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Journal of Gastroenterology Mar 2024We have previously reported apolipoprotein A2-isoforms (apoA2-is) as candidate plasma biomarkers for early-stage pancreatic cancer. The aim of this study was the...
BACKGROUND
We have previously reported apolipoprotein A2-isoforms (apoA2-is) as candidate plasma biomarkers for early-stage pancreatic cancer. The aim of this study was the clinical development of apoA2-is.
METHODS
We established a new enzyme-linked immunosorbent sandwich assay for apoA2-is under the Japanese medical device Quality Management System requirements and performed in vitro diagnostic tests with prespecified end points using 2732 plasma samples. The clinical equivalence and significance of apoA2-is were compared with CA19-9.
RESULTS
The point estimate of the area under the curve to distinguish between pancreatic cancer (n = 106) and healthy controls (n = 106) was higher for apoA2-ATQ/AT [0.879, 95% confidence interval (CI): 0.832-0.925] than for CA19-9 (0.849, 95% CI 0.793-0.905) and achieved the primary end point. The cutoff apoA2-ATQ/AT of 59.5 μg/mL was defined based on a specificity of 95% in 2000 healthy samples, and the reliability of specificities was confirmed in two independent healthy cohorts as 95.3% (n = 106, 95% CI 89.4-98.0%) and 95.8% (n = 400, 95% CI 93.3-97.3%). The sensitivities of apoA2-ATQ/AT for detecting both stage I (47.4%) and I/II (50%) pancreatic cancers were higher than those of CA19-9 (36.8% and 46.7%, respectively). The combination of apoA2-ATQ/AT (cutoff, 59.5 μg/mL) and CA19-9 (37 U/mL) increased the sensitivity for pancreatic cancer to 87.7% compared with 69.8% for CA19-9 alone. The clinical performance of apoA2-is was blindly confirmed by the National Cancer Institute Early Detection Research Network.
CONCLUSIONS
The clinical performance of ApoA2-ATQ/AT as a blood biomarker is equivalent to or better than that of CA19-9.
Topics: Humans; CA-19-9 Antigen; Biomarkers, Tumor; Apolipoprotein A-II; Reproducibility of Results; Early Detection of Cancer; Pancreatic Neoplasms; Protein Isoforms
PubMed: 38261000
DOI: 10.1007/s00535-023-02072-w -
Journal of Controlled Release :... Mar 2024Efficient delivery of therapeutics to the central nervous system (CNS) remains a major challenge for the treatment of neurological diseases. Huntington disease (HD) is a...
Efficient delivery of therapeutics to the central nervous system (CNS) remains a major challenge for the treatment of neurological diseases. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion mutation in the HTT gene which codes for a toxic mutant huntingtin (mHTT) protein. Pharmacological reduction of mHTT in the CNS using antisense oligonucleotides (ASO) ameliorates HD-like phenotypes in rodent models of HD, with such therapies being investigated in clinical trials for HD. In this study, we report the optimization of apolipoprotein A-I nanodisks (apoA-I NDs) as vehicles for delivery of a HTT-targeted ASO (HTT ASO) to the brain and peripheral organs for HD. We demonstrate that apoA-I wild type (WT) and the apoA-I K133C mutant incubated with a synthetic lipid, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, can self-assemble into monodisperse discoidal particles with diameters <20 nm that transmigrate across an in vitro blood-brain barrier model of HD. We demonstrate that apoA-I NDs are well tolerated in vivo, and that apoA-I K133C NDs show enhanced distribution to the CNS and peripheral organs compared to apoA-I WT NDs following systemic administration. ApoA-I K133C conjugated with HTT ASO forms NDs (HTT ASO NDs) that induce significant mHTT lowering in the liver, skeletal muscle and heart as well as in the brain when delivered intravenously in the BACHD mouse model of HD. Furthermore, HTT ASO NDs increase the magnitude of mHTT lowering in the striatum and cortex compared to HTT ASO alone following intracerebroventricular administration. These findings demonstrate the potential utility of apoA-I NDs as biocompatible vehicles for enhancing delivery of mutant HTT lowering ASOs to the CNS and peripheral organs for HD.
Topics: Mice; Animals; Oligonucleotides, Antisense; Apolipoprotein A-I; Huntington Disease; Oligonucleotides; Brain; Huntingtin Protein; Disease Models, Animal
PubMed: 38215984
DOI: 10.1016/j.jconrel.2024.01.011 -
BMC Cancer Jan 2024Apolipoprotein A1 (ApoA1) is a member of the apolipoprotein family with diverse functions. It is associated with the pathogenesis and prognosis of several types of...
BACKGROUND
Apolipoprotein A1 (ApoA1) is a member of the apolipoprotein family with diverse functions. It is associated with the pathogenesis and prognosis of several types of tumors. However, the role of serum apolipoprotein A1 (ApoA1) in the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. This study aimed to elucidate its influence on clinical outcomes in patients with DLBCL.
METHODS
We retrospectively analyzed a cohort of 1583 consecutive DLBCL patients admitted to the Fujian Medical University Union Hospital between January 2011 and December 2021. 949 newly diagnosed DLBCL patients who met the inclusion criteria were enrolled for statistical analysis. Receiver operating characteristic curve analysis was performed to determine the optimal cut-off value for serum ApoA1 levels for prognostic prediction among patients with DLBCL. The correlations between serum ApoA1 levels and clinical and laboratory parameters were analyzed. Prognostic significance was analyzed using univariate and multivariate Cox proportional hazards models.
RESULTS
Newly diagnosed patients with DLBCL demonstrated low serum ApoA1 levels (< 0.925 g/L), had more B symptoms, higher levels of serum lactate dehydrogenase (LDH) (>upper limit of normal), poorer performance status (Eastern Cooperative Oncology Group score of 2-4), higher percentage of advanced stage and non-germinal center B-cell (non-GCB) subtype, more cases of > 1 extranodal site, higher International Prognostic Index (IPI) score (3-5), and higher incidence of relapse or refractory diseases compared with those with high serum ApoA1 levels (≥ 0.925 g/L). Low serum ApoA1 levels were an independent adverse prognostic factor for overall survival (OS) but not progression-free survival (PFS).
CONCLUSIONS
Low serum ApoA1 levels were associated with poor treatment response and inferior survival in newly diagnosed patients with DLBCL.
Topics: Humans; Apolipoprotein A-I; Lymphoma, Large B-Cell, Diffuse; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies
PubMed: 38212711
DOI: 10.1186/s12885-024-11818-5 -
International Journal of Molecular... Dec 2023Infertility affects millions worldwide, posing a significant global health challenge. The proteomic analysis of follicular fluid provides a comprehensive view of the...
Infertility affects millions worldwide, posing a significant global health challenge. The proteomic analysis of follicular fluid provides a comprehensive view of the complex molecular landscape within ovarian follicles, offering valuable information on the factors influencing oocyte development and on the overall reproductive health. The follicular fluid is derived from the plasma and contains various proteins that can have different roles in oocyte health and infertility, and this fluid is a critical microenvironment for the developing oocytes as well. Using the high-performance liquid chromatography-mass spectrometry method, we investigated the protein composition of the follicular fluid, and after classification, we carried out relative quantification of the identified proteins in the pregnant (P) and non-pregnant (NP) groups. Based on the protein-protein interaction analysis, albumin and apolipoprotein A1 (ApoA1) were found to be hub proteins, and the quantitative comparison of the P and NP groups resulted in a significantly lower concentration of ApoA1 and high-density lipoprotein cholesterol in the P group. As both molecules are involved in the cholesterol transport, we also investigated their role in the development of oocytes and in the prediction of fertility.
Topics: Female; Humans; Pregnancy; Apolipoprotein A-I; Cholesterol, HDL; Fertility; Follicular Fluid; Infertility; Proteomics; Reproduction
PubMed: 38203658
DOI: 10.3390/ijms25010486 -
Journal of Molecular Biology Feb 2024Amyloid resistance is the inability or the reduced susceptibility of an organism to develop amyloidosis. In this study we have analysed the molecular basis of the...
Amyloid resistance is the inability or the reduced susceptibility of an organism to develop amyloidosis. In this study we have analysed the molecular basis of the resistance to systemic AApoAII amyloidosis, which arises from the formation of amyloid fibrils from apolipoprotein A-II (ApoA-II). The disease affects humans and animals, including SAMR1C mice that express the C allele of ApoA-II protein, whereas other mouse strains are resistant to development of amyloidosis due to the expression of other ApoA-II alleles, such as ApoA-IIF. Using cryo-electron microscopy, molecular dynamics simulations and other methods, we have determined the structures of pathogenic AApoAII amyloid fibrils from SAMR1C mice and analysed the structural effects of ApoA-IIF-specific mutational changes. Our data show that these changes render ApoA-IIF incompatible with the specific fibril morphologies, with which ApoA-II protein can become pathogenic in vivo.
Topics: Animals; Mice; Amyloid; Amyloidosis; Apolipoprotein A-II; Cryoelectron Microscopy; Alleles; Molecular Dynamics Simulation; Mutation; Mice, Mutant Strains
PubMed: 38199491
DOI: 10.1016/j.jmb.2024.168441 -
Investigative Ophthalmology & Visual... Jan 2024Apolipoprotein A1 (APOA1) is a potential crucial protein and treatment goal for pathological myopia in humans. This study set out to discover the function of APOA1 in...
PURPOSE
Apolipoprotein A1 (APOA1) is a potential crucial protein and treatment goal for pathological myopia in humans. This study set out to discover the function of APOA1 in scleral remodeling in myopia and its underlying mechanisms.
METHODS
A myopic cell model was induced using hypoxia. Following loss- and gain-of function experiments, the expression of the myofibroblast transdifferentiation-related and collagen production-related factors Forkhead box M1 (FOXM1), APOA1, and methyltransferase-like 3 (METTL3) in the myopic cell model was examined by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. The proliferation and apoptosis were determined by Cell Counting Kit-8 assay and flow cytometry, respectively. Chromatin immunoprecipitation (ChIP) was employed to examine FOXM1 enrichment in the METTL3 promoter, methylated RNA immunoprecipitation (Me-RIP) to examine the N6-methyladenosine (m6A) modification level of APOA1, and photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) to examine the binding between METTL3 and APOA1.
RESULTS
Hypoxia-induced human scleral fibroblasts (HSFs) had high APOA1 and FOXM1 expression and low METTL3 expression. FOXM1 knockdown elevated METTL3 expression and downregulated APOA1 expression. FOXM1 was enriched in METTL3 promoter. APOA1 or FOXM1 knockdown or METTL3 overexpression reversed the hypoxia-induced elevation in vinculin, paxillin, and α-smooth muscle actin (α-SMA) levels and apoptosis and the reduction in collagen, type I, alpha 1 (COL1A1) level and cell proliferation in HSFs. METTL3 or YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) knockdown or APOA1 overexpression reversed the impacts of FOXM1 knockdown on vinculin, paxillin, α-SMA, and COL1A1 expression and cell proliferation and apoptosis.
CONCLUSIONS
FOXM1 elevated the m6A methylation level of APOA1 by repressing METTL3 transcription and enhanced APOA1 mRNA stability and transcription by reducing the YTHDF2-recognized m6A methylated transcripts.
Topics: Humans; Apolipoprotein A-I; Paxillin; Vinculin; Myopia, Degenerative; Transcription Factors; Hypoxia; Methyltransferases; Forkhead Box Protein M1; RNA-Binding Proteins
PubMed: 38190128
DOI: 10.1167/iovs.65.1.19 -
Frontiers in Endocrinology 2023Research has shown that the disordered serum lipid profile may be associated with the risk of differentiated thyroid cancer (DTC). Whether this association reflect...
BACKGROUND
Research has shown that the disordered serum lipid profile may be associated with the risk of differentiated thyroid cancer (DTC). Whether this association reflect causal effect is still unclear. The aim of this study was to evaluate the causality of circulating lipoprotein lipids on DTC.
METHODS
Mendelian randomization (MR) analysis was conducted to evaluate the relationship between the circulating lipoprotein lipids and DTC risk using single-nucleotide polymorphisms (SNPs) from a genome-wide association (GWA) study containing a high-incidence Italian population of 690 cases samples with DTC and 497 controls.
RESULTS
Univariate and multivariate mendelian randomization analysis demonstrated that 'total cholesterol', 'HDL cholesterol', 'apolipoprotein B' and 'ratio of apolipoprotein B to apolipoprotein A1' were correlated with DTC. According to sensitivity analysis, our results were reliable. Furthermore, multivariate analysis revealed that there is no causative association between DTC and any of the many cause factors when they interact with one another, suggesting that there was a deep interaction between the four factors, which could affect each other. Finally, the mechanism of the related effects each other as well as the target genes with significant SNP regulatory effects in DTC was explored by conducting functional enrichment analysis and constructing the regulatory networks.
CONCLUSIONS
We obtained four exposure factors (total cholesterol, HDL cholesterol, apolipoprotein B and ratio of apolipoprotein B to apolipoprotein A1) closely related to DTC, which laid a theoretical foundation for the treatment of DTC.
Topics: Humans; Apolipoprotein A-I; Genome-Wide Association Study; Mendelian Randomization Analysis; Adenocarcinoma; Apolipoproteins B; Cholesterol, HDL; Lipid Metabolism Disorders; Thyroid Neoplasms
PubMed: 38189054
DOI: 10.3389/fendo.2023.1291445 -
Reproductive Sciences (Thousand Oaks,... Jun 2024Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, which can lead to adverse fetal outcomes, including preterm labor and intrauterine...
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, which can lead to adverse fetal outcomes, including preterm labor and intrauterine death. The pathogenesis of ICP is still unclear. We hypothesized that pathological index leads to abnormal placenta changes in ICP. Investigation of these differences in protein expression in parallel profiling is essential to understand the comprehensive pathophysiological mechanism underlying ICP. The present study screened differentially expressed proteins (DEPs) as novel diagnostic markers for ICP. Proteomic profiles of placental tissues from 32 ICP patients and 24 healthy volunteers (controls) were analyzed. Our founding was valid by following western blotting and immunohistochemistry staining, respectively. The association of the key protein expression with clinicopathological features of ICP was further analyzed. A total of 178 DEPs were identified between the ICP and control groups. Functional enrichment analysis showed these proteins were significantly enriched in the PPAR singling pathway by KEGG and PPARα/RXRα activation by IPA. Apolipoprotein A2 (APOA2) was the only upregulated protein, which uniquely identified in ICP groups and related to both pathways. Validation of western blotting and immunohistochemical staining analysis showed significantly higher APOA2 expression in the ICP group than in the control group. Furthermore, the expression of APOA2 is associated with clinicopathological features in ICP groups. Receiver operating characteristic (ROC) curve analyses showed that the AUC of APOA2 was 0.8984 (95% confidence interval (CI): 0.772-1.000). This study has identified up-regulated APOA2 associated with PPAR singling pathway and PPARα/RXRα activation in ICP. Thus, APOA2 may be involved in ICP pathogenesis, serving as a novel biomarker for its diagnosis.
Topics: Humans; Female; Cholestasis, Intrahepatic; Pregnancy; Proteomics; Biomarkers; Adult; Pregnancy Complications; Placenta; Apolipoprotein A-II; Case-Control Studies
PubMed: 38177949
DOI: 10.1007/s43032-023-01437-z -
European Journal of Medical Research Jan 2024The study was performed to explore the association between blood lipids and cognitive impairment in patients with type 2 diabetes mellitus (T2DM).
OBJECTIVE
The study was performed to explore the association between blood lipids and cognitive impairment in patients with type 2 diabetes mellitus (T2DM).
METHODS
This study included 336 patients with T2DM. Relevant clinical data including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A1, apolipoprotein B were collected, and the Mini-Mental State Examination (MMSE) score and Montreal Cognitive Assessment (MoCA) score were used to assess the cognitive function in patients with T2DM.
RESULTS
Serum apolipoprotein A1 levels were significantly increased in T2DM patients with cognitive impairment compared with T2DM patients without cognitive impairment (p = 0.017). Serum apolipoprotein A1 levels were significantly negatively correlated with MoCA score (r = - 0.143, p = 0.009) and MMSE score (r = - 0.132, p = 0.016) in patients with T2DM. In multivariable-adjusted regression model, serum apolipoprotein A1 was independently associated with cognitive impairment in patients with T2DM (OR = 5.201, p = 0.024).
CONCLUSION
Serum apolipoprotein A1 is associated with cognitive impairment in patients with T2DM, but not TC, TG, HDL-C, LDL-C, and apolipoprotein B, indicating that increased serum apolipoprotein A1 may be a risk factor of cognitive impairment in patients with T2DM.
Topics: Humans; Diabetes Mellitus, Type 2; Apolipoprotein A-I; Cholesterol, LDL; Lipids; Triglycerides; Cholesterol, HDL; Cognitive Dysfunction
PubMed: 38167163
DOI: 10.1186/s40001-023-01574-w -
European Review For Medical and... Dec 2023Patients with pancreatic diseases are at increased risk of cardiovascular events. Investigating various apolipoprotein forms as important atherogenesis components may...
OBJECTIVE
Patients with pancreatic diseases are at increased risk of cardiovascular events. Investigating various apolipoprotein forms as important atherogenesis components may improve cardiovascular risk (CVR) prediction. This study aimed to investigate CVR factors in patients with chronic pancreatitis.
PATIENTS AND METHODS
The study enrolled 70 patients (40 males and 30 females, mean age 55.2 years) with chronic pancreatitis and treated pancreatic exocrine insufficiency. We assessed CVR by apolipoproteins A-I, A-II, B, and C-III, lipid profile; score systems [SCORE risk chart and Framingham Risk Score (FRS)], diabetes mellitus; chronic pancreatitis by M-ANNHEIM classification. Statistics were performed via SPSS v. 22.
RESULTS
Low apolipoprotein A-I and high apolipoprotein B levels with increased atherogenic potential were observed in 37 and 26 patients. 45.71% demonstrated a high risk of myocardial infarction with high apolipoprotein B/apolipoprotein A-I ratio. Men are at higher CVR risk. Apolipoproteins A-I and A-II correlated with the cardioprotective high-density lipoprotein (HDL) in contrast to apolipoproteins B and C-III, which correlated strongly with low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG). Increased CVR assessed by FRS correlated with significantly lower apolipoprotein A-I and higher apolipoprotein B and apolipoprotein B/apolipoprotein A-I ratio. With the increase in chronic pancreatitis severity, we observed decreased apolipoproteins and increased apolipoprotein B/apolipoprotein A-I ratio.
CONCLUSIONS
Apolipoproteins are valuable CVR indicators. Further studies are required to establish a CVR screening panel in this population.
Topics: Male; Female; Humans; Middle Aged; Apolipoprotein A-I; Cardiovascular Diseases; Risk Factors; Apolipoproteins; Apolipoproteins B; Triglycerides; Atherosclerosis; Heart Disease Risk Factors; Pancreatitis, Chronic; Cholesterol, HDL
PubMed: 38164866
DOI: 10.26355/eurrev_202312_34802