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Advanced glycation end products (AGEs) are compounds formed via non-enzymatic reactions between reducing sugars and amino acids or proteins. AGEs can accumulate in various tissues and organs and have been implicated in the development and progression of various diseases, including lung diseases. The receptor of advanced glycation end products (RAGE) is a receptor that can bind to advanced AGEs and induce several cellular processes such as inflammation and oxidative stress. Several studies have shown that both AGEs and RAGE play a role in the pathogenesis of lung diseases, such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, and acute lung injury. Moreover, the soluble form of the receptor for advanced glycation end products (sRAGE) has demonstrated its ability to function as a decoy receptor, possessing beneficial characteristics such as anti-inflammatory, antioxidant, and anti-fibrotic properties. These qualities make it an encouraging focus for therapeutic intervention in managing pulmonary disorders. This review highlights the current understanding of the roles of AGEs and (s)RAGE in pulmonary diseases and their potential as biomarkers and therapeutic targets for preventing and treating these pathologies.
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Productos Finales de Glicación Avanzada , Enfermedades Pulmonares , Receptor para Productos Finales de Glicación Avanzada , Humanos , Productos Finales de Glicación Avanzada/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Enfermedades Pulmonares/metabolismo , Animales , Estrés Oxidativo/fisiologíaRESUMEN
The early detection of gynecological cancers, which is critical for improving patient survival rates, is challenging because of the vague early symptoms and the diagnostic limitations of current approaches. This comprehensive review delves into the game-changing potential of infrared (IR) spectroscopy, a noninvasive technology used to transform the landscape of cancer diagnosis in gynecology. By collecting the distinctive vibrational frequencies of chemical bonds inside tissue samples, Fourier-transform infrared (FTIR) spectroscopy provides a 'molecular fingerprint' that outperforms existing diagnostic approaches. We highlight significant advances in this field, particularly the identification of discrete biomarker bands in the mid- and near-IR spectra. Proteins, lipids, carbohydrates, and nucleic acids exhibited different absorption patterns. These spectral signatures not only serve to distinguish between malignant and benign diseases, but also provide additional information regarding the cellular changes associated with cancer. To underscore the practical consequences of these findings, we examined studies in which IR spectroscopy demonstrated exceptional diagnostic accuracy. This review supports the use of IR spectroscopy in normal clinical practice, emphasizing its capacity to detect and comprehend the intricate molecular underpinnings of gynecological cancers.
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Neoplasias de los Genitales Femeninos , Humanos , Femenino , Neoplasias de los Genitales Femeninos/diagnóstico , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Biomarcadores de Tumor/análisis , Espectrofotometría Infrarroja/métodos , Detección Precoz del Cáncer/métodosRESUMEN
Vitamin D-binding protein (DBP), also known as Gc-globulin, is a protein that affects several physiological processes, including the transport and regulation of vitamin D metabolites. Genetic polymorphisms in the DBP gene have a significant impact on vitamin D levels and may have implications for disease risk. DBP polymorphisms are linked to differential immune responses, which could influence the onset of juvenile diseases. This narrative review examines the various roles of DBP, with a focus on bone health, immunological regulation, and lipid metabolism in children. Chronic disorders affected by DBP polymorphisms include bone abnormalities, autoimmune diseases, cardiovascular issues, childhood asthma, allergies, cystic fibrosis, acute liver failure, celiac disease, inflammatory bowel disease, and chronic kidney disease. Future research should focus on identifying the processes that underpin the many roles that DBP plays and developing customized therapeutics to improve health outcomes in the juvenile population.
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Proteína de Unión a Vitamina D , Humanos , Proteína de Unión a Vitamina D/genética , Proteína de Unión a Vitamina D/metabolismo , Niño , Salud Infantil , Vitamina D/metabolismo , Metabolismo de los Lípidos , Polimorfismo GenéticoRESUMEN
Age-related macular degeneration (AMD) is an age-related disorder that is a global public health problem. The non-enzymatic Maillard reaction results in the formation of advanced glycation end products (AGEs). Accumulation of AGEs in drusen plays a key role in AMD. AGE-reducing drugs may contribute to the prevention and treatment of AGE-related disease. Fructosamine oxidase (FAOD) acts on fructosyl lysine and fructosyl valine. Based upon the published results of fructosamine 3-kinase (FN3K) and FAOD obtained in cataract and presbyopia, we studied ex vivo FAOD treatment as a non-invasive AMD therapy. On glycolaldehyde-treated porcine retinas, FAOD significantly reduced AGE autofluorescence (p = 0.001). FAOD treatment results in a breakdown of AGEs, as evidenced using UV fluorescence, near-infrared microspectroscopy on stained tissue sections of human retina, and gel permeation chromatography. Drusen are accumulations of AGEs that build up between Bruch's membrane and the retinal pigment epithelium. On microscopy slides of human retina affected by AMD, a significant reduction in drusen surface to 45 ± 21% was observed following FAOD treatment. Enzymatic digestion followed by mass spectrometry of fructose- and glucose-based AGEs (produced in vitro) revealed a broader spectrum of substrates for FAOD, as compared to FN3K, including the following: fructosyllysine, carboxymethyllysine, carboxyethyllysine, and imidazolone. In contrast to FN3K digestion, agmatine (4-aminobutyl-guanidine) was formed following FAOD treatment in vitro. The present study highlights the therapeutic potential of FAOD in AMD by repairing glycation-induced damage.
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Productos Finales de Glicación Avanzada , Degeneración Macular , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/metabolismo , Degeneración Macular/patología , Humanos , Productos Finales de Glicación Avanzada/metabolismo , Animales , Porcinos , Retina/metabolismo , Retina/efectos de los fármacos , Retina/patología , Aminoácido OxidorreductasasRESUMEN
Next to prostate-specific antigen, no biochemical biomarkers have been implemented to guide patient follow-up after primary therapy for localized prostate cancer (PCa). We evaluated the prognostic potential of urine N-glycome in terms of event-free survival (EFS) in patients undergoing primary therapy for PCa. The prognostic features of the urine N-glycosylation profile at diagnosis, assessed in 77 PCa patients, were determined in terms of EFS next to standard clinical parameters. The majority of patients were diagnosed with International Society of Urological Pathology grade ≤ 3 (82%) T1-2 tumors (79%) and without pelvic lymph node invasion (96%). The patients underwent active surveillance (14%), robot-assisted laparoscopic prostatectomy (48%), or external beam radiotherapy (37%). Decreased ratios of biantennary core-fucosylation were noted in patients who developed an event, which was linked to a shorter EFS in both the intention-to-treat cohort and all subcohort analyses. Combining the urine N-glycan biomarker with the D'Amico Risk Classification for PCa resulted in an improved nomogram for patient classification after primary therapy. The rate of urine N-glycan biantennary core-fucosylation, typically linked to more aggressive disease status, is lower in patients who eventually developed an event following primary therapy and subsequently in patients with a worse EFS. The combination of urine N-glycan biomarkers together with clinical parameters could, therefore, improve the post-therapy follow-up of patients with PCa.
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BACKGROUND: Assessing vitamin D status, typically evaluated using serum or plasma 25-hydroxy vitamin D [25(OH)D] concentration, is complex because of various influencing factors. METHODS: Seasonality significantly affects intra-individual variability in 25(OH)D levels. This variation can be addressed by employing cosinor functions that are tailored to the geographical location of the patient to correct for seasonal effects. In addition to seasonality, genetic factors, such as DBP polymorphism and body composition, particularly adiposity, play crucial roles. Dialysis patients with DBP 2-2 phenotype exhibit higher vitamin D requirements. Genotyping/phenotyping of DBP allows for better tailored vitamin D supplementation. The lipid-soluble nature of vitamin D also interacts with plasma components such as serum triglycerides, which can influence vitamin D measurements. Adiposity, which is negatively correlated with vitamin D concentration, necessitates body mass-based mathematical adjustments for accurate vitamin D assessment in subjects with extreme BMI values. CONCLUSIONS: Accordingly, vitamin D replacement therapy must be personalized, taking into account factors such as body size and seasonal variations, to effectively reach the target serum 25(OH)D concentrations.
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Estaciones del Año , Vitamina D , Humanos , Vitamina D/sangre , Vitamina D/análogos & derivados , Deficiencia de Vitamina D/sangreRESUMEN
Chronic kidney disease (CKD) is a growing health concern with a complex etiological landscape. Among the numerous factors implicated, vitamin D binding protein (VDBP) has emerged as a focal point of scientific studies because of its critical role in vitamin D metabolism and immune modulation. The relationship between VDBP and CKD reveals a complex web of molecular and biochemical details that have great potential for improving diagnostic understanding and treatment strategies for CKD. This review summarizes the multifaceted roles of VDBP, including its molecular dynamics, interactions with vitamin D, and subsequent implications for kidney function. The main focus of the discussion is how VDBP affects bone mineral homeostasis, highlighted by the dysregulation of calcium and phosphorus metabolism, which is a part of the pathophysiology of CKD. The discussion also touches on the immunomodulatory scope of VDBP and how it may reduce the chronic inflammatory environment that accompanies CKD. The diagnostic potential of VDBP as a biomarker for CKD has been rigorously examined, highlighting its capacity to improve early detection and prognostic assessment. Modification of VDBP activity has the potential to slow the course of CKD and improve patient outcomes. Furthermore, a detailed examination of the genetic polymorphisms of VDBP and their implications for CKD susceptibility and treatment responsiveness provides a perspective for personalized medical methods. Prospects for the future depend on the expansion of studies that try to understand the molecular mechanisms underlying the VDBP-CKD interaction, in addition to clinical trials that evaluate the effectiveness of VDBP-focused treatment approaches.
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Insuficiencia Renal Crónica , Proteína de Unión a Vitamina D , Vitamina D , Humanos , Proteína de Unión a Vitamina D/metabolismo , Proteína de Unión a Vitamina D/genética , Insuficiencia Renal Crónica/metabolismo , Vitamina D/metabolismo , Vitamina D/uso terapéutico , Biomarcadores/metabolismoRESUMEN
Background: Tyrosine kinase inhibitors (TKIs) are associated with kidney function deterioration. A shift is ongoing towards glomerular filtration rate (GFR) equations based on other protein markers, such as cystatin C (CSTC) and ß-trace protein (BTP). We evaluated various GFR equations for monitoring of kidney function in actively treated oncology patients. Methods: We monitored 110 patients receiving a TKI. Blood and urine were collected during therapy. Serum analysis included creatinine (Cr), CSTC and BTP; for consequent GFR determination. Urine was analysed for protein, albumin, immunoglobulin G, and α-1-microglobulin. A similar analysis was done in a patient subgroup receiving immune checkpoint inhibitors (ICI) as prior or subsequent line of therapy. Results: Cr remained constant during TKI treatment (P = 0.7753), whereas a significant decrease in CSTC (from week 2 onward, P < 0.0001) and BTP (at weeks 2 and 4, P = 0.0100) were noticed. Consequently, GFR estimations, using CSTC and/or BTP as a biochemical parameter, showed an apparent increase in GFR, whereas this was not observed for Cr-related GFR estimations. As a result, the GFR gap (ΔGFR) was significantly different from week 2 onward between Cr-based and CSTC-based GFR and between BTP-based and CSTC-based GFR. Glomerular damage was noticed with significant increase in urine protein-to-creatinine ratio, albumin-to-creatinine ratio and immunoglobulin G (all P < 0.0001). No change in α-1-microglobulin was seen. ICI treatment had no effect on Cr (P = 0.2262), CSTC (P = 0.7341), and BTP concentrations (P = 0.3592). Conclusion: GFR equations, in which CSTC is incorporated, fail to correctly estimate the GFR in oncology patients treated with TKIs. As TKI-treated patients show clear signs of glomerular injury, further assessment is needed on how to correctly monitor the kidney function in actively treated oncology patients.
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BACKGROUND: Augmented renal clearance (ARC) holds a risk of subtherapeutic drug concentrations. Knowledge of patient-, disease-, and therapy-related factors associated with ARC would allow predicting which patients would benefit from intensified dosing regimens. This study aimed to identify ARC predictors and to describe ARC time-course in critically ill children, using iohexol plasma clearance (CLiohexol) to measure glomerular filtration rate (GFR). METHODS: This is a retrospective analysis of data from the "IOHEXOL" study which validated GFR estimating formulas (eGFR) against CLiohexol. Critically ill children with normal serum creatinine were included, and CLiohexol was performed as soon as possible after pediatric intensive care unit (PICU) admission (CLiohexol1) and repeated (CLiohexol2) after 48-72 h whenever possible. ARC was defined as CLiohexol exceeding normal GFR for age plus two standard deviations. RESULTS: Eighty-five patients were included; 57% were postoperative patients. Median CLiohexol1 was 122 mL/min/1.73 m2 (IQR 75-152). Forty patients (47%) expressed ARC on CLiohexol1. Major surgery other than cardiac surgery and eGFR were found as independent predictors of ARC. An eGFR cut-off value of 99 mL/min/1.73 m2 and 140 mL/min/1.73 m2 was suggested to identify ARC in children under and above 2 years, respectively. ARC showed a tendency to persist on CLiohexol2. CONCLUSIONS: Our findings raise PICU clinician awareness about increased risk for ARC after major surgery and in patients with eGFR above age-specific thresholds. This knowledge enables identification of patients with an ARC risk profile who would potentially benefit from a dose increase at initiation of treatment to avoid underexposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179564, registered retrospectively on January 5, 2022.
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Enfermedad Crítica , Yohexol , Niño , Humanos , Creatinina , Enfermedad Crítica/terapia , Tasa de Filtración Glomerular , Pruebas de Función Renal , Estudios RetrospectivosRESUMEN
A public debate idealing with nitrogen (N) emissions is ongoing. Government reports use models in which the major N producers are agriculture and industry. Flemish NOx emission amounted to 26.4 kt N accompanied by an ammonia emission of 34.0 kt N. Major sources of Flemish N emission are agriculture (59% of total emission) and transport (21%); 95 percent of the ammonia emission is reported to come from agriculture. In this government's view, it looks like Flanders is unpopulated. In Flanders, 6,800,000 inhabitants show an average urea production of 20 g/day, or 3.65 kg N/year. This urea production eventually ends up in wastewaters as ammonia. Human urea production represents the grand total of 24.8 kl N/year. However, this contribution is made invisible in the statistics. Flemish reports mention a grand total of 33 kt/year, so Flemish numbers appear to be incomplete. Human production has not been taken into account. When calculating human N excretion in Flanders, 24.8 kt N/12.322 km2 is obtained, corresponding to an additional N load of ± 20 kg/ha. Implementing human N excretion into the calculation thoroughly changes the situation: adding human N production results in peak loads of 40 kg N/ha. The human nitrogen input is comparable with the heavily criticized contribution by agriculture. Policy should take into account the real size of the problem and not selectively focus on partial problems.
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Amoníaco , Nitrógeno , Humanos , Urea , Agricultura/métodosRESUMEN
The expansion of people speaking Bantu languages is the most dramatic demographic event in Late Holocene Africa and fundamentally reshaped the linguistic, cultural and biological landscape of the continent1-7. With a comprehensive genomic dataset, including newly generated data of modern-day and ancient DNA from previously unsampled regions in Africa, we contribute insights into this expansion that started 6,000-4,000 years ago in western Africa. We genotyped 1,763 participants, including 1,526 Bantu speakers from 147 populations across 14 African countries, and generated whole-genome sequences from 12 Late Iron Age individuals8. We show that genetic diversity amongst Bantu-speaking populations declines with distance from western Africa, with current-day Zambia and the Democratic Republic of Congo as possible crossroads of interaction. Using spatially explicit methods9 and correlating genetic, linguistic and geographical data, we provide cross-disciplinary support for a serial-founder migration model. We further show that Bantu speakers received significant gene flow from local groups in regions they expanded into. Our genetic dataset provides an exhaustive modern-day African comparative dataset for ancient DNA studies10 and will be important to a wide range of disciplines from science and humanities, as well as to the medical sector studying human genetic variation and health in African and African-descendant populations.
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ADN Antiguo , Emigración e Inmigración , Genética de Población , Lenguaje , Humanos , África Occidental , Conjuntos de Datos como Asunto , República Democrática del Congo , ADN Antiguo/análisis , Emigración e Inmigración/historia , Efecto Fundador , Flujo Génico/genética , Variación Genética/genética , Historia Antigua , Lenguaje/historia , Lingüística/historia , Zambia , Mapeo GeográficoAsunto(s)
Gotas Lipídicas , Infecciones Urinarias , Humanos , Citometría de Flujo , Urinálisis , Eritrocitos , OrinaRESUMEN
Advanced glycation end products (AGEs), by-products of glucose metabolism, have been linked to the emergence of cardiovascular disorders (CVD). AGEs can cause tissue damage in four different ways: (1) by altering protein function, (2) by crosslinking proteins, which makes tissue stiffer, (3) by causing the generation of free radicals, and (4) by activating an inflammatory response after binding particular AGE receptors, such as the receptor for advanced glycation end products (RAGE). It is suggested that the soluble form of RAGE (sRAGE) blocks ligand-mediated pro-inflammatory and oxidant activities by serving as a decoy. Therefore, several studies have investigated the possible anti-inflammatory and anti-oxidant characteristics of sRAGE, which may help lower the risk of CVD. According to the results of various studies, the relationship between circulating sRAGE, cRAGE, and esRAGE and CVD is inconsistent. To establish the potential function of sRAGE as a therapeutic target in the treatment of cardiovascular illnesses, additional studies are required to better understand the relationship between sRAGE and CVD. In this review, we explored the potential function of sRAGE in different CVD, highlighting unanswered concerns and outlining the possibilities for further investigation.
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Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismoRESUMEN
Haptoglobin (Hp) is a polymorphic protein that was initially described as a hemoglobin (Hb)-binding protein. The major functions of Hp are to scavenge Hb, prevent iron loss, and prevent heme-based oxidation. Hp regulates angiogenesis, nitric oxide homeostasis, immune responses, and prostaglandin synthesis. Genetic polymorphisms in the Hp gene give rise to different phenotypes, including Hp 1-1, Hp 2-1, and Hp 2-2. Extensive research has been conducted to investigate the association between Hp polymorphisms and several medical conditions including cardiovascular disease, inflammatory bowel disease, cancer, transplantation, and hemoglobinopathies. Generally, the Hp 2-2 phenotype is associated with increased disease risk and poor outcomes. Over the years, the Hp 2 allele has spread under genetic pressures. Individuals with the Hp 2-2 phenotype generally exhibit lower levels of CD163 expression in macrophages. The decreased expression of CD163 may be associated with the poor antioxidant capacity in the serum of subjects carrying the Hp 2-2 phenotype. However, the Hp 1-1 phenotype may confer protection in some cases. The Hp1 allele has strong antioxidant, anti-inflammatory, and immunomodulatory properties. It is important to note that the benefits of the Hp1 allele may vary depending on genetic and environmental factors as well as the specific disease or condition under consideration. Therefore, the Hp1 allele may not necessarily confer advantages in all situations, and its effects may be context-dependent. This review highlights the current understanding of the role of Hp polymorphisms in cardiovascular disease, inflammatory bowel disease, cancer, transplantation, hemoglobinopathies, and polyuria.
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OBJECTIVES: Well-standardized procedures in the pre-analytical phase of urine diagnostics is of utmost importance to obtain reliable results. We investigated the effect of different urine collection methods and the associated urine transfer tubes on urine test strip and particle results. METHODS: In total, 146 selected urine samples were subdivided into three different collection containers and subsequently transferred into its accompanying transfer tube (BD, Greiner, Sarstedt vacuum and Sarstedt aspiration). As reference, the original urine sample was directly measured on the analyser. Both chemical test strip analysis (Sysmex UC-3500) and fluorescence flow cytometry particle analysis (Sysmex UF-5000) were performed on all samples. RESULTS: No statistically significant differences in test strip results were found between the studied transfer methods. On the contrary, transfer of urine samples to the secondary tubes affected their particle counts. Clinically significant reductions in counts of renal tubular epithelial cells and hyaline casts were observed using the BD and Greiner transfer tubes and in counts of pathological casts using the BD, Greiner and Sarstedt vacuum tubes. CONCLUSIONS: The results of this study indicate that the use of urine transfer tubes may impact counts of fragile urine particles. Clinical laboratories need to be aware about the variation that urine collection methods can induce on urine particle counts.
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Células Epiteliales , Urinálisis , Humanos , Urinálisis/métodos , Citometría de Flujo/métodos , Vacio , Concienciación , OrinaAsunto(s)
Albuminuria , Urinálisis , Humanos , Creatinina/orina , Albuminuria/diagnóstico , Albuminuria/orina , AlbúminasRESUMEN
Growth differentiation factor-15 (GDF-15) is a GDF subfamily member with potential kidney protective functions. Its nephroprotective activity is associated with both inflammation downregulation and upregulation of nephroprotective factors with anti-inflammatory activity, such as Klotho in tubular cells. However, GDF-15 has diverse and partially opposing functions depending on the state of the cells and the microenvironment. Increased GDF-15 levels have been linked to an increased risk of incident chronic kidney disease and a faster decline in kidney function in various renal disorders, including diabetic nephropathy, IgA nephropathy, lupus nephritis, anti-glomerular basement membrane nephritis, primary membranous nephropathy, kidney transplantation, Fabry disease and amyloidosis. The mechanisms underlying these effects are not yet fully understood. In this review, we will summarize GDF-15's potential role as a biomarker for kidney function in the general population, as well as in some specific kidney diseases.
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Enfermedades Renales , Insuficiencia Renal Crónica , Humanos , Factor 15 de Diferenciación de CrecimientoRESUMEN
The consensus in aging is that inflammation, cellular senescence, free radicals, and epigenetics are contributing factors. Skin glycation through advanced glycation end products (AGEs) has a crucial role in aging. Additionally, it has been suggested that their presence in scars leads to elasticity loss. This manuscript reports fructosamine-3-kinase (FN3K) and fructosyl-amino acid oxidase (FAOD) in counteracting skin glycation by AGEs. Skin specimens were obtained (n = 19) and incubated with glycolaldehyde (GA) for AGE induction. FN3K and FAOD were used as monotherapy or combination therapy. Negative and positive controls were treated with phosphate-buffered saline and aminoguanidine, respectively. Autofluorescence (AF) was used to measure deglycation. An excised hypertrophic scar tissue (HTS) (n = 1) was treated. Changes in chemical bonds and elasticity were evaluated using mid-infrared spectroscopy (MIR) and skin elongation, respectively. Specimens treated with FN3K and FAOD in monotherapy achieved an average decrease of 31% and 33% in AF values, respectively. When treatments were combined, a decrease of 43% was achieved. The positive control decreased by 28%, whilst the negative control showed no difference. Elongation testing of HTS showed a significant elasticity improvement after FN3K treatment. ATR-IR spectra demonstrated differences in chemical bounds pre- versus post-treatment. FN3K and FAOD can achieve deglycation and the effects are most optimal when combined in one treatment.