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Despite targeting different coagulation cascade sites, all Food and Drug Administration-approved anticoagulants present an elevated risk of bleeding, including potentially life-threatening intracranial hemorrhage. Existing studies have not thoroughly investigated the efficacy and safety of sulfonate polymers in animal models and fully elucidate the precise mechanisms by which these polymers act. The activity and safety of sulfonated di- and triblock copolymers containing poly(sodium styrenesulfonate) (PSSS), poly(sodium 2-acrylamido-2-methylpropanesulfonate) (PAMPS), poly(ethylene glycol) (PEG), poly(sodium methacrylate) (PMAAS), poly(acrylic acid) (PAA), and poly(sodium 11-acrylamidoundecanoate) (PAaU) blocks are synthesized and assessed. PSSS-based copolymers exhibit greater anticoagulant activity than PAMPS-based ones. Their activity is mainly affected by the total concentration of sulfonate groups and molecular weight. PEG-containing copolymers demonstrate a better safety profile than PAA-containing ones. The selected copolymer PEG47-PSSS32 exhibits potent anticoagulant activity in rodents after subcutaneous and intravenous administration. Heparin Binding Copolymer (HBC) completely reverses the anticoagulant activity of polymer in rat and human plasma. No interaction with platelets is observed. Selected copolymer targets mainly factor XII and fibrinogen, and to a lesser extent factors X, IX, VIII, and II, suggesting potential application in blood-contacting biomaterials for anticoagulation purposes. Further studies are needed to explore its therapeutic applications fully.
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Background: We aimed to explore the predictive role of soluble urokinase plasminogen activator receptor (suPAR) in patients undergoing coronary angiography by systematically evaluating its association with adverse cardiovascular events at 10 years follow-up. Methods: The KORONEF study was a single-center, observational, prospective study with 492 subjects included. In the multivariable Cox regression model, we checked the impact of suPAR, neutrophil elastase, myeloperoxidase, and DNase 1 on long-term outcomes. Results: The mean study population age was 64.4 ± 9.9 years, and there were 37.2% women. We divided the population into tertiles of suPAR levels (T1 0.793-2.135 ng/mL; T2 2.136-2.868 ng/mL; and T3 2.872-8.677 ng/mL). Patients with higher suPAR concentrations were more often females (tertile 1 vs. tertile 3: 27.4% vs. 50.6%, p < 0.001) and older age (60.8 ± 8.7 years vs. 68.8 ± 9.5 years, p < 0.001). They also characterized higher incidence of diabetes (17.7% vs. 38.0%, p < 0.001), previous myocardial infarction (22% vs. 44.8%, p < 0.001), and chronic kidney disease (3% vs. 18.4%, p < 0.001), but lower incidence of dyslipidemia (54.3% vs. 35.6%). The 10-year all-cause death rates were 14.6% vs. 34.1%, HR 2.68, 95% CI 1.66-4.33, p < 0.001 for tertile 2, and 14.6% vs. 39.9%, HR 3.24, 95% CI 2.03-5.17, p < 0.001 for tertile 3. The optimal cut-off suPAR value of 2.39 ng/mL provided a sensitivity of 66.9% and a specificity of 54.6% in predicting all-cause death. Conclusions: The association of elevated suPAR with increased mortality risk suggests its potential relevance in predicting long-term outcomes and may help inform more individualized management strategies for high-risk patients.
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BACKGROUND: Understanding the multifactorial nature of major depressive disorder (MDD) is crucial for tailoring treatments. However, the complex interplay of various factors underlying the development and progression of MDD poses significant challenges. Our previous study demonstrated improvements in cognitive functions in MDD patients undergoing treatment with selective serotonin reuptake inhibitors (SSRIs) supplemented with Lactobacillus plantarum 299v (LP299v). METHODS: To elucidate the biochemical mechanisms underlying cognitive functions improvements, we explored underlying metabolic changes. We employed multi-platform metabolomics, including LC-QTOF-MS and CE-TOF-MS profiling, alongside chiral LC-QqQ-MS analysis for amino acids. RESULTS: Supplementation of SSRI treatment with LP299v intensified the reduction of long-chain acylcarnitines, potentially indicating improved mitochondrial function. LP299v supplementation reduced N-acyl taurines more than four times compared to the placebo, suggesting a substantial impact on restoring biochemical balance. The LP299v-supplemented group showed increased levels of oxidized glycerophosphocholine (oxPC). Additionally, LP299v supplementation led to higher levels of sphingomyelins, L-histidine, D-valine, and p-cresol. LIMITATIONS: This exploratory study suggests potential metabolic pathways influenced by LP299v supplementation. However, the need for further research hinders the ability to draw definitive conclusions. CONCLUSIONS: Observed metabolic changes were linked to mitochondrial dysfunction, inflammation, oxidative stress, and gut microbiota disruption. Despite the subtle nature of this alterations, our research successfully detected these differences and connected them to the metabolic disruptions associated with MDD. Our findings emphasise the intricate relationship between metabolism, gut microbiota, and mental health prompting further research into the mechanisms of action of probiotics in MDD treatment.
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INTRODUCTION: Given their association with inflammatory processes and oxidative stress, tryptophan metabolites involved in the kynurenine pathway (KP) play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D). OBJECTIVES: The study aimed to examine the relationship between the parameters of HFpEF, as determined by transthoracic echocardiography, and metabolites of the KP. PATIENTS AND METHODS: We prospectively included 120 patients with HFpEF, 60 with and 60 without T2D, and 55 controls. Highperformance liquid chromatography was used to quantify the serum metabolites of KP. Echocardiography was used to assess left ventricular systolic and diastolic function. RESULTS: The patients with HFpEF and T2D showed an increase in tryptophan, kynurenine, and anthranilic acid concentrations (P = 0.001, P <0.001, and P <0.001, respectively) with a concomitant decrease in 3hydroxykynurenine (P <0.001) and quinolinic acid (P = 0.003), as compared with those with HFpEF without T2D. Left ventricular and left atrial remodeling was more pronounced in the group with T2D, but differences between these parameters did not reach statistical significance. Left ventricular global longitudinal strain was lower in the subgroup of patients with HFpEF and T2D than in the subgroup without T2D (P = 0.003). CONCLUSIONS: The study showed altered tryptophan metabolism in patients with HFpEF, highlighting a possible connection. The findings suggest potential implications for targeted therapeutic strategies focusing on tryptophan metabolism and cardiac function in patients with HFpEF and T2D.
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Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Quinurenina , Volumen Sistólico , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Insuficiencia Cardíaca/fisiopatología , Masculino , Quinurenina/sangre , Quinurenina/metabolismo , Anciano , Persona de Mediana Edad , Estudios Prospectivos , Ecocardiografía , Triptófano/sangre , Triptófano/metabolismo , ortoaminobenzoatosRESUMEN
This review discusses the potential of targeting the kynurenine pathway (KP) in the treatment of inflammatory diseases. The KP, responsible for the catabolism of the amino acid tryptophan (TRP), produces metabolites that regulate various physiological processes, including inflammation, cell cycle, and neurotransmission. These metabolites, although necessary to maintain immune balance, may accumulate excessively during inflammation, leading to systemic disorders. Key KP enzymes such as indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), tryptophan 2,3-dioxygenase (TDO), and kynurenine 3-monooxygenase (KMO) have been considered promising therapeutic targets. It was highlighted that both inhibition and activation of these enzymes may be beneficial, depending on the specific inflammatory disorder. Several inflammatory conditions, including autoimmune diseases, for which modulation of KP activity holds therapeutic promise, have been described in detail. Preclinical studies suggest that this modulation may be an effective treatment strategy for diseases for which treatment options are currently limited. Taken together, this review highlights the importance of further research on the clinical application of KP enzyme modulation in the development of new therapeutic strategies for inflammatory diseases.
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Inflamación , Quinurenina , Humanos , Quinurenina/metabolismo , Inflamación/tratamiento farmacológico , Animales , Terapia Molecular Dirigida , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidoresRESUMEN
INTRODUCTION: Psoriasis is a frequent and incurable skin disease that is an important issue in contemporary dermatology, although its pathogenesis is still uncertain. Gasdermin A (GSDMA) is a member of the gasdermin protein family which are able to cause pore formation in cellular membranes leading to cell death called pyroptosis. OBJECTIVE: Our aim was to investigate the role of GSDMA in psoriatic patients. METHOD: The study enrolled 60 patients with active plaque-type psoriasis and 30 sex- and age-matched volunteers without dermatoses. GSDMA concentration was assessed in serum and urine samples of all participants using ELISA. GSDMA tissue expression was assessed by immunohistochemistry. RESULTS: GSDMA serum concentration was significantly higher in patients compared to controls, whereas urinary GSDMA/creatinine ratio was insignificantly lower. GSDMA tissue expression was more prominent in psoriatic plaque compared to non-lesional patients' skin and healthy skin of subjects without dermatoses. There was a strong negative correlation between GSDMA serum concentration and ALT activity. GSDMA did not correlate with PASI or psoriasis duration. CONCLUSIONS: Obtained results point to the probable involvement of GSDMA in psoriasis. GSDMA overexpression may probably lead to keratinocytes hyperproliferation and be responsible for triggering inflammation in psoriatic skin. Serum GSDMA could become psoriasis biomarker, whereas urinary GSDMA, not at this point.
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BACKGROUND: The identification of clinical factors affecting the gray-scale median (GSM) and determination of GSM diagnostic utility for differentiating between symptomatic and asymptomatic internal carotid artery (ICA) stenosis. METHODS: This study included 45 patients with asymptomatic and 40 patients with symptomatic ICA stenosis undergoing carotid endarterectomy (CEA). Echolucency of carotid plaque was determined using computerized techniques for the GSM analysis. Study groups were compared in terms of clinical risk factors, coexisting comorbidities, and used pharmacotherapy. RESULTS: Mean GSM values in the symptomatic group were significantly lower than in the asymptomatic group (p < 0.001). Both in the univariate as well as in the multiple regression analysis, GSM was significantly correlated with D-dimers and fasting plasma glucose levels and tended to correlate with ß-adrenoceptor antagonist use in the symptomatic group. In asymptomatic patients, GSM was associated with the presence of grade 2 and grade 3 hypertension, and tended to correlate with the use of metformin, sulfonylureas, and statin. Independent factors for GSM in this group remained as grade 3 hypertension and statin's therapy. The receiver operating characteristic (ROC) analysis revealed that GSM differentiated symptomatic from asymptomatic ICA stenosis with sensitivity and specificity of 73% and 80%, respectively. CONCLUSION: The completely diverse clinical parameters may affect GSM in symptomatic and asymptomatic patients undergoing CEA, whose clinical characteristics were similar in terms of most of the compared parameters. GSM may be a clinically useful parameter for differentiating between symptomatic and asymptomatic ICA stenosis.
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Background: We aimed to characterize the population of consecutive patients undergoing coronary angiography with simultaneous renal artery angiography and assess prognostic factors at a 10 year follow-up. Methods: The KORONEF study was a prospective, single-center, observational, and descriptive study with 492 patients included. We analyzed several baseline demographics, clinical and periprocedural characteristics, and laboratory data, and we assessed the results of coronary angiography and renal artery angiography. Results: The study population consisted of 37.2% women, and the mean age was 64.4 ± 9.9 years (min. 30 years, max. 89 years). Angiography revealed significant renal artery stenosis (RAS) in 35 (7.1%) patients. Among patients with significant RAS (≥50%), we observed more women (57.1% vs. 35.7%, p = 0.011), and patients were older (69.1 ± 10.4 years vs. 64.0 ± 9.7 years, p = 0.005). In the whole population, all-cause death was reported in 29.9% of patients, myocardial infarction (MI) rate-in 11.8%, and stroke-in 4.9%. In the multivariable analysis, independent predictors of death were age 65-75 years (HR 2.88), age > 75 years (HR 8.07), diabetes (HR 1.59), previous MI (HR 1.64), chronic kidney disease (HR 2.22), unstable angina (HR 0.37), and left ventricular ejection fraction > 60% (HR 0.43). Conclusions: Over a 10 year follow-up, the all-cause death rate was 29.9%, showing no statistically significant differences between patients with and without significant RAS.
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Psoriasis is one of the most common skin diseases and a crucial issue to manage in contemporary dermatology. The search for the details of its pathogenesis, markers and treatment is continuously ongoing. Our aim was to investigate the role of gasdermin B (GSDMB) in psoriasis, the second protein from the gasdermin family, involved in cell death and proliferation. GSDMB serum and urinary concentrations have never been studied in psoriatics, neither tissue expression of GSDMB by immunohistochemistry. The study included 60 psoriatic patients and 30 volunteers without dermatoses as controls. The serum and urinary GSDMB were evaluated by ELISA. Tissue expression of GSDMB was analyzed by immunohistochemistry. The serum and absolute urine concentrations of GSDMB were significantly higher in psoriatic patients than controls without skin diseases (p = 0.0137, p = 0.039 respectively). Urinary GSDMB/creatinine concentration ratio was significantly lower in patients compared to controls (p = 0.0241). The expression of GSDMB in the dermis and epidermis was significantly more prevalent in psoriatic plaque compared to the non-lesional skin and healthy skin of controls (p = 0.0012, p = 0.017, respectively). Serum GSDMB correlated positively with the age of patients (R = 0.41; p = 0.001). Our study adds to the current state of knowledge about psoriasis concerning the potential involvement of GSDMB. Possibly it could be engaged in keratinocytes migration, which requires further research. Elevated serum GSDMB and decreased urinary GSDMB/creatinine concentration ratio could potentially be investigated as psoriasis biomarkers. GSDMB could be investigated in the future as a potential therapeutic target.
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Background: The purpose of the study was to determine whether the use of ß-adrenoceptor antagonists (ß-blockers) can affect metalloproteinase 2 (MMP-2) and its tissue inhibitor (TIMP-2) in patients with chronic kidney disease (CKD) on conservative treatment. Methods: The circulating MMP-2/TIMP-2 system, proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the marker of oxidative stress-Cu/Zn superoxide dismutase (Cu/Zn SOD)-were measured in 23 CKD patients treated with ß-blockers [ß-blockers (+)] and in 27 CKD patients not receiving the above medication [ß-blockers (-)]. Results: The levels of MMP-2, TIMP-2, and IL-6 were significantly lower in the ß-blockers (+) than in the ß-blockers (-) group, whereas Cu/Zn SOD concentrations were not affected by ß-blocker use. There was a strong, independent association between MMP-2 and TIMP-2 in both analyzed patient groups. In the ß-blockers (+) group, MMP-2 levels were indirectly related to the signs of inflammation, whereas in the ß-blockers (-) group, the alterations in the MMP-2/TIMP-2 system were associated with the oxidative stress marker and CKD etiology. Conclusions: This study is the first to suggest that the use of ß-blockers was associated with the reduction in IL-6 and the MMP-2/TIMP-2 system in CKD, providing a pharmacological rationale for the use of ß-blockers to reduce inflammation and abnormal vascular remodeling in CKD.
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Naltrexone (NTX) is a non-selective antagonist of opioid receptors, primarily used in the therapy of opioid and alcohol dependence. Low-dose naltrexone (LDN) exhibits antagonistic action against the opioid growth factor receptor (OGFr), whose signaling is associated with the survival, proliferation, and invasion of cancer cells. The mechanism of action of LDN depends on the dose and duration of the OGFr blockade, leading to a compensatory increase in the synthesis of the opioid growth factor (OGF), which has an inhibitory effect on carcinogenesis. Numerous studies on in vitro and in vivo models provide evidence of LDN's positive impact on inhibiting the OGF-OGFr axis in cancers. LDN's unique mechanism of action on cancer cells, lack of direct cytotoxic effect, and immunomodulating action form the basis for its use as an adjuvant in chemotherapy and immunotherapy of cancerous lesions.
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Indoxyl sulfate (IS), an agonist of aryl hydrocarbon receptors (AhR), can accumulate in patients with chronic kidney disease, but its direct effect on bone is not clear. The present study investigated the effect of chronic exposure to low (100 mg/kg b.w.; 100 IS) and high (200 mg/kg b.w.; 200 IS) dose of IS on bone AhR pathway, sirtuins (SIRTs) expression, oxidative DNA damage and bone mineral status in Wistar rats. The accumulation of IS was observed only in trabecular bone tissue in both doses. The differences were observed in the bone parameters, depending on the applied IS dose. The exposure to 100 IS increased AhR repressor (AhRR)-CYP1A2 gene expression, which was associated with SIRT-1, SIRT-3 and SIRT-7 expression. At the low dose group, the oxidative DNA damage marker was unchanged in the bone samples, and it was inversely related to the abovementioned SIRTs expression. In contrast, the exposure to 200 IS reduced the expression of AhRR, CYP1A, SIRT-3 and SIRT-7 genes compared to 100 IS. The level of oxidative DNA damage was higher in trabecular bone in 200 IS group. Femoral bone mineral density was decreased, and inverse relations were noticed between the level of trabecular oxidative DNA damage and parameters of bone mineral status. In conclusion, IS modulates AhR-depending signaling affecting SIRTs expression, oxidative DNA damage and bone mineral status in a dose dependent manner.
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Indicán , Sirtuinas , Humanos , Ratas , Animales , Ratas Wistar , Receptores de Hidrocarburo de Aril/metabolismo , Estrés Oxidativo , Expresión Génica , Sirtuinas/genética , Sirtuinas/metabolismoRESUMEN
Psoriasis is a complex disease that nowadays is considered not only a dermatosis but a kind of systemic disorder associated with many accompanying diseases. Metabolic complications leading to cardiovascular incidences are the cause of increased mortality in psoriatic patients. Galectins (gal) are beta-galactoside-binding lectins that exert different functions, including engagement in metabolic processes. Our aim was to assess the concentrations of gal-1, 2 and 12 in psoriatics, to establish their potential clinical implications, including in metabolic complications. Plasma galectins were assessed by ELISA in 60 psoriatic patients and 30 controls without dermatoses and a negative family history of psoriasis. Plasma concentrations of all galectins were significantly higher in patients than controls (gal-1 with p < 0.001, gal-2 and 12 with p < 0.05). There were no correlations between galectins concentrations and psoriasis severity in PASI or disease duration (p > 0.05). Gal-1 and 12 were significantly negatively correlated with GFR (p < 0.05, p < 0.01, respectively) and gal-2 with HDL (p < 0.05). Gal-2 was significantly positively correlated with CRP (p < 0.05) and gal-12 with fasting glucose (p < 0.01). Based on the results and given the reported role of galectins in metabolic disorders we may conclude that gal-1, 2 and 12 could be potentially engaged in metabolic complications in psoriatics, most probably in atherosclerosis. Gal-2 could be perhaps further investigated as a marker of metabolically induced inflammation in psoriasis, gal-1 and gal-12 as predictors of renal impairment in psoriatics due to metabolic disorders. Potentially, gal-12 could be considered in the future as a marker of carbohydrate metabolism disorders in psoriatics.
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Enfermedades Metabólicas , Psoriasis , Humanos , Galectina 3/metabolismo , Galectinas/metabolismo , Galectina 2RESUMEN
Psoriasis is an important issue in daily dermatological practice. Not only is it an aesthetic defect but it is also a matter of decreased life quality and economic burden. However frequent, the pathogenesis of psoriasis remains uncertain despite numerous investigations. Gasdermins are a family of six proteins. Gasdermin D (GSDMD) is the best-studied from this group and is involved in the processes of inflammation, proliferation, and death of cells, especially pyroptosis. GSDMD has never been studied in psoriatic sera or urine before. Our study involved 60 patients with psoriasis and 30 volunteers without dermatoses as controls. Serum and urinary GSDMD concentrations were examined by ELISA. The tissue expression of GSDMD was assessed by immunohistochemistry. The serum-GSDMD concentration was insignificantly higher in the patients than controls. There were no differences in the urinary-GSDMD concentrations between the patients and controls. Strong tissue expression of GSDMD was significantly more prevalent in psoriatic plaque than in the non-lesional skin and healthy skin of the controls. There was no correlation between the serum-GSDMD concentrations and the psoriasis severity in PASI, age, or disease duration. Taking into consideration the documented role of gasdermins in cell proliferation and death, the increased expression of GSDMD in psoriatic skin may demonstrate the potential involvement of this protein in psoriasis pathogenesis. Neither serum, nor urinary GSDMD can be currently considered a psoriasis biomarker; however, future studies may change this perspective.
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Líquidos Corporales , Psoriasis , Humanos , Gasderminas , Piel , Psoriasis/genética , Proliferación Celular , Proteínas de Unión a Fosfato/genética , Proteínas Citotóxicas Formadoras de PorosRESUMEN
Psoriasis is a frequent and incurable skin disease whose pathogenesis is still not fully understood. It is characterized by immune disturbances leading to hyperproliferation and improper differentiation of keratinocytes. Gasdermin E (GSDME) is a protein from the gasdermin family involved in the processes of inflammation and cell death based on apoptosis, necroptosis and pyroptosis. It has never been studied in psoriatics' sera or urine before. Our study enrolled 60 patients with psoriasis and 30 volunteers without dermatoses as controls. Serum and urinary GSDME concentrations were examined by ELISA and tissue expression of GSDME by immunohistochemistry. Serum GSDME concentration was significantly higher in patients than controls (p < 0.05). There were no differences in urinary GSDME concentrations between patients and controls. GSDME expression was significantly higher in the psoriatic plaque than non-lesional patients' skin and compared to controls (both p < 0.001). There was no correlation between serum GSDME or its lesional expression and psoriasis severity, age or disease duration. GSDME serum concentration was significantly negatively correlated with BMI, triglycerides and glucose concentrations. The obtained results suggest the engagement of GSDME in psoriasis pathogenesis. It could potentially become a new non-invasive psoriasis marker. Considering its pro-apoptotic influence, GSDME could be compensatively elevated to direct cells towards apoptosis, whereas under other circumstances, it may lead to pyroptosis and sustain inflammation. GSDME may exert a protective influence on the metabolic complications in psoriasis which requires further studies.
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Líquidos Corporales , Psoriasis , Humanos , Gasderminas , Piel , InflamaciónRESUMEN
INTRODUCTION: Psoriasis, one of the most frequent dermatoses, strongly associated with metabolic disorders which increase patients' comorbidity and mortality. Hence, it is essential to look for markers of such complications. Our aim was to assess the clinical utility of urinary tumor necrosis factor alpha (TNFα), endothelin 1 (ET-1) and α1-acid glycoprotein (α1AGP) as well as their serum concentrations as markers of metabolic complications in psoriatics, and to examine the relations of these markers to clinical and demographic parameters. METHODS: The study involved 60 patients with plaque psoriasis and 30 volunteers without skin diseases (the control group). Serum and urinary concentrations of TNFα, ET-1 and α1AGP were measured by ELISA. Psoriasis severity was assessed using the psoriasis activity and severity index (PASI). Routine laboratory investigations were additionally performed. RESULTS: All serum markers were significantly higher in the patients compared to the controls. TNFα was undetectable in the urine in half of the patients. The urinary ET-1/creatinine concentration ratio was significantly lower in the psoriatics than the controls, whereas the absolute urinary α1AGP was significantly higher and the α1AGP/creatinine ratio was insignificantly different. There was no correlation between serum or urinary markers and PASI. All serum markers were higher in patients with psoriasis lasting less than 15 years. CONCLUSIONS: Serum TNFα, ET-1 and α1AGP seem to be useful biomarkers of metabolic syndrome in psoriatics. ET-1 could perhaps become a urinary marker of metabolic disorders in psoriatics, but further studies are required to confirm that a decreased ET-1 concentration in urine is a reliable predictive tool. Increased urinary α1AGP also requires more in-depth research as a potential marker. TNFα urine assessment does not seem to be useful for screening for metabolic disorders in psoriatics. Serum or urinary TNFα, ET-1 and α1AGP do not seem to be associated with psoriasis severity or duration.
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BACKGROUND: Seeing that there are no data about associations between serotonin gene polymorphism and tryptophan catabolite concentration during PEG-IFN-α2a treatment, the aim of the current study is to examine (a) the associations between polymorphisms within the HTR1A, TPH2, and 5-HTT genes and the severity of depression symptoms and (b) the relationships among rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms and indoleamine 2,3-dioxygenase (IDO) activity, as well as kynurenine (KYN), tryptophan (TRP), kynurenic acid (KA), and anthranilic acid (AA) concentrations. MATERIALS AND METHODS: The study followed a prospective, longitudinal, single-center cohort design. The severity of the depressive symptoms of 101 adult patients with chronic HCV infections was measured during PEG-IFN-α2a/RBV treatment. We used the Montgomery-Åsberg Depression Rating Scale (MADRS) to assess the severity of depressive symptoms. The subjects were evaluated six times-at baseline and at weeks 2, 4, 8, 12, and 24. At all the time points, MADRS score, as well as KYN, TRP, KA, and AA concentrations, and IDO activity were measured. At baseline, rs6295, rs4570625, and 5-HTTLPR rs25531polymorphisms were assessed. RESULTS: Subjects with C/C genotypes of 5-HT1A and lower-expressing alleles (S/S, LG/LG, and S/LG) of 5-HTTLPR scored the highest total MADRS scores and recorded the highest increase in MADRS scores during treatment. We found associations between TRP concentrations and the TPH-2 and 5-HTTLPR rs25531 genotypes. CONCLUSIONS: Our findings provide new data that we believe can help better understand infection-induced depression as a distinct type of depression.
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Depresión , Hepatitis C Crónica , Interferón alfa-2 , Triptófano , Adulto , Humanos , Antivirales/uso terapéutico , Depresión/genética , Depresión/metabolismo , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/genética , Interferón alfa-2/efectos adversos , Interferón alfa-2/farmacología , Interferón alfa-2/uso terapéutico , Quinurenina , Polietilenglicoles/farmacología , Polimorfismo Genético , Estudios Prospectivos , Receptor de Serotonina 5-HT1A/genética , Ribavirina/efectos adversos , Ribavirina/farmacología , Ribavirina/uso terapéutico , Triptófano/efectos de los fármacos , Triptófano/metabolismo , Triptófano Hidroxilasa/genética , Triptófano Oxigenasa/genéticaRESUMEN
In the last few decades, there has been a growing interest in Bruton's tyrosine kinase (BTK) and the compounds that target it. BTK is a downstream mediator of the B-cell receptor (BCR) signaling pathway and affects B-cell proliferation and differentiation. Evidence demonstrating the expression of BTK on the majority of hematological cells has led to the hypothesis that BTK inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias and lymphomas. However, a growing body of experimental and clinical data has demonstrated the significance of BTK, not just in B-cell malignancies, but also in solid tumors, such as breast, ovarian, colorectal, and prostate cancers. In addition, enhanced BTK activity is correlated with autoimmune disease. This gave rise to the hypothesis that BTK inhibitors can be beneficial in the therapy of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren's syndrome (SS), allergies, and asthma. In this review article, we summarize the most recent findings regarding this kinase as well as the most advanced BTK inhibitors that have been developed to date and their clinical applications mainly in cancer and chronic inflammatory disease patients.
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Enfermedades Autoinmunes , Neoplasias , Humanos , Agammaglobulinemia Tirosina Quinasa/metabolismo , Enfermedades Autoinmunes/tratamiento farmacológico , Transducción de Señal , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND: Glioblastoma (GB) is the most malignant primary brain tumor. Therefore, introduction of new treatment options is critically important. The aim of this study was to assess local treatment with α emitters [ 213 Bi]Bi-DOTA-substance P (SP) and [ 225 Ac]Ac-DOTA-SP. METHODS: Treatment was performed as salvage therapy in patients with recurrent primary and secondary GB. [ 213 Bi]Bi-DOTA-SP with injected activity 1.85 GBq per cycle was used in 20 primary (48.2 ± 11.8 years old) and in 9 secondary (38.8 ± 10.8 years old) GB patients and [ 225 Ac]Ac-DOTA-SP in 15 primary (45.1 ± 9.9 years old) and in 6 secondary (37.8 ± 6.4 years old) GB patients with a dose escalation scheme (10, 20, and 30 MBq). RESULTS: Local treatment with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP was well tolerated with only few adverse effects. There was no statistically significant difference between [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP groups in survival parameters. For primary GB, survival parameters of patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows(in months): progression-free survival time, 2.7 versus 2.4; OS-d (overall survival from time of diagnosis to death from any cause), 23.6 versus 21.0; OS-t (overall survival from the start of treatment to death from any cause), 7.5 versus 5.0; and OS-r (overall survival from recurrence in primary tumors to death from any cause), 10.9 versus 12.0. Survival parameters of secondary GB patients treated with [ 213 Bi]Bi-DOTA-SP and [ 225 Ac]Ac-DOTA-SP were as follows (in months): progression-free survival time, 5.8 versus 2.4; OS-d, 52.3 versus 65.0; OS-t, 16.4 versus 16.0; and OS-c (overall survival from conversion into secondary GB multiforme to death from any cause), 18.4 versus 36.0. CONCLUSIONS: The similarity results of 213 Bi or 225 Ac may suggest that the local treatment of brain tumors can be greatly simplified. The experience to date shows that local radioisotope treatment of brain tumors requires further dosimetry studies, taking into account the complexity of biological processes.