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Molecules (Basel, Switzerland) Dec 2023Recombinant human interferon alpha-2b (rIFN) is widely used in antiviral and anticancer immunotherapy. However, the high efficiency of interferon therapy is accompanied...
Recombinant human interferon alpha-2b (rIFN) is widely used in antiviral and anticancer immunotherapy. However, the high efficiency of interferon therapy is accompanied by a number of side effects; this problem requires the design of a new class of interferon molecules with reduced cytotoxicity. In this work, IFN was modified via genetic engineering methods by merging it with the blood plasma protein apolipoprotein A-I in order to reduce acute toxicity and improve the pharmacokinetics of IFN. The chimeric protein was obtained via biosynthesis in the yeast . The yield of ryIFN-ApoA-I protein when cultivated on a shaker in flasks was 30 mg/L; protein purification was carried out using reverse-phase chromatography to a purity of 95-97%. The chimeric protein demonstrated complete preservation of the biological activity of IFN in the model of vesicular stomatitis virus and SARS-CoV-2. In addition, the chimeric form had reduced cytotoxicity towards Vero cells and increased cell viability under viral load conditions compared with commercial IFN-a2b preparations. Analysis of the pharmacokinetic profile of ryIFN-ApoA-I after a single subcutaneous injection in mice showed a 1.8-fold increased half-life of the chimeric protein compared with ryIFN.
Topics: Chlorocebus aethiops; Humans; Mice; Animals; Interferon-alpha; Recombinant Fusion Proteins; Apolipoproteins A; Apolipoprotein A-I; Vero Cells; Recombinant Proteins; Interferon alpha-2
PubMed: 38138504
DOI: 10.3390/molecules28248014 -
International Journal of Molecular... May 2024CIGB-258, a 3 kDa peptide from heat shock protein 60, exhibits synergistic anti-inflammatory activity with apolipoprotein A-I (apoA-I) in reconstituted high-density...
Synergistic Anti-Inflammatory Activity of Lipid-Free Apolipoprotein (apo) A-I and CIGB-258 in Acute-Phase Zebrafish via Stabilization of the apoA-I Structure to Enhance Anti-Glycation and Antioxidant Activities.
CIGB-258, a 3 kDa peptide from heat shock protein 60, exhibits synergistic anti-inflammatory activity with apolipoprotein A-I (apoA-I) in reconstituted high-density lipoproteins (rHDLs) via stabilization of the rHDL structure. This study explored the interactions between CIGB-258 and apoA-I in the lipid-free state to assess their synergistic effects in the structural and functional enhancement of apoA-I and HDL. A co-treatment of lipid-free apoA-I and CIGB-258 inhibited the cupric ion-mediated oxidation of low-density lipoprotein (LDL) and a lowering of oxidized species in the dose-responsive manner of CIGB-258. The co-presence of CIGB-258 caused a blue shift in the wavelength of maximum fluorescence (WMF) of apoA-I with protection from proteolytic degradation. The addition of apoA-I:CIGB-258, with a molar ratio of 1:0.1, 1:0.5, and 1:1, to HDL and HDL remarkably enhanced the antioxidant ability against LDL oxidation up to two-fold higher than HDL alone. HDL-associated paraoxonase activities were elevated up to 28% by the co-addition of apoA-I and CIGB-258, which is linked to the suppression of Cu-mediated HDL oxidation with the slowest electromobility. Isothermal denaturation by a urea treatment showed that the co-presence of CIGB-258 attenuated the exposure of intrinsic tryptophan (Trp) and increased the mid-points of denaturation from 2.33 M for apoA-I alone to 2.57 M for an apoA-I:CIGB-258 mixture with a molar ratio of 1:0.5. The addition of CIGB-258 to apoA-I protected the carboxymethyllysine (CML)-facilitated glycation of apoA-I with the prevention of Trp exposure. A co-treatment of apoA-I and CIGB-258 synergistically safeguarded zebrafish embryos from acute death by CML-toxicity, suppressing oxidative stress and apoptosis. In adult zebrafish, the co-treatment of apoA-I+CIGB-258 exerted the highest anti-inflammatory activity with a higher recovery of swimming ability and survivability than apoA-I alone or CIGB-258 alone. A co-injection of apoA-I and CIGB-258 led to the lowest infiltration of neutrophils and interleukin (IL)-6 generation in hepatic tissue, with the lowest serum triglyceride, aspartate transaminase, and alanine transaminase levels in plasma. In conclusion, the co-presence of CIGB-258 ameliorated the beneficial functionalities of apoA-I, such as antioxidant and anti-glycation activities, by enhancing the structural stabilization and protection of apoA-I. The combination of apoA-I and CIGB-258 synergistically enforced the anti-inflammatory effect against CML toxicity in embryos and adult zebrafish.
Topics: Apolipoprotein A-I; Animals; Zebrafish; Antioxidants; Anti-Inflammatory Agents; Lipoproteins, HDL; Lipoproteins, LDL; Oxidation-Reduction; Drug Synergism
PubMed: 38791598
DOI: 10.3390/ijms25105560 -
Journal of Sport and Health Science May 2024Adenosine triphosphatase inhibitory factor 1 (IF1) is a key protein involved in energy metabolism. IF1 has been linked to various age-related diseases, although its...
BACKGROUND
Adenosine triphosphatase inhibitory factor 1 (IF1) is a key protein involved in energy metabolism. IF1 has been linked to various age-related diseases, although its relationship with physical activity (PA) remains unclear. Additionally, the apolipoprotein A-I (apoA-I), a PA-modulated lipoprotein, could play a role in this relationship because it shares a binding site with IF1 on the cell-surface ATP synthase. We examined here the associations between chronic PA and plasma IF1 concentrations among older adults, and we investigated whether apoA-I mediated these associations.
METHODS
In the present work, 1096 healthy adults (63.8% females) aged 70 years and over who were involved in the Multidomain Alzheimer Prevention Trial study were included. IF1 plasma concentrations (square root of ng/mL) were measured at the 1-year visit of the Multidomain Alzheimer Prevention Trial, while PA levels (square root of metabolic equivalent task min/week) were assessed using questionnaires administered each year from baseline to the 3-year visit. Multiple linear regressions were performed to investigate the associations between the first-year mean PA levels and IF1 concentrations. Mediation analyses were conducted to examine whether apoA-I mediated these associations. Mixed-effect linear regressions were carried out to investigate whether the 1-year visit IF1 concentrations predicted subsequent changes in PA.
RESULTS
Multiple linear regressions indicated that first-year mean PA levels were positively associated with IF1 concentrations (B = 0.021; SE = 0.010; p = 0.043). Mediation analyses revealed that about 37.7% of this relationship was mediated by apoA-I (B = 0.008; SE = 0.004; p = 0.023). Longitudinal investigations demonstrated that higher concentrations of IF1 at the 1-year visit predicted a faster decline in PA levels over the subsequent 2 years (time × IF1: B = -0.148; SE = 0.066; p = 0.025).
CONCLUSION
This study demonstrates that regular PA is associated with plasma IF1 concentrations, and it suggests that apoA-I partly mediates this association. Additionally, this study finds that baseline concentrations of IF1 can predict future changes in PA. However, further research is needed to fully understand the mechanisms underlying these observations.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Alzheimer Disease; Apolipoprotein A-I; ATPase Inhibitory Protein; Exercise
PubMed: 37748689
DOI: 10.1016/j.jshs.2023.09.009 -
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 -
Frontiers in Public Health 2024Sepsis constitutes a significant global healthcare burden. Studies suggest a correlation between educational attainment and the likelihood of developing sepsis. Our goal...
OBJECTIVE
Sepsis constitutes a significant global healthcare burden. Studies suggest a correlation between educational attainment and the likelihood of developing sepsis. Our goal was to utilize Mendelian randomization (MR) in order to examine the causal connection between educational achievement (EA) and sepsis, while measuring the mediating impacts of adjustable variables.
METHODS
We collected statistical data summarizing educational achievement (EA), mediators, and sepsis from genome-wide association studies (GWAS). Employing a two-sample Mendelian randomization (MR) approach, we calculated the causal impact of education on sepsis. Following this, we performed multivariable MR analyses to assess the mediation proportions of various mediators, including body mass index (BMI), smoking, omega-3 fatty acids, and apolipoprotein A-I(ApoA-I).
RESULTS
Genetic prediction of 1-SD (4.2 years) increase in educational attainment (EA) was negatively correlated with sepsis risk (OR = 0.83, 95% CI 0.71 to 0.96). Among the four identified mediators, ranked proportionally, they including BMI (38.8%), smoking (36.5%), ApoA-I (6.3%) and omega-3 (3.7%). These findings remained robust across a variety of sensitivity analyses.
CONCLUSION
The findings of this study provided evidence for the potential preventive impact of EA on sepsis, which may be influenced by factors including and metabolic traits and smoking. Enhancing interventions targeting these factors may contribute to reducing the burden of sepsis.
Topics: Humans; Apolipoprotein A-I; Genome-Wide Association Study; Mendelian Randomization Analysis; Smoking; Educational Status; Sepsis
PubMed: 38362221
DOI: 10.3389/fpubh.2024.1330606 -
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 -
Lipids in Health and Disease Feb 2024Dyslipidemia is significantly more common in those with concurrent chronic kidney disease (CKD) and chronic heart failure (CHF). Sacubitril/valsartan has showcased its...
BACKGROUND AND OBJECTIVE
Dyslipidemia is significantly more common in those with concurrent chronic kidney disease (CKD) and chronic heart failure (CHF). Sacubitril/valsartan has showcased its influence on both cardiac and renal functions, extending its influence to the modulation of lipid metabolism pathways. This study aimed to examine how sacubitril/valsartan affects lipid metabolism within the context of CKD and CHF.
METHODS
This study adopted a retrospective design, focusing on a single center and involving participants who were subjected to treatment with sacubitril/valsartan and valsartan. The investigation assessed the treatment duration, with a particular emphasis on recording blood lipid indicators, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A (ApoA), and apolipoprotein B (ApoB). Furthermore, cardiac and renal functions, blood pressure, potassium levels, and other factors influencing the blood lipids were analyzed in both groups at identical time points.
RESULTS
After 16 weeks of observation, the sacubitril/valsartan group exhibited lower TG levels compared to the valsartan group. Noteworthy was the fact that individuals undergoing sacubitril/valsartan treatment experienced an average reduction of 0.84 mmol/L in TG levels, in stark contrast to the valsartan group, which registered a decline of 0.27 mmol/L (P < 0.001). The sacubitril/valsartan group exhibited elevated levels of HDL-C and ApoA in comparison to the valsartan group (P = 0.023, P = 0.030). While TC, LDL-C, and ApoB decreased compared to baseline, the differences between groups were not statistical significance. Regarding cardiac indicators, there was an observed enhancement in the left ventricular ejection fraction (LVEF) within the sacubitril/valsartan group when compared to the baseline, and it was noticeably higher than that of the valsartan group. Spearman correlation analysis and multiple linear regression analysis revealed that medication, body mass index(BMI), and hemoglobin A1c (HbA1c) had a direct influencing effect on TG levels.
CONCLUSION
Sacubitril/valsartan demonstrated improvements in lipid metabolism and cardiac indicators in patients with CKD and CHF. Specifically, it presented promising benefits in reducing TG levels. In addition, both BMI and HbA1c emerged as influential factors contributing to alterations in TG levels, independent of the administration of sacubitril/valsartan.
Topics: Humans; Retrospective Studies; Stroke Volume; Cholesterol, LDL; Glycated Hemoglobin; Lipid Metabolism; Tetrazoles; Ventricular Function, Left; Valsartan; Heart Failure; Biphenyl Compounds; Renal Insufficiency, Chronic; Drug Combinations; Apolipoproteins A; Apolipoproteins B; Apolipoproteins; Aminobutyrates
PubMed: 38419057
DOI: 10.1186/s12944-024-02051-x -
Cancer Immunology, Immunotherapy : CII Nov 2023Serum lipids have been identified to be used as prognostic biomarkers in several types of cancer. The primary objective of this study was to evaluate the prognostic...
BACKGROUND
Serum lipids have been identified to be used as prognostic biomarkers in several types of cancer. The primary objective of this study was to evaluate the prognostic value of serum lipids in metastatic colorectal cancer (mCRC) patients received anti-PD-1 therapy.
METHODS
Pretreatment and the alteration of serum lipids, including apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), cholesterol (CHO), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) after 2 courses of anti-PD1 therapy, were collected. Kaplan-Meier survival and cox regression analysis were performed to identify the prognostic values on overall survival (OS). Finally, those significant predictors from multivariate analysis were used to construct a nomogram for the prediction of prognosis.
RESULTS
Baseline ApoB, CHO, HDL-C, LDL-C and early changes of ApoB, ApoA-I, HDL-C were statistically significant in the ROC analysis, showing good discriminatory ability in terms of OS. In multivariate analysis, treatment lines, lung metastasis, baseline HDL-C (low vs. high, HR, 6.30; 95% CI 1.82-21.80; P = 0.004) and early changes in HDL-C (reduction vs. elevation, HR, 4.59, 95% CI 1.20-17.63; P = 0.026) independently predicted OS. The area under the time-dependent ROC curve at 1 year, 2 years and 3 years consistently demonstrated the satisfactory accuracy and predictive value of the nomogram (AUC: 0.88, 0.85, 0.84).
CONCLUSION
Overall, high level at baseline and an early elevation of HDL-C are correlated with better outcomes in mCRC patients treated with anti-PD1 therapy. The constructed nomogram indicated that the factors are strong predictive markers for response and prognosis to anti-PD-1 therapy in metastatic colorectal cancer.
Topics: Humans; Apolipoprotein A-I; Apolipoproteins B; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Colorectal Neoplasms; Nomograms; Prognosis; Retrospective Studies; Immune Checkpoint Inhibitors
PubMed: 37589756
DOI: 10.1007/s00262-023-03519-y -
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 -
Frontiers in Endocrinology 2024The existing research on the association between apolipoproteins (Apos) and erectile dysfunction (ED) primarily relies on observational studies and does not distinguish...
The existing research on the association between apolipoproteins (Apos) and erectile dysfunction (ED) primarily relies on observational studies and does not distinguish between organic and psychogenic causes when diagnosing ED. It is difficult to believe that Apos play a role in psychogenic ED. To address these issues, our study explored the causal relationship between lipoproteins and ED using Mendelian randomization (MR) analysis and differentiate between organic and psychogenic ED through the use of nocturnal penile tumescence and rigidity (NPTR) monitoring. Multivariate MR analysis revealed significant causal associations between high-density lipoprotein (HDL), Apo A1, and Apo B/A1 with ED (OR and 95% CI were 0.33 (0.14-0.78), 3.58 (1.52-8.43), and 0.30 (0.13-0.66)). we conducted statistical and analytical analyses on the data of 212 patients using multivariate analyses and receiver operating characteristic (ROC) curves. Patients with organic ED had significantly lower levels of HDL, Apo A1 and Apo A1/B, whereas patients with organic ED had considerably higher levels of Apo B and low-density lipoprotein (LDL). The diagnostic value of Apos in predicting the risk of organic ED was evaluated using ROC curves. The results indicated that Apo A1 and Apo A1/B demonstrated good predictive value. HDL, Apo A1, and Apo A1/B have been identified as risk factors for ED in our study. Furthermore, our research highlights the significance of Apo A1 and Apo A1/Apo B in the development of organic ED and suggests their potential use as indicators to assess the risks associated with organic ED.
Topics: Humans; Male; Mendelian Randomization Analysis; Erectile Dysfunction; Case-Control Studies; Middle Aged; Apolipoproteins; Adult; Apolipoprotein A-I; Lipoproteins, HDL
PubMed: 38938512
DOI: 10.3389/fendo.2024.1359015