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Vancomycin, a first-line drug for treating methicillin-resistant Staphylococcus aureus infections, is associated with acute kidney injury (AKI). This study involved an evaluation of biomarkers for AKI detection and their comparison with traditional serum creatinine (SCr). We prospectively enrolled patients scheduled to receive intravenous vancomycin for methicillin-resistant S aureus infection. Blood samples for pharmacokinetic assessment and SCr and cystatin C (CysC) measurements were collected at baseline and on days 3, 7, and 10 from the initiation of vancomycin administration (day 1). Urinary biomarkers, including kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin, and clusterin, were collected from days 1 to 7 and adjusted for urinary creatinine levels. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Of the 42 patients, 6 experienced vancomycin-induced AKI. On day 7, the change from baseline eGFR using CysC (ΔeGFRCysC) showed a stronger correlation with vancomycin area under the curve (r = -0.634, P < .001) than that using SCr (ΔeGFRSCr; r = -0.437, P = .020). ΔeGFRSCr showed no significant correlation with vancomycin pharmacokinetic in patients with body mass index ≥23. The median (interquartile range) level of KIM-1 (μg/mg) was significantly higher in the AKI group (0.006 [0.005-0.008]) than in the non-AKI group (0.004 [0.001-0.005]) (P = .039, Mann-Whitney U test), with area under the receiver operating characteristic curve (95% confidence interval) of 0.788 (0.587-0.990). Serum CysC, particularly in overweight individuals or those with obesity, along with urinary KIM-1 are important predictors of vancomycin-induced AKI. These results may aid in selecting better biomarkers than traditional SCr for detecting vancomycin-induced AKI., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

COVID-19 is an infectious disease caused by the SARS-CoV-2 virus. Glycoprotein clusterin (CLU) has many functions such as phagocyte recruitment, complement system inhibition, apoptosis inhibition, hormone and lipid transport, as well as in the immune response. The study aimed to assess the changes in CLU concentrations and the profile and degree of CLU glycosylation between patients with severe COVID-19, convalescents, and healthy subjects (control). The profile and degree of serum CLU N-glycosylation were analyzed using lectin-ELISA with specific lectins. CLU concentrations were significantly lower and relative reactivities of CLU glycans with SNA ( Sambucus nigra agglutinin) were significantly higher in severe COVID-19 patients in comparison to convalescents and the control group. The relative reactivities of CLU glycans with MAA ( Maackia amurensis agglutinin), together with relative reactivity with LCA ( Lens culinaris agglutinin), were also significantly higher in patients with severe COVID-19 than in convalescents and the control group, but they also significantly differed between convalescents and control. The development of acute inflammation in the course of severe COVID-19 is associated with a decrease in CLU concentration, accompanied by an increase in the expression of α2,3-linked sialic acid, and core fucose. Both of these parameters can be included as useful glycomarkers differentiating patients with severe COVID-19 from convalescents and the control group, as well as convalescents and healthy subjects.

Background: Reliable blood biomarkers are crucial for early detection and treatment evaluation of cognitive impairment, including Alzheimer's disease and other dementias., Objective: To examine whether plasma biomarkers and their combination are different between older people with mild cognitive impairment (MCI) and cognitively normal individuals, and to explore their relations with cognitive performance., Methods: This cross-sectional study included 250 older adults, including 124 participants with MCI, and 126 cognitively normal participants. Plasma brain-derived neurotrophic factor (BDNF), irisin and clusterin were measured, and BDNF/irisin ratio was calculated. Global cognition was evaluated by the Montreal Cognitive Assessment., Results: Plasma irisin levels, but not BDNF, were significantly different between MCI group and cognitively normal group. Higher irisin concentration was associated with an increased probability for MCI both before and after controlling covariates. By contrast, plasma BDNF concentration, but not irisin, was linearly correlated with cognitive performance after adjusting for covariates. Higher BDNF/irisin ratios were not only correlated with better cognitive performance, but also associated with lower risks of MCI, no matter whether we adjusted for covariates. Plasma BDNF and irisin concentrations increased with aging, whereas BDNF/irisin ratios remained stable. No significant results of clusterin were observed., Conclusions: Plasma BDNF/irisin ratio may be a reliable indicator which not only reflects the odds of the presence of MCI but also directly associates with cognitive performance.

Background: The identification of circulating biomarkers associated with the risk of type 2 diabetes (T2D) is useful for improving the current prevention strategies in the most at-risk patients. Here, we aimed to investigate the association of plasma apolipoprotein concentrations in prediabetes subjects with the incidence of new-onset T2D during follow-up., Methods: In the IT-DIAB prospective study, 307 participants with impaired fasting glucose levels (fasting plasma glucose [FPG]: 110-125 mg/dL) were followed yearly for 5 years. The onset of T2D was defined as a first FPG value ≥ 126 mg/dL during follow-up. Apolipoprotein (apo)A-I, A-II, A-IV, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a) plasma concentrations were determined by mass spectrometry. Correlations between apolipoproteins and metabolic parameters at baseline were assessed by Spearman's coefficients. Kaplan-Meier curves were drawn using a ternary approach based on terciles and incident T2D. The association between plasma apolipoproteins concentrations and the incidence of T2D was determined using Cox proportional-hazards models., Results: During a median follow-up of 5-year, 115 participants (37.5%) developed T2D. After adjustment for age, sex, body mass index, FPG, HbA 1c , and statin use, the plasma levels of apoC-I, apoC-II, apoC-III, apoE, apoF, apoH, apoJ, and apoL1 were positively associated with a high risk for T2D. After further adjustment for plasma triglycerides, only apoE (1 SD natural-log-transformed hazard ratio: 1.28 [95% confidence interval: 1.06; 1.54]; p = 0.010), apoF (1.22 [1.01; 1.48]; p = 0.037), apoJ (1.24 [1.03; 1.49]; p = 0.024), and apoL1 (1.26 [1.05; 1.52]; p = 0.014) remained significantly associated with the onset of T2D. Kaplan-Meier survival curves also showed that the lower third of plasma apoE levels (< 5.97 mg/dL) was significantly associated with a lower risk of conversion to T2D (log-rank test, p = 0.002) compared to the middle and upper thirds., Conclusions: The plasma apoE levels are positively associated with the risk of T2D in prediabetes subjects, independently of traditional risk factors. The possible associations of apoF, apoJ, and apoL1 with T2D risk also pave the way for further investigations. Trial registration This trial was registered at clinicaltrials.gov as NCT01218061 and NCT01432509., (© 2022. The Author(s).)

Aim: Using proteomics, we previously found that serum levels of glycosylated (Glyc) forms of apolipoprotein J (ApoJ), a cytoprotective and anti-oxidant protein, decrease in the early phase of acute myocardial infarction (AMI). We aimed to investigate: (i) ApoJ-Glyc intracellular distribution and secretion during ischaemia; (ii) the early changes in circulating ApoJ-Glyc during AMI; and (iii) associations between ApoJ-Glyc and residual ischaemic risk post-AMI., Methods and Results: Glycosylated apolipoprotein J was investigated in: (i) cells from different organ/tissue origin; (ii) a pig model of AMI; (iii) de novo AMI patients (n = 38) at admission within the first 6 h of chest pain onset and without troponin T elevation at presentation (early AMI); (iv) ST-elevation myocardial infarction patients (n = 212) who were followed up for 6 months; and (v) a control group without any overt cardiovascular disease (n = 144). Inducing simulated ischaemia in isolated cardiac cells resulted in an increased intracellular accumulation of non-glycosylated ApoJ forms. A significant decrease in ApoJ-Glyc circulating levels was seen 15 min after ischaemia onset in pigs. Glycosylated apolipoprotein J levels showed a 45% decrease in early AMI patients compared with non-ischaemic patients (P < 0.0001), discriminating the presence of the ischaemic event (area under the curve: 0.934; P < 0.0001). ST-elevation myocardial infarction patients with lower ApoJ-Glyc levels at admission showed a higher rate of recurrent ischaemic events and mortality after 6-month follow-up (P = 0.008)., Conclusions: These results indicate that ischaemia induces an intracellular accumulation of non-glycosylated ApoJ and a reduction in ApoJ-Glyc secretion. Glycosylated apolipoprotein J circulating levels are reduced very early after ischaemia onset. Its continuous decrease indicates a worsening in the evolution of the cardiac event, likely identifying patients with sustained ischaemia after AMI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Enhanced serum secreted clusterin (sCLU) protein was associated with progression, poor prognosis and chemotherapy sensitivity evaluation in malignant patients. However, the clinical significance of serum sCLU protein levels in patients with invasive breast cancer (IBC) is unknown. In this study, the serum sCLU protein in 2648 patients with IBC was detected. The diagnostic value and treatment responses of serum sCLU protein in patients with IBC were also performed. The results showed that the serum sCLU protein level was significantly higher in IBC patients compared to the healthy controls (P < 0.0001), and strongly correlated with higher clinical tumor stage (P < 0.001), lymph node metastasis (P < 0.001), shorter overall survival (OS) (P = 0.032) and disease-free survival (DFS) (P = 0.029), respectively. Using the cutoff value of 18.46 μg/mL, the sensitivity and specificity were 86.26% and 73.46% to separate IBC patients from noncancerous and healthy controls. The postoperative patients showed lower serum sCLU levels compared to the preoperative patients (P = 0.003). The chemoresistant patients showed higher serum sCLU levels compared to the chemosensitive patients (P < 0.001). These data indicated that serum sCLU levels are effective indicators for diagnosis and chemotherapy sensitivity evaluation in patients with IBC.

Purpose: We investigated whether serum clusterin levels could reflect the current antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-specific indices., Materials and Methods: Fifty-seven patients with AAV and 40 healthy controls were included in this study. AAV-specific indices included the Short-Form 36-Item Health Survey Physical and Mental Component Summaries (SF-36 PCS and MCS) scores, Birmingham vasculitis activity score (BVAS), five-factor score (FFS), and vasculitis damage index. Clinical and laboratory data and AAV-specific indices were obtained at blood collection. The highest tertile of BVAS (≥16) was defined as high activity of AAV., Results: The median age of AAV patients was 64.0 years and 19 patients were male. SF-36 PCS score (r=0.328), SF-36 MCS score (r=0.289), BVAS (r=-0.404), erythrocyte sedimentation rate (r=-0.336), and C-reactive protein levels (r=-0.421) were significantly correlated with serum clusterin levels. In the multivariable linear regression analysis using AAV-specific indices and serum clusterin levels, both FFS (β=0.412) and serum clusterin levels (β=-0.250) were significantly associated with BVAS. When the optimal serum clusterin cut-off level for high activity of AAV was identified as 130.45 µg/mL, patients with serum clusterin level ≤130.45 µg/mL had a significantly higher risk for high activity of AAV than did those without (relative risk 7.194). Patients with AAV exhibited significantly lower serum clusterin levels than did healthy controls (168.2 µg/mL vs. 230.5 µg/mL)., Conclusion: Serum clusterin levels could reflect the current disease activity in patients with AAV., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2021.)

Objective: There are discrepancies about the relationship of IL-6, clusterin and irisin with obesity and obesity associated insulin resistance and also about their sexual dimorphism. This study aimed at evaluating the circulating levels of IL-6, clusterin and irisin in obese subjects of both sexes who had different grades of obesity and examining their sexual dimorphism and their association with insulin resistance., Methods: This study included 176 non-diabetic subjects of both sexes who were classified according to their sex into two groups; the male and the female groups. The male group (88 men) was classified according to BMI into; group 1 (22 lean men), group 2 (22 class I obese men), group 3 (22 class II obese men) and group 4 (22 class III obese men). The female group (88 women) was classified according to BMI exactly as the male group. Metabolic parameters, IL-6, clusterin, and irisin levels were measured. Data were analyzed by ANOVA test, post hoc Tukey's test and independent t -test. Pearson correlation was used to assess the association between variables., Results: In obese subjects of both sexes, circulating IL-6, clusterin and irisin levels were significantly elevated and positively correlated with HOMA-IR. Obese males showed significantly higher HOMA-IR, IL-6, clusterin and irisin levels than obese females., Conclusion: Obesity in both sexes, especially in males was associated with high levels of IL-6, clusterin and irisin and worsened the metabolic pattern. Circulating IL-6, clusterin and irisin may represent possible therapeutic targets for insulin resistance in obese subjects.

Background: Apolipoprotein J (ApoJ) is present in both plasma and tissues, including brain. Growing evidence suggest that this protein may play an early role on the development of the two most common forms of dementia, Alzheimer's disease (AD) and vascular dementia (VD)., Objective: To evaluate whether serum ApoJ levels might be able to predict the progression to AD, VD, or mixed dementia (AD&VD) in individuals with mild cognitive impairment (MCI)., Methods: Serum ApoJ was measured in 196 MCI subjects (aged ≥60 years) with a median follow up of 2.9 years., Results: One hundred thirty-two of the enrolled MCI subjects converted to dementia. Among these, 45% developed AD, 33% mixed dementia, 13% VD (VD), and 9% other forms of dementia. A significant trend toward a progressive reduction in the incidence of dementia, regardless of the type, from tertile I (83.1%), to tertile II (63.1%), to tertile III (56.1%) was observed (p = 0.003). After adjustment for potential confounders, a twofold increase in the risk of conversion to dementia was found in subjects belonging to tertile I of Apo J compared with tertile III; the risk increased after two years of follow up, while no differences emerged within the first 2 years., Conclusions: Our results suggest that in MCI subjects, low APOJ levels may be associated with increased risk of developing dementia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In the seminal plasma (n = 118) and serum (n = 90) clusterin (CLU) the fucosylation and the expression of selected fucosyltransferases (FUTs) were analyzed. Samples from infertile men were divided into groups based on the results of the standard semen analysis: normozoospermic (N), teratozoospermic (T), asthenoteratozoospermic (AT) and oligoasthenoteratozoospermic (OAT). The CLU fucosylation was analyzed using lectin-ELISAs with biotinylated lectins specific to α1,3-, α1,2-linked antennary fucose, and α1,6-linked core fucose (LTA, UEA, and LCA, respectively). The concentrations of FUT3 and FUT4, reflecting the expression of Le oligosaccharide structures, were measured using ELISA tests. The differences in serum CLU and FUT4 concentrations, and in the expression of core fucose and antennary fucose α1,2-linked in CLU glycans between the N group and other groups examined suggest that the disturbances in sperm count, motility, and morphology are not the only cause of male infertility. Lack of similarities between levels of examined parameters in blood serum and seminal plasma may suggest the differences in mechanisms leading to glycoproteins glycosylation. It confirmed the observed differences in concentrations of seminal plasma CLU, FUT3, and FUT4 between the OAT group and N, T, AT groups, indicating that decreased sperm count may be related to these parameters expression. The serum CLU concentrations and expression of core fucose and fucose α1,2-linked in CLU, seem to be good markers differentiating normozoospermic men from those with abnormal sperm parameters, which was not observed for seminal plasma., (© 2021. The Author(s).)

Clusterin (CLU) is a molecular chaperone that participates in a variety of biological processes. Recent studies indicate its possible involvement in the development of bone erosions and autoimmunity. The aim of this study was to investigate its serum concentrations in patients with early rheumatoid arthritis (RA) and to explore their potential relationship with disease activity and treatment response. Serum levels of CLU were measured in 52 patients before and 3 months after the initiation of treatment and in 52 healthy individuals. CLU levels at baseline were significantly increased in patients with early RA compared with healthy subjects (p < 0.0001). After 3 months of treatment, the levels of CLU decreased and reached concentrations comparable to those in controls. Even though there was no relationship between CLU levels and disease activity at baseline, CLU levels positively correlated with disease activity at months 3, 6 and 12 after treatment initiation. Using ROC analysis, lower CLU baseline levels predicted achieving the therapeutic target of low disease activity and remission at months 3, 6 and 12. In summary, we found increased serum concentrations of clusterin in treatment-naïve patients with early rheumatoid arthritis, and we suggest clusterin as a predictive biomarker of disease activity and treatment response.

Context: Data on the presence/quantification of the neurotrophic adipokines retinol-binding protein-4 (RBP4), clusterin, and pigment epithelium-derived factor (PEDF) in human cerebrospinal fluid (CSF) are scarce and migration of these adipokines across of the blood-brain barrier (BBB) is uncertain., Objective: This work aimed to quantify RBP4, PEDF, and clusterin in paired serum and CSF samples of patients undergoing neurological evaluation., Methods: A total of 268 patients (109 male, 159 female) were included. Adipokine serum and CSF concentrations were measured by enzyme-linked immunosorbent assay in duplicate., Results: RBP4 was abundant in serum (mean, 31.9 ± 24.2 μg/mL). The serum concentrations were approximately 145 times higher than in CSF (CSF to serum RBP4 ratio, 8.2 ± 4.3 × 10-3). PEDF was detectable in serum (mean, 30.2 ± 11.7 μg/mL) and concentrations were approximately 25 times higher than in CSF (CSF to serum PEDF ratio, 42.3 ± 15.6 × 10-3). Clusterin serum concentrations were abundant with mean levels of 346.0 ± 114.6 μg/mL, which were approximately 40 times higher than CSF levels (CSF to serum clusterin ratio, 29.6 ± 23.4 × 10-3). RBP4 and PEDF serum levels correlated positively with CSF levels, which were increased in overweight/obese patients and in type 2 diabetic patients. The CSF concentrations of all 3 adipokines increased with BBB dysfunction. RBP4 in CSF correlated positively with inflammatory parameters. In detail, only RBP4 showed the kinetics and associations that are mandatory for a putative mediator of the fat-brain axis., Conclusion: RBP4, PEDF, and clusterin are permeable to the BBB and increase with the measure of BBB dysfunction. RBP4 represents an inflammatory neurotrophic adipokine and is a promising mediator of the fat-brain axis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Hypertension disorder of pregnancy (HDP) is one of the leading causes of maternal and foetal illness. The aim of the current study was to identify and verify novel serum markers for HDP., Methods: A label-free LC-MS/MS method was used to establish the serum proteomic profiles of 12 pre-HDP (before clinical diagnosis of HDP) pregnancies and verify prioritized candidates in the verification set of 48 pre-HDP pregnancies. These biomarkers were revalidated by ELISA in an independent cohort of 88 pre-HDP pregnancies. Subsequently, the candidate biomarkers were histologically analysed by immunohistochemistry, and function was evaluated in TEV-1 cells., Results: We identified 33 proteins with significantly increased abundance and 14 with decreased abundance (peptide FDR ≤ 1%, P < 0.05). Complement was one of the top enriched components in the pre-HDP group compared with the control group. Three complement factors (CLU, CFHR5, and CRP) were significantly increased in the three sets, of which CLU was a critical factor for the development of HDP (OR = 1.22, P < 0.001). When these three factors and body weight were combined, the AUC was 0.74, with a sensitivity of 0.67 and specificity of 0.68 for HDP prediction compared with normal pregnancy. In addition, inflammation-induced CLU could inhibit the invasion of TEV-1 cells., Conclusions: Complement proteins may play an essential role in the occurrence of HDP by acting on trophoblast cells. CLU may be a high-risk factor for HDP, and the models combining candidates show reasonable screening efficiency of HDP in the first half of pregnancy.

Aim: Obstructive sleep apnea (OSA) activates the complement system; however, the levels of membrane attack complex (MAC) are unaltered suggesting regulatory mechanisms. Our aim was to investigate complement factor H (CFH) and clusterin, two important complement regulators in OSA. Materials & methods: We analyzed clusterin and CFH levels in plasma of 86 patients with OSA and 33 control subjects. Results: There was no difference in CFH levels between patients (1099.4/784.6-1570.5/μg/ml) and controls (1051.4/652.0-1615.1/μg/ml, p = 0.72). Clusterin levels were higher in patients with OSA (309.7/217.2-763.2/μg/ml vs 276.1/131.0-424.3/μg/ml, p = 0.048) with a trend for a positive correlation with disease severity (p = 0.073). Conclusion: Increase in clusterin levels may be protective in OSA by blocking the MAC formation.

The cardiometabolic syndrome involves a clustering of metabolic and cardiovascular factors which increase the risk of patients developing both Type 2 Diabetes Mellitus and cardio/cerebrovascular disease. Although the mechanistic underpinnings of this link remain uncertain, key factors include insulin resistance, excess visceral adiposity, atherogenic dyslipidemia, and endothelial dysfunction. Of these, a state of resistance to insulin action in overweight/obese patients appears to be central to the pathophysiologic process. Given the increasing prevalence of obesity-related Type 2 Diabetes, coupled with the fact that cardiovascular disease is the number one cause of mortality in this patient population, a more thorough understanding of the cardiometabolic syndrome and potential options to mitigate its risk is imperative. Inherent in the pathogenesis of insulin resistance is an underlying state of chronic inflammation, at least partly in response to excess adiposity. Within obese adipose tissue, an immunomodulatory shift occurs, involving a preponderance of pro-inflammatory immune cells and cytokines/adipokines, along with antigen presentation by adipocytes. Therefore, various adipokines differentially expressed by obese adipocytes may have a significant effect on cardiometabolism. Clusterin is a molecular chaperone that is widely produced by many tissues throughout the body, but is also preferentially overexpressed by obese compared lean adipocytes and relates strongly to multiple components of the cardiometabolic syndrome. Herein, we summarize the known and potential roles of circulating and adipocyte-specific clusterin in cardiometabolism and discuss potential further investigations to determine if clusterin is a viable target to attenuate both metabolic and cardiovascular disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wittwer and Bradley.)

Background: Prostate-specific antigen (PSA) has been the most popular diagnostic marker for prostate cancer. The frequent occurrence of low PSA values (<10 ng/ml) in patients with highly suspicious prostate cancer, however, has undermined the accuracy of clinical examinations. The aim of this study was to develop a better resolution for diagnosing prostate cancer to overcome the disadvantage of PSA., Methods: We focused on the glycosylation status of patients' serum proteins and conducted comprehensive lectin microarray analyses to characterize N- and O-glycans using sera from prostate cancer and benign prostatic diseases. Next, we retrieved candidate serum proteins with characteristic glycan structures using lectin-immobilized beads and identified them by quantitative mass spectrometry using a technique referred to as isobaric tag for relative and absolute quantitation (iTRAQ) labeling. Finally, we constructed a new assay to quantify a candidate glycoprotein with the newly identified glycans., Results: Lectin microarray analyses revealed that sera from patients with prostate cancer had a higher affinity for Jacalin, Amaranthus caudatus (ACA) lectin, and Maclura pomifera (MPA) lectin, compared with that from patients with benign prostatic diseases and normal subjects, suggesting that O-glycosylated proteins are more abundant in sera from patients with prostate cancer. Then, serum glycoproteins preferentially adsorbed onto Jacalin-Agarose as well as biotin-ACA/and biotin-MPA/streptavidin-immobilized magnetic beads were isolated, labeled with iTRAQ, and identified using quantitative mass spectrometry. It was found that the ACA- and MPA-recognizable clusterin was more enriched in patients' sera from prostate cancer compared with those from benign prostatic diseases. Following this discovery, we constructed a Luminex-based assay to quantify O-glycosylated clusterin, in which total serum clusterin was first captured on anti-clusterin antibody-immobilized beads, and then clusterin-associated O-glycans were determined by the pair of biotin-MPA and streptavidin-phycoerythrin. When PSA values registered less than 10 ng/ml, the corresponding serum level of MPA-recognized clusterin determined by this assay was beneficial for distinguishing the patients with prostate cancer from the patients with benign prostatic disease., Conclusion: For PSA values that measure less than 10 ng/ml, the serum O-glycosylated clusterin level can be a complementary indicator for the malignancy of prostate cancer., (© 2020 Wiley Periodicals LLC.)

Background: To compare the aqueous humor (AH) and the serum clusterin levels of patients with pseudoexfoliation syndrome (PEX), pseudoexfoliation glaucoma (PEXG), and primary open-angle glaucoma (POAG) with each other and with an age- and sex-matched control group., Methods: This prospective, cross-sectionalstudy evaluated 92 eyes from 92 adult cases of uncomplicated phacoemulsification and posterior chamber intraocular lens (IOL) implantation. The cases were divided into PEX, PEXG, POAG, and control groups. Serum samples were taken from the antecubital vein just before the surgery, and the AH samples were aspirated at the beginning of the surgery. Kruskal-Wallis H, One-way ANOVA, Mann-Whitney U with Bonferroni correction and Chi-Square tests were used for statistical analysis., Results: The serum clusterin levels were the highest in the PEXG group, but no statistically significant differences were observed between the groups (p=0.633). The mean AH clusterin levels were 286.79±29.64 μg/mL in the PEXG group, 263.92±31.70 μg/mL in the PEX group, 272.59±49.71 μg/mL in the POAG group, and 193.50±62.38 μg/mL in the control group (p< 0.001). This came out to be 1.48 times increase for the PEXG group, 1.36 for the PEX group, and 1.41 for the POAG group when compared with the control subjects., Conclusions: A higher level of clusterin in the anterior chamber was found to be associated with PEX and PEXG. In addition, a high level of anterior chamber clusterin in POAG, which is a new finding, showed that this molecule might be important not only in pseudoexfoliation, but also other types of glaucoma like POAG.

Diagnosing acute kidney injury remains a challenge since the established renal biomarkers, serum creatinine (sCr) and symmetric dimethylarginine (SDMA) reflect glomerular function and not tubular injury. Sensitive tubular markers such as urinary clusterin (uClust) and cystatin B (uCysB) have been proposed to detect AKI at an earlier stage. Since envenomation by the European adder (Vipera berus berus) could serve as a spontaneous disease model of AKI we investigated these new biomarkers in affected dogs. Concentrations of uClust and uCysB as well as sCr and SDMA were analyzed retrospectively in stored samples from 26 dogs with snake envenomation and 13 healthy controls. Higher concentrations of uClust (P < 0.012) and uCysB (P < 0.001) were observed in the snake-envenomed group. Normalization of uClust and uCysB to urinary creatinine did not alter the results. No differences were observed in sCr and SDMA between the snake-envenomed group and the healthy control group. Spearman rank correlation analysis revealed a strong association of uClust with uCysB in the snake-envenomed dogs (r = 0.75 P < 0.001) but not in the healthy controls. The high percentage of snake-envenomed dogs with increased uClust and uCysB concentrations in the absence of increased sCr and SDMA suggests renal tubular injury in the affected dogs. Larger prospective case-controlled studies are warranted to evaluate the clinical utility and prognostic value of these biomarkers., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Alzheimer's disease (AD) is the most common form of dementia and biomarkers are essential to help in the diagnosis of this disease. Image techniques and cerebrospinal fluid (CSF) biomarkers are limited in their use because they are expensive or invasive. Thus, the search for blood-borne biomarkers is becoming central to the medical community., Objective: The main objective of this study is the evaluation of three serum proteins as potential biomarkers in AD patients., Methods: We recruited 27 healthy controls, 19 mild cognitive impairment patients, and 17 AD patients. Using the recent A/T/N classification we split our population into two groups (AD and control). We used ELISA kits to determine Aβ42, tau, and p-tau in CSF and clusterin, PKR, and RAGE in serum., Results: The levels of serum clusterin, PKR, and RAGE were statistically different in the AD group compared to controls. These proteins showed a statistically significant correlation with CSF Aβ42. So, they were selected to generate an AD detection model showing an AUC-ROC of 0.971 (CI 95%, 0.931-0.998)., Conclusion: The developed model based on serum biomarkers and other co-variates could reflect the AD core pathology. So far, not one single blood-biomarker has been described, with effectiveness offering high sensitivity and specificity. We propose that the complexity of AD pathology could be reflected in a set of biomarkers also including clinical features of the patients.

Background: Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute deterioration of liver function and high short-term mortality. Clusterin, with biological functions similar to small heat shock proteins, can protect cells from apoptosis induced by various stressors. The aim of this study was to detect the level of serum clusterin in hepatitis B virus- (HBV-) related ACLF and to assess the predictive value of clusterin for the short-term prognosis of HBV-ACLF., Methods: We detected serum clusterin by ELISA in 108 HBV-ACLF patients, 63 HBV-non-ACLF patients, and 44 normal controls., Results: Serum clusterin was markedly lower in HBV-ACLF patients (median, 51.09  μ g/mL) than in HBV-non-ACLF patients (median, 188.56  μ g/mL) and normal controls (median, 213.45  μ g/mL; all P < 0.05). Nonsurviving HBV-ACLF patients who died within 90 days had much lower clusterin levels than did surviving patients, especially those who died within 28 days (nonsurvival group vs. survival group: 39.82 ± 19.34 vs. 72.26 ± 43.52, P < 0.001; survival time ≤ 28 vs. survival time > 28: median 28.39 vs. 43.22, P = 0.013). The results showed that for identifying HBV-ACLF, the sensitivity of clusterin (93.7%) was similar to the sensitivities of the international normalized ratio (INR; 94.4%) and total bilirubin (TBIL; 94.8%), but its specificity (90.7%) was higher than that of prothrombin activity (PTA; 65.8%) and TBIL (69.8%) and was similar to INR (88.9%). As the concentration of clusterin increased, the mortality of HBV-ACLF patients decreased significantly from 59.3% to 7.0%. Clusterin had better ability for predicting the prognosis of HBV-ACLF patients than did the model for end-stage liver disease (MELD) score and the chronic liver failure consortium (CLIF-C) ACLF score (MELD vs. clusterin: P = 0.012; CLIF-C ACLF vs. clusterin: P = 0.031)., Conclusion: Serum clusterin is a potential biomarker for HBV-ACLF which can be used to assess clinical severity and the short-term prognosis of patients with this disease and may help clinicians identify HBV-ACLF with greater specificity and improved prognostic accuracy than existing prognostic markers., Competing Interests: All authors have declared that they do not have any conflicts of interest in this manuscript., (Copyright © 2020 Huimin Liu et al.)

Wild-type transthyretin-associated (ATTRwt) amyloidosis is an age-related disease that causes heart failure in older adults. This disease frequently features cardiac amyloid fibril deposits that originate from dissociation of the tetrameric protein, transthyretin (TTR). Unlike hereditary TTR (ATTRm) amyloidosis, where amino acid replacements destabilize the native protein, in ATTRwt amyloidosis, amyloid-forming TTR lacks protein sequence alterations. The initiating cause of fibril formation in ATTRwt amyloidosis is unclear, and thus, it seems plausible that other factors are involved in TTR misfolding and unregulated accumulation of wild-type TTR fibrils. We believe that clusterin (CLU, UniProtKB P10909), a plasma circulating glycoprotein, plays a role in the pathobiology of ATTRwt amyloidosis. Previously, we have suggested a role for CLU in ATTRwt amyloidosis based on our studies showing that (1) CLU codeposits with non-native TTR in amyloid fibrils from ATTRwt cardiac tissue, (2) CLU interacts only with non-native (monomeric and aggregated) forms of TTR, and (3) CLU serum levels in patients with ATTRwt are significantly lower compared to healthy controls. In the present study, we provide comprehensive detail of compositional findings from mass spectrometry analyses of amino acid and glycan content of CLU purified from ATTRwt and control sera. The characterization of oligosaccharide content in serum CLU derived from patients with ATTRwt amyloidosis is novel data. Moreover, results comparing CLU oligosaccharide variations between patient and healthy controls are original and provide further evidence for the role of CLU in ATTRwt pathobiology, possibly linked to disease-specific structural features that limit the chaperoning capacity of CLU.

This study aimed to determine whether circulating levels of clusterin (CLU), an extracellular chaperone implicated in cholestatic and fibrotic processes, are associated with clinical parameters of post-operative BA patients and could serve as a BA biomarker. Ninety-six BA patients and 56 healthy controls were recruited. Circulating CLU levels were measured using enzyme-linked immunosorbent assay. Circulating CLU levels were significantly reduced in BA patients - especially those with worse outcomes including jaundice, severe liver fibrosis, and late-stage of hepatic dysfunction. Multivariate linear regression analysis revealed that circulating CLU levels were negatively associated with outcome parameters indicating jaundice status, degree of fibrosis, and liver dysfunction, but positively correlated with serum albumin and platelet number of BA patients. Lower circulating CLU levels were considerably associated with poor survival of post-operative BA patients. Receiver-operating characteristic curve analysis demonstrated a diagnostic value of circulating CLU as a non-invasive indicator for poor outcomes of BA patients (AUC = 0.85), with a sensitivity of 81.5% and a specificity of 73.5%. All findings indicate that reduced circulating CLU might reflect poor outcomes of BA patients and have potential as a novel biomarker for the disease severity following Kasai-operation.

Purpose: Risk stratification in chronic systolic heart failure (HF) is critical to identify the patients who may benefit from advanced therapies. It is aimed at identifying new biomarkers to improve prognosis evaluation and help to better understand HF physiopathology., Experimental Design: Prognostic evaluation is performed in 198 patients with chronic systolic HF: 99 patients who died from cardiovascular cause within three years are individually matched for age, sex, and HF etiology (ischemic vs not) with 99 patients who are alive after three years of HF evaluation. A proteomic profiling of 15 apolipoproteins (Apo) is performed: Apo-A1, -A2, -A4, -B100, -C1, -C2, -C3, -C4, -D, -E, -F, -H, -J, -L1, and -M using LC-MRM-MS., Results: In univariate analysis, the levels of Apo-B100 and -L1 are significantly lower and the levels of Apo-C1, -J, and -M are significantly higher in patients who died from cardiovascular cause as compared with patients alive. In the final statistical model, Apo-C1, Apo-J, and Apo-M improve individually the prediction of cardiovascular death. Ingenuity pathway analysis indicates these three Apo in a network associated with lipid metabolism, atherosclerosis signaling, and retinoid X receptor activation., Conclusions: Proteomic profiling of apolipoproteins using LC-MRM-MS might be useful in clinical practice for risk stratification of HF patients., (© 2020 Wiley-VCH GmbH.)

Introduction: The concept of anesthesia, in which kidney perfusion is optimized, the use of nephrotoxic drugs is avoided, and general anesthesia with protective and preconditioning properties of the graft is applied, is a key element of the therapeutic strategy in kidney transplantation (KTx)., Material and Method: A total of 86 patients (mean age: 49.4 ± 14.0 years, 66% men) with end-stage renal disease who underwent KTx between 2012 and 2015 were included in this retrospective study. Our aim was to assess the effect of oxygen content in arterial blood and selected hemodynamic parameters on the graft function and the occurrence of delayed graft failure., Results: No differences were found in baseline characteristics, indication for transplantation, and surgical technique used among study population. No correlation was found between oxygen delivery exponents and both standard markers of renal function and new biochemical markers (eg, IL-18, clusterin, and neutrophil gelatinase-associated lipocalin [NGAL])., Discussion: In our study, hemodynamic parameters measured at scheduled intervals did not exceed the physiological range, which might have been the reason for the lack of correlation between the function of graft and the described hemodynamic conditions. At the same time, in the observed ranges of perfusion pressure during optimization of the oxygen content, no correlations were found with the postoperative function of the transplanted kidney. That observation could be a valuable conclusion for reducing the tendency of maintaining high blood pressure with the abuse of catecholamines, especially vasoconstrictors, and volume therapy, whose negative effect on tissue perfusion is unequivocal., (Copyright © 2020 Elsevier Inc. All rights reserved.)

To explore plasma protein panels as potential biomarkers to screen for mild cognitive impairment (MCI) among elderly Chinese individuals with different educational backgrounds. Forty-four illiterate, 36 lower education (1-6 years), and 55 higher education (7 years or more) elderly individuals were included in the present study. Among all subjects, 67 were healthy individuals and 68 were diagnosed with MCI. Fifty plasma proteins in blood samples collected from these subjects were analyzed via the Luminex assay. Binary logistic regression was utilized to explore diagnostic models for MCI among the three educational subgroups. Then, receiver operating characteristic (ROC) curves were conducted for the clinical validity of the MCI models. Among the analyzed proteins, clusterin was used in the model of MCI among the total sample with a sensitivity (se) of 67.6%, a specificity (sp) of 59.7%, and a classification rate of 63.68%. The MCI model for the illiterate group included cystatin C, plasminogen activator inhibitor-1, and apolipoprotein A-I (se: 71.4%, sp.: 82.6%, accuracy: 77.25%). The sensitivity, specificity, and classification rate of the diagnostic model of MCI in elderly adults with lower education (human serum albumin) were each 75.0%. Additionally, the sensitivity, specificity, and accuracy rate of the diagnostic model for MCI elderly individuals with higher education (alpha-acid glycoprotein + soluble intercellular adhesion molecule-1 + pancreatic polypeptide) were 77.8%, 89.3%, and 83.60%, respectively. The performance of diagnostic models for MCI based on different educational levels is superior to that of diagnostic models for MCI without grouping by educational level.

The aim of the present study was to (1) investigate the relationship between late-onset Alzheimer's disease (AD) and DNA methylation levels in six of the top seven AD-associated genes identified through a meta-analysis of recent genome wide association studies, APOE, BIN1, PICALM, CR1, CLU, and ABCA7, in blood, and (2) examine its applicability to the diagnosis of AD. We examined methylation differences at CpG island shores in the six genes using Sanger sequencing, and one of two groups of 48 AD patients and 48 elderly controls was used for a test or replication analysis. We found that methylation levels in three out of the six genes, CR1, CLU, and PICALM, were significantly lower in AD subjects. The combination of CLU methylation levels and the APOE genotype classified AD patients with AUC = 0.84 and 0.80 in the test and replication analyses, respectively. Our study implicates methylation differences at the CpG island shores of AD-associated genes in the onset of AD and suggests their diagnostic value., Competing Interests: The authors have declared that no competing interests exist. K.S. is affiliated with Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: Plasma clusterin, a promising biomarker of Alzheimer disease (AD), has been associated with diabetes mellitus (DM). However, clusterin has not been investigated considering a relationship with both DM and AD. In this study, we aimed to investigate the individual and interactive relationships of plasma clusterin levels with both diseases., Design: Cross-sectional observation study., Methods: We classified participants by the severity of cognitive (normal cognition, mild cognitive impairment [MCI], and AD) and metabolic (healthy control, prediabetes, and DM) impairments. We evaluated the cognitive and metabolic functions of the participants with neuropsychological assessments, brain magnetic resonance imaging, and various blood tests, to explore potential relationships with clusterin., Results: Plasma clusterin levels were higher in participants with AD and metabolic impairment (prediabetes and DM). A two-way ANCOVA revealed no synergistic, but an additive effect of AD and DM on clusterin. Clusterin was negatively correlated with cognitive scores. It was also associated with metabolic status indicated by glycated hemoglobin A1c (HbA1c), the Homeostatic Model Assessment for Insulin Resistance index, and fasting C-peptide. It showed correlations between medial temporal atrophy and periventricular white matter lesions, indicating neurodegeneration and microvascular insufficiency, respectively. Further mediation analysis to understand the triadic relationship between clusterin, AD, and DM revealed that the association between DM and AD was significant when clusterin is considered as a mediator of their relationship., Conclusions: Clusterin is a promising biomarker of DM as well as of AD. Additionally, our data suggest that clusterin may have a role in linking DM with AD as a potential mediator., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Clusterin (CLU), also known as apolipoprotein J, is a widely expressed, heterodimeric, glycoprotein, important in tumourigenesis, apoptosis and immunoregulation. In humans, CLU expression has been associated with anaplastic large cell and Hodgkin's lymphoma. In this study, serum CLU levels in dogs with multicentric lymphoma (MLSA) were compared with healthy control dogs, using both western blot and enzyme-linked immunosorbent assay (ELISA). Western blot confirmed the presence of CLU in dog sera at the predicted molecular weight and the relative levels detected correlated with the levels detected by ELISA. CLU level analysis by ELISA found treatment naïve dogs with MLSA had a significantly (P < .001) lower serum CLU level compared with healthy controls. However, there was no significant difference between MLSA dogs prior to treatment and in complete remission. The wide variation in serum CLU levels may limit its potential as a single candidate biomarker for MLSA, although any prognostic predictive value of serum CLU concentrations has yet to be assessed., (© 2019 John Wiley & Sons Ltd.)

Objective: Cerebral microbleeds (CMBs) are associated with higher risk of stroke and dementia, predating clinical diagnosis by several years. CMB are considered markers of cerebral small vessel disease (CSVD): hypertensive (deep CMB) and cerebral amyloid angiopathy (lobar CMB). We related plasma β-Amyloid (40, 42 and their ratio), clusterin, and tau levels to CMB to elucidate their role as biomarkers for the angiopathies represented by CMB., Methods: Dementia, stroke, and other neurological disease-free Framingham Heart Study participants with available CMB and biomarker measurements were included. We related biomarker levels (standardized for analyses) to CMB presence overall and stratified by brain topography (any, lobar, deep), using multivariable logistic regression analyses., Results: CMB were observed in 208 (5.7%) participants (mean age 57 years, 54% women). After multivariable adjustment, Aβ1-40 was associated with any CMB (OR (95%CI) 1.20 (0.99, 1.45) P = 0.062)) and lobar CMB (OR (95%CI) 1.33 (1.05, 1.68) P = 0.019), but not with deep CMB. Log-Aβ1-42 levels were not associated with CMB overall. Clusterin was related to mixed CMB (1.70 [1.05, 2.74], P = 0.031). Tau levels were associated with any CMB (OR (95%CI) 1.26 (1.07, 1.49) P = 0.006), lobar CMB (OR (95%CI) 1.26 (1.05, 1.52) P = 0.013), and with deep CMB (OR (95% CI) 1.46 (1.13, 1.89) P = 0.004)., Interpretation: We found that plasma Aβ1-40 and Tau are associated with CMB but further studies are needed to confirm their role in hemorrhage prone CSVD represented by CMB and as indicators of ongoing subclinical neuronal injury., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Clusterin exerts anti-inflammatory, cytoprotective and anti-apoptotic effects. Both an increase and decrease of clusterin in acute myocardial infarction (AMI) has been reported. We aimed to clarify the role of clusterin as a systemic biomarker in AMI. AMI was induced by percutaneous left anterior artery (LAD) occlusion for 90 min followed by reperfusion in 24 pigs. Contrast ventriculography was performed after reperfusion to assess left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV) and left ventricular end systolic volume (LVESV) and additional cMRI + late enhancement to measure infarct size and LV functions at day 3 and week 6 post-MI. Blood samples were collected at prespecified timepoints. Plasma clusterin and other biomarkers (cTnT, NT-proBNP, neprilysin, NGAL, ET-1, osteopontin, miR21, miR29) were measured by ELISA and qPCR. Gene expression profiles of infarcted and remote region 3 h ( n = 5) and 3 days ( n = 5) after AMI onset were analysed by RNA-sequencing. AMI led to an increase in LVEDV and LVESV during 6-week, with concomitant elevation of NT-proBNP 3-weeks after AMI. Plasma clusterin levels were increased immediately after AMI and returned to normal levels until 3-weeks. Plasma NGAL, ET-1 and miR29 was significantly elevated at 3 weeks follow-up, miR21 increased after reperfusion and at 3 weeks post-AMI, while circulating neprilysin levels did not change. Elevated plasma clusterin levels 120 min after AMI onset suggest that clusterin might be an additional early biomarker of myocardial ischemia., Competing Interests: The authors declare no conflict of interest.

Background: Cerebral malaria (CM), is a life-threatening childhood malaria syndrome with high mortality. CM is associated with impaired consciousness and neurological damage. It is not fully understood, as yet, why some children develop CM. Presented here is an observation from longitudinal studies on CM in a paediatric cohort of children from a large, densely-populated and malaria holoendemic, sub-Saharan, West African metropolis., Methods: Plasma samples were collected from a cohort of children with CM, severe malarial anaemia (SMA), uncomplicated malaria (UM), non-malaria positive healthy community controls (CC), and coma and anemic patients without malaria, as disease controls (DC). Proteomic two-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry were used in a discovery cohort to identify plasma proteins that might be discriminatory among these clinical groups. The circulatory levels of identified proteins of interest were quantified by ELISA in a prospective validation cohort., Results: The proteome analysis revealed differential abundance of circulatory complement-lysis inhibitor (CLI), also known as Clusterin (CLU). CLI circulatory level was low at hospital admission in all children presenting with CM and recovered to normal level during convalescence (p < 0.0001). At acute onset, circulatory level of CLI in the CM group significantly discriminates CM from the UM, SMA, DC and CC groups., Conclusions: The CLI circulatory level is low in all patients in the CM group at admission, but recovers through convalescence. The level of CLI at acute onset may be a specific discriminatory marker of CM. This work suggests that CLI may play a role in the pathophysiology of CM and may be useful in the diagnosis and follow-up of children presenting with CM.

Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity.

Thoracic aortic aneurysm (TAA), a serious cardiovascular disease that causes morbidity and mortality worldwide. At present, few biomarkers can accurately diagnose the appearance of TAA before dissection or rupture. Our research has the intention to investigate the developing applicable biomarkers for TAA promising clinically diagnostic biomarkers or probable regulatory targets for TAA. In our research, we built correlation networks utilizing the expression profile of peripheral blood mononuclear cell obtained from a public microarray data set (GSE9106). Furthermore, we chose the turquoise module, which has the strongest significance with TAA and was further analyzed. Fourteen genes that overlapped with differentially expressed proteins in the medial aortic layer were obtained. Subsequently, we verified the results applying quantitative polymerase chain reaction (Q-PCR) to our clinical specimen. In general, the Q-PCR results coincide with the majority of the expression profile. Fascinatingly, a notable change occurred in CLU, DES, MYH10, and FBLN5. In summary, using weighted gene coexpression analysis, our study indicates that CLU, DES, MYH10, and FBLN5 were identified and validated to be related to TAA and might be candidate biomarkers or therapeutic targets for TAA., (© 2019 Wiley Periodicals, Inc.)

Aim: To explore the prognostic value of clusterin (CLU) in hepatocellular carcinoma (HCC) patients treated with oxaliplatin (OXA)., Methods: Relative expression of plasma CLU mRNA was examined via fluorescence quantitative real-time PCR (qRT-PCR), and CLU protein level in tissue samples was detected through immunohistochemistry. Chi-square test was used to analyze the relationship between CLU mRNA expression and clinical features of HCC patients treated with OXA. Kaplan-Meier method was performed to assess overall survival for the patients, and prognostic value of CLU in HCC patients was estimated via Cox regression analysis., Results: CLU expression in plasma and tissue specimens was significantly higher among HCC patients than in non-malignant controls (P < 0.001 for both). Moreover, elevated CLU mRNA was closely related to tumor stage, lymph node metastasis and response to OXA (P < 0.05). HCC patients with high CLU expression showed poor response to OXA. In addition, low CLU levels predicted long overall survival time among the study subjects (20.8 vs. 36.6 months, P < 0.001). CLU was an independent prognostic indicator for HCC patients treated with OXA (HR = 2.587, 95%CI = 1.749-3.828, P < 0.001)., Conclusion: CLU may be a novel prognostic marker for HCC patients treated with OXA., (© 2020 The Author(s).)

We investigated the neuroprotective effects of baicalin and the role of gut microbiota in a mouse model of cerebral ischemia-reperfusion injury. Repeated cerebral ischemia-reperfusion significantly increased plasma levels of trimethylamine (TMA), trimethylamine- N -oxide (TMAO), and clusterin (a neuroinflammation biomarker). These changes correlated with cognitive decline; short-term memory deficits; abnormal long term potentiation (LTP); decreased functional connectivity (FC) between various brain regions; reduced plasticity and dendritic spine density in the hippocampus; increased levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNFα; and altered the gut microbial composition. Treatment with 50-100 mg/Kg baicalin for 7 days after cerebral ischemia-reperfusion significantly restored normal plasma levels of TMA, TMAO, and clusterin. Baicalin treatment also suppressed neuroinflammation, remodeled the gut microbial composition back to normal, and improved cognition, memory, LTP, cerebral FC, and hippocampal neuronal plasticity. The neuroprotective effects of baicalin were diminished when mice undergoing repeated cerebral ischemia-reperfusion were pretreated with broad-spectrum antibiotics to deplete gut microbial populations. This suggests the neuroprotective effects of baicalin in cerebral ischemia-reperfusion injury are mediated by the gut microbiota. It thus appears that baicalin ameliorates neuropathology in a repeated cerebral ischemia-reperfusion model mice by remodeling the gut microbiota.

Background: Circulating apolipoprotein J (ApoJ) is closely associated with insulin resistance; however, the effect of exercise on circulating ApoJ levels and the association of ApoJ with metabolic indices remain unknown. Here, we investigated whether a combined exercise can alter the circulating ApoJ level, and whether these changes are associated with metabolic indices in patients with type 2 diabetes mellitus., Methods: Postmenopausal women with type 2 diabetes mellitus were randomly assigned into either an exercise (EXE, n =30) or control (CON, n =15) group. Participants in the EXE group were enrolled in a 12-week program consisting of a combination of aerobic and resistance exercises. At baseline, 4, 8, and 12 weeks, body composition and metabolic parameters including homeostatic model assessment of insulin resistance (HOMA-IR) and serum ApoJ levels were assessed., Results: In the EXE group, ApoJ levels decreased 26.3% and 19.4%, relative to baseline, at 8 and 12 weeks, respectively. Between-group differences were significant at 8 and 12 weeks ( P <0.05 and P <0.001, respectively). In the EXE group, 12 weeks of exercise resulted in significant decreases in body weight, percent body fat, and HOMA-IR indices. Concurrently, weight-adjusted appendicular skeletal muscle mass (ASM/wt) was increased in the EXE group compared with the CON group. Importantly, changes in the ApoJ level were significantly correlated with changes in ASM/wt., Conclusion: Exercise training resulted in a significant decrease in the circulating ApoJ level, with changes in ApoJ associated with an improvement in some insulin resistance indices. These data suggest that circulating ApoJ may be a useful metabolic marker for assessing the effects of exercise on insulin resistance., Competing Interests: This work was supported by grants from the National Institutes of Health (R01DK111529 and R01DK106076 to Young-Bum Kim), R&D project grant from Yuhan pharmaceutical corporation (to Sang Soo Kim) and National Research Foundation of Korea (2018R1C1B6002854 to Sang Soo Kim)., (Copyright © 2020 Korean Diabetes Association.)

Progress in the preclinical and clinical development of neuroprotective and antiepileptogenic treatments for traumatic brain injury (TBI) necessitates the discovery of prognostic biomarkers for post-injury outcome. Our previous mRNA-seq data revealed a 1.8-2.5 fold increase in clusterin mRNA expression in lesioned brain areas in rats with lateral fluid-percussion injury (FPI)-induced TBI. On this basis, we hypothesized that TBI leads to increases in the brain levels of clusterin protein, and consequently, increased plasma clusterin levels. For evaluation, we induced TBI in adult male Sprague-Dawley rats (n = 80) by lateral FPI. We validated our mRNA-seq findings with RT-qPCR, confirming increased clusterin mRNA levels in the perilesional cortex (FC 3.3, p < 0.01) and ipsilateral thalamus (FC 2.4, p < 0.05) at 3 months post-TBI. Immunohistochemistry revealed a marked increase in extracellular clusterin protein expression in the perilesional cortex and ipsilateral hippocampus (7d to 1 month post-TBI), and ipsilateral thalamus (14d to 12 months post-TBI). In the thalamus, punctate immunoreactivity was most intense around activated microglia and mitochondria. Enzyme-linked immunoassays indicated that an acute 15% reduction, rather than an increase in plasma clusterin levels differentiated animals with TBI from sham-operated controls (AUC 0.851, p < 0.05). Our findings suggest that plasma clusterin is a candidate biomarker for acute TBI diagnosis.

The complement system is now a therapeutic target for the management of serious and life-threatening conditions such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, glomerulonephritis and other diseases caused by complement deficiencies or genetic variants. As complement therapeutics expand into more clinical conditions, monitoring complement activation is increasingly important, as is the baseline levels of complement activation fragments in blood or other body fluid levels. Although baseline complement levels have been reported in the literature, the majority of these data were generated using non-standard assays and with variable sample handling, potentially skewing results. In this study, we examined the plasma and serum levels of the soluble membrane attack complex of complement (sMAC). sMAC is formed in the fluid phase when complement is activated through the terminal pathway. It binds the regulatory proteins vitronectin and/or clusterin and cannot insert into cell membranes, and can serve as a soluble diagnostic marker in infectious disease settings, as previously shown for intraventricular shunt infections. Here we show that in healthy adults, serum sMAC levels were significantly higher than those in plasma, that plasma sMAC levels were similar between in African Americans and Caucasians and that plasma sMAC levels increase with age. Plasma sMAC levels were significantly higher in virally suppressed people living with HIV (PLWH) compared to non-HIV infected healthy donors. More specifically, PLWH with CD4 + T cell counts below 200 had even greater sMAC levels, suggesting diagnostic value in monitoring sMAC levels in this group., (© 2019 British Society for Immunology.)

Objective: Clinical evidence has linked low HDL (high-density lipoprotein) cholesterol levels with high cardiovascular disease risk; however, its significance as a therapeutic target remains unestablished. We hypothesize that HDLs functional heterogeneity is comprised of metabolically distinct proteins, each on distinct HDL sizes and that are affected by diet. Approach and Results: Twelve participants were placed on 2 healthful diets high in monounsaturated fat or carbohydrate. After 4 weeks on each diet, participants completed a metabolic tracer study. HDL was isolated by Apo (apolipoprotein) A1 immunopurification and separated into 5 sizes. Tracer enrichment and metabolic rates for 8 HDL proteins-ApoA1, ApoA2, ApoC3, ApoE, ApoJ, ApoL1, ApoM, and LCAT (lecithin-cholesterol acyltransferase)-were determined by parallel reaction monitoring and compartmental modeling, respectively. Each protein had a unique, size-specific distribution that was not altered by diet. However, carbohydrate, when replacing fat, increased the fractional catabolic rate of ApoA1 and ApoA2 on alpha3 HDL; ApoE on alpha3 and alpha1 HDL; and ApoM on alpha2 HDL. Additionally, carbohydrate increased the production of ApoC3 on alpha3 HDL and ApoJ and ApoL1 on the largest alpha0 HDL. LCAT was the only protein studied that diet did not affect. Finally, global proteomics showed that diet did not alter the distribution of the HDL proteome across HDL sizes., Conclusions: This study demonstrates that HDL in humans is composed of a complex system of proteins, each with its own unique size distribution, metabolism, and diet regulation. The carbohydrate-induced hypercatabolic state of HDL proteins may represent mechanisms by which carbohydrate alters the cardioprotective properties of HDL.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a neurological complication of primary Sjögren's syndrome (pSS). Objective: We aimed to explore potential serological differences between pSS patients with and without NMOSD. Methods: There were 4 pSS patients with NMOSD and 8 pSS patients without NMOSD enrolled as the screening group for two-dimensional difference gel electrophoresis (DIGE) analysis. Then differential expressed protein spots between groups were identified by MALDI-TOF/TOF MS. The levels of the identified potential biomarkers were verified by ELISA in a second independent cohort including 22 pSS patients with NMOSD, 26 pSS without NMOSD and 30 NMOSD patients. Results: Nine proteins were identified significantly differently expressed (more than 1.5-fold, p < 0.05) between these two groups. Serum levels of clusterin and complement factor H (CFH) were further verified by ELISA. Results showed that the serum clusterin was significantly higher in NMOSD with pSS than without (298.33 ± 184.52 vs. 173.49 ± 63.03 ng/ml, p < 0.01), while the levels of CFH were lower in pSS patients with NMOSD than without (24.19 ± 1.79 vs. 25.87 ± 3.98 ng/ml, p < 0.01). Conclusion: This is the first study of serological comparative proteomics between pSS patients with and without NMOSD. Serum clusterin and CFH might be potential biomarkers for pSS patients with NMOSD and play important role in the pathogenesis of the disease but needs further verification., (Copyright © 2019 Qiao, Deng, Wang, Zhang, Fei, Xu, Zhao and Li.)

Several biomarkers have been studied to diagnose or to detect the phenotype of asthma. Clusterin is a sensitive cellular biosensor of oxidative stress and has been studied as a biomarker for inflammatory diseases. We aimed to study serum clusterin level in atopic versus non-atopic childhood asthma and its relation to disease severity. This case-control study included 160 children; 120 stable asthmatic children and 40 apparently healthy children. Asthmatic children were further subdivided into atopic and non-atopic. All children were subjected to medical history taking, clinical examination, and laboratory investigations including complete blood count, serum IgE, serum clusterin level and spirometry before and after bronchodilator therapy. In comparison to controls, patients had significantly higher eosinophils count which was higher in atopic than non-atopic group, also serum IgE level was higher in the atopic asthmatics (118.1 ± 16.2 U/ml) than in both the non-atopic asthmatics (81.2 ± 6.1 U/ml) and the controls (76.3 ± 11.6 U/ml). There was statistical significant difference in serum levels of Clusterin which were highest in the atopic group (182.5 ± 33.5 ng/l), followed by the non-atopic patients (127.5 ± 32.5 ng/l) and lowest in the controls (46.09 ± 7.01 ng/l). Moreover, the higher the severity of asthma, the higher was the level of serum clusterin. In conclusion serum level of clusterin was higher in atopic than non-atopic asthmatic children and it increases significantly with increased severity of the disease.

Ischemic stroke is a devastating neurological disease that can cause permanent brain damage, but to date, few biomarkers are available to reliably assess the severity of injury during acute onset. In this study, quantitative proteomic analysis of ischemic mouse brain detected the increase in expression levels of clusterin (CLU) and cystatin C (CST3). Since CLU is a secretary protein, serum samples (n = 70) were obtained from acute ischemic stroke (AIS) patients within 24 h of stroke onset and together with 70 matched health controls. Analysis of CLU levels indicated significantly higher levels in AIS patients than healthy controls (14.91 ± 4.03 vs. 12.79 ± 2.22 ng/L; P = 0.0004). Analysis of serum CST3 also showed significant increase in AIS patients as compared with healthy controls (0.90 ± 0.19 vs. 0.84 ± 0.12 ng/L; P = 0.0064). The serum values of CLU were also positively correlated with the NIH Stroke Scale (NIHSS) scores, the time interval after stroke onset, as well as major stroke risk factors associated with lipid profile. These data demonstrate that elevated levels of serum CLU and CST3 are independently associated with AIS and may serve as peripheral biomarkers to aid clinical assessment of AIS and its severity. This pilot study thus contributes to progress toward preclinical proteomic screening by using animal models and allows translation of results from bench to bedside.

Introduction: Carotid endarterectomy (CEA) is a surgical procedure used in the prevention of ischemic stroke. However, this procedure can cause complications of ischemia-reperfusion injury to the brain. Clusterin (CLU) is a cytoprotective chaperone protein that is released from neurons in response to various neurological injuries. The objective of the study was to report the changes in serum CLU concentrations of patients undergoing CEA. Materials and methods: The study involved 25 patients with severe internal carotid artery stenosis. Serum samples were taken from patients at three different times: within 24 hours preoperatively to CEA, 12 hours postoperatively, and 48 hours postoperatively. Serum CLU concentrations were measured using a commercially available enzyme-linked immunosorbent assay. Results: When compared to concentrations preoperatively, the serum CLU concentration initially decreased during the 12 hours following CEA. However, 48 hours following the procedure there was an increase in the CLU concentration. After statistical analysis, differences were detected in serum CLU concentration between all three recorded measurements ( P  < 0.05). Conclusion: Data from our study indicate that serum CLU concentrations are affected after CEA. We hypothesize that serum CLU concentrations may depend on brain ischemia-reperfusion injury following this surgical procedure.

Aim: Assessment of the feasibility and reliability of immune-inflammatory biomarker measurements. Methods: The following biomarkers were assessed in 207 predominantly healthy participants at baseline and after 4 months: MMF, TGF-β, suPAR and clusterin. Results: Intraclass correlation coefficients (95% CIs) ranged from good for TGF-β (0.75 [95% CI: 0.33-0.90]) to excellent for MMF (0.81 [95% CI: 0.64-0.90]), clusterin (0.83 [95% CI: 0.78-0.87]) and suPAR (0.91 [95% CI: 0.88-0.93]). Measurement of TGF-β was challenged by the large number of values below the detection limit. Conclusion: Single measurements of suPAR, clusterin and MMF could serve as feasible and reliable biomarkers of immune-inflammatory pathways in biomedical research.

Background: Clusterin plays an important role in the cardiovascular system, and serum levels of clusterin are higher in coronary artery disease patients. Here, we measured serum clusterin levels in premature coronary artery disease (PCAD) patients and explored the association of these levels with PCAD risk., Methods: Serum samples and general clinical information were obtained from 672 subjects including 364 PCAD subjects, 126 non-PCAD subjects, and 182 controls., Results: Serum clusterin levels were higher in PCAD patients than in controls, particularly in males with body mass index (BMI) < 25 kg/m 2 (P < 0.0001). Compared with the lowest tertile of clusterin, the odds ratio of PCAD in the highest tertile was higher in both a univariate and three adjustment models, and it was 3.146-fold higher in Model 3. This association was especially significant in subgroups with BMI < 25 kg/m 2 , total cholesterol < 5.7 mmol/L, high-density lipoprotein cholesterol ≥ 1.0 mmol/L, Urea < 7.14 mmol/L, and estimated glomerular filtration rate < 90 mL/min/1.73 m 2 . Serum clusterin may be a potential diagnostic biomarker for PCAD (sensitivity 60.7%, specificity 51.6%, area under the curve 0.595 [95% CI, 0.544-0.647], P < 0.0001), and a combination of clusterin with clinical variables in Model 3 resulted in improved diagnostic accuracy (sensitivity 86.3%, specificity 64.2%, area under the curve 0.829 [95% CI, 0.782-0.877], P < 0.0001)., Conclusions: Serum clusterin levels were increased in PCAD patients, especially for males with BMI < 25 kg/m 2 . Higher clusterin levels were independently associated with the presence of PCAD, particularly in subjects with normal BMI, lower total cholesterol, urea, estimated glomerular filtration rate, and higher high-density lipoprotein cholesterol. Clusterin might be a potential diagnostic biomarker for PCAD patients, especially in combination with clinical variables., (© 2019 John Wiley & Sons, Ltd.)

Background: Plasma clusterin has been reported to be associated with the pathology, prevalence, severity, and rapid clinical progress of Alzheimer's Disease (AD). However, whether plasma clusterin can be used as a biomarker of AD is inconsistent and even conflicting., Objective: We conducted this study to evaluate the potential of plasma clusterin as the biomarker of AD., Method: PubMed, Embase, and Cochrane databases were systematically searched for studies on the relationship between plasma clusterin levels and AD diagnosis, risk and disease severity. We also compared the difference in Cerebrospinal Fluid (CSF) clusterin levels between AD and control groups. We converted and pooled data using standardized mean difference, Pearson linear regression model and the Cox regression model., Results: A total of 17 articles and 7228 individuals, including 1936 AD were included. The quality ranged from moderate to high. There was no difference in plasma clusterin between AD and control groups (SMD= 0.19 [-0.10, 0.48], p=0.20). Plasma clusterin levels were not correlated with the risk (RR=1.03 [0.97-1.09], p=0.31), the MMSE scores (R=0.33 [-0.06, 0.71], p= 0.09), and the integrated neuropsychological measurements (R=0.21 [-0.20, 0.63], p=0.31) of AD. Additionally, there was no difference in CSF clusterin between AD and control groups (SMD=1.94 [ -0.49, 4.37], p=0.12)., Conclusion: Our meta-analysis suggested no relationship between plasma clusterin levels and the diagnosis, risk, and disease severity of AD and no difference in the CSF clusterin between AD and the control groups. Overall, there is no evidence to support plasma clusterin as a biomarker of AD based on the pooled results., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Oxidative stress plays a pivotal and early role in the pathophysiology of Alzheimer's disease (AD). There is convincing evidence that oxidative alterations in AD and in mild cognitive impairment (MCI) patients are not limited to the brain but are extended to the blood compartment. However, the oxidative pattern in plasma is still inconclusive. Moreover, their potential association with the clinical scores MMSE (Mini-Mental State Examination) and MoCA (Montreal Cognitive Assessment) is poorly investigated. The aim of our study was to establish a pattern of blood-based redox alterations in prodromal AD and their evolution during the progression of the disease. Our results showed a reduction in the total antioxidant capacity (TAC) and an increase of the stress-response proteins apolipoprotein J (ApoJ) and Klotho in MCI subjects. For the first time, we evidenced circulating-proteasome activity. We found that the alteration of the circulating-proteasome activity is associated with the accumulation of oxidized proteins in plasma form early AD. Interestingly, the TAC, the levels of vitamin D and the activity of proteasome were positively associated to the clinical scores MMSE and MoCA. The levels of protein carbonyls and of ApoJ were negatively associated to the MMSE and MoCA scores. The levels of apolipoprotein D (ApoD) were not different between groups. Interestingly, the receiver operating characteristic (ROC) curves analysis indicated that these redox markers provide a fair classification of different groups with high accuracy. Overall, our results strengthen the notion that some specific oxidative markers could be considered as non-invasive blood-based biomarkers for an early MCI diagnosis and AD progression., (Copyright © 2018. Published by Elsevier Inc.)

Canagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor that is currently available for the management of type 2 diabetes mellitus. The present study investigated the effect of canagliflozin on cisplatin (CP)-induced nephrotoxicity in mice. The animals were divided into four groups (n = 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) cisplatin (20 mg/kg) on day 7, respectively. The third and fourth groups were given a single intraperitoneal (i.p.) injection of CP (20 mg/kg) on day 7 and canagliflozin (10 mg/kg/day) and (30 mg/kg/day), for 10 days, respectively. At day 11, animals were anesthetized and blood collected and kidneys were removed. CP significantly increased the plasma urea, creatinine, cystatin C, and clusterin concentrations and neutrophil gelatinase-associated lipocalin (NGAL) activity. In addition, CP increased urinary albumin/creatinine ratio, N-acetyl-β-D-glucosaminidase (NAG) activity, and liver-type fatty acid-binding protein (L-FABP) concentrations and reduced creatinine clearance. CP also significantly increased the plasma concentration of inflammatory cytokines [plasma tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1β)] and significantly reduced antioxidant indices [catalase, glutathione reductase (GR), and superoxide dismutase (SOD)]. Histopathologically, CP caused a remarkable renal damage compared with control. Canagliflozin significantly ameliorated CP-induced biochemical and histopathological changes. The protective effect of canagliflozin is most likely due to anti-inflammatory and antioxidant effects. Our results show that administration of canagliflozin reversed the biochemical and histopathological indices of CP-induced nephrotoxicity in mice.