#METABOLOMICS WORKBENCH sharmarishi2004_20210220_172201 DATATRACK_ID:2503 STUDY_ID:ST001708 ANALYSIS_ID:AN002782 PROJECT_ID:PR001093 VERSION 1 CREATED_ON February 22, 2021, 3:23 pm #PROJECT PR:PROJECT_TITLE Oxylipin biosynthesis reinforces cellular senescence through a RAS/p53 feedback PR:PROJECT_TITLE loop and allows detection of senolysis PR:PROJECT_SUMMARY Cellular senescence is a stress or damage response that causes a permanent PR:PROJECT_SUMMARY proliferative arrest and secretion of numerous factors with potent biological PR:PROJECT_SUMMARY activities. This senescence-associated secretory phenotype (SASP) has been PR:PROJECT_SUMMARY characterized largely for secreted proteins that participate in embryogenesis, PR:PROJECT_SUMMARY wound healing, inflammation and many age-related pathologies. By contrast, lipid PR:PROJECT_SUMMARY components of the SASP are understudied. We show that senescent cells activate PR:PROJECT_SUMMARY the biosynthesis of several oxylipins that promote segments of the SASP and PR:PROJECT_SUMMARY reinforce the proliferative arrest. Notably, senescent cells synthesize and PR:PROJECT_SUMMARY accumulate an unstudied intracellular prostaglandin, PR:PROJECT_SUMMARY 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released PR:PROJECT_SUMMARY 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and PR:PROJECT_SUMMARY in vivo. This and other prostaglandin D2-related lipids promote the senescence PR:PROJECT_SUMMARY arrest and SASP by activating RAS signaling. These data identify an important PR:PROJECT_SUMMARY aspect of cellular senescence and a method to detect senolysis. PR:INSTITUTE Buck Institute for Research on Aging PR:LAST_NAME Sharma PR:FIRST_NAME Rishi PR:ADDRESS 8001 Redwood Blvd, Novato, CA, 94945, USA PR:EMAIL sharmarishi2004@yahoo.co.in PR:PHONE 5084392367 #STUDY ST:STUDY_TITLE Oxylipin biosynthesis reinforces cellular senescence through a RAS/p53 feedback ST:STUDY_TITLE loop and allows detection of senolysis ST:STUDY_SUMMARY Cellular senescence is a stress or damage response that causes a permanent ST:STUDY_SUMMARY proliferative arrest and secretion of numerous factors with potent biological ST:STUDY_SUMMARY activities. This senescence-associated secretory phenotype (SASP) has been ST:STUDY_SUMMARY characterized largely for secreted proteins that participate in embryogenesis, ST:STUDY_SUMMARY wound healing, inflammation and many age-related pathologies. By contrast, lipid ST:STUDY_SUMMARY components of the SASP are understudied. We show that senescent cells activate ST:STUDY_SUMMARY the biosynthesis of several oxylipins that promote segments of the SASP and ST:STUDY_SUMMARY reinforce the proliferative arrest. Notably, senescent cells synthesize and ST:STUDY_SUMMARY accumulate an unstudied intracellular prostaglandin, ST:STUDY_SUMMARY 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released ST:STUDY_SUMMARY 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and ST:STUDY_SUMMARY in vivo. This and other prostaglandin D2-related lipids promote the senescence ST:STUDY_SUMMARY arrest and SASP by activating RAS signaling. These data identify an important ST:STUDY_SUMMARY aspect of cellular senescence and a method to detect senolysis ST:INSTITUTE Buck Institute for Research on Aging ST:LAST_NAME Sharma ST:FIRST_NAME Rishi ST:ADDRESS 8001 Redwood Blvd, Novato, CA, 94945, USA ST:EMAIL sharmarishi2004@yahoo.co.in ST:PHONE 5084392367 #SUBJECT SU:SUBJECT_TYPE Cultured cells SU:SUBJECT_SPECIES Mus musculus SU:TAXONOMY_ID 10090 #SUBJECT_SAMPLE_FACTORS: SUBJECT(optional)[tab]SAMPLE[tab]FACTORS(NAME:VALUE pairs separated by |)[tab]Raw file names and additional sample data SUBJECT_SAMPLE_FACTORS - A-121 Factor:Mouse plasma RAW_FILE_NAME=A-121.d SUBJECT_SAMPLE_FACTORS - Ctl_61120 Factor:SEN Cells_Ctls RAW_FILE_NAME=Ctl_61120.d SUBJECT_SAMPLE_FACTORS - IR_15_60120 Factor:SENCells_IR RAW_FILE_NAME=IR_15_60120.d SUBJECT_SAMPLE_FACTORS - IR_DOXOABT_1 Factor:DOXOABT RAW_FILE_NAME=IR_DOXOABT_1.d #COLLECTION CO:COLLECTION_SUMMARY Cell culture: Human fetal lung fibroblasts (IMR-90) and HEPG2 cells were CO:COLLECTION_SUMMARY cultured in Dulbecco’s modified eagle medium (DMEM - Gibco) supplemented with CO:COLLECTION_SUMMARY 10% FBS and penicillin/streptomycin (Gibco). HUVEC cells were obtained from the CO:COLLECTION_SUMMARY ATCC and cultured using the ATCC protocol and culture media. Quiescence was CO:COLLECTION_SUMMARY induced by replacing culture media with media containing 0.2% FBS for 72 h CO:COLLECTION_SUMMARY before analysis. All cells were cultured at 3% O2, and used prior to 40 CO:COLLECTION_SUMMARY population doublings, other than replicative senescent cells, which were CO:COLLECTION_SUMMARY cultured until replicative exhaustion. All cells were mycoplasma free. Mouse CO:COLLECTION_SUMMARY Plasma: Animal experiments were conducted using a protocol approved by the CO:COLLECTION_SUMMARY Institutional Animal Care and Use Committee of the Buck Institute. For DOXO CO:COLLECTION_SUMMARY treatments, 10-16 wk old p16-3MR mice received one intraperitoneal (i.p.) CO:COLLECTION_SUMMARY injection of 10 mg/kg of doxorubicin hydrochloride in PBS, and treated 5 d later CO:COLLECTION_SUMMARY with GCV or vehicle. GCV was administered via daily i.p. injections for 5 CO:COLLECTION_SUMMARY consecutive days at 25 mg/kg in PBS. Control mice were injected with an equal CO:COLLECTION_SUMMARY volume of PBS. Mice were euthanized and tissues collected 10 d after DOXO CO:COLLECTION_SUMMARY challenge. For aging studies, C57BL/6 mice were aged for 6 or 24 mo, at which CO:COLLECTION_SUMMARY point mice were euthanized and tissues collected for analysis. For the biomarker CO:COLLECTION_SUMMARY studies, mice with challenged with DOXO as above, and given either vehicle or CO:COLLECTION_SUMMARY ABT-263 6 weeks after DOXO challenge. Whole blood was collected by cardiac CO:COLLECTION_SUMMARY puncture into EDTA-tubes (lavender caps – BD Biosciences) and spun at 2000g CO:COLLECTION_SUMMARY for 5 minutes. For urine collection, mice were placed in plastic containers CO:COLLECTION_SUMMARY prior to euthanasia. CO:SAMPLE_TYPE Blood (plasma) #TREATMENT TR:TREATMENT_SUMMARY Cell culture: Human fetal lung fibroblasts (IMR-90) and HEPG2 cells were TR:TREATMENT_SUMMARY cultured in Dulbecco’s modified eagle medium (DMEM - Gibco) supplemented with TR:TREATMENT_SUMMARY 10% FBS and penicillin/streptomycin (Gibco). HUVEC cells were obtained from the TR:TREATMENT_SUMMARY ATCC and cultured using the ATCC protocol and culture media. Quiescence was TR:TREATMENT_SUMMARY induced by replacing culture media with media containing 0.2% FBS for 72 h TR:TREATMENT_SUMMARY before analysis. All cells were cultured at 3% O2, and used prior to 40 TR:TREATMENT_SUMMARY population doublings, other than replicative senescent cells, which were TR:TREATMENT_SUMMARY cultured until replicative exhaustion. All cells were mycoplasma free. Mouse TR:TREATMENT_SUMMARY Plasma: Animal experiments were conducted using a protocol approved by the TR:TREATMENT_SUMMARY Institutional Animal Care and Use Committee of the Buck Institute. For DOXO TR:TREATMENT_SUMMARY treatments, 10-16 wk old p16-3MR mice received one intraperitoneal (i.p.) TR:TREATMENT_SUMMARY injection of 10 mg/kg of doxorubicin hydrochloride in PBS, and treated 5 d later TR:TREATMENT_SUMMARY with GCV or vehicle. GCV was administered via daily i.p. injections for 5 TR:TREATMENT_SUMMARY consecutive days at 25 mg/kg in PBS. Control mice were injected with an equal TR:TREATMENT_SUMMARY volume of PBS. Mice were euthanized and tissues collected 10 d after DOXO TR:TREATMENT_SUMMARY challenge. For aging studies, C57BL/6 mice were aged for 6 or 24 mo, at which TR:TREATMENT_SUMMARY point mice were euthanized and tissues collected for analysis. For the biomarker TR:TREATMENT_SUMMARY studies, mice with challenged with DOXO as above, and given either vehicle or TR:TREATMENT_SUMMARY ABT-263 6 weeks after DOXO challenge. Whole blood was collected by cardiac TR:TREATMENT_SUMMARY puncture into EDTA-tubes (lavender caps – BD Biosciences) and spun at 2000g TR:TREATMENT_SUMMARY for 5 minutes. For urine collection, mice were placed in plastic containers TR:TREATMENT_SUMMARY prior to euthanasia. #SAMPLEPREP SP:SAMPLEPREP_SUMMARY Protocol for Lipid Extraction (10.24.2019) Lipid Biomarker for Senolysis Study SP:SAMPLEPREP_SUMMARY 1. 80% MeOH was added to each sample 500µL to plasma samples 100µL to urine SP:SAMPLEPREP_SUMMARY sample 2. Transfer the contents to 9 mL glass tube and add 1.0 mL of CHCl3 SP:SAMPLEPREP_SUMMARY (containing 200 ng/mL FA 17:0 Saturated). Vortex mix for 5 minutes. 3. Place the SP:SAMPLEPREP_SUMMARY glass tube into a 15mL polypropylene culture tube with Kimi wipes inserted at SP:SAMPLEPREP_SUMMARY bottom as a cushion. Wrap the culture tube with paraffin and place in SP:SAMPLEPREP_SUMMARY centrifuge. This will prevent glass tube being shattered in the centrifuge. 4. SP:SAMPLEPREP_SUMMARY Centrifuge at 4°C for 10 minutes 3000rpm. 5. After spinning there will be two SP:SAMPLEPREP_SUMMARY distinct layers, the top layer is the aqueous layer containing the aqueous SP:SAMPLEPREP_SUMMARY metabolites (80% MeOH) and bottom layer which contains lipids. 6. Transfer the SP:SAMPLEPREP_SUMMARY lower layer into 1.5ml vials. 7. Transfer from the 1.5mL tube the exact amount SP:SAMPLEPREP_SUMMARY of each sample into the MS/HPLC glass vial and dry down using nitrogen gas. 8. SP:SAMPLEPREP_SUMMARY Reconstitute the lipids with 80µL chloroform. 9. Transfer upper layer SP:SAMPLEPREP_SUMMARY (metabolites) into labeled vials and store at -80°C, if possible. Samples SP:SAMPLEPREP_SUMMARY stored in -80°C. Sample volume submitted -Plasma samples=50µL Urine samples= SP:SAMPLEPREP_SUMMARY 10µL Sample volume in each vial- Plasma samples µL and Urine samples µL SP:SAMPLEPREP_SUMMARY -submitted to mass spec All samples were split in half ½ given to CW for SP:SAMPLEPREP_SUMMARY further testing other 1/2 in -80°C #CHROMATOGRAPHY CH:CHROMATOGRAPHY_TYPE Reversed phase CH:INSTRUMENT_NAME Agilent 6520 CH:COLUMN_NAME Phenomenex Kinetex C18 (150 x 2.1mm, 2.6 um) #ANALYSIS AN:ANALYSIS_TYPE MS #MS MS:INSTRUMENT_NAME Agilent 6520 QTOF MS:INSTRUMENT_TYPE QToF MS:MS_TYPE ESI MS:ION_MODE NEGATIVE MS:MS_COMMENTS Full scan mode was used. Data processed using profinder software #MS_METABOLITE_DATA MS_METABOLITE_DATA:UNITS Peak Area MS_METABOLITE_DATA_START Samples A-121 Ctl_61120 IR_15_60120 IR_DOXOABT_1 Factors Factor:Mouse plasma Factor:SEN Cells_Ctls Factor:SENCells_IR Factor:DOXOABT Acetaminophen 611775 Cer 18:0;3/18:0;1 611775 DAG 12:0-16:1 94764 191511 DAG 14:0-16:1 10626 61422 DAG 16:0-18:1 90200 DAG 18:1-18:1 13960 Ergosterol 41928 Gemfibrozil 65073 128741 154892 192382 IPC 18:0;2/18:0;0 8317 18640 IPC 18:0;3/16:0;2 43337 IPC 18:0;3/22:0;1 46737 LPA 14:0 38625 57629 67293 91643 LPE 18:0 124148 LPE 18:1 17297 15216 LPI 16:0 155580 LPI 18:0 20462 LPS 18:1 48179 Norethynodrel 6425 101459 135195 152762 OOB-PC 81087 PA 12:0-16:0 15058 9844 PC 16:0-16:1 113023 PC 16:0-18:0 140371 PC(10:0/24:0) 140371 PC(11:0/23:0) 140371 PC(12:0/17:2(9Z,12Z)) 33376 PC(12:0/19:1(9Z)) 172486 PC(12:0/20:1(11Z)) 113023 PC(12:0/22:0) 140371 PC(12:0/22:1(11Z)) 107070 PC(13:0/18:1(9Z)) 172486 PC(13:0/18:2(9Z,12Z)) 267552 81400 PC(13:0/19:1(9Z)) 113023 PC(13:0/21:0) 140371 PC(13:0/22:4(7Z,10Z,13Z,16Z)) 374927 PC(14:0/17:1(9Z)) 184966 PC(14:0/17:2(9Z,12Z)) 267552 81400 PC(14:0/18:1(11Z)) 113023 PC(14:0/18:1(9Z)) 113023 PC(14:0/20:0) 140371 PC(14:0/20:1(11Z)) 107070 PC(14:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)) 53181 PC(14:1(9Z)/15:1(9Z)) 33376 PC(14:1(9Z)/17:0) 172486 PC(14:1(9Z)/17:1(9Z)) 267552 81400 PC(14:1(9Z)/18:0) 113023 PC(14:1(9Z)/20:0) 107070 PC(14:1(9Z)/22:5(4Z,7Z,10Z,13Z,16Z)) 53181 PC(14:1(9Z)/22:5(7Z,10Z,13Z,16Z,19Z)) 53181 PC(15:0/0:0) 28114 14977 PC(15:0/16:1(9Z)) 184966 PC(15:0/17:1(9Z)) 113023 PC(15:0/19:0) 140371 PC(15:0/19:1(9Z)) 107070 PC(15:0/20:4(5Z,8Z,11Z,14Z)) 2049489 PC(15:1(9Z)/0:0) 17297 15216 PC(15:1(9Z)/14:1(9Z)) 33376 PC(15:1(9Z)/16:0) 172486 PC(15:1(9Z)/16:1(9Z)) 267552 81400 PC(15:1(9Z)/19:0) 107070 PC(15:1(9Z)/20:3(8Z,11Z,14Z)) 2049489 PC(15:1(9Z)/22:6(4Z,7Z,10Z,13Z,16Z,19Z)) 32085 PC(16:0/15:1(14)) 184966 PC(16:0/15:1(9Z)) 172486 PC(16:0/16:1(9Z)) 113023 PC(16:0/18:0) 140371 PC(16:0/18:1(11E)) 107070 PC(16:0/18:1(11Z)) 107070 PC(16:0/18:1(6E)) 107070 PC(16:0/18:1(6Z)) 107070 PC(16:0/18:1(9E)) 107070 PC(16:0/18:1(9Z)) 107070 PC(16:1(9Z)/15:0) 172486 PC(16:1(9Z)/15:1(9Z)) 267552 81400 PC(16:1(9Z)/16:0) 113023 PC(16:1(9Z)/18:0) 107070 PC(16:1(9Z)/20:5(5Z,8Z,11Z,14Z,17Z)) 53181 PC(17:0/0:0) 89286 PC(17:0/14:1(9Z)) 172486 PC(17:0/15:1(9Z)) 113023 PC(17:0/17:0) 140371 PC(17:0/17:1(9Z)) 107070 PC(17:0/18:4(6Z,9Z,12Z,15Z)) 2049489 PC(17:1(9Z)/14:0) 184966 PC(17:1(9Z)/14:1(9Z)) 267552 81400 PC(17:1(9Z)/15:0) 113023 PC(17:1(9Z)/17:0) 107070 PC(17:1(9Z)/18:3(6Z,9Z,12Z)) 374927 PC(17:1(9Z)/18:3(9Z,12Z,15Z)) 374927 PC(17:2(9Z,12Z)/0:0) 100924 PC(17:2(9Z,12Z)/12:0) 33376 PC(17:2(9Z,12Z)/14:0) 267552 81400 PC(17:2(9Z,12Z)/18:2(9Z,12Z)) 2049489 PC(17:2(9Z,12Z)/20:5(5Z,8Z,11Z,14Z,17Z)) 32085 PC(18:0/14:1(9Z)) 113023 PC(18:0/16:0) 140371 PC(18:0/16:1(9Z)) 107070 PC(18:1(11Z)/14:0) 113023 PC(18:1(11Z)/16:0) 107070 PC(18:1(9Z)/13:0) 172486 PC(18:1(9Z)/14:0) 113023 PC(18:1(9Z)/16:0) 107070 PC(18:2(9Z,12E)/17:2(9Z,11E)) 2049489 PC(18:2(9Z,12Z)/13:0) 267552 81400 PC(18:2(9Z,12Z)/17:2(9Z,12Z)) 2049489 PC(18:2(9Z,12Z)/18:4(6Z,9Z,12Z,15Z)) 53181 PC(18:3(6Z,9Z,12Z)/17:1(9Z)) 2049489 PC(18:3(6Z,9Z,12Z)/18:3(6Z,9Z,12Z)) 53181 PC(18:3(6Z,9Z,12Z)/18:3(9Z,12Z,15Z)) 53181 PC(18:3(9E,11E,13E)/18:3(9E,11E,13E)) 53181 PC(18:3(9Z,12Z,15Z)/17:1(9Z)) 2049489 PC(18:3(9Z,12Z,15Z)/18:3(6Z,9Z,12Z)) 53181 PC(18:3(9Z,12Z,15Z)/18:3(9Z,12Z,15Z)) 53181 PC(18:4(6Z,9Z,12Z,15Z)/17:0) 2049489 PC(18:4(6Z,9Z,12Z,15Z)/18:2(9Z,12Z)) 53181 PC(18:4(9E,11E,13E,15E)/18:2(9Z,12Z)) 53181 PC(19:0/15:0) 140371 PC(19:0/15:1(9Z)) 107070 PC(19:1(9Z)/12:0) 172486 PC(19:1(9Z)/13:0) 113023 PC(19:1(9Z)/15:0) 107070 PC(20:0/14:0) 140371 PC(20:0/14:1(9Z)) 107070 PC(20:1(11Z)/12:0) 113023 PC(20:1(11Z)/14:0) 107070 PC(20:3(8Z,11Z,14Z)/15:1(9Z)) 2049489 PC(20:4(5Z,8Z,11Z,14Z)/15:0) 374927 PC(20:5(5Z,8Z,11Z,14Z,17Z)/16:1(9Z)) 53181 PC(20:5(5Z,8Z,11Z,14Z,17Z)/17:2(9Z,12Z)) 32085 PC(21:0/13:0) 140371 PC(22:0/12:0) 140371 PC(22:1(11Z)/12:0) 107070 PC(22:4(7Z,10Z,13Z,16Z)/13:0) 2049489 PC(22:5(4Z,7Z,10Z,13Z,16Z)/14:1(9Z)) 53181 PC(22:5(7Z,10Z,13Z,16Z,19Z)/14:1(9Z)) 53181 PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/14:0) 53181 PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/15:1(9Z)) 32085 PC(24:1(15Z)/0:0) 15667 PC(36:0/16:0) 6911 PC(O-1:0/16:0) 89286 PC(O-14:0/18:1(9Z)) 10957 PC(O-14:0/22:0) 100655 70051 PC(O-15:0/2:0) 89286 PC(O-16:0/1:0) 89286 PC(O-16:0/16:1(9Z)) 10957 PC(O-16:0/17:2(9Z,12Z)) 23115 PC(O-16:0/20:0) 100655 70051 PC(O-18:0/14:1(9Z)) 10957 PC(O-20:0/16:0) 100655 70051 PC(O-20:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)) 1350914 PC(O-22:0/22:3(10Z,13Z,16Z)) 14337 PC(O-22:1(13Z)/22:2(13Z,16Z)) 14337 PC(P-15:0/0:0) 57898 63112 PC(P-16:0/16:0) 10957 PC(P-16:0/17:1(9Z)) 23115 PC(P-16:0/20:5(5Z,8Z,11Z,14Z,17Z)) 509910 PC(P-17:0/0:0) 37673 PC(P-18:0/14:0) 10957 PC(P-18:0/15:1(9Z)) 23115 PC(P-20:0/0:0) 310050 PC(P-20:0/12:0) 10957 PC(P-20:0/19:1(9Z)) 3749 26277 67393 PE 16:0-18:1 172486 PE 16:1-16:1 33376 PE 16:1-18:1 267552 81400 PE 18:0-16:1 184966 PECPC 25693 PG 16:0-18:1 6305 PG 18:1-18:1 53213 PGJ2_Class_1 71597 PGJ2_Class 42637 40417 41091 PHHdiA-PC 30840 PHODiA-PC 81602 PI 12:0-18:0 37722 PI 14:0-16:0 37722 PI 14:0-18:1 49225 PI 16:0-16:1 49225 P-IsoPGA2-PC 479985 POB-PC 1517760 Procainamide 118550 394882 456817 709023 Progesterone 348339 802691 979669 1258979 PS 18:0-18:1 278533 Quinidine 24157 36410 24277 31701 Quinine 24157 36410 24277 31701 TAG 14:0-16:0-16:0 7329 TAG 14:0-16:1-22:0 138085 TAG 14:0-18:1-20:0 138085 TAG 16:0-16:0-18:0 13687 TAG 16:0-16:1-26:0 9990 TAG 16:0-18:0-18:1 138085 TAG 16:0-18:1-24:0 9990 TAG 16:1-18:0-18:0 138085 TAG 18:0-18:1-22:0 9990 MS_METABOLITE_DATA_END #METABOLITES METABOLITES_START metabolite_name [ret] A-121 [ret] Ctl_61120 [ret] IR_15_60120 [ret] IR_DOXOABT_1 Mass (avg) RSD (Mass, ppm) Acetaminophen 28.9 599.5445 Cer 18:0;3/18:0;1 28.9 599.5445 DAG 12:0-16:1 26.274 26.211 510.4251 1.51 DAG 14:0-16:1 30.807 30.765 538.4513 10.02 DAG 16:0-18:1 31.313 594.5274 DAG 18:1-18:1 29.661 620.5387 Ergosterol 27.133 396.3371 Gemfibrozil 15.267 15.314 15.252 15.31 250.1568 1.26 IPC 18:0;2/18:0;0 22.994 22.987 809.582 6.71 IPC 18:0;3/16:0;2 31.464 829.5313 IPC 18:0;3/22:0;1 27.739 897.6362 LPA 14:0 18.499 18.597 18.585 18.442 382.2151 2.04 LPE 18:0 16.126 481.3153 LPE 18:1 16.173 16.161 479.2968 3.35 LPI 16:0 16.126 572.2957 LPI 18:0 32.284 600.3231 LPS 18:1 29.712 523.2907 Norethynodrel 18.398 18.496 18.332 18.341 298.194 0.93 OOB-PC 16.176 605.3643 PA 12:0-16:0 22.742 22.89 592.4121 4.07 PC 16:0-16:1 30.921 731.5454 PC 16:0-18:0 28.096 761.5908 PC(10:0/24:0) 28.096 761.5908 PC(11:0/23:0) 28.096 761.5908 PC(12:0/17:2(9Z,12Z)) 30.31 687.4837 PC(12:0/19:1(9Z)) 13.243 717.532 PC(12:0/20:1(11Z)) 30.921 731.5454 PC(12:0/22:0) 28.096 761.5908 PC(12:0/22:1(11Z)) 30.959 759.5805 PC(13:0/18:1(9Z)) 13.243 717.532 PC(13:0/18:2(9Z,12Z)) 32.032 32.121 715.5123 0.42 PC(13:0/19:1(9Z)) 30.921 731.5454 PC(13:0/21:0) 28.096 761.5908 PC(13:0/22:4(7Z,10Z,13Z,16Z)) 12.94 767.5468 PC(14:0/17:1(9Z)) 32.777 717.5322 PC(14:0/17:2(9Z,12Z)) 32.032 32.121 715.5123 0.42 PC(14:0/18:1(11Z)) 30.921 731.5454 PC(14:0/18:1(9Z)) 30.921 731.5454 PC(14:0/20:0) 28.096 761.5908 PC(14:0/20:1(11Z)) 30.959 759.5805 PC(14:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)) 24.141 777.5325 PC(14:1(9Z)/15:1(9Z)) 30.31 687.4837 PC(14:1(9Z)/17:0) 13.243 717.532 PC(14:1(9Z)/17:1(9Z)) 32.032 32.121 715.5123 0.42 PC(14:1(9Z)/18:0) 30.921 731.5454 PC(14:1(9Z)/20:0) 30.959 759.5805 PC(14:1(9Z)/22:5(4Z,7Z,10Z,13Z,16Z)) 24.141 777.5325 PC(14:1(9Z)/22:5(7Z,10Z,13Z,16Z,19Z)) 24.141 777.5325 PC(15:0/0:0) 17.486 17.474 481.3148 0.54 PC(15:0/16:1(9Z)) 32.777 717.5322 PC(15:0/17:1(9Z)) 30.921 731.5454 PC(15:0/19:0) 28.096 761.5908 PC(15:0/19:1(9Z)) 30.959 759.5805 PC(15:0/20:4(5Z,8Z,11Z,14Z)) 28.282 767.5453 PC(15:1(9Z)/0:0) 16.173 16.161 479.2968 3.35 PC(15:1(9Z)/14:1(9Z)) 30.31 687.4837 PC(15:1(9Z)/16:0) 13.243 717.532 PC(15:1(9Z)/16:1(9Z)) 32.032 32.121 715.5123 0.42 PC(15:1(9Z)/19:0) 30.959 759.5805 PC(15:1(9Z)/20:3(8Z,11Z,14Z)) 28.282 767.5453 PC(15:1(9Z)/22:6(4Z,7Z,10Z,13Z,16Z,19Z)) 25.866 789.5309 PC(16:0/15:1(14)) 32.777 717.5322 PC(16:0/15:1(9Z)) 13.243 717.532 PC(16:0/16:1(9Z)) 30.921 731.5454 PC(16:0/18:0) 28.096 761.5908 PC(16:0/18:1(11E)) 30.959 759.5805 PC(16:0/18:1(11Z)) 30.959 759.5805 PC(16:0/18:1(6E)) 30.959 759.5805 PC(16:0/18:1(6Z)) 30.959 759.5805 PC(16:0/18:1(9E)) 30.959 759.5805 PC(16:0/18:1(9Z)) 30.959 759.5805 PC(16:1(9Z)/15:0) 13.243 717.532 PC(16:1(9Z)/15:1(9Z)) 32.032 32.121 715.5123 0.42 PC(16:1(9Z)/16:0) 30.921 731.5454 PC(16:1(9Z)/18:0) 30.959 759.5805 PC(16:1(9Z)/20:5(5Z,8Z,11Z,14Z,17Z)) 24.141 777.5325 PC(17:0/0:0) 17.641 509.3473 PC(17:0/14:1(9Z)) 13.243 717.532 PC(17:0/15:1(9Z)) 30.921 731.5454 PC(17:0/17:0) 28.096 761.5908 PC(17:0/17:1(9Z)) 30.959 759.5805 PC(17:0/18:4(6Z,9Z,12Z,15Z)) 28.282 767.5453 PC(17:1(9Z)/14:0) 32.777 717.5322 PC(17:1(9Z)/14:1(9Z)) 32.032 32.121 715.5123 0.42 PC(17:1(9Z)/15:0) 30.921 731.5454 PC(17:1(9Z)/17:0) 30.959 759.5805 PC(17:1(9Z)/18:3(6Z,9Z,12Z)) 12.94 767.5468 PC(17:1(9Z)/18:3(9Z,12Z,15Z)) 12.94 767.5468 PC(17:2(9Z,12Z)/0:0) 15.671 505.3158 PC(17:2(9Z,12Z)/12:0) 30.31 687.4837 PC(17:2(9Z,12Z)/14:0) 32.032 32.121 715.5123 0.42 PC(17:2(9Z,12Z)/18:2(9Z,12Z)) 28.282 767.5453 PC(17:2(9Z,12Z)/20:5(5Z,8Z,11Z,14Z,17Z)) 25.866 789.5309 PC(18:0/14:1(9Z)) 30.921 731.5454 PC(18:0/16:0) 28.096 761.5908 PC(18:0/16:1(9Z)) 30.959 759.5805 PC(18:1(11Z)/14:0) 30.921 731.5454 PC(18:1(11Z)/16:0) 30.959 759.5805 PC(18:1(9Z)/13:0) 13.243 717.532 PC(18:1(9Z)/14:0) 30.921 731.5454 PC(18:1(9Z)/16:0) 30.959 759.5805 PC(18:2(9Z,12E)/17:2(9Z,11E)) 28.282 767.5453 PC(18:2(9Z,12Z)/13:0) 32.032 32.121 715.5123 0.42 PC(18:2(9Z,12Z)/17:2(9Z,12Z)) 28.282 767.5453 PC(18:2(9Z,12Z)/18:4(6Z,9Z,12Z,15Z)) 24.141 777.5325 PC(18:3(6Z,9Z,12Z)/17:1(9Z)) 28.282 767.5453 PC(18:3(6Z,9Z,12Z)/18:3(6Z,9Z,12Z)) 24.141 777.5325 PC(18:3(6Z,9Z,12Z)/18:3(9Z,12Z,15Z)) 24.141 777.5325 PC(18:3(9E,11E,13E)/18:3(9E,11E,13E)) 24.141 777.5325 PC(18:3(9Z,12Z,15Z)/17:1(9Z)) 28.282 767.5453 PC(18:3(9Z,12Z,15Z)/18:3(6Z,9Z,12Z)) 24.141 777.5325 PC(18:3(9Z,12Z,15Z)/18:3(9Z,12Z,15Z)) 24.141 777.5325 PC(18:4(6Z,9Z,12Z,15Z)/17:0) 28.282 767.5453 PC(18:4(6Z,9Z,12Z,15Z)/18:2(9Z,12Z)) 24.141 777.5325 PC(18:4(9E,11E,13E,15E)/18:2(9Z,12Z)) 24.141 777.5325 PC(19:0/15:0) 28.096 761.5908 PC(19:0/15:1(9Z)) 30.959 759.5805 PC(19:1(9Z)/12:0) 13.243 717.532 PC(19:1(9Z)/13:0) 30.921 731.5454 PC(19:1(9Z)/15:0) 30.959 759.5805 PC(20:0/14:0) 28.096 761.5908 PC(20:0/14:1(9Z)) 30.959 759.5805 PC(20:1(11Z)/12:0) 30.921 731.5454 PC(20:1(11Z)/14:0) 30.959 759.5805 PC(20:3(8Z,11Z,14Z)/15:1(9Z)) 28.282 767.5453 PC(20:4(5Z,8Z,11Z,14Z)/15:0) 12.94 767.5468 PC(20:5(5Z,8Z,11Z,14Z,17Z)/16:1(9Z)) 24.141 777.5325 PC(20:5(5Z,8Z,11Z,14Z,17Z)/17:2(9Z,12Z)) 25.866 789.5309 PC(21:0/13:0) 28.096 761.5908 PC(22:0/12:0) 28.096 761.5908 PC(22:1(11Z)/12:0) 30.959 759.5805 PC(22:4(7Z,10Z,13Z,16Z)/13:0) 28.282 767.5453 PC(22:5(4Z,7Z,10Z,13Z,16Z)/14:1(9Z)) 24.141 777.5325 PC(22:5(7Z,10Z,13Z,16Z,19Z)/14:1(9Z)) 24.141 777.5325 PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/14:0) 24.141 777.5325 PC(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/15:1(9Z)) 25.866 789.5309 PC(24:1(15Z)/0:0) 28.341 605.4407 PC(36:0/16:0) 28.745 1013.8766 PC(O-1:0/16:0) 17.641 509.3473 PC(O-14:0/18:1(9Z)) 27.28 717.5661 PC(O-14:0/22:0) 12.843 12.835 775.6427 1.52 PC(O-15:0/2:0) 17.641 509.3473 PC(O-16:0/1:0) 17.641 509.3473 PC(O-16:0/16:1(9Z)) 27.28 717.5661 PC(O-16:0/17:2(9Z,12Z)) 29.949 729.5628 PC(O-16:0/20:0) 12.843 12.835 775.6427 1.52 PC(O-18:0/14:1(9Z)) 27.28 717.5661 PC(O-20:0/16:0) 12.843 12.835 775.6427 1.52 PC(O-20:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)) 28.446 847.6458 PC(O-22:0/22:3(10Z,13Z,16Z)) 29.661 881.7239 PC(O-22:1(13Z)/22:2(13Z,16Z)) 29.661 881.7239 PC(P-15:0/0:0) 17.991 18.029 465.3202 0.63 PC(P-16:0/16:0) 27.28 717.5661 PC(P-16:0/17:1(9Z)) 29.949 729.5628 PC(P-16:0/20:5(5Z,8Z,11Z,14Z,17Z)) 31.931 763.5523 PC(P-17:0/0:0) 20.466 493.3523 PC(P-18:0/14:0) 27.28 717.5661 PC(P-18:0/15:1(9Z)) 29.949 729.5628 PC(P-20:0/0:0) 29.957 535.396 PC(P-20:0/12:0) 27.28 717.5661 PC(P-20:0/19:1(9Z)) 22.843 22.928 22.836 813.6711 12.13 PE 16:0-18:1 13.243 717.532 PE 16:1-16:1 30.31 687.4837 PE 16:1-18:1 32.032 32.121 715.5123 0.42 PE 18:0-16:1 32.777 717.5322 PECPC 16.126 809.5141 PG 16:0-18:1 23.045 748.5243 PG 18:1-18:1 32.121 774.5407 PGJ2_Class_1 17.54 344.2327 PGJ2_Class 18.092 17.979 17.987 344.2314 3.57 PHHdiA-PC 8.55 651.3765 PHODiA-PC 17.691 665.3904 PI 12:0-18:0 23.449 782.496 PI 14:0-16:0 23.449 782.496 PI 14:0-18:1 22.991 808.5122 PI 16:0-16:1 22.991 808.5122 P-IsoPGA2-PC 31.868 811.5366 POB-PC 15.671 579.3534 Procainamide 17.085 17.082 17.171 17.027 235.1651 0.4 Progesterone 18.853 18.951 19.039 18.947 314.2247 0.93 PS 18:0-18:1 12.979 789.5514 Quinidine 15.267 15.365 15.403 15.31 324.1844 3.57 Quinine 15.267 15.365 15.403 15.31 324.1844 3.57 TAG 14:0-16:0-16:0 32.89 778.7046 TAG 14:0-16:1-22:0 31.328 860.7816 TAG 14:0-18:1-20:0 31.328 860.7816 TAG 16:0-16:0-18:0 31.414 834.7664 TAG 16:0-16:1-26:0 29.207 944.8771 TAG 16:0-18:0-18:1 31.328 860.7816 TAG 16:0-18:1-24:0 29.207 944.8771 TAG 16:1-18:0-18:0 31.328 860.7816 TAG 18:0-18:1-22:0 29.207 944.8771 METABOLITES_END #END