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BACKGROUND Cardiac arrest (CA) is a global public health challenge. This study explored the predictors of mortality and their interactions utilizing machine learning algorithms and their related mortality odds among patients following CA. MATERIAL AND METHODS The study retrospectively investigated 161 medical records of CA patients admitted to the Intensive Care Unit (ICU). The random forest classifier algorithm was used to assess the parameters of mortality. The best classification trees were chosen from a set of 100 trees proposed by the algorithm. Conditional mortality odds were investigated with the use of logistic regression models featuring interactions between variables. RESULTS In the logistic regression model, male sex was associated with 5.68-fold higher mortality odds. The mortality odds among the asystole/pulseless electrical activity (PEA) patients were modulated by body mass index (BMI) and among ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT) patients were by serum albumin concentration (decrease by 2.85-fold with 1 g/dl increase). Procalcitonin (PCT) concentration, age, high-sensitivity C-reactive protein (hsCRP), albumin, and potassium were the most influential parameters for mortality prediction with the use of the random forest classifier. Nutritional status-associated parameters (serum albumin concentration, BMI, and Nutritional Risk Score 2002 [NRS-2002]) may be useful in predicting mortality in patients with CA, especially in patients with PCT >0.17 ng/ml, as showed by the decision tree chosen from the random forest classifier based on goodness of fit (AUC score). CONCLUSIONS Mortality in patients following CA is modulated by many co-existing factors. The conclusions refer to sets of conditions rather than universal truths. For individual factors, the 5 most important classifiers of mortality (in descending order of importance) were PCT, age, hsCRP, albumin, and potassium.
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Paro Cardíaco , Aprendizaje Automático , Humanos , Masculino , Paro Cardíaco/mortalidad , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Unidades de Cuidados Intensivos , Algoritmos , Modelos Logísticos , Factores de Riesgo , Pronóstico , Adulto , Índice de Masa CorporalRESUMEN
Colorectal cancer (CRC) is among the most prevalent and lethal malignancies. Lipidomic investigations have revealed numerous disruptions in lipid profiles across various cancers. Studies on CRC exhibit potential for identifying novel diagnostic or prognostic indicators through lipidomic signatures. This review examines recent literature regarding lipidomic markers for CRC. PubMed database was searched for eligible articles concerning lipidomic biomarkers of CRC. After selection, 36 articles were included in the review. Several studies endeavor to establish sets of lipid biomarkers that demonstrate promising potential to diagnose CRC based on blood samples. Phosphatidylcholine, phosphatidylethanolamine, ceramides, and triacylglycerols (TAGs) appear to offer the highest diagnostic accuracy. In tissues, lysophospholipids, ceramides, and TAGs were among the most altered lipids, while unsaturated fatty acids also emerged as potential biomarkers. In-depth analysis requires both cell culture and animal studies. CRC involves multiple lipid metabolism alterations. Although numerous lipid species have been suggested as potential diagnostic markers, the establishment of standardized methods and the conduct of large-scale studies are necessary to facilitate their clinical application.
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Biomarcadores de Tumor , Neoplasias Colorrectales , Lipidómica , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/metabolismo , Lipidómica/métodos , Biomarcadores de Tumor/sangre , Pronóstico , Metabolismo de los Lípidos , AnimalesRESUMEN
Glycation is a physiological process that determines the aging of the organism, while in states of metabolic disorders it is significantly intensified. High concentrations of compounds such as reducing sugars or reactive aldehydes derived from lipid oxidation, occurring for example in diabetes, atherosclerosis, dyslipidemia, obesity or metabolic syndrome, lead to increased glycation of proteins, lipids and nucleic acids. The level of advanced glycation end-products (AGEs) in the body depends on rapidity of their production and the rate of their removal by the urinary system. AGEs, accumulated in the extracellular matrix of the blood vessels and other organs, cause irreversible changes in the biochemical and biomechanical properties of tissues. As a consequence, micro- and macroangiopathies appear in the system, and may contribute to the organ failure, like kidneys and heart. Elevated levels of AGEs also increase the risk of Alzheimer's disease and various cancers. In this paper, we propose a new classification due to modified amino acid residues: arginyl-AGEs, monolysyl-AGEs and lysyl-arginyl-AGEs and dilysyl-AGEs. Furthermore, we describe in detail the effect of AGEs on the pathogenesis of metabolic and old age diseases, such as diabetic complications, atherosclerosis and neurodegenerative diseases. We summarize the currently available data on the diagnostic value of AGEs and present the AGEs as a therapeutic goal in a wide range of medical problems, including SARS-CoV-2 infection and so-called long COVID.
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COVID-19 , Productos Finales de Glicación Avanzada , SARS-CoV-2 , Productos Finales de Glicación Avanzada/metabolismo , Humanos , COVID-19/metabolismo , COVID-19/virología , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Complicaciones de la Diabetes/metabolismo , Aterosclerosis/metabolismo , Enfermedades Neurodegenerativas/metabolismoRESUMEN
Better understanding of molecular changes leading to neoplastic transformation is prerequisite to optimize risk assessment and chemopreventive and surveillance strategies. Data on macrophage inflammatory proteins (MIPs) in colorectal carcinogenesis are scanty and their clinical relevance remains unknown. Therefore, transcript and protein expression of CCL3, CCL4, CXCL2, and CCL19 were determined in 173 and 62 patients, respectively, using RT-qPCR and immunohistochemistry with reference to polyps' characteristics. The likelihood of malignancy was modeled using probit regression. With the increasing malignancy potential of hyperplastic-tubular-tubulo-villous-villous polyps, the expression of CCL3, CCL4, and CCL19 in lesions decreased. CCL19 expression decreased also in normal mucosa while that of CXCL2 increased. Likewise, lesion CCL3 and lesion and normal mucosa CCL19 decreased and normal CXCL2 increased along the hyperplasia-low-high dysplasia grade. The bigger the lesion, the lower CCL3 and higher CXCL2 in normal mucosa. Singular polyps had higher CCL3, CCL4, and CCL19 levels in normal mucosa. CCL3, CCL4 and CXCL2 modulated the likelihood of malignancy associated with traditional risk factors. There was no correlation between the protein and mRNA expression of CCL3 and CCL19. In summary, the polyp-adjacent mucosa contributes to gaining potential for malignancy by polyps. MIPs may help in specifying cancerization probability estimated based on standard risk factors.
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Pólipos del Colon , Neoplasias Colorrectales , Humanos , Pólipos del Colon/genética , Pólipos del Colon/patología , Neoplasias Colorrectales/patología , Proteínas Inflamatorias de Macrófagos , Factores de Riesgo , HiperplasiaRESUMEN
BACKGROUND: There is a growing body of evidence for an important role of the apelinergic system in the modulation of cardiovascular homeostasis. The aim of our study was to (1) examine the relationship between apelin serum concentration at index myocardial infarction (MI) and atrioventricular conduction disorders (AVCDs) at 12-month follow-up, and (2) investigate the association between initial apelin concentration and the novel marker of post-MI scar (Q/QRS ratio) at follow-up. METHODS: In 84 patients with MI with complete revascularization, apelin peptide serum concentrations for apelin-13, apelin-17, elabela (ELA) and apelin receptor (APJ) were measured on day one of hospitalization; at 12-month follow-up, 54 of them underwent thorough examination that included 12-lead electrocardiography (ECG), Holter ECG monitoring and echocardiography. RESULTS: The mean age was 58.9 years. At 12-month follow-up, AVCDs were diagnosed in 21.4% of subjects, with AV first-degree block in 16.7% and sinoatrial arrest in 3.7%. ELA serum concentration at index MI correlated positively with the occurrence of AVCD (p = 0.003) and heart rate (p = 0.005) at 12-month follow-up. The apelin-13 serum concentration at index MI correlated negatively with the Q/QRS ratio. CONCLUSIONS: The apelin peptide concentration during an acute phase of MI impacts the development of AVCD and the value of Q/QRS ratio in MI survivors.
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The COVID-19 pandemic has had a significant impact on global public health, with long-term consequences that are still largely unknown. This study aimed to assess the data regarding acute cardiovascular hospital admissions in five European centers before and during the pandemic. A multicenter, multinational observational registry was created, comparing admissions to the emergency departments during a 3-months period in 2020 (during the pandemic) with the corresponding period in 2019 (pre-pandemic). Data on patient demographics, COVID-19 test results, primary diagnosis, comorbidities, heart failure profile, medication use, and laboratory results were collected. A total of 8778 patients were included in the analysis, with 4447 patients in 2019 and 4331 patients in 2020. The results showed significant differences in the distribution of cardiovascular diseases between the two years. The frequency of pulmonary embolism (PE) increased in 2020 compared to 2019, while acute heart failure (AHF) and other cardiovascular diseases decreased. The odds of PE incidence among hospitalized patients in 2020 were 1.316-fold greater than in 2019. The incidence of AHF was 50.83% less likely to be observed in 2020, and the odds for other cardiovascular diseases increased by 17.42% between the 2 years. Regarding acute coronary syndrome (ACS), the distribution of its types differed between 2019 and 2020, with an increase in the odds of ST-segment elevation myocardial infarction (STEMI) in 2020. Stratification based on sex revealed further insights. Among men, the incidence of AHF decreased in 2020, while other cardiovascular diseases increased. In women, only the incidence of STEMI showed a significant increase. When analyzing the influence of SARS-CoV-2 infection, COVID-positive patients had a higher incidence of PE compared to COVID-negative patients. COVID-positive patients with ACS also exhibited symptoms of heart failure more frequently than COVID-negative patients. These findings provide valuable information on the impact of the COVID-19 pandemic on acute cardiovascular hospital admissions. The increased incidence of PE and changes in the distribution of other cardiovascular diseases highlight the importance of monitoring and managing cardiovascular health during and post pandemic period. The differences observed between sexes emphasize the need for further research to understand potential sex-specific effects of COVID-19 on cardiovascular outcomes.
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Síndrome Coronario Agudo , COVID-19 , Insuficiencia Cardíaca , Embolia Pulmonar , Infarto del Miocardio con Elevación del ST , Masculino , Humanos , Femenino , COVID-19/epidemiología , Pandemias , Infarto del Miocardio con Elevación del ST/epidemiología , SARS-CoV-2 , Síndrome Coronario Agudo/epidemiología , Insuficiencia Cardíaca/epidemiología , Embolia Pulmonar/epidemiologíaRESUMEN
Given that one of the crucial events in the pathogenesis of inflammatory bowel disease is the loss of homeostasis between Th17 and Treg cells, targeting the specific molecules of the Th17/Treg axis developmental pathway is a promising strategy for inflammatory bowel disease prevention and treatment. The current study aimed to assess the impact of cornelian cherry (Cornus mas L.) extract, rich in iridoids and polyphenols known for their potential anti-inflammatory activity, at two doses (20 or 100 mg/kg) on the crucial factors for Th17/Treg cell differentiation in the course of experimental colitis and compare this action with that of sulfasalazine. This study was conducted on the biobank colon tissue samples collected during the previous original experiment, in which colitis in rats was induced by trinitrobenzenesulfonic acid (TNBS). The levels of IL-6, RORγt, total STAT3, p-STAT3, and Foxp3 were determined by ELISA. The expression of PIAS3 mRNA was quantified by qPCR. Cornelian cherry extract at a dose of 100 mg/kg counteracted the TNBS-induced elevation of IL-6, RORγt, and p-STAT3 levels and a decrease in Foxp3 level and PIAS3 mRNA expression, while given concomitantly with sulfasalazine was more effective than sulfasalazine alone in reversing the TNBS-induced changes in IL-6, RORγt, total STAT3, p-STAT3, Foxp3 levels, and PIAS3 mRNA expression. The beneficial effect of cornelian cherry extract on experimental colitis may be due to its immunomodulatory activity reflected by the influence on factors regulating the Th17/Treg axis.
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Colitis , Cornus , Enfermedades Inflamatorias del Intestino , Ratas , Animales , Linfocitos T Reguladores , Ácido Trinitrobencenosulfónico/efectos adversos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Interleucina-6/farmacología , Sulfasalazina/farmacología , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Células Th17 , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: CD163, a cell membrane surface molecule specifically expressed by macrophages with an anti-inflammatory phenotype, participates in innate immunity. The purpose of the study was to evaluate the clinical utility of sCD163 in septic patients in comparison to other parameters associated with infections, mainly PCT, CRP and IL-18. METHODS: Serum samples were obtained from 40 septic patients on the ICU admission day, 3rd and 5th study days. The control group consisted of 30 healthy volunteers from whom the specimen was collected once. An enzyme-linked immunosorbent assay (ELISA) was used to determine the concentrations of sCD163 and IL-18. CRP and PCT records, among others, were provided by the hospital. RESULTS: Septic shock was associated with the highest concentrations of sCD163 and IL-18. Admission values of sCD163 significantly contributed to mortality prediction in septic patients. CONCLUSIONS: The concentration of sCD163 determined on the ICU admission day may potentially be utilized in estimation of the odds of death among septic patients.
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Sepsis , Humanos , Biomarcadores , Calcitonina , Mortalidad Hospitalaria , Unidades de Cuidados Intensivos , Interleucina-18RESUMEN
Sepsis is a life-threatening organ dysfunction caused by the dysregulation of the host's response to an infection, where the dominant mechanism is tissue hypoperfusion. Currently, the marker used to define tissue disorders is lactate levels, which may be elevated in other disease states as well. Renin is an essential hormone for the proper functioning of the renin-angiotensin-aldosterone (RASS) system. It is secreted in the glomerular apparatus in response to hypoperfusion. This study aimed to assess the usefulness of renin as a marker of tissue hypoperfusion in patients with sepsis and septic shock. A final group of 48 patients treated for sepsis and septic shock in the intensive care unit was included. Blood samples for renin quantification were collected in the morning as a part of routine blood analysis on the first, third, and fifth days. Sepsis was diagnosed in 19 patients (39.6%), and septic shock was diagnosed in 29 patients (60.4%). There was no significant difference in renin concentration between patients who received and did not receive continuous renal replacement therapy (CRRT) on any study day. Therefore, all samples were analyzed together in subsequent analyses. There was a significant difference in renin concentration between sepsis survivors and non-survivors on the third (31.5 and 119.9 pg/mL, respectively) and fifth (18.2 and 106.7 pg/mL, respectively) days. As a survival marker, renin was characterized by 69% and 71% overall accuracy if determined on the third and fifth days, respectively. There was a significant difference in renin concentration between sepsis and septic shock patients on the first (45.8 and 103.4 pg/mL, respectively) and third (24.7 and 102.1 pg/mL, respectively) days. At an optimal cut-off of 87 pg/mL, renin had very good specificity and a positive likelihood ratio. Renin was a strong predictor of mortality in patients with sepsis and septic shock. Further, the level of renin in patients with septic shock was significantly higher than in patients with sepsis. In combination with the assessment of lactate concentration, renin seems to be the optimal parameter for monitoring tissue hypoperfusion and could be helpful for septic shock diagnosis, as well as for identifying candidate patients for CRRT.
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Sepsis , Choque Séptico , Biomarcadores , Humanos , Lactatos , Perfusión , Renina , Choque Séptico/terapiaRESUMEN
Despite the fact that phytochemicals of Cornaceae species have long been discussed as possible auxiliary agents in contemporary treatment, the insights on their properties remain relatively scarce. This study focuses on Cornus mas L. (Cornelian cherry), the extracts of which are reported to exert a pleiotropic effect shown in both in vivo and in vitro studies. This study aimed to explore the cytotoxic effect of extracts from fruits of red (Cornus mas L. 'Podolski') and yellow (Cornus mas L. 'Yantarnyi' and 'Flava') Cornelian cherries on two melanoma cell lines (A375 and MeWo). The extracts were characterized in the context of the concentration of bioactive compounds of antioxidative properties. Cytotoxicity was investigated with the use of the following two assays: SRB and MTT. An additional, alternative protocol for the SRB assay was used in this study so as to account for possible bias. Cytotoxicity was assessed as a difference in the whole time series of cell viability, instead of analyzing differences in raw values (often found in the literature). Both extracts from Cornus mas L. induced cytotoxicity in both A375 and MeWo cell lines, although the response of these cells was different. Moreover, based on this study, there is no evidence for claiming a different magnitude of cytotoxicity between these two extracts.
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Cornus , Melanoma , Antioxidantes/química , Línea Celular , Cornus/química , Frutas/química , Melanoma/tratamiento farmacológico , Extractos Vegetales/análisis , Extractos Vegetales/farmacologíaRESUMEN
Ilex paraguariensis, the holly tree, is a plant with recognized biological properties, whose aqueous infusions are known as "Yerba mate", that regulate lipid metabolism, reduce obesity, and improve brain stimulation. In the present study, the effect of standardized saponin and terpenoid fractions of a European taxon, Ilex aquifolium, on blood biochemical parameters in a rat model of metabolic disorder, (fa/fa) Zucker, are presented. The profiles of the volatile fractions of two species and six European varieties of Ilex were investigated. After selecting the best variety, the saponin and terpenoid fractions were isolated and standardized, and animals were fed 10 mg kg−1 b.w. for 8 weeks. A statistically significant decrease in liver adiposity was observed, confirmed by histology and quantitative identification (gas chromatography−mass spectrometry analyses of hepatic lipids. RT-qPCR analysis of gene expression in the aorta revealed that the administration of the terpenoid fraction downregulated LOX-1, suggesting a reduction in atherosclerotic stimuli. In addition, a statistically significant reduction (p < 0.05) in PPARγ for the saponin fraction was observed in the liver. The expression of the ACAT-1 gene in the liver, responsible for the formation of cholesterol esters, increased significantly in the group receiving the terpenoid fraction compared to the control, which was also confirmed by the analysis of individual blood biochemical parameters. The opposite effect was observed for saponins. Taking the above into account, it is shown for the first time that Ilex aquifolium can be a source of compounds that positively influence lipid metabolism.
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Ilex paraguariensis , Ilex , Saponinas , Animales , Ilex paraguariensis/química , Metabolismo de los Lípidos , Obesidad/tratamiento farmacológico , Extractos Vegetales/química , Hojas de la Planta/química , Ratas , Ratas Zucker , Saponinas/análisis , Saponinas/farmacología , Terpenos/análisis , Terpenos/farmacologíaRESUMEN
Parkinson's disease (PD)-a neurodegenerative disorder (NDD) characterized by progressive destruction of dopaminergic neurons within the substantia nigra of the brain-is associated with the formation of Lewy bodies containing mainly α-synuclein. HDL-related proteins such as paraoxonase 1 and apolipoproteins A1, E, D, and J are implicated in NDDs, including PD. Apolipoprotein J (ApoJ, clusterin) is a ubiquitous, multifunctional protein; besides its engagement in lipid transport, it modulates a variety of other processes such as immune system functionality and cellular death signaling. Furthermore, being an extracellular chaperone, ApoJ interacts with proteins associated with NDD pathogenesis (amyloid ß, tau, and α-synuclein), thus modulating their properties. In this review, the association of clusterin with PD is delineated, with respect to its putative involvement in the pathological mechanism and its application in PD prognosis/diagnosis.
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The expression of monocyte chemotactic proteins (MCPs) in colorectal polyps and their suitability as targets for chemoprevention is unknown, although MCP expression and secretion can be modulated by non-steroidal inflammatory drugs. This study was designed to determine the expression patterns of MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 at the protein (immunohistochemistry; n = 62) and transcriptional levels (RTqPCR; n = 173) in colorectal polyps with reference to the polyp malignancy potential. All chemokines were significantly upregulated in polyps at the protein level but downregulated at the transcriptional level by 1.4-(CCL2), 1.7-(CCL7), and 2.3-fold (CCL8). There was an inverse relation between the immunoreactivity toward chemokine proteins and the number of corresponding transcripts in polyps (CCL2 and CCL7) or in normal mucosa (CCL8). The downregulation of chemokine transcripts correlated with the presence of multiple polyps (CCL2 and CCL8), a larger polyp size (CCL2, CCL7, and CCL8), predominant villous growth patterns (CCL2, CCL7 and CCL8), and high-grade dysplasia (CCL2 and CCL8). In conclusion, MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7 chemokines are counter-regulated at the protein and transcriptional levels. Chemokine-directed chemopreventive strategies should therefore directly neutralize MCP proteins or target molecular pathways contributing to their enhanced translation or reduced degradation, rather than aiming at CCL2, CCL7 or CCL8 expression.
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The mechanisms underlying the antineoplastic effects of oxicams have not been fully elucidated. We aimed to assess the effect of classic and novel oxicams on the expression/secretion of macrophage-associated chemokines (RTqPCR/Luminex xMAP) in colorectal adenocarcinoma cells, and on the expression of upstream the non-steroidal anti-inflammatory drug (NSAID)-activated genes NAG1, NFKBIA, MYD88, and RELA, as well as at the chemokine profiling in colorectal tumors. Meloxicam downregulated CCL4 9.9-fold, but otherwise the classic oxicams had a negligible/non-significant effect. Novel analogues with a thiazine ring substituted with arylpiperazine and benzoyl moieties significantly modulated chemokine expression to varying degree, upregulated NAG1 and NFKBIA, and downregulated MYD88. They inhibited CCL3 and CCL4, and their effect on CCL2 and CXCL2 depended on the dose and exposure. The propylene linker between thiazine and piperazine nitrogens and one arylpiperazine fluorine substituent characterized the most effective analogue. Only CCL19 and CXCL2 were not upregulated in tumors, nor was CXCL2 in tumor-adjacent tissue compared to normal mucosa. Compared to adjacent tissue, CCL4 and CXCL2 were upregulated, while CCL2, CCL8, and CCL19 were downregulated in tumors. Tumor CCL2 and CCL7 increased along with advancing T and CCL3, and CCL4 along with the N stage. The introduction of arylpiperazine and benzoyl moieties into the oxicam scaffold yields effective modulators of chemokine expression, which act by upregulating NAG1 and interfering with NF-κB signaling.
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Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Meloxicam/farmacología , Piroxicam/farmacología , Anciano , Antiinflamatorios no Esteroideos/química , Antineoplásicos/química , Células CACO-2 , Quimiocinas/antagonistas & inhibidores , Quimiocinas/metabolismo , Neoplasias Colorrectales/metabolismo , Femenino , Células HCT116 , Humanos , Macrófagos/metabolismo , Masculino , Meloxicam/análogos & derivados , Piroxicam/análogos & derivadosRESUMEN
Molecular mechanisms underlying the beneficial effect of sitagliptin repurposed for hepatic ischemia-reperfusion injury (IRI) are poorly understood. We aimed to evaluate the impact of IRI and sitagliptin on the hepatic profile of eicosanoids (LC-MS/MS) and expression/concentration (RTqPCR/ELISA) of GLP-1/GLP-1R, SDF-1α/CXCR4 and VIP/VPAC1, VPAC2, and PAC1 in 36 rats. Animals were divided into four groups and subjected to ischemia (60 min) and reperfusion (24 h) with or without pretreatment with sitagliptin (5 mg/kg) (IR and SIR) or sham-operated with or without sitagliptin pretreatment (controls and sitagliptin). PGI2, PGE2, and 13,14-dihydro-PGE1 were significantly upregulated in IR but not SIR, while sitagliptin upregulated PGD2 and 15-deoxy-12,14-PGJ2. IR and sitagliptin non-significantly upregulated GLP-1 while Glp1r expression was borderline detectable. VIP concentration and Vpac2 expression were downregulated in IR but not SIR, while Vpac1 was significantly downregulated solely in SIR. IRI upregulated both CXCR4 expression and concentration, and sitagliptin pretreatment abrogated receptor overexpression and downregulated Sdf1. In conclusion, hepatic IRI is accompanied by an elevation in proinflammatory prostanoids and overexpression of CXCR4, combined with downregulation of VIP/VPAC2. Beneficial effects of sitagliptin during hepatic IRI might be mediated by drug-induced normalization of proinflammatory prostanoids and upregulation of PGD2 and by concomitant downregulation of SDF-1α/CXCR4 and reinstating VIP/VCAP2 signaling.
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Hepatopatías/tratamiento farmacológico , Prostaglandinas/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Fosfato de Sitagliptina/administración & dosificación , Animales , Quimiocina CXCL12/genética , Cromatografía Liquida , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Hepatopatías/etiología , Ratas , Receptores CXCR4/genética , Receptores de Tipo II del Péptido Intestinal Vasoactivo/genética , Daño por Reperfusión/complicaciones , Transducción de Señal/efectos de los fármacos , Fosfato de Sitagliptina/farmacología , Espectrometría de Masas en Tándem , Péptido Intestinal Vasoactivo/genéticaRESUMEN
Heat shock proteins HSPA1/Hsp70α and HSP90AA1/Hsp90α are crucial for cancer growth but their expression pattern in colorectal polyps or whether they can be modulated by oxicams is unknown. We quantified (RTqPCR) HSPA1 and HSP90AA1 expression in 50 polyp-normal pairs in relation to polyp malignancy potential and examined the effect of piroxicam, meloxicam and five novel analogues on HSPA1 and HSP90AA1 expression (mRNA/protein) in colorectal adenocarcinoma lines. HSPA1 and HSP90AA1 were upregulated in polyps by 3- and 2.9-fold. Expression ratios were higher in polyps with higher dysplasia grade and dominant villous growth pattern, mostly a result of diminished gene expression in normal tissue. Classic oxicams had negligible/non-significant effect on HSP expression. Their most effective analogue inhibited HSPA1 protein and gene by 2.5-fold and 5.7-fold in Caco-2 and by 11.5-fold and 6.8-fold in HCT116 and HSPA1 protein in HT-29 by 1.9-fold. It downregulated HSP90AA1 protein and gene by 1.9-fold and 3.7-fold in Caco-2 and by 2-fold and 5.0-fold in HCT116. HSPA1 and HSP90AA1 are upregulated in colorectal polyps reflecting their potential for malignancy. HSPA1 in cancer cells and, to lesser degree, HSP90AA1 can be reduced by oxicam analogues with thiazine ring substituted via propylene linker by arylpiperazine pharmacophore with fluorine substituents and by benzoyl moiety.
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Neoplasias Colorrectales , Proteínas de Choque Térmico , Células CACO-2 , Pólipos del Colon , Humanos , TiazinasRESUMEN
Sepsis, defined as a dysregulated host response to infection, causes the interruption of homeostasis resulting in metabolic changes. An examination of patient metabolites, such as amino acids, during the early stage of sepsis may facilitate diagnosing and assessing the severity of the sepsis. The aim of this study was to compare patterns of urine and serum amino acids relative to sepsis, septic shock and survival. Urine and serum samples were obtained from healthy volunteers (n = 15) once or patients (n = 15) within 24 h of a diagnosis of sepsis or septic shock. Concentrations of 25 amino acids were measured in urine and serum samples with liquid chromatography-electrospray mass spectrometry. On admission in the whole cohort, AAA, ABA, mHis, APA, Gly-Pro and tPro concentrations were significantly lower in the serum than in the urine and Arg, Gly, His, hPro, Leu, Ile, Lys, Orn, Phe, Sarc, Thr, Tyr, Asn and Gln were significantly higher in the serum than in the urine. The urine Gly-Pro concentration was significantly higher in septic shock than in sepsis. The serum Cit concentration was significantly lower in septic shock than in sepsis. The urine ABA, mHis and Gly-Pro, and serum Arg, hPro and Orn concentrations were over two-fold higher in the septic group compared to the control group. Urine and serum amino acids measured in septic patients on admission to the ICU may shed light on a patient's metabolic condition during sepsis or septic shock.
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Aminoácidos/sangre , Aminoácidos/orina , Sepsis/diagnóstico , Choque Séptico/diagnóstico , Anciano , Anciano de 80 o más Años , Cromatografía Liquida/métodos , Enfermedad Crítica , Femenino , Voluntarios Sanos , Humanos , Masculino , Memoria Episódica , Persona de Mediana Edad , Sepsis/sangre , Sepsis/orina , Choque Séptico/sangre , Choque Séptico/orina , Análisis de Supervivencia , Espectrometría de Masas en Tándem/métodosRESUMEN
The effects of the apelinergic system components apelin (AP) and elabela (ELA) in the regulation of human cardiovascular homeostasis, and data concerning the relationship between ELA and AP and coronary artery disease (CAD) are yet unknown. The aim of the study was the evaluation of AP, ELA and APJ-receptor levels in the plasma of patients with chronic coronary syndromes (CCS) and acute coronary syndromes (ACS). The study group consisted of 114 patients with CAD and 33 healthy controls. Patients were divided into two groups: with CCS (n = 30) and ACS (n = 84). Routine laboratory tests and plasma ELA, AP-17, AP-13 and APJ receptor levels were measured. Echocardiographic data were analyzed in all patients. Levels of AP-17 and ELA were significantly lower in CCS than in healthy controls and ACS patients. We demonstrated significant increase of levels of plasma apelinergic system peptides, especially ELA and AP-17 in ACS patients compared with healthy controls and CCS, suggestive of compensating up-regulation mechanisms. There is a relationship between circulating ELA and AP-17 levels and classical, biochemical markers of ischemia and left ventricular ejection faction as well.
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Advanced glycation end-products (AGEs) contribute to vascular complications and organ damage in diabetes. The unique AGE epitope (AGE10) has recently been identified in human serum using synthetic melibiose-derived AGE (MAGE). We aimed at developing ELISA for AGE10 quantification, determining whether AGE10 is present in diabetic patients (n = 82), and evaluating its association with diabetic complications. In a competitive ELISA developed, the reaction of synthetic MAGE with anti-MAGE was inhibited by physiological AGE10 present in serum. In this assay, new murine IgE anti-MAGE monoclonal antibodies, which do not recognize conventional AGEs, a synthetic MAGE used to coat the plate, and LMW-MAGE (low molecular mass MAGE) necessary to plot a standard curve were used. AGE10 was significantly higher in patients with microangiopathy, in whom it depended on treatment, being lower in patients treated with aspirin. AGE10 levels were positively correlated with estimated glomerular filtration rate (eGFR) and negatively with creatinine. As a marker of stage ≥3 chronic kidney disease or microangiopathy, AGE10 displayed moderate overall accuracy (respectively, 69% and 71%) and good sensitivity (82.6% and 83.3%) but poor specificity (58.1% and 57.8%). In conclusion, newly developed immunoassay allows for AGE10 quantification. AGE10 elevation is associated with microangiopathy while its decrease accompanies stage ≥3 chronic kidney disease.
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A possibility of repurposing sitagliptin, a well-established antidiabetic drug, for alleviating injury caused by ischemia-reperfusion (IR) is being researched. The aim of this study was to shed some light on the molecular background of the protective activity of sitagliptin during hepatic IR. The expression and/or concentration of inflammation and oxidative stress-involved factors have been determined in rat liver homogenates using quantitative RT-PCR and Luminex® xMAP® technology and markers of nitrative and halogenative stress were quantified using targeted metabolomics (LC-MS/MS). Animals (n = 36) divided into four groups were treated with sitagliptin (5 mg/kg) (S and SIR) or saline solution (C and IR), and the livers from IR and SIR were subjected to ischemia (60 min) and reperfusion (24 h). The midkine expression (by 2.2-fold) and the free 3-nitrotyrosine (by 2.5-fold) and IL-10 (by 2-fold) concentration were significantly higher and the Nox4 expression was lower (by 9.4-fold) in the IR than the C animals. As compared to IR, the SIR animals had a lower expression of interleukin-6 (by 4.2-fold) and midkine (by 2-fold), a lower concentration of 3-nitrotyrosine (by 2.5-fold) and a higher Nox4 (by 2.9-fold) and 3-bromotyrosine (by 1.4-fold). In conclusion, IR disturbs the oxidative, nitrative and halogenative balance and aggravates the inflammatory response in the liver, which can be attenuated by low doses of sitagliptin.