Serum anti-AP3D1 antibodies are risk factors for acute ischemic stroke related with atherosclerosis

Li, Shu Yang; Yoshida, Yoichi; Kobayashi, Eiichi; Kubota, Masaaki; Matsutani, Tomoo; Mine, Seiichiro; Machida, Toshio; Maezawa, Yoshiro; Takemoto, Minoru; Yokote, Koutaro; Kobayashi, Yoshio; Takizawa, Hirotaka; Sata, Michio; Yamagishi, Kazumasa; Iso, Hiroyasu; Sawada, Norie; Tsugane, Shoichiro; Kobayashi, Sohei; Matsushita, Kazuhiro; Nomura, Fumio; Matsubara, Hisahiro; Sumazaki, Makoto; Ito, Masaaki; Yajima, Satoshi; Shimada, Hideaki; Iwase, Katsuro; Ashino, Hiromi; Wang, Hao; Goto, Katsuya; Tomiyoshi, Go; Shinmen, Natsuko; Nakamura, Rika; Kuroda, Hideyuki; Iwadate, Yasuo; Hiwasa, Takaki

doi:10.1038/s41598-021-92786-9

Cited by 16 publications

(15 citation statements)

References 63 publications

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“…Tumor-associated autoantibodies are produced early during tumorigenesis, can be measured before clinical symptoms appear ( 90 ), are early indicators of abnormal cellular processes during tumorigenesis, and are associated with malignant transformations ( 91 ). The early stages of AS are sometimes accompanied by low levels of tissue destruction, protein leakage from disrupted cells, and elevated autoantibody expression ( 92 ). AS autoantibodies are the driving factors of inflammation, risk factors of AS-related diseases, and protective (anti-AS) factors.…”

Section: Discussionmentioning

confidence: 99%

Serum Anti-BRAT1 is a Common Molecular Biomarker for Gastrointestinal Cancers and Atherosclerosis

Liu

Shimada

et al. 2022

Front. Oncol.

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Atherosclerosis (AS) and cancers are major global causes of mortality and morbidity. They also share common modifiable pathogenesis risk factors. As the same strategies used to predict AS could also detect certain cancers, we sought novel serum antibody biomarkers of cancers in atherosclerotic sera sampled by liquid biopsy. Using serological antigen identification by cDNA expression cloning (SEREX) and western blot, we screened and detected the antigens BRCA1-Associated ATM Activator 1 (BRAT1) and WD Repeat Domain 1 (WDR1) in the sera of patients with transient ischemic attacks (TIA). Amplified luminescence proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) established the upregulation of serum BRAT1 antibody (BRAT1-Abs) and WDR1 antibody (WDR1-Abs) in patients with AS-related diseases compared with healthy subjects. ROC and Spearman’s correlation analyses showed that BRAT1-Abs and WDR1-Abs could detect AS-related diseases. Thus, serum BRAT1-Abs and WDR1-Abs are potential AS biomarkers. We used online databases and AlphaLISA detection to compare relative antigen and serum antibody expression and found high BRAT1 and BRAT1-Abs expression in patients with GI cancers. Significant increases (> 0.6) in the AUC for BRAT1-Ab vs. esophageal squamous cell carcinoma (ESCC), gastric cancer, and colorectal cancer suggested that BRAT1-Ab exhibited better predictive potential for GI cancers than WDR1-Ab. There was no significant difference in overall survival (OS) between BRAT1-Ab groups (P = 0.12). Nevertheless, a log-rank test disclosed that the highest serum BRAT1-Ab levels were associated with poor ESCC prognosis at 5–60 weeks post-surgery. We validated the foregoing conclusions by comparing serum BRAT1-Ab and WDR1-Ab levels based on the clinicopathological characteristics of the patients with ESCC. Multiple statistical approaches established a correlation between serum BRAT1-Ab levels and platelet counts. BRAT1-Ab upregulation may enable early detection of AS and GI cancers and facilitate the delay of disease progression. Thus, BRAT1-Ab is a potential antibody biomarker for the diagnosis of AS and GI cancers and strongly supports the routine clinical application of liquid biopsy in chronic disease detection and diagnosis.

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Section: Discussionmentioning

confidence: 99%

Serum Anti-BRAT1 is a Common Molecular Biomarker for Gastrointestinal Cancers and Atherosclerosis

Liu

Shimada

et al. 2022

Front. Oncol.

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“…Atherosclerosis is one of the major causes of ischemic stroke ( 24 ) and the primary cause of CKD ( 5 ). Autoantibodies have been found to develop alongside atherosclerosis ( 13 , 14 ). Some of these autoantibodies may have causal or suppressive effects on disease development.…”

Section: Discussionmentioning

confidence: 99%

“…The mixture was incubated for 7-21 days at room temperature in the dark. Chemiluminescence was read on an EnSpire Alpha (PerkinElmer, Inc.) microplate reader (PerkinElmer, Inc.), as previously described ( 13 , 22 ).…”

Section: Methodsmentioning

confidence: 99%

Serum anti‑TSTD2 antibody as a biomarker for atherosclerosis‑induced ischemic stroke and chronic kidney disease

Kubota

Zhang

et al. 2022

Med Int

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autoantibodies can be used in the early diagnosis and treatment of atherosclerosis-related diseases. Using Protoarray ® screening of samples from patients with atherosclerosis, the present study identified thiosulfate sulfurtransferase-like domain-containing 2 (tStD2) as a novel atherosclerosis antigen. the serum tStD2 antibody levels were then quantified using an amplified luminescent proximity homogeneous assay-linked immunosorbent assay. this demonstrated the levels of tStD2 antibodies (tStD2-abs) to be significantly higher in patients with acute cerebral infarction or chronic kidney disease than in healthy donors. the tStD2-ab levels were also found to be higher in males, older adults, smokers, in those who consumed alcohol regularly, and in those with hypertension. Furthermore, Spearman's rank correlation analysis revealed tStD2-ab levels to be strongly associated with measures of atherosclerosis severity, including plaque scores, intima-media thickness of the carotid artery and the cardio-ankle vascular index. thus, tStD2-abs may thus be a promising novel biomarker for atherosclerosis-related cerebral infarction and kidney disease.

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“…The reaction mixture was incubated at room temperature for 6-8 h, followed by incubation with anti-human IgG-conjugated acceptor beads (2.5 µL at 40 µg/mL) and glutathione-conjugated donor beads (2.5 µL at 40 µg/mL) at room temperature in the dark for 1-14 days. Emissions were read on an EnSpire Alpha microplate reader (PerkinElmer) as described previously [15,[18][19][20]. Speci c reactions were calculated by subtracting the alpha counts of the GST control from the counts of GST-fusion proteins.…”

Section: Patients and Healthy Donor Seramentioning

confidence: 99%

GADD34 activates p53 and may have utility as a marker of atherosclerosis

Tomiyoshi

Nakamura

Shinmen

et al. 2022

Preprint

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We previously identified growth arrest and DNA-damage-inducible gene 34 (GADD34) as a marker of ischemic stroke. In the present study, serum levels of anti-GADD34 antibodies were found to be significantly higher in patients with acute ischemic stroke or chronic kidney disease compared to healthy donors. We then examined the biological function of GADD34 by transfection into human osteosarcoma U2OS cells. Knockdown of GADD34 by siRNA resulted in enhanced cell proliferation, which was suppressed by knockdown of MDM2. Luciferase reporter assays revealed that the transactivation ability of p53 enhanced by genotoxic anticancer drugs such as camptothecin and etoposide was further potentiated by the presence of GADD34 and attenuated by co-transfection with p53 shRNA expression plasmids. Western blotting demonstrated increased p53 protein levels after treatment with camptothecin, which was also potentiated by GADD34 but suppressed by GADD34 siRNA, ATM siRNA, and wortmannin, an ATM inhibitor. GADD34 levels increased in response to treatment with camptothecin or adriamycin, and this increase was attenuated by MDM2 siRNA. Immunoprecipitation with anti-GADD34 antibodies followed by Western blotting with anti-MDM2 antibodies indicated ubiquitination of GADD34 is mediated by MDM2. Accordingly, GADD34 may function as a ubiquitination decoy to reduce p53 ubiquitination and increase p53 protein levels. Increased neuronal death due to activation of p53 by GADD34 may account for the elevated serum levels of anti-GADD34 antibodies observed in patients with acute ischemic stroke.

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Serum anti-AP3D1 antibodies are risk factors for acute ischemic stroke related with atherosclerosis

Cited by 16 publications

References 63 publications

Serum Anti-BRAT1 is a Common Molecular Biomarker for Gastrointestinal Cancers and Atherosclerosis

Serum Anti-BRAT1 is a Common Molecular Biomarker for Gastrointestinal Cancers and Atherosclerosis

Serum anti‑TSTD2 antibody as a biomarker for atherosclerosis‑induced ischemic stroke and chronic kidney disease

GADD34 activates p53 and may have utility as a marker of atherosclerosis

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