{"database":"Pride","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Xlsx":["ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/08/PXD071991/vanderHoevenR_20241107_02_DIA_Results.xlsx"],"Txt":["ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/08/PXD071991/checksum.txt"],"Other":["ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/08/PXD071991/vanderHoevenR_20241107_02_DIA_20.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/08/PXD071991/vanderHoevenR_20241107_02_DIA_13.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/08/PXD071991/vanderHoevenR_20241107_02_DIA_10.zip","ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/08/PXD071991/vanderHoevenR_20241107_02_DIA_02.zip"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"labhead_mail":["ransome-vanderhoeven@uiowa.edu"],"submitter":["Ransome van der Hoeven"],"technology_type":["Mass Spectrometry","Data-independent acquisition"],"software":[""],"submitter_keywords":[""],"full_dataset_link":["https://www.ebi.ac.uk/pride/archive/projects/PXD071991"],"sample_protocol":["Proteins were extracted using 8M urea made in 50mM Tris pH 8.0 and quantified using Qubit 4 Fluorometer. Proteins from each sample underwent reduction, alkylation, and purification through chloroform/methanol extraction before digestion with sequencing-grade modified porcine trypsin (Promega). The resulting tryptic peptides were separated using a reverse-phase Ion-Opticks-TS analytical column (25 cm × 75 µm, 1.7 µm C18 resin) connected to an EASY-Spray nano-source, maintained at 55°C with a Heater THOR Controller (Ion-Opticks). Peptides were initially trapped on a PepMap Neo trap column (300 µm × 5 mm) and subsequently eluted using a Vanquish Neo UHPLC nano system (Thermo Fisher Scientific), which kept samples at 11°C before injection. Peptide elution occurred at a flow rate of 0.35 µL/min under a gradient starting at 98% Buffer A/2% Buffer B, shifting to 96/4 at 0.1 minutes, and gradually changing to 56/44 by 9.1 minutes. A column wash followed, transitioning from 45/55 at 11.7 minutes to 1/99 at 16.8 minutes, and finally re-equilibrating to 98/2 at 17.0 minutes. The eluted peptides were ionized by electrospray (2.5 kV) and analyzed with an Orbitrap Astral mass spectrometer (Thermo Fisher Scientific). Precursor spectra were recorded within a mass range of 380–980 Th at a resolution of 240,000, with an AGC target set to 200% and a maximum injection time of 3 ms. DIA acquisition included 85 isolation windows (7 Th each) across the same mass range, with an AGC target of 100%, a maximum injection time of 3 ms, and an RF lens setting of 40%. Buffer compositions are as follows. Buffer A: 0.1% formic acid, 0.5% acetonitrile in water. Buffer B: 80% acetonitrile, 20% water, 0.1% formic acid."],"repository":["Pride"],"modification":[""],"quantification_method":[""],"data_protocol":["Following data collection, LC-MS/MS spectra were analyzed using Spectronaut (Biognosys v19.1) against the UniProt Caenorhabditis elegans database (May 2024) with a direct DIA workflow. Protein and precursor identification thresholds were set at a 1% q-value cutoff, with decoy generation enabled. Protein inference was conducted using the IDPicker algorithm, with maxLFQ applied for quantification, MS2-level intensity measurements, no cross-run normalization, and protein grouping based on median peptide and precursor quantities. Protein MS2 intensity data were evaluated for quality with ProteiNorm, normalized using variance stabilization normalization, and statistically analyzed with proteoDA. Differential protein expression analysis was performed using linear models for microarray data (limma) combined with empirical Bayes (eBayes) smoothing. Proteins with an FDR-adjusted p-value < 0.05 and a fold change greater than 1.5 were considered for bioinformatics analysis. File names with vanderHoevenR_20241107_02_DIA_02.zip is Wild type (No metformin);  vanderHoevenR_20241107_02_DIA_10.zip is wild type (metformin treated); vanderHoevenR_20241107_02_DIA_13.zip is MDT-15 (no metformin); vanderHoevenR_20241107_02_DIA_20.zip is MDT-15 (metformin treated)"],"omics_type":["Proteomics"],"labhead":["Ransome van"],"instrument_platform":[""],"labhead_affiliation":["Associate Professor Iowa Institute for Oral Health Research Department of Periodontics  University of Iowa College of Dentistry and Dental Clinics N423 Dental Science Building 801 Newton Rd,  Iowa City, IA  52242"],"submission_type":["PARTIAL"],"species":["Caenorhabditis Elegans"],"publication":["42503569 Al Hatem A, Balasubramaniam B, Villhauer A, Naji AK, van der Hoeven R. p38 MAPK and MDT-15 mediate SKN-1-dependent metformin-induced protection against mitis group streptococci in Caenorhabditis elegans. Geroscience. 2026 10.1007/s11357-026-02405-6"],"submitter_mail":["ransome-vanderhoeven@uiowa.edu"],"submitter_affiliation":["Associate Professor\nIowa Institute for Oral Health Research\nDepartment of Periodontics \nUniversity of Iowa College of Dentistry and Dental Clinics\nN423 Dental Science Building\n801 Newton Rd\nIowa City, IA - 52242"],"submitter_country":["United States"],"pubmed_abstract":["Mitis group streptococci are opportunistic pathogens residing in the oral cavity, where they produce hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), a key virulence factor contributing to their pathogenesis. We previously demonstrated that these bacteria kill the nematode Caenorhabditis elegans through H<sub>2</sub>O<sub>2</sub> production. Metformin, a widely used biguanide drug for managing blood glucose levels, has shown promising effects on aging by extending lifespan in worms and mice, and has also demonstrated potential cancer treatment. Additionally, pretreatment with metformin enhances the survival of worms and triggers an immune response via the p38 MAPK pathway against various pathogenic bacteria. Based on these observations, we investigated metformin's potential as a therapeutic agent against mitis group streptococcal infections and its underlying mechanisms in the current study. Pretreatment of worms with metformin provided significant dose-dependent protection from streptococcal-derived H<sub>2</sub>O<sub>2</sub>. This protective effect was attributed to the activation of the oxidative stress response transcription factor SKN-1/NRF2. Further analysis revealed that the p38 MAPK pathway and the transcription mediator complex protein MDT-15 are essential for the activation of SKN-1 by metformin. Interestingly, SKN-1 activity, mediated by MDT-15, was found to be independent of the p38 MAPK pathway. Our findings establish that metformin-mediated protection against mitis group streptococcal infections relies on the coordinated action of SKN-1, the p38 MAPK pathway, and MDT-15. These insights suggest that metformin could be a valuable therapeutic agent in combating these infections. Future research should focus on further elucidating the molecular mechanisms involved and exploring the potential clinical applications of metformin in treating these bacterial infections."],"pubmed_title":["p38 MAPK and MDT-15 mediate SKN-1-dependent metformin-induced protection against mitis group streptococci in Caenorhabditis elegans."],"pubmed_authors":["Al Hatem Ali A, Balasubramaniam Boopathi B, Villhauer Alissa A, Naji Ali K AK, van der Hoeven Ransome R"],"additional_accession":[]},"is_claimable":false,"name":"p38 MAPK and MDT-15 Mediate SKN-1–Dependent Metformin-Induced Protection Against Mitis Group Streptococci in Caenorhabditis elegans ","description":"Mitis group streptococci are opportunistic pathogens residing in the oral cavity, where they produce hydrogen peroxide (H2O2), a key virulence factor contributing to their pathogenesis. We previously demonstrated that these bacteria kill the nematode Caenorhabditis elegans through H2O2 production. Metformin, a widely used biguanide drug for managing blood glucose levels, has shown promising effects on aging by extending lifespan in worms and mice, and has also demonstrated potential cancer treatment. Additionally, pretreatment with metformin enhances the survival of worms and triggers an immune response via the p38 MAPK pathway against various pathogenic bacteria. Based on these observations, we investigated metformin's potential as a therapeutic agent against mitis group streptococcal infections and its underlying mechanisms in the current study. Pretreatment of worms with metformin provided significant dose-dependent protection from streptococcal-derived H2O2. This protective effect was attributed to the activation of the oxidative stress response transcription factor SKN-1/NRF2. Further analysis revealed that the p38 MAPK pathway and the transcription mediator complex protein MDT-15 are essential for the activation of SKN-1 by metformin. Interestingly, SKN-1 activity, mediated by MDT-15, was found to be independent of the p38 MAPK pathway. Our findings establish that metformin-mediated protection against mitis group streptococcal infections relies on the coordinated action of SKN-1, the p38 MAPK pathway, and MDT-15. These insights suggest that metformin could be a valuable therapeutic agent in combating these infections. Future research should focus on further elucidating the molecular mechanisms involved and exploring the potential clinical applications of metformin in treating these bacterial infections.","dates":{"publication":"2026-08-07","submission":"2025-12-15"},"accession":"PXD071991","cross_references":{"TAXONOMY":["NEWT:68239","NEWT:108018","NEWT:377960","NEWT:1131","NEWT:190486","NEWT:2042546","NEWT:148942","NEWT:295546","NEWT:258594","NEWT:1126","NEWT:1129","NEWT:89187","NEWT:309807","NEWT:89184","NEWT:309800","NEWT:1323429","NEWT:876138","NEWT:44271","NEWT:193516","NEWT:2315688","NEWT:44270","NEWT:592321","NEWT:1073882","NEWT:6819","NEWT:428386","NEWT:1117","NEWT:498257","NEWT:10036","NEWT:32264","NEWT:10034","NEWT:661410","NEWT:488003","NEWT:224326","NEWT:376619","NEWT:3765","NEWT:2433","NEWT:3767","NEWT:433727","NEWT:135622","NEWT:672127","NEWT:656061","NEWT:37965","NEWT:656064","NEWT:3760","NEWT:36630","NEWT:381198","NEWT:418106","NEWT:10029","NEWT:913645","NEWT:2492962","NEWT:641809","NEWT:44250","NEWT:317447","NEWT:5530","NEWT:868565","NEWT:135674","NEWT:1562698","NEWT:1177","NEWT:11308","NEWT:12637","NEWT:2164133","NEWT:1180","NEWT:2767846","NEWT:1343074","NEWT:314344","NEWT:108061","NEWT:224308","NEWT:49928","NEWT:160621","NEWT:110368","NEWT:1916073","NEWT:1310161","NEWT:1230383","NEWT:77133","NCBITaxon:5207","NEWT:1310165","NEWT:114727","NEWT:5516","NEWT:498211","NEWT:347256","NEWT:5518","NEWT:398007","NEWT:1527468","NEWT:498217","NEWT:498216","NEWT:11320","NEWT:1410384","NEWT:1310173","NEWT:37919","NEWT:161934","NEWT:156587","NEWT:1148","NEWT:5508","NEWT:135666","NEWT:419481","NEWT:5507","NEWT:1140","NCBITaxon:2157","NEWT:2066563","NEWT:1143","NEWT:1462472","NEWT:1336795","NEWT:644042","NEWT:709964","NEWT:3712","NEWT:3711","NEWT:3714","NEWT:65121","NEWT:3716","NEWT:3715","NEWT:2065263","NEWT:1549675","NEWT:177437","NEWT:9014","NEWT:10891","NEWT:118221","NEWT:34869","NEWT:226126","NEWT:1616117","NEWT:34865","NEWT:28174","NEWT:550537","NEWT:284812","NEWT:3701","NEWT:3702","NEWT:1245466","NEWT:3704","NEWT:1246791","NEWT:34875","NEWT:1431297","NEWT:9005","NEWT:34871","NEWT:9006","NEWT:33548","NEWT:1883426","NEWT:657321","NEWT:1423687","NEWT:657322","NEWT:10886","NEWT:3708","NEWT:536231","NEWT:219813","NEWT:1301262","NEWT:2305479","NEWT:215451","NEWT:460519","NEWT:272843","NEWT:272844","NEWT:1348799","NEWT:55784","NEWT:485","NEWT:2709072","NEWT:2499525","NEWT:467144","NEWT:142786","NEWT:28196","NEWT:2853422","NEWT:487","NEWT:1679718","NEWT:387344","NEWT:480","NEWT:67767","NEWT:46835","NEWT:216778","NEWT:376686","NEWT:237610","EFO:0001352","NEWT:219809","NEWT:219808","NEWT:119562","NEWT:1883446","NEWT:1233435","NEWT:118223","NEWT:141469","NEWT:272831","NEWT:987059","NEWT:491","NEWT:422203","NEWT:460523","NEWT:2423","NEWT:85694","NEWT:85692","NEWT:911045","NEWT:3750","NEWT:123606","NEWT:291146","NEWT:29466","NEWT:233271","NEWT:3745","NEWT:1715989","NCBITaxon:4751","NEWT:3747","NEWT:278161","NEWT:415978","NEWT:410289","NEWT:191701","NEWT:9054","NEWT:472","NEWT:29459","NEWT:34839","NEWT:476","NEWT:1380096","NEWT:28128","NEWT:470","NEWT:41122","NEWT:1328300","NEWT:748693","NCBITaxon:50557","NEWT:63363","NEWT:3735","NEWT:29491","NEWT:911022","NEWT:446","NEWT:153481","NEWT:714485","NEWT:445","NEWT:2003758","NEWT:29486","NEWT:63366","NEWT:64697","NEWT:63367","NEWT:29488","NEWT:215402","NEWT:3726","NEWT:30455","NEWT:28141","NEWT:9030","NEWT:9031","NEWT:3728","NEWT:108931","NEWT:219799","NEWT:1325292","NEWT:219798","NEWT:548","NEWT:150475","NEWT:546","NEWT:256737","NEWT:51350","NEWT:8694","NEWT:8692","NEWT:542","NEWT:394503","NEWT:13076","NEWT:219785","NEWT:451515","NEWT:8673","NEWT:550","NEWT:10804","NEWT:554","NEWT:451516","NEWT:552","NEWT:1325291","NEWT:42410","NEWT:40686","NEWT:1225786","NEWT:771870","NEWT:8665","NEWT:51338","NEWT:9995","NEWT:28112","NEWT:49012","NEWT:28110","NEWT:10832","NEWT:311339","NEWT:507601","NEWT:520","NEWT:64657","NEWT:186441","NEWT:2585209","NEWT:643680","NEWT:214092","NEWT:40697","NEWT:13095","NEWT:162425","NEWT:242124","NEWT:9986","NEWT:8654","NEWT:536","NEWT:8658","NEWT:1268063","NEWT:8657","NEWT:9983","NEWT:8655","NEWT:595495","NEWT:80833","NEWT:479096","NEWT:28108","NEWT:28104","NEWT:1114957","NEWT:568703","NEWT:568708","NEWT:51315","NEWT:52641","NEWT:353152","NEWT:116597","NEWT:353153","NEWT:116598","NEWT:227377","NEWT:1774284","NEWT:27689","NEWT:207769","NEWT:40674","NEWT:51329","NCBITaxon:1763","NEWT:443906","NEWT:13037","NEWT:519","NEWT:941638","NEWT:511","NEWT:7394","NEWT:6063","NEWT:404330","NEWT:1328388","NEWT:13064","NEWT:529120","NEWT:300641","NEWT:39655","NEWT:38323","NEWT:206411","NEWT:80869","NEWT:214053","NEWT:80863","NEWT:665890","NEWT:52639","NEWT:52638","NEWT:8697","NEWT:861109","NEWT:8695","NEWT:1196866","NEWT:6039","NEWT:510516","NEWT:1045775","NEWT:1123869","NCBITaxon:1335626","NEWT:7370","NEWT:280406","NEWT:83906","NEWT:99488","NEWT:99487","NEWT:1134506","NEWT:255470","NEWT:762903","NEWT:27697","NEWT:86185","NEWT:9935","NEWT:266940","NEWT:287889","NEWT:9938","NEWT:1028307","NEWT:52603","NEWT:92867","NEWT:92866","NEWT:1344414","NEWT:202950","NEWT:741158","NEWT:1293091","NEWT:202956","NEWT:483179","NEWT:315750","NEWT:99490","NEWT:632957"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