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Frontiers in Immunology 2023The human 25-kDa Lipocalin 2 (LCN2) was first identified and purified as a protein that in part is associated with gelatinase from neutrophils. This protein shows a high... (Review)
Review
The human 25-kDa Lipocalin 2 (LCN2) was first identified and purified as a protein that in part is associated with gelatinase from neutrophils. This protein shows a high degree of sequence similarity with the deduced sequences of rat α-microglobulin-related protein and the mouse protein 24p3. Based on its typical lipocalin fold, which consists of an eight-stranded, anti-parallel, symmetrical β-barrel fold structure it was initially thought that LCN2 is a circulating protein functioning as a transporter of small lipophilic molecules. However, studies in null mice have shown that LCN2 has bacteriostatic properties and plays a key role in innate immunity by sequestering bacterial iron siderophores. Numerous reports have further shown that LCN2 is involved in the control of cell differentiation, energy expenditure, cell death, chemotaxis, cell migration, and many other biological processes. In addition, important roles for LCN2 in health and disease have been identified in null mice and multiple molecular pathways required for regulation of expression have been identified. Nevertheless, although six putative receptors for LCN2 have been proposed, there is a fundamental lack in understanding of how these cell-surface receptors transmit and amplify LCN2 to the cell. In the present review we summarize the current knowledge on LCN2 receptors and discuss inconsistencies, misinterpretations and false assumptions in the understanding of these potential LCN2 receptors.
Topics: Humans; Mice; Animals; Rats; Lipocalin-2; Lipocalins; Membrane Transport Proteins; Cell Death; Cell Differentiation; Mice, Knockout
PubMed: 37638032
DOI: 10.3389/fimmu.2023.1229885 -
Annals of Medicine Dec 2023Beta-2-microglobulin (B2M), cystatin C and lipocalin-2 (LCN-2) are established renal biomarkers, yet their roles in stroke have not been fully evaluated. We aimed to...
INTRODUCTION
Beta-2-microglobulin (B2M), cystatin C and lipocalin-2 (LCN-2) are established renal biomarkers, yet their roles in stroke have not been fully evaluated. We aimed to investigate the relationship of B2M, cystatin C, and LCN-2 with stroke risk in a general Chinese population.
METHODS
We used ordinal regression to study the relationship between serum B2M, cystatin C, and LCN-2 with stroke risk in 1060 participants (mean age 45.4 ± 10.8 years, 46% male) from the Shenzhen-Hong Kong United Network on Cardiovascular Disease (SHUN-CVD) study. Stroke risk was classified into low-risk, middle-risk and high-risk groups according to the China National Stroke Screening Survey criteria. Serum biomarker levels were measured using immunoturbidimetric assays. Participants with valid data on serum biomarker levels and stroke risk were included in the analysis.
RESULTS
The number of participants in the low-risk, middle-risk and high-risk stroke risk groups were 663, 143 and 254 respectively. Elevated serum B2M, cystatin C, and LCN-2 levels were associated with being male, overweight/obesity, hypertension, alcohol consumption and smoking. Serum B2M, cystatin C and LCN-2 levels were significantly associated with stroke risk in the overall population (B2M: = 0.595, < .001; cystatin C: = 3.718, < .001; LCN-2: = 0.564, < .001) after adjustment for age.
CONCLUSION
Elevated serum B2M, cystatin C and LCN-2 levels are associated with stroke risk. They may be novel biomarkers for clinicians to assess stroke risk.Key messagesSerum beta-2-microglobulin, cystatin C and lipocalin-2 levels are significantly associated with stroke risk.Beta-2-microglobulin, cystatin C and lipocalin-2 may serve as useful biomarkers for stroke risk stratification in the general population.
Topics: Humans; Male; Adult; Middle Aged; Female; Cystatin C; Lipocalin-2; East Asian People; Biomarkers; Stroke; Creatinine
PubMed: 37155257
DOI: 10.1080/07853890.2023.2203516 -
Frontiers in Nephrology 2023Dialysis patients experience 10-20 times higher cardiovascular mortality than the general population. The high burden of both conventional and nontraditional risk... (Review)
Review
Dialysis patients experience 10-20 times higher cardiovascular mortality than the general population. The high burden of both conventional and nontraditional risk factors attributable to loss of renal function can explain higher rates of cardiovascular disease (CVD) morbidity and death among dialysis patients. As renal function declines, uremic toxins accumulate in the blood and disrupt cell function, causing cardiovascular damage. Hemodialysis patients have many cardiovascular complications, including sudden cardiac death. Peritoneal dialysis puts dialysis patients with end-stage renal disease at increased risk of CVD complications and emergency hospitalization. The current standard of care in this population is based on observational data, which has a high potential for bias due to the paucity of dedicated randomized clinical trials. Furthermore, guidelines lack specific guidelines for these patients, often inferring them from non-dialysis patient trials. A crucial step in the prevention and treatment of CVD would be to gain better knowledge of the influence of these predisposing risk factors. This review highlights the current evidence regarding the influence of advanced chronic disease on the cardiovascular system in patients undergoing renal dialysis.
PubMed: 37840653
DOI: 10.3389/fneph.2023.1198560 -
Heliyon Oct 2023Cancer stands as one of the prominent global causes of death, with its incidence burden continuously increasing, leading to a substantial rise in mortality rates. Cancer... (Review)
Review
Cancer stands as one of the prominent global causes of death, with its incidence burden continuously increasing, leading to a substantial rise in mortality rates. Cancer treatment has seen the development of various strategies, each carrying its drawbacks that can negatively impact the quality of life for cancer patients. The challenge remains significant within the medical field to establish a definitive cancer treatment that minimizes complications and limitations. In the forthcoming years, exploring new strategies to surmount the failures in cancer treatment appears to be an unavoidable pursuit. Among these strategies, immunology-based ones hold substantial promise in combatting cancer and immune-related disorders. A particular subset of this approach identifies "eat me" and "Don't eat me" signals in cancer cells, contrasting them with their counterparts in non-cancerous cells. This distinction could potentially mark a significant breakthrough in treating diverse cancers. By delving into signal transduction and engineering novel technologies that utilize distinct "eat me" and "Don't eat me" signals, a valuable avenue may emerge for advancing cancer treatment methodologies. Macrophages, functioning as vital components of the immune system, regulate metabolic equilibrium, manage inflammatory disorders, oversee fibrosis, and aid in the repair of injuries. However, in the context of tumor cells, the overexpression of "Don't eat me" signals like CD47, PD-L1, and beta-2 microglobulin (B2M), an anti-phagocytic subunit of the primary histocompatibility complex class I, enables these cells to evade macrophages and proliferate uncontrollably. Conversely, the presentation of an "eat me" signal, such as Phosphatidylserine (PS), along with alterations in charge and glycosylation patterns on the cellular surface, modifications in intercellular adhesion molecule-1 (ICAM-1) epitopes, and the exposure of Calreticulin and PS on the outer layer of the plasma membrane represent universally observed changes on the surface of apoptotic cells, preventing phagocytosis from causing harm to adjacent non-tumoral cells. The current review provides insight into how signaling pathways and immune cells either stimulate or obstruct these signals, aiming to address challenges that may arise in future immunotherapy research. A potential solution lies in combination therapies targeting the "eat me" and "Don't eat me" signals in conjunction with other targeted therapeutic approaches. This innovative strategy holds promise as a novel avenue for the future treatment of cancer.
PubMed: 37822610
DOI: 10.1016/j.heliyon.2023.e20507 -
American Journal of Kidney Diseases :... Dec 2023Older adults represent nearly half of all hospitalized patients and are vulnerable to inappropriate dosing of medications eliminated through the kidneys. However, few... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE & OBJECTIVE
Older adults represent nearly half of all hospitalized patients and are vulnerable to inappropriate dosing of medications eliminated through the kidneys. However, few studies in this population have evaluated the performance of equations for estimating the glomerular filtration rate (GFR)-particularly those that incorporate multiple filtration markers.
STUDY DESIGN
Cross-sectional diagnostic test substudy of a randomized clinical trial.
SETTING & PARTICIPANTS
Adults≥65 years of age presenting to the emergency department of Copenhagen University Hospital Amager and Hvidovre in Hvidovre, Denmark, between October 2018 and April 2021.
TESTS COMPARED
Measured GFR (mGFR) determined using 99mTc-DTPA plasma clearance compared with estimated GFR (eGFR) calculated using 6 different equations based on creatinine; 3 based on creatinine and cystatin C combined; and 2 based on panels of markers including creatinine, cystatin C, β-trace protein (BTP) and/or β-microglobulin (B2M).
OUTCOME
The performance of each eGFR equation compared with mGFR with respect to bias, relative bias, inaccuracy (1-P30), and root mean squared error (RMSE).
RESULTS
We assessed eGFR performance for 106 patients (58% female, median age 78.3 years, median mGFR 62.9mL/min/1.73m). Among the creatinine-based equations, the 2009 CKD-EPI equation yielded the smallest relative bias (+4.2%). Among the creatinine-cystatin C combination equations, the 2021 CKD-EPI equation yielded the smallest relative bias (-3.4%), inaccuracy (3.8%), and RMSE (0.139). Compared with the 2021 CKD-EPI, the CKD-EPI equation yielded a smaller RMSE (0.136) but larger relative bias (-4.0%) and inaccuracy (5.7%).
LIMITATIONS
Only White patients were included; only a subset of patients from the original clinical trial underwent GFR measurement; and filtration marker concentration can be affected by subclinical changes in volume status.
CONCLUSIONS
The 2009 CKD-EPI, 2021 CKD-EPI, and CKD-EPI equations performed best and notably outperformed their respective full-age spectrum equations. The addition of cystatin C to creatinine-based equations improved performance, while the addition of BTP and/or B2M yielded minimal improvement.
FUNDING
Grants from public sector industry (Amgros I/S) and government (Capital Region of Denmark).
TRIAL REGISTRATION
Registered at ClinicalTrials.gov with registration number NCT03741283.
PLAIN-LANGUAGE SUMMARY
Inaccurate kidney function assessment can lead to medication errors, a common cause of hospitalization and early readmission among older adults. Several novel methods have been developed to estimate kidney function based on a panel of kidney function markers that can be measured from a single blood sample. We evaluated the accuracy of these new methods (relative to a gold standard method) among 106 hospitalized older adults. We found that kidney function estimates combining 2 markers (creatinine and cystatin C) were highly accurate and noticeably more accurate than estimates based on creatinine alone. Estimates incorporating additional markers such as β-trace protein and β-microglobulin did not further improve accuracy.
Topics: Humans; Female; Aged; Male; Glomerular Filtration Rate; Cystatin C; Creatinine; Cross-Sectional Studies; Renal Insufficiency, Chronic; Biomarkers
PubMed: 37516299
DOI: 10.1053/j.ajkd.2023.05.004 -
FASEB BioAdvances Nov 2023β-microglobulin (β-m) is a plasma protein derived from physiological shedding of the class I major histocompatibility complex (MHCI), causing human systemic...
β-microglobulin (β-m) is a plasma protein derived from physiological shedding of the class I major histocompatibility complex (MHCI), causing human systemic amyloidosis either due to persistently high concentrations of the wild-type (WT) protein in hemodialyzed patients, or in presence of mutations, such as D76N β-m, which favor protein deposition in the adulthood, despite normal plasma levels. Here we describe a new transgenic Caenorhabditis elegans () strain expressing human WT β-m at high concentrations, mimicking the condition that underlies dialysis-related amyloidosis (DRA) and we compare it to a previously established strain expressing the highly amyloidogenic D76N β-m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with β-m levels rather than with the presence of mutations, being more pronounced in WT β-m worms. β-m expression also has a deep impact on the nematodes' proteomic and metabolic profiles. Most significantly affected processes include protein degradation and stress response, amino acids metabolism, and bioenergetics. Molecular alterations are more pronounced in worms expressing WT β-m at high concentration compared to D76N β-m worms. Altogether, these data show that β-m is a proteotoxic protein in vivo also in its wild-type form, and that concentration plays a key role in modulating pathogenicity. Our transgenic nematodes recapitulate the distinctive features subtending DRA compared to hereditary β-m amyloidosis (high levels of non-mutated β-m vs. normal levels of variant β-m) and provide important clues on the molecular bases of these human diseases.
PubMed: 37936921
DOI: 10.1096/fba.2023-00073 -
International Journal of Molecular... Sep 2023To assess the relationship between endothelial dysfunction and serum cytokines, anti-SSA and anti-SSB antibodies, beta-2 microglobulin levels, focus score and EULAR...
To assess the relationship between endothelial dysfunction and serum cytokines, anti-SSA and anti-SSB antibodies, beta-2 microglobulin levels, focus score and EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) in primary Sjögren's syndrome (pSS) patients. The study included 90 patients with pSS and 45 healthy subjects, matched for age and gender, as controls. Serum beta-2 microglobulin, total cholesterol, HDL-cholesterol, triglycerides, TNF-α, and IL-6 were analyzed in both the groups. Patients with pSS were also tested for antinuclear antibodies, anti-SAA (anti-Sjögren's syndrome-related antigen A) antibodies, anti-SSB (anti-Sjögren syndrome related antigen B) antibodies, and focus score (the histopathologic one, based on minor salivary gland biopsy). Endothelial dysfunction was assessed by means of flow-mediated dilation (FMD) in the brachial artery. Data are presented as mean ± standard deviation. Statistical analysis was performed using the -test and the Pearson's correlation. Differences were considered to be statistically significant if the value of < 0.05. Endothelial dysfunction was identified in pSS patients ( < 0.00001). The serum levels of cytokines (TNF-α, respective IL-6) and beta-2 microglobulin were increased in pSS patients compared with controls ( < 0.00001). Endothelial dysfunction (expressed as FMD%) was correlated with focus score, ESSDAI, levels of anti-SSA and anti-SSB antibodies, beta-2 microglobulin, IL-6, and TNF-α, with statistical significance. Endothelial dysfunction is present in pSS patients and is associated with a high focus score and activity as well as increased concentrations of antibodies, pro-inflammatory cytokines, and beta 2-microglobulin.
Topics: Humans; Interleukin-6; Sjogren's Syndrome; Tumor Necrosis Factor-alpha; Vascular Diseases; Antibodies, Antinuclear; Cytokines; Biomarkers
PubMed: 37762225
DOI: 10.3390/ijms241813918 -
Toxics Jun 2023The most common causes of chronic kidney disease, diabetes, and hypertension are significant public health issues worldwide. Exposure to the heavy metal pollutant,...
The most common causes of chronic kidney disease, diabetes, and hypertension are significant public health issues worldwide. Exposure to the heavy metal pollutant, cadmium (Cd), which is particularly damaging to the kidney, has been associated with both risk factors. Increased levels of urinary β-microglobulin (βM) have been used to signify Cd-induced kidney damage and circulating levels have been linked to blood pressure control. In this study we investigated the pressor effects of Cd and βM in 88 diabetics and 88 non-diabetic controls, matched by age, gender and locality. The overall mean serum βM was 5.98 mg/L, while mean blood Cd and Cd excretion normalized to creatinine clearance (C) as E/C were 0.59 µg/L and 0.0084 µg/L of filtrate (0.95 µg/g creatinine), respectively. The prevalence odds ratio for hypertension rose by 79% per every ten-fold increase in blood Cd concentration. In all subjects, systolic blood pressure (SBP) showed positive associations with age (β = 0.247), serum βM (β = 0.230), and E/C (β = 0.167). In subgroup analysis, SBP showed a strong positive association with E/C (β = 0.303) only in the diabetic group. The covariate-adjusted mean SBP in the diabetics of the highest E/C tertile was 13.8 mmHg higher, compared to the lowest tertile ( = 0.027). An increase in SBP associated with Cd exposure was insignificant in non-diabetics. Thus, for the first time, we have demonstrated an independent effect of Cd and βM on blood pressure, thereby implicating both Cd exposure and βM in the development of hypertension, especially in diabetics.
PubMed: 37368616
DOI: 10.3390/toxics11060516