, Vol: 24, ISSN: 1474-7596

BACKGROUND: The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. RESULTS: Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. CONCLUSIONS: These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.

Journal article

Liew F, Talwar S, Cross A, Willett B, Scott S, Logan N, Siggins M, Swieboda D, Sidhu J, Efstathiou C, Moore S, Davis C, Mohamed N, Nunag J, King C, Thompson AAR, Rowland-Jones S, Docherty A, Chalmers J, Ho L-P, Horsley A, Raman B, Poinasamy K, Marks M, Kon OM, Howard L, Wootton D, Dunachie S, Quint J, Evans R, Wain L, Fontanella S, de Silva T, Ho A, Harrison E, Baillie JK, Semple MG, Brightling C, Thwaites R, Turtle L, Openshaw Pet al., 2023, SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination, EBioMedicine, Vol: 87, Pages: 1-14, ISSN: 2352-3964

Background:Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced.Methods:In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data.Findings:Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination.Interpretation:The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.Funding:This

Journal article

Garcia-Segura ME, Durainayagam BR, Liggi S, Graça G, Jimenez B, Dehghan A, Tzoulaki I, Karaman I, Elliott P, Griffin JLet al., 2023, Pathway-based integration of multi-omics data reveals lipidomics alterations validated in an Alzheimer´s Disease mouse model and risk loci carriers, Journal of Neurochemistry, Vol: 164, Pages: 57-76, ISSN: 0022-3042

Alzheimer´s Disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of the importance of metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these datasets using gene ontology, transcription factor, pathway, and cell-type enrichment analyses. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic dataset derived from cortical tissue of ABCA-7 null mice, a mouse model of one of the genes associated with late onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and genes associated with AD risk. We found 203 DE transcripts, 164 DE proteins and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetics metabolic pathways were significantly over-represented across the AD multi-omics datasets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modelled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms (SNP)-metabolite associations, of which 70% corresponded to lipid classes. These results support the importance of lipid metabolism dysregulation in AD and highlight the suitability of mapping AD multi-omics data into GSMNs to identify metabol

Journal article

Pinto GDA, Murgia A, Lai C, Ferreira CS, Goes VA, Guimaraes DDAB, Ranquine LG, Reis DL, Struchiner CJ, Griffin JL, Burton GJ, Torres AG, El-Bacha Tet al., 2022, Sphingolipids and acylcarnitines are altered in placentas from women with gestational diabetes mellitus, BRITISH JOURNAL OF NUTRITION, ISSN: 0007-1145

Journal article

Vink E, Davis C, MacLean A, Pascall D, McDonald SE, Gunson R, Hardwick HE, Oosthuyzen W, Openshaw PJM, Baillie JK, Semple MG, Ho Aet al., 2022, Viral coinfections in hospitalized Coronavirus disease 2019 patients recruited to the international severe acute respiratory and emerging infections consortium WHO clinical characterisation protocol UK study, Open Forum Infectious Diseases, Vol: 9, Pages: 1-10, ISSN: 2328-8957

BackgroundWe conducted this study to assess the prevalence of viral coinfection in a well characterized cohort of hospitalized coronavirus disease 2019 (COVID-19) patients and to investigate the impact of coinfection on disease severity.MethodsMultiplex real-time polymerase chain reaction testing for endemic respiratory viruses was performed on upper respiratory tract samples from 1002 patients with COVID-19, aged <1 year to 102 years old, recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK study. Comprehensive demographic, clinical, and outcome data were collected prospectively up to 28 days post discharge.ResultsA coinfecting virus was detected in 20 (2.0%) participants. Multivariable analysis revealed no significant risk factors for coinfection, although this may be due to rarity of coinfection. Likewise, ordinal logistic regression analysis did not demonstrate a significant association between coinfection and increased disease severity.ConclusionsViral coinfection was rare among hospitalized COVID-19 patients in the United Kingdom during the first 18 months of the pandemic. With unbiased prospective sampling, we found no evidence of an association between viral coinfection and disease severity. Public health interventions disrupted normal seasonal transmission of respiratory viruses; relaxation of these measures mean it will be important to monitor the prevalence and impact of respiratory viral coinfections going forward.

Journal article

Mustafa NM, Elabd NE, Selim LA, Abdou DM, Griffin JLet al., 2022, Creatine Deficiency Syndromes: Comparison of Screening Methods and Characterization of Four Novel Intronic Variants, CLINICA CHIMICA ACTA, Vol: 536, Pages: 70-76, ISSN: 0009-8981

Journal article

Tyagi T, Jain K, Yarovinsky TO, Chiorazzi M, Du J, Castro C, Griffin J, Korde A, Martin KA, Takyar SS, Flavell RA, Patel AA, Hwa Jet al., 2022, Platelet-derived TLT-1 promotes tumor progression by suppressing CD8<SUP>+</SUP> T cells, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 220, ISSN: 0022-1007

Journal article

Dehghan A, Pinto RC, Karaman I, Huang J, Durainayagam BR, Ghanbari M, Nazeer A, Zhong Q, Liggi S, Whiley L, Mustafa R, Kivipelto M, Solomon A, Ngandu T, Kanekiyo T, Aikawa T, Radulescu CI, Barnes SJ, Graça G, Chekmeneva E, Camuzeaux S, Lewis MR, Kaluarachchi MR, Ikram MA, Holmes E, Tzoulaki I, Matthews PM, Griffin JL, Elliott Pet al., 2022, Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease., Proceedings of the National Academy of Sciences of USA, Vol: 119, Pages: 1-12, ISSN: 0027-8424

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.

Journal article

Mocciaro G, DAmore S, Jenkins B, Kay R, Murgia A, Herrera-Marcos LV, Neun S, Sowton AP, Hall Z, Palma-Duran SA, Palasciano G, Reimann F, Murray A, Suppressa P, Sabbà C, Moschetta A, Koulman A, Griffin JL, Vacca Met al., 2022, Lipidomic approaches to study HDL metabolism in patients with central obesity diagnosed with metabolic syndrome, International Journal of Molecular Sciences, Vol: 23, Pages: 6786-6786, ISSN: 1422-0067

The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors characterised by central obesity, atherogenic dyslipidaemia, and changes in the circulating lipidome; the underlying mechanisms that lead to this lipid remodelling have only been partially elucidated. This study used an integrated “omics” approach (untargeted whole serum lipidomics, targeted proteomics, and lipoprotein lipidomics) to study lipoprotein remodelling and HDL composition in subjects with central obesity diagnosed with MetS (vs. controls). Compared with healthy subjects, MetS patients showed higher free fatty acids, diglycerides, phosphatidylcholines, and triglycerides, particularly those enriched in products of de novo lipogenesis. On the other hand, the “lysophosphatidylcholines to phosphatidylcholines” and “cholesteryl ester to free cholesterol” ratios were reduced, pointing to a lower activity of lecithin cholesterol acyltransferase (LCAT) in MetS; LCAT activity (directly measured and predicted by lipidomic ratios) was positively correlated with high-density lipoprotein cholesterol (HDL-C) and negatively correlated with body mass index (BMI) and insulin resistance. Moreover, many phosphatidylcholines and sphingomyelins were significantly lower in the HDL of MetS patients and strongly correlated with BMI and clinical metabolic parameters. These results suggest that MetS is associated with an impairment of phospholipid metabolism in HDL, partially led by LCAT, and associated with obesity and underlying insulin resistance. This study proposes a candidate strategy to use integrated “omics” approaches to gain mechanistic insights into lipoprotein remodelling, thus deepening the knowledge regarding the molecular basis of the association between MetS and atherosclerosis.

Journal article

Brockmoller SF, Bucher E, Mueller BM, Budczies J, Hilvo M, Griffin JL, Oresic M, Kallioniemi O, Iljin K, Loibl S, Darb-Esfahani S, V Sinn B, Klauschen F, Prinzler J, Bangemann N, Ismaeel F, Fiehn O, Dietel M, Denkert Cet al., 2022, Integration of Metabolomics and Expression of Glycerol-3-phosphate Acyltransferase (GPAM) in Breast Cancer-Link to Patient Survival, Hormone Receptor Status, and Metabolic Profiling (vol 11, pg 850, 2012), JOURNAL OF PROTEOME RESEARCH, Vol: 21, Pages: 1787-1787, ISSN: 1535-3893

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Hall Z, Oakley F, Vacca M, Griffin JLet al., 2022, Reply., Hepatology, Vol: 75, Pages: 1347-1348, ISSN: 0270-9139

Journal article

Climaco Pinto R, Karaman I, Lewis MR, Hällqvist J, Kaluarachchi M, Graça G, Chekmeneva E, Durainayagam B, Ghanbari M, Ikram MA, Zetterberg H, Griffin J, Elliott P, Tzoulaki I, Dehghan A, Herrington D, Ebbels Tet al., 2022, Finding correspondence between metabolomic features in untargeted liquid chromatography-mass spectrometry metabolomics datasets., Analytical Chemistry, Vol: 94, Pages: 5493-5503, ISSN: 0003-2700

Integration of multiple datasets can greatly enhance bioanalytical studies, for example, by increasing power to discover and validate biomarkers. In liquid chromatography-mass spectrometry (LC-MS) metabolomics, it is especially hard to combine untargeted datasets since the majority of metabolomic features are not annotated and thus cannot be matched by chemical identity. Typically, the information available for each feature is retention time (RT), mass-to-charge ratio (m/z), and feature intensity (FI). Pairs of features from the same metabolite in separate datasets can exhibit small but significant differences, making matching very challenging. Current methods to address this issue are too simple or rely on assumptions that cannot be met in all cases. We present a method to find feature correspondence between two similar LC-MS metabolomics experiments or batches using only the features' RT, m/z, and FI. We demonstrate the method on both real and synthetic datasets, using six orthogonal validation strategies to gauge the matching quality. In our main example, 4953 features were uniquely matched, of which 585 (96.8%) of 604 manually annotated features were correct. In a second example, 2324 features could be uniquely matched, with 79 (90.8%) out of 87 annotated features correctly matched. Most of the missed annotated matches are between features that behave very differently from modeled inter-dataset shifts of RT, MZ, and FI. In a third example with simulated data with 4755 features per dataset, 99.6% of the matches were correct. Finally, the results of matching three other dataset pairs using our method are compared with a published alternative method, metabCombiner, showing the advantages of our approach. The method can be applied using M2S (Match 2 Sets), a free, open-source MATLAB toolbox, available at https://github.com/rjdossan/M2S.

Journal article

McNally BD, Ashley DF, Hänschke L, Daou HN, Watt NT, Murfitt SA, MacCannell ADV, Whitehead A, Bowen TS, Sanders FWB, Vacca M, Witte KK, Davies GR, Bauer R, Griffin JL, Roberts LDet al., 2022, Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle., Nat Commun, Vol: 13

The endoplasmic reticulum (ER) regulates cellular protein and lipid biosynthesis. ER dysfunction leads to protein misfolding and the unfolded protein response (UPR), which limits protein synthesis to prevent cytotoxicity. Chronic ER stress in skeletal muscle is a unifying mechanism linking lipotoxicity to metabolic disease. Unidentified signals from cells undergoing ER stress propagate paracrine and systemic UPR activation. Here, we induce ER stress and lipotoxicity in myotubes. We observe ER stress-inducing lipid cell non-autonomous signal(s). Lipidomics identifies that palmitate-induced cell stress induces long-chain ceramide 40:1 and 42:1 secretion. Ceramide synthesis through the ceramide synthase 2 de novo pathway is regulated by UPR kinase Perk. Inactivation of CerS2 in mice reduces systemic and muscle ceramide signals and muscle UPR activation. The ceramides are packaged into extracellular vesicles, secreted and induce UPR activation in naïve myotubes through dihydroceramide accumulation. This study furthers our understanding of ER stress by identifying UPR-inducing cell non-autonomous signals.

Journal article

Närhi F, Moonesinghe SR, Shenkin SD, Drake TM, Mulholland RH, Donegan C, Dunning J, Fairfield CJ, Girvan M, Hardwick HE, Ho A, Leeming G, Nguyen-Van-Tam JS, Pius R, Russell CD, Shaw CA, Spencer RG, Turtle L, Openshaw PJM, Baillie JK, Harrison EM, Semple MG, Docherty AB, ISARIC4C investigatorset al., 2022, Implementation of corticosteroids in treatment of COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK: prospective, cohort study., The Lancet Digital Health, Vol: 4, Pages: e220-e234, ISSN: 2589-7500

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70-0·89], p=0·0001, for 70-79 years; 0·52 [0·46-0·58], p<0·0001, for >80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75-80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant wom

Journal article

Seyres D, Cabassi A, Lambourne JJ, Burden F, Farrow S, McKinney H, Batista J, Kempster C, Pietzner M, Slingsby O, Cao TH, Quinn PA, Stefanucci L, Sims MC, Rehnstrom K, Adams CL, Frary A, Ergüener B, Kreuzhuber R, Mocciaro G, D'Amore S, Koulman A, Grassi L, Griffin JL, Ng LL, Park A, Savage DB, Langenberg C, Bock C, Downes K, Wareham NJ, Allison M, Vacca M, Kirk PDW, Frontini Met al., 2022, Transcriptional, epigenetic and metabolic signatures in cardiometabolic syndrome defined by extreme phenotypes., Clin Epigenetics, Vol: 14

BACKGROUND: This work is aimed at improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis by generating a multi-omic disease signature. METHODS/RESULTS: We combined classic plasma biochemistry and plasma biomarkers with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (morbidly obese and lipodystrophy) and lean individuals to identify the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells. Our analyses showed that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, 6 months after bariatric surgery, revealed the loss of the abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurred via the establishment of novel gene expression landscapes. NETosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. CONCLUSIONS: We showed that the morbidly obese and lipodystrophy groups, despite some differences, shared a common cardiometabolic syndrome signature. We also showed that this could be used to discriminate, amongst the normal population, those individuals with a higher likelihood of presenting with the disease, even when not displaying the classic features.

Journal article

Dejnirattisai W, Huo J, Zhou D, Zahradník J, Supasa P, Liu C, Duyvesteyn HME, Ginn HM, Mentzer AJ, Tuekprakhon A, Nutalai R, Wang B, Dijokaite A, Khan S, Avinoam O, Bahar M, Skelly D, Adele S, Johnson SA, Amini A, Ritter TG, Mason C, Dold C, Pan D, Assadi S, Bellass A, Omo-Dare N, Koeckerling D, Flaxman A, Jenkin D, Aley PK, Voysey M, Costa Clemens SA, Naveca FG, Nascimento V, Nascimento F, Fernandes da Costa C, Resende PC, Pauvolid-Correa A, Siqueira MM, Baillie V, Serafin N, Kwatra G, Da Silva K, Madhi SA, Nunes MC, Malik T, Openshaw PJM, Baillie JK, Semple MG, Townsend AR, Huang K-YA, Tan TK, Carroll MW, Klenerman P, Barnes E, Dunachie SJ, Constantinides B, Webster H, Crook D, Pollard AJ, Lambe T, OPTIC Consortium, ISARIC4C Consortium, Paterson NG, Williams MA, Hall DR, Fry EE, Mongkolsapaya J, Ren J, Schreiber G, Stuart DI, Screaton GRet al., 2022, SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses, Cell, Vol: 185, Pages: 467-484.e15, ISSN: 0092-8674

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.

Journal article

Adebayo AS, Roman M, Yusoff S, Gulston M, Joel-David L, Anthony B, Lai FY, Murgia A, Eagle-Hemming B, Sheikh S, Kumar T, Aujla H, Dott W, Griffin JL, Murphy GJ, Wozniak MJet al., 2022, Gene and metabolite expression dependence on body mass index in human myocardium, SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322

Journal article

Charidemou E, Tsiarli MA, Theophanous A, Yilmaz V, Pitsouli C, Strati K, Griffin JL, Kirmizis Aet al., 2022, Histone acetyltransferase NAA40 modulates acetyl-CoA levels and lipid synthesis., BMC Biol, Vol: 20

BACKGROUND: Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular metabolite levels have been reported to affect chromatin modifications. However, whether epigenetic modifiers also affect the levels of these metabolites and thereby impinge on downstream metabolic pathways remains largely unknown. Here, we tested this notion by investigating the function of N-alpha-acetyltransferase 40 (NAA40), the enzyme responsible for N-terminal acetylation of histones H2A and H4, which has been previously implicated with metabolic-associated conditions such as age-dependent hepatic steatosis and calorie-restriction-mediated longevity. RESULTS: Using metabolomic and lipidomic approaches, we found that depletion of NAA40 in murine hepatocytes leads to significant increase in intracellular acetyl-CoA levels, which associates with enhanced lipid synthesis demonstrated by upregulation in de novo lipogenesis genes as well as increased levels of diglycerides and triglycerides. Consistently, the increase in these lipid species coincide with the accumulation of cytoplasmic lipid droplets and impaired insulin signalling indicated by decreased glucose uptake. However, the effect of NAA40 on lipid droplet formation is independent of insulin. In addition, the induction in lipid synthesis is replicated in vivo in the Drosophila melanogaster larval fat body. Finally, supporting our results, we find a strong association of NAA40 expression with insulin sensitivity in obese patients. CONCLUSIONS: Overall, our findings demonstrate that NAA40 affects the levels of cellular acetyl-CoA, thereby impacting lipid synthesis and insulin signalling. This study reveals a novel path through which histone-modifying enzymes influence cellular metabolism with potential implications in metabolic disorders.

Journal article

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