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1.
AAPS PharmSciTech ; 25(6): 149, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38954224

RESUMO

Silibinin (SIL) Encapsulated Nanoliquid Crystalline (SIL-NLCs) particles were prepared to study neuroprotective effect against amyloid beta (Aß1-42) neurotoxicity in Balb/c mice model. Theses NLCs were prepared through hot emulsification and probe sonication technique. The pharmacodynamics was investigatigated on Aß1-42 intracerebroventricular (ICV) injected Balb/c mice. The particle size, zeta potential and drug loading were optimized to be 153 ± 2.5 nm, -21 mV, and 8.2%, respectively. Small angle X-ray (SAXS) and electron microscopy revealed to crystalline shape of SIL-NLCs. Thioflavin T (ThT) fluroscence and circular dichroism (CD) technique were employed to understand monomer inhibition effect of SIL-NLCs on Aß1-4. In neurobehavioral studies, SIL-NLCs exhibited enhanced mitigation of memory impairment induced on by Aß1-42 in T-maze and new object recognition test (NORT). Whereas biochemical and histopathological estimation of brain samples showed reduction in level of Aß1-42 aggregate, acetylcholine esterase (ACHE) and reactive oxygen species (ROS). SIL-NLCs treated animal group showed higher protection against Aß1-42 toxicity compared to free SIL and Donopezil (DPZ). Therefore SIL-NLCs promises great prospect in neurodegenerative diseases such as Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides , Camundongos Endogâmicos BALB C , Fármacos Neuroprotetores , Fragmentos de Peptídeos , Silibina , Animais , Peptídeos beta-Amiloides/toxicidade , Peptídeos beta-Amiloides/metabolismo , Camundongos , Silibina/farmacologia , Silibina/administração & dosagem , Fragmentos de Peptídeos/toxicidade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Tamanho da Partícula , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Modelos Animais de Doenças , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Acetilcolinesterase/metabolismo
2.
Scand Cardiovasc J ; 58(1): 2373090, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38957080

RESUMO

OBJECTIVES: Electrocardiogram (ECG) and measurement of plasma brain natriuretic peptides (BNP) are established markers of right ventricular dysfunction (RVD) in the setting of acute pulmonary embolism (PE) but their value at long-term follow-up is largely unknown. The purpose of this prospective study was to determine the prevalence of ECG abnormalities, describe levels of N-terminal proBNP (NT-proBNP), and establish their association with dyspnea at long-term follow-up after PE. DESIGN: All Swedish patients diagnosed with acute PE in 2005 (n = 5793) were identified through the Swedish National Patient Registry. Surviving patients in 2007 (n = 3510) were invited to participate. Of these, 2105 subjects responded to a questionnaire about dyspnea and comorbidities. Subjects with dyspnea or risk factors for development of chronic thromboembolic pulmonary hypertension were included in the study in a secondary step, which involved collection of blood samples and ECG registration. RESULTS: Altogether 49.3% had a completely normal ECG. The remaining participants had a variety of abnormalities, 7.2% had atrial fibrillation/flutter (AF). ECG with any sign of RVD was found in 7.2% of subjects. Right bundle branch block was the most common RVD sign with a prevalence of 6.4%. An abnormal ECG was associated with dyspnea. AF was associated with dyspnea, whereas ECG signs of RVD were not. 61.2% of subjects had NT-proBNP levels above clinical cut-off (>125 ng/L). The degree of dyspnea did not associate independently with NT-proBNP levels. CONCLUSIONS: We conclude that the value of ECG and NT-proBNP in long term follow-up after PE lies mostly in differential diagnostics.


Assuntos
Biomarcadores , Dispneia , Eletrocardiografia , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Valor Preditivo dos Testes , Embolia Pulmonar , Sistema de Registros , Humanos , Embolia Pulmonar/sangue , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/fisiopatologia , Fragmentos de Peptídeos/sangue , Masculino , Feminino , Peptídeo Natriurético Encefálico/sangue , Suécia/epidemiologia , Biomarcadores/sangue , Idoso , Estudos Prospectivos , Dispneia/sangue , Dispneia/diagnóstico , Dispneia/epidemiologia , Dispneia/fisiopatologia , Dispneia/etiologia , Pessoa de Meia-Idade , Fatores de Tempo , Prevalência , Disfunção Ventricular Direita/sangue , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/etiologia , Fatores de Risco , Idoso de 80 Anos ou mais , Prognóstico , Função Ventricular Direita , Bloqueio de Ramo/sangue , Bloqueio de Ramo/diagnóstico , Bloqueio de Ramo/epidemiologia , Bloqueio de Ramo/fisiopatologia
3.
Clin Lab ; 70(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38965968

RESUMO

BACKGROUND: European Society of Cardiology (ESC) guidelines recommend measuring natriuretic peptides (BNP or NT-proBNP) in patients with suspected heart failure (HF) as a first-line tool. HF should be ruled-out if concen-trations of NT-proBNP are below 300 ng/L and 125 ng/L for acute HF and chronic HF, respectively. METHODS: Patients with suspected HF referred for transthoracic echocardiography (TTE) were enrolled; NT-pro-BNP concentrations were obtained from medical charts (measurement < 48 hours) or prospectively measured on the day of TTE. RESULTS: Out of 109 patients, NT-proBNP was measured by the referring department before TTE in 40 patients (36.7%), and 37.5% of these patients had NT-proBNP concentration below the rule-out threshold. NT-proBNP was measured in additional 38 patients on the day of TTE. Overall, 38.5% of the patients had a NT-proBNP concentration below the threshold value. CONCLUSIONS: Natriuretic peptides are not routinely measured in patients with suspected HF; systematic measurement would reduce unnecessary TTE by at least 38.5%.


Assuntos
Ecocardiografia , Insuficiência Cardíaca , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Humanos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Projetos Piloto , Feminino , Masculino , Ecocardiografia/métodos , Peptídeo Natriurético Encefálico/sangue , Idoso , Fragmentos de Peptídeos/sangue , Pessoa de Meia-Idade , Biomarcadores/sangue , Idoso de 80 Anos ou mais , Estudos Prospectivos , Peptídeos Natriuréticos/sangue
4.
Medicine (Baltimore) ; 103(27): e38756, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38968488

RESUMO

Physical exercise requires integrated autonomic and cardiovascular adjustments to maintain homeostasis. We aimed to observe acute posture-related changes in blood pressure, and apply a portable noninvasive monitor to measure the heart index for detecting arrhythmia among elite participants of a 246-km mountain ultra-marathon. Nine experienced ultra-marathoners (8 males and 1 female) participating in the Run Across Taiwan Ultra-marathon in 2018 were enrolled. The runners' Heart Spectrum Blood Pressure Monitor measurements were obtained in the standing and supine positions before and immediately after the race. Their high-sensitivity troponin T and N-terminal proB-type natriuretic peptide levels were analyzed 1 week before and immediately after the event. Heart rate was differed significantly in the immediate postrace assessment compared to the prerace assessment, in both the standing (P = .011; d = 1.19) and supine positions (P = .008; d = 1.35). Postural hypotension occurred in 4 (44.4%) individuals immediately postrace. In 3 out of 9 (33.3%) recruited finishers, the occurrence of premature ventricular complex signals in the standing position was detected; premature ventricular complex signal effect was observed in the supine position postrace in only 1 participant (11.1%). Premature ventricular complex signal was positively correlated with running speed (P = .037). Of the 6 individuals who completed the biochemical tests postrace, 2 (33.3%) had high-sensitivity troponin T and 6 (100%) had N-terminal proB-type natriuretic peptide values above the reference interval. A statistically significant increase was observed in both the high-sensitivity troponin T (P = .028; d = 1.97), and N-terminal proB-type natriuretic peptide (P = .028; d = 2.91) levels postrace compared to prerace. In conclusion, significant alterations in blood pressure and heart rate were observed in the standing position, and postexercise (postural) hypotension occurred among ultra-marathoners. The incidence of premature ventricular complexes was higher after the race than before.


Assuntos
Sistema Nervoso Autônomo , Pressão Sanguínea , Frequência Cardíaca , Corrida de Maratona , Peptídeo Natriurético Encefálico , Troponina T , Humanos , Feminino , Masculino , Sistema Nervoso Autônomo/fisiologia , Frequência Cardíaca/fisiologia , Corrida de Maratona/fisiologia , Adulto , Troponina T/sangue , Pessoa de Meia-Idade , Pressão Sanguínea/fisiologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Taiwan , Complexos Ventriculares Prematuros/fisiopatologia , Complexos Ventriculares Prematuros/diagnóstico , Hipotensão Ortostática/fisiopatologia , Postura/fisiologia
5.
Neurology ; 103(3): e209625, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-38950311

RESUMO

BACKGROUND AND OBJECTIVES: Prolonged cardiac monitoring (PCM) increases atrial fibrillation (AF) detection after ischemic stroke, but access is limited, and it is burdensome for patients. Our objective was to assess whether midregional proatrial natriuretic peptide (MR-proANP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) could classify people who are unlikely to have AF after ischemic stroke and allow better targeting of PCM. METHODS: We analyzed people from the Biomarker Signature of Stroke Aetiology (BIOSIGNAL) study with ischemic stroke, no known AF, and ≥3 days cardiac monitoring. External validation was performed in the Preventing Recurrent Cardioembolic Stroke: Right Approach, Right Patient (PRECISE) study of 28 days of cardiac monitoring in people with ischemic stroke or transient ischemic attack and no known AF. The main outcome is no AF detection. We assessed the discriminatory value of MR-proANP and NT-proBNP combined with clinical variables to identify people with no AF. A decision curve analysis was performed with combined data to determine the net reduction in people who would undergo PCM using the models based on a 15% threshold probability for AF detection. RESULTS: We included 621 people from the BIOSIGNAL study. The clinical multivariable prediction model included age, NIH Stroke Scale score, lipid-lowering therapy, creatinine, and smoking status. The area under the receiver-operating characteristic curve (AUROC) for clinical variables was 0.68 (95% CI 0.62-0.74), which improved with the addition of log10MR-proANP (0.72, 0.66-0.78; p = 0.001) or log10NT-proBNP (0.71, 0.65-0.77; p = 0.009). Performance was similar for the models with log10MR-proANP vs log10NT-proBNP (p = 0.28). In 239 people from the PRECISE study, the AUROC for clinical variables was 0.68 (0.59-0.76), which improved with the addition of log10NT-proBNP (0.73, 0.65-0.82; p < 0.001) or log10MR-proANP (0.79, 0.72-0.86; p < 0.001). Performance was better for the model with log10MR-proANP vs log10NT-proBNP (p = 0.03). The models could reduce the number of people who would undergo PCM by 30% (clinical and log10MR-proANP), 27% (clinical and log10NT-proBNP), or 20% (clinical only). DISCUSSION: MR-proANP and NT-proBNP help classify people who are unlikely to have AF after ischemic stroke. Measuring MR-proANP or NT-proBNP could reduce the number of people who need PCM by 30%, without reducing the amount of AF detected. TRIAL REGISTRATION INFORMATION: NCT02274727; clinicaltrials.gov/study/NCT02274727.


Assuntos
Fibrilação Atrial , Fator Natriurético Atrial , Biomarcadores , AVC Isquêmico , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Humanos , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/complicações , Masculino , Feminino , Idoso , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Pessoa de Meia-Idade , Fator Natriurético Atrial/sangue , Biomarcadores/sangue , AVC Isquêmico/sangue , AVC Isquêmico/diagnóstico , Estudos de Coortes , Idoso de 80 Anos ou mais , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia
6.
Sci Rep ; 14(1): 15083, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956086

RESUMO

The EMMY trial was a multicentre, investigator-initiated, placebo-controlled, double-blind trial, which enrolled 476 patients immediately following AMI and the first study demonstrating a significant reduction in NT-proBNP-levels as well as significant improvements in cardiac structure and function in patients after acute myocardial infarction treated with empagliflozin vs. placebo. However, hardly any data are available investigating the prognostic role of baseline electrocardiogram metrics in SGLT2-inhibitor-treated patients. This post-hoc analysis investigated the association of baseline ECG metrics collected in one centre of the trial (181 patients) with changes in structural and functional cardiac parameters as well as cardiac biomarkers in response to Empagliflozin treatment. A total of 181 patients (146 men; mean age 58 ± 14 years) were included. Median PQ-interval was 156 (IQR 144-174) milliseconds (ms), QRS width 92 (84-98) ms, QTc interval 453 (428-478) ms, Q-wave duration 45 (40-60) ms, Q-wave amplitude 0.40 (0.30-0.70) millivolt (mV), and heart rate was 71 (64-85) bpm. For functional cardiac parameters (LVEF and E/e') of the entire cohort, a greater decrease of E/e' from baseline to week 26 was observed in shorter QRS width (P = 0.005).Structural cardiac endpoints were only found to have a significant positive correlation between LVEDD and Q wave duration (P = 0.037). Higher heart rate was significantly correlated with better response in LVEF (P = 0.001), E/e' (P = 0.021), and NT-proBNP (P = 0.005). Empagliflozin-treatment showed no interaction with the results. Baseline ECG characteristics post AMI are neither predictive for beneficial NTproBNP effects of Empagliflozin post AMI, nor for functional or structural changes within 26 weeks post AMI.


Assuntos
Compostos Benzidrílicos , Biomarcadores , Ecocardiografia , Eletrocardiografia , Glucosídeos , Infarto do Miocárdio , Humanos , Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Feminino , Biomarcadores/sangue , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Idoso , Método Duplo-Cego , Peptídeo Natriurético Encefálico/sangue , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Fragmentos de Peptídeos/sangue
7.
Nat Commun ; 15(1): 5539, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38956096

RESUMO

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C2N Diagnostics' PrecivityAD test for Aß42 and Aß40. Compared to white individuals, Black individuals had higher average plasma Aß42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aß40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aß42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Fragmentos de Peptídeos , População Branca , Humanos , Peptídeos beta-Amiloides/sangue , Masculino , Feminino , Doença de Alzheimer/sangue , Doença de Alzheimer/etnologia , Estudos Longitudinais , Idoso , Fragmentos de Peptídeos/sangue , Biomarcadores/sangue , Negro ou Afro-Americano , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , População Negra
8.
Sci Rep ; 14(1): 16084, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38992063

RESUMO

Cerebrospinal fluid (CSF) core biomarkers of Alzheimer's disease (AD), including amyloid peptide beta-42 (Aß42), Aß42/40 ratio, and phosphorylated tau (pTau), are precious tools for supporting AD diagnosis. However, their use in clinical practice is limited due to the invasiveness of CSF collection. Thus, there is intensive research to find alternative, noninvasive, and widely accessible biological matrices to measure AD core biomarkers. In this study, we measured AD core biomarkers in saliva and plasma by a fully automated platform. We enrolled all consecutive patients with cognitive decline. For each patient, we measured Aß42, Aß40, and pTau levels in CSF, saliva, and plasma by Lumipulse G1200 (Fujirebio). We included forty-two patients, of whom 27 had AD. Levels of all biomarkers significantly differed in the three biofluids, with saliva having the lowest and CSF the highest levels of Aß42, Aß40, and pTau. A positive correlation of pTau, Aß42/40 ratio, and pTau/Aß42 ratio levels in CSF and plasma was detected, while no correlation between any biomarker in CSF and saliva was found. Our findings suggest that plasma but not saliva could represent a surrogate biofluid for measuring core AD biomarkers. Specifically, plasma Aß42/40 ratio, pTau/Aß42 ratio, and pTau could serve as surrogates of the corresponding CSF biomarkers.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Saliva , Proteínas tau , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/metabolismo , Saliva/metabolismo , Saliva/química , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Masculino , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/análise , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Proteínas tau/análise , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/análise , Medições Luminescentes/métodos , Idoso de 80 Anos ou mais
9.
Diabetes Res Clin Pract ; 213: 111764, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38960044

RESUMO

AIMS: To investigate the effect of hyperglycemia and empagliflozin on cardiorenal injury and inflammation in patients with uncomplicated type 1 diabetes (T1D). METHODS: Serum cardiac (sST2, Gal-3, cTnT), kidney injury (KIM-1, NGAL), inflammatory (sTNFR1, sTNFR2), and hemodynamic (NT-proBNP, EPO) markers were assessed post-hoc in two separate T1D cohorts. The glycemic clamp trial (NCT02344602) evaluated 49 adults with T1D and 27 controls under euglycemic and acute hyperglycemic conditions. The crossover BETWEEN trial (NCT02632747) investigated empagliflozin 25 mg plus ramipril for 4 weeks compared to placebo-ramipril for 4 weeks in 30 adults with T1D. RESULTS: In the glycemic clamp study, hyperglycemia acutely increased levels of NT-proBNP (p = 0.0003) and sTNFR2 (p = 0.003). BETWEEN participants treated with empagliflozin exhibited a paradoxical subacute rise in NT-proBNP (p = 0.0147) compared to placebo, independent of hematocrit. Individuals with higher baseline levels of sST2 and sTNFR1 had greater empagliflozin-associated reductions in systolic blood pressure and greater activation of renin-angiotensin-aldosterone system (RAAS) mediators, whereas those with higher baseline levels of KIM-1 and sTNFR1 had greater glomerular filtration rate (GFR) dip. CONCLUSION: The protective mechanisms of SGLT2 inhibition on blood pressure, RAAS activation, and renal hemodynamics are apparent in the subset of people with uncomplicated T1D with adverse cardiorenal and inflammatory markers.


Assuntos
Compostos Benzidrílicos , Biomarcadores , Diabetes Mellitus Tipo 1 , Glucosídeos , Hiperglicemia , Inflamação , Humanos , Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/sangue , Masculino , Feminino , Biomarcadores/sangue , Adulto , Hiperglicemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/sangue , Pessoa de Meia-Idade , Estudos Cross-Over , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Fragmentos de Peptídeos , Peptídeo Natriurético Encefálico
10.
Alzheimers Res Ther ; 16(1): 149, 2024 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-38961406

RESUMO

BACKGROUND: Enlarged choroid plexus (ChP) volume has been reported in patients with Alzheimer's disease (AD) and inversely correlated with cognitive performance. However, its clinical diagnostic and predictive value, and mechanisms by which ChP impacts the AD continuum remain unclear. METHODS: This prospective cohort study enrolled 607 participants [healthy control (HC): 110, mild cognitive impairment (MCI): 269, AD dementia: 228] from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1, 2021, and December 31, 2022. Of the 497 patients on the AD continuum, 138 underwent lumbar puncture for cerebrospinal fluid (CSF) hallmark testing. The relationships between ChP volume and CSF pathological hallmarks (Aß42, Aß40, Aß42/40, tTau, and pTau181), neuropsychological tests [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), and Activities of Daily Living (ADL) scores], and multimodal neuroimaging measures [gray matter volume, cortical thickness, and corrected cerebral blood flow (cCBF)] were analyzed using partial Spearman's correlation. The mediating effects of four neuroimaging measures [ChP volume, hippocampal volume, lateral ventricular volume (LVV), and entorhinal cortical thickness (ECT)] on the relationship between CSF hallmarks and neuropsychological tests were examined. The ability of the four neuroimaging measures to identify cerebral Aß42 changes or differentiate among patients with AD dementia, MCI and HCs was determined using receiver operating characteristic analysis, and their associations with neuropsychological test scores at baseline were evaluated by linear regression. Longitudinal associations between the rate of change in the four neuroimaging measures and neuropsychological tests scores were evaluated on the AD continuum using generalized linear mixed-effects models. RESULTS: The participants' mean age was 65.99 ± 8.79 years. Patients with AD dementia exhibited the largest baseline ChP volume than the other groups (P < 0.05). ChP volume enlargement correlated with decreased Aß42 and Aß40 levels; lower MMSE and MoCA and higher NPI and ADL scores; and lower volume, cortical thickness, and cCBF in other cognition-related regions (all P < 0.05). ChP volume mediated the association of Aß42 and Aß40 levels with MMSE scores (19.08% and 36.57%), and Aß42 levels mediated the association of ChP volume and MMSE or MoCA scores (39.49% and 34.36%). ChP volume alone better identified cerebral Aß42 changes than LVV alone (AUC = 0.81 vs. 0.67, P = 0.04) and EC thickness alone (AUC = 0.81 vs.0.63, P = 0.01) and better differentiated patients with MCI from HCs than hippocampal volume alone (AUC = 0.85 vs. 0.81, P = 0.01), and LVV alone (AUC = 0.85 vs.0.82, P = 0.03). Combined ChP and hippocampal volumes significantly increased the ability to differentiate cerebral Aß42 changes and patients among AD dementia, MCI, and HCs groups compared with hippocampal volume alone (all P < 0.05). After correcting for age, sex, years of education, APOE ε4 status, eTIV, and hippocampal volume, ChP volume was associated with MMSE, MoCA, NPI, and ADL score at baseline, and rapid ChP volume enlargement was associated with faster deterioration in NPI scores with an average follow-up of 10.03 ± 4.45 months (all P < 0.05). CONCLUSIONS: ChP volume may be a novel neuroimaging marker associated with neurodegenerative changes and clinical AD manifestations. It could better detect the early stages of the AD and predict prognosis, and significantly enhance the differential diagnostic ability of hippocampus on the AD continuum.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Plexo Corióideo , Disfunção Cognitiva , Neuroimagem , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Feminino , Masculino , Idoso , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/patologia , Estudos Prospectivos , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Neuroimagem/métodos , Biomarcadores/líquido cefalorraquidiano , Pessoa de Meia-Idade , Testes Neuropsicológicos , Imageamento por Ressonância Magnética/métodos , Proteínas tau/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano
11.
Alzheimers Res Ther ; 16(1): 146, 2024 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-38961441

RESUMO

BACKGROUND: Increasing evidence supports the use of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation for diagnosis of dementia. However, their performance for positive and differential diagnosis of dementia with Lewy bodies (DLB) in clinical settings is still uncertain. METHODS: We conducted a retrospective biomarker study in two tertiary memory centers, Paris Lariboisière and CM2RR Strasbourg, France, enrolling patients with DLB (n = 104), Alzheimer's disease (AD, n = 76), and neurological controls (NC, n = 27). Measured biomarkers included plasma Aß40/Aß42 ratio, p-tau181, NfL, and GFAP using SIMOA and plasma YKL-40 and sTREM2 using ELISA. DLB patients with available CSF analysis (n = 90) were stratified according to their CSF Aß profile. RESULTS: DLB patients displayed modified plasma Aß ratio, p-tau181, and GFAP levels compared with NC and modified plasma Aß ratio, p-tau181, GFAP, NfL, and sTREM2 levels compared with AD patients. Plasma p-tau181 best differentiated DLB from AD patients (ROC analysis, area under the curve [AUC] = 0.80) and NC (AUC = 0.78), and combining biomarkers did not improve diagnosis performance. Plasma p-tau181 was the best standalone biomarker to differentiate amyloid-positive from amyloid-negative DLB cases (AUC = 0.75) and was associated with cognitive status in the DLB group. Combining plasma Aß ratio, p-tau181 and NfL increased performance to identify amyloid copathology (AUC = 0.79). Principal component analysis identified different segregation patterns of biomarkers in the DLB and AD groups. CONCLUSIONS: Amyloid, tau, neurodegeneration and neuroinflammation plasma biomarkers are modified in DLB, albeit with moderate diagnosis performance. Plasma p-tau181 can contribute to identify Aß copathology in DLB.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Doença por Corpos de Lewy , Proteínas tau , Humanos , Doença por Corpos de Lewy/sangue , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Feminino , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Masculino , Idoso , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Estudos Retrospectivos , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Axônios/patologia , Doenças Neuroinflamatórias/sangue , Doenças Neuroinflamatórias/diagnóstico , Doenças Neuroinflamatórias/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/sangue , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Receptores Imunológicos/sangue , Diagnóstico Diferencial , Glicoproteínas de Membrana
12.
Neurology ; 103(3): e209605, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-38986053

RESUMO

BACKGROUND AND OBJECTIVES: Cognitive decline rates in Alzheimer disease (AD) vary greatly. Disease-modifying treatments may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid-positive patients with mild cognitive impairment (MCI) or mild dementia. METHODS: From the Amsterdam Dementia Cohort, we selected amyloid-positive participants with MCI or mild dementia and at least 2 longitudinal Mini-Mental State Examination (MMSE) measurements. Amyloid positivity was based on CSF AD biomarker concentrations or amyloid PET. We used linear mixed modeling to predict MMSE over time, describing trajectories using a cubic time curve and interactions between linear time and the baseline predictors age, sex, baseline MMSE, APOE ε4 dose, CSF ß-amyloid (Aß) 1-42 and pTau, and MRI total brain and hippocampal volume. Backward selection was used to reduce model complexity. These models can predict MMSE over follow-up or the time to an MMSE value. MCI and mild dementia were modeled separately. Internal 5-fold cross-validation was performed to calculate the explained variance (R2). RESULTS: In total, 961 participants were included (age 65 ± 7 years, 49% female), 310 had MCI (MMSE 26 ± 2) and 651 had mild dementia (MMSE 22 ± 4), with 4 ± 2 measurements over 2 (interquartile range 1-4) years. Cognitive decline rates increased over time for both MCI and mild dementia (model comparisons linear vs squared vs cubic time fit; p < 0.05 favoring a cubic fit). For MCI, backward selection retained age, sex, and CSF Aß1-42 and pTau concentrations as time-varying effects altering the MMSE trajectory. For mild dementia, retained time-varying effects were Aß1-42, age, APOE ε4, and baseline MMSE. R2 was 0.15 for the MCI model and 0.26 for mild dementia in internal cross-validation. A hypothetical patient with MCI, baseline MMSE 28, and CSF Aß1-42 of 925 pg/mL was predicted to reach an MMSE of 20 after 6.0 years (95% CI 5.4-6.7) and after 8.6 years with a hypothetical treatment reducing decline by 30%. DISCUSSION: We constructed models for MCI and mild dementia that predict MMSE over time. These models could inform patients about their potential cognitive trajectory and the remaining uncertainty and aid in conversations about individualized potential treatment effects.


Assuntos
Peptídeos beta-Amiloides , Disfunção Cognitiva , Demência , Fragmentos de Peptídeos , Humanos , Feminino , Masculino , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Demência/diagnóstico por imagem , Demência/líquido cefalorraquidiano , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Imageamento por Ressonância Magnética , Biomarcadores/líquido cefalorraquidiano , Testes de Estado Mental e Demência , Estudos de Coortes , Progressão da Doença , Encéfalo/diagnóstico por imagem , Encéfalo/patologia
13.
Sci Rep ; 14(1): 15996, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987609

RESUMO

Alzheimer's disease (AD) is a neurological condition that is connected with a decline in a person's memory as well as their cognitive ability. One of the key topics of AD research has been the exploration of metabolic causes. We investigated the effects of treadmill exercise and intranasal insulin on learning and memory impairment and the expression of IGF1, BDNF, and GLUT4 in hypothalamus. The animals were put into 9 groups at random. In this study, we examined the impact of insulin on spatial memory in male Wistar rats and analyzed the effects of a 4-week pretreatment of moderate treadmill exercise and insulin on the mechanisms of improved hypothalamic glucose metabolism through changes in gene and protein expression of IGF1, BDNF, and GLUT4. We discovered that rat given Aß25-35 had impaired spatial learning and memory, which was accompanied by higher levels of Aß plaque burden in the hippocampus and lower levels of IGF1, BDNF, and GLUT4 mRNA and protein expression in the hypothalamus. Additionally, the administration of exercise training and intranasal insulin results in the enhancement of spatial learning and memory impairments, the reduction of plaque burden in the hippocampus, and the enhancement of the expression of IGF1, BDNF, and GLUT4 in the hypothalamus of rats that were treated with Aß25-35. Our results show that the improvement of learning and spatial memory due to the improvement of metabolism and upregulation of the IGF1, BDNF, and GLUT4 pathways can be affected by pretreatment exercise and intranasal insulin.


Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Transportador de Glucose Tipo 4 , Hipotálamo , Fator de Crescimento Insulin-Like I , Insulina , Condicionamento Físico Animal , Ratos Wistar , Transdução de Sinais , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/terapia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Insulina/metabolismo , Ratos , Hipotálamo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Transportador de Glucose Tipo 4/genética , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Administração Intranasal , Fragmentos de Peptídeos , Memória Espacial/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos
14.
BMC Cardiovasc Disord ; 24(1): 341, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969996

RESUMO

BACKGROUND: The study evaluated the performance of the Mindray N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a healthy population in China, focusing on creating a reference range for future clinical applications adjusted according to different demographics. METHODS: The study measured NT-proBNP in 2277 healthy individuals. We analyzed age and sex-stratified data, performed precision, accuracy, linearitcvy, and detection limit studies, and evaluated method comparison and consistency between Roche and Mindray assays on 724 serum samples. We used Excel 2010, Medcalc, and GraphPad Prism 9. RESULTS: In males, the 97.5th centile NT-proBNP concentration at age < 45, 45 to 54, 55 to 64, 65 to 74 and ≧ 75 were 89.4 ng/L, 126 ng/L, 206 ng/L, 386 ng/L and 522 ng/L, respectively. In females, the concentration of NT-proBNP at the same age was 132 ng/L, 229 ng/L, 262 ng/L, 297 ng/L and 807 ng/L, respectively. The repeatability precision coefficient of variation (CV%) for NT-proBNP was between 0.86 and 1.65 in analytical performance. In contrast, the reproducibility precision (CV%) for NT-proBNP was between 1.52 and 3.22, respectively. The study found a bias of accuracy of 3.73% in low-value samples (concentration: 148.69) and 7.31% in high-value samples (concentration: 1939.08). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 125 ng/L were 96.6%, 92.3%, 84.2%, and 98.5%, respectively. In contrast, those of 300 ng/L were 94.0%, 98.2%, 95.7% and 97.5%, respectively. CONCLUSIONS: The Mindray NT-proBNP assay showed increased levels in both males and females with age, with higher levels in women. It performs well and aligns with manufacturer specifications. We recommend adjusting cutoff values based on demographic factors.


Assuntos
Biomarcadores , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Valor Preditivo dos Testes , Humanos , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Biomarcadores/sangue , Reprodutibilidade dos Testes , Adulto , China , Valores de Referência , Fatores Sexuais , Fatores Etários , Voluntários Saudáveis , Idoso de 80 Anos ou mais , Adulto Jovem , Limite de Detecção
15.
Scand Cardiovasc J ; 58(1): 2373083, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39024033

RESUMO

OBJECTIVE: This paper was performed to decipher the serum microRNA (miR)-125b-5p expression in patients with dilated cardiomyopathy (DCM) combined with heart failure (HF) and its effect on myocardial fibrosis. METHODS: Serum miR-125b-5p expression, LVEDD, LVESD, LVEF, LVFS, and NT-proBNP levels were evaluated in clinical samples. A rat DCM model was established by continuous intraperitoneal injection of adriamycin and treated with miR-125b-5p agomir and its negative control. Cardiac function, serum TNF-α, hs-CRP, and NT-proBNP levels, pathological changes in myocardial tissues, cardiomyocyte apoptosis, and the expression levels of miR-125b-5p and fibrosis-related factors were detected in rats. RESULTS: In comparison to the control group, the case group had higher levels of LVEDD, LVESD, and NT-pro-BNP, and lower levels of LVEF, LVFS, and miR-125b-5p expression levels. Overexpression of miR-125b-5p effectively led to the improvement of cardiomyocyte hypertrophy and collagen arrangement disorder in DCM rats, the reduction of blue-stained collagen fibers in the interstitial myocardium, the reduction of the levels of TNF-α, hs-CRP, and NT-proBNP and the expression levels of TGF-1ß, Collagen I, and α-SMA, and the reduction of the number of apoptosis in cardiomyocytes. CONCLUSION: Overexpression of miR-125b-5p is effective in ameliorating myocardial fibrosis.


Assuntos
Apoptose , Cardiomiopatia Dilatada , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca , MicroRNAs , Miocárdio , Função Ventricular Esquerda , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/patologia , MicroRNAs/sangue , MicroRNAs/genética , MicroRNAs/metabolismo , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Masculino , Humanos , Miocárdio/patologia , Miocárdio/metabolismo , Pessoa de Meia-Idade , Feminino , Estudos de Casos e Controles , Ratos Sprague-Dawley , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/sangue , Peptídeo Natriurético Encefálico/genética , Remodelação Ventricular , Fragmentos de Peptídeos/sangue , Adulto , MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Idoso , Volume Sistólico
16.
Sci Rep ; 14(1): 16386, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39013974

RESUMO

Presepsin (P-SEP) is a specific biomarker for sepsis. Monocytes produce P-SEP by phagocytosing neutrophil extracellular traps (NETs). Herein, we investigated whether M1 macrophages (M1 MΦs) are the primary producers of P-SEP after NET phagocytosis. We co-cultured M1 MΦs and NETs from healthy participants, measured P-SEP levels in the culture medium supernatant, and detected P-SEP using western blotting. When NETs were co-cultured with M1 MΦs, the P-SEP level of the culture supernatant was high. Notably, we demonstrated, for the first time, the intracellular kinetics of P-SEP production by M1 MΦs via NET phagocytosis: M1 MΦs produced P-SEP intracellularly 15 min after NET phagocytosis and then released it extracellularly. In a sepsis mouse model, the blood NET ratio and P-SEP levels, detected using ELISA, were significantly increased (p < 0.0001). Intracellular P-SEP analysis via flow cytometry demonstrated that lung, liver, and kidney MΦs produced large amounts of P-SEP. Therefore, we identified these organs as the origin of M1 MΦs that produce P-SEP during sepsis. Our data indicate that the P-SEP level reflects the trend of NETs, suggesting that monitoring P-SEP can be used to both assess NET-induced organ damage in the lungs, liver, and kidneys during sepsis and determine treatment efficacy.


Assuntos
Armadilhas Extracelulares , Receptores de Lipopolissacarídeos , Macrófagos , Fagocitose , Sepse , Animais , Humanos , Armadilhas Extracelulares/metabolismo , Macrófagos/metabolismo , Camundongos , Sepse/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Neutrófilos/metabolismo , Fragmentos de Peptídeos/metabolismo , Modelos Animais de Doenças , Técnicas de Cocultura
17.
CNS Neurosci Ther ; 30(7): e14857, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39014454

RESUMO

AIMS: Apply established cerebrospinal fluid (CSF) and serum biomarkers and novel combined indicators based on the amyloid/tau/neurodegeneration (ATN) framework to improve diagnostic and prognostic power in patients with rapidly progressive dementias (RPDs). METHODS: CSF and serum biomarkers of Alzheimer's disease (AD) common neuropathology including Aß42, Aß40, p-Tau, and t-Tau were measured in cognitively normal (CN) controls (n = 33) and three RPD groups with rapidly progressive AD (rpAD, n = 23), autoimmune encephalitis (AE, n = 25), and Creutzfeldt-Jakob disease (CJD, n = 28). Logistic regression and multiple linear regression were used for producing combined indicators and prognostic assessment, respectively, including A&T, A&N, T&N, A&T&N, etc. RESULTS: Combined diagnostic indicator with A&T&N had the potential for differentiating AE from other types of RPDs, identifying 62.51% and 75% of AE subjects based on CSF and serum samples, respectively, compared to 39.13% and 37.5% when using autoantibodies. CSF t-Tau was associated with survival in the CJD group (adjusted R-Square = 0.16, p = 0.02), and its prognosis value improved when using combined predictors based on the ATN framework (adjusted R-Square = 0.273, p = 0.014). CONCLUSION: Combined indicators based on the ATN framework provide a novel perspective for establishing biomarkers for early recognition of RPDs due to treatment-responsive causes.


Assuntos
Peptídeos beta-Amiloides , Biomarcadores , Demência , Progressão da Doença , Proteínas tau , Humanos , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Prognóstico , Demência/diagnóstico , Demência/sangue , Demência/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/sangue , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Idoso de 80 Anos ou mais
18.
J Am Coll Cardiol ; 84(4): 323-336, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39019527

RESUMO

BACKGROUND: Comprehensive uptitration of neurohormonal blockade targets fundamental mechanisms underlying development of congestion and may be an additional approach for decongestion after acute heart failure (AHF). OBJECTIVES: This hypothesis was tested in the STRONG-HF (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by N-Terminal Pro-Brain Natriuretic Peptide Testing of Heart Failure Therapies) trial. METHODS: In STRONG-HF, patients with AHF were randomized to the high-intensity care (HIC) arm with fast up-titration of neurohormonal blockade or to usual care (UC). Successful decongestion was defined as an absence of peripheral edema, pulmonary rales, and jugular venous pressure <6 cm. RESULTS: At baseline, the same proportion of patients in both arms had successful decongestion (HIC 48% vs UC 46%; P = 0.52). At day 90, higher proportion of patients in the HIC arm (75%) experienced successful decongestion vs the UC arm (68%) (P = 0.0001). Each separate component of the congestion score was significantly better in the HIC arm (all, P < 0.05). Additional markers of decongestion also favored the HIC: weight reduction (adjusted mean difference: -1.36 kg; 95% CI: -1.92 to -0.79 kg), N-terminal pro-B-type natriuretic peptide level, and lower orthopnea severity (all, P < 0.001). More effective decongestion was achieved despite a lower mean daily dose of loop diuretics at day 90 in the HIC arm. Among patients with successful decongestion at baseline, those in the HIC arm had a significantly better chance of sustaining decongestion at day 90. Successful decongestion in all subjects was associated with a lower risk of 180-day HF readmission or all-cause death (HR: 0.40; 95% CI: 0.27-0.59; P < 0.0001). CONCLUSIONS: In STRONG-HF, intensive uptitration of neurohormonal blockade was associated with more efficient and sustained decongestion at day 90 and a lower risk of the primary endpoint.


Assuntos
Insuficiência Cardíaca , Peptídeo Natriurético Encefálico , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Peptídeo Natriurético Encefálico/sangue , Resultado do Tratamento , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/sangue
19.
Anal Chim Acta ; 1317: 342887, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39030019

RESUMO

BACKGROUND: Procollagen type III N-terminal peptide (P-III-NP) is a fibrosis biomarker associated with liver and cardiac fibrosis. Despite the value of P-III-NP as a biomarker, its analysis currently relies on enzyme-linked immunosorbent assays (ELISA) and radioimmunoassays (RIA), which require more than 3 h. To facilitate early diagnosis and treatment through rapid biomarker testing, we developed a one-step immunoassay for P-III-NP using a quenchbody, which is a fluorescence-labeled immunosensor for immediate signal generation. RESULTS: To create quenchbodies, the total mRNA of P-III-NP antibodies was extracted from early-developed hybridoma cells, and genes of variable regions were obtained through cDNA synthesis, inverse PCR, and sequencing. A single-chain variable fragment (scFv) with an N-terminal Cys-tag was expressed in E. coli Shuffle T7, resulting in a final yield of 9.8 mg L-1. The fluorescent dye was labeled on the Cys-tag of the anti-P-III-NP scFv using maleimide-thiol click chemistry, and the spacer arm lengths between the maleimide-fluorescent dyes were compared. Consequently, a TAMRA-C6-labeled quenchbody exhibited antigen-dependent fluorescence signals and demonstrated its ability to detect P-III-NP at concentrations as low as 0.46 ng mL-1 for buffer samples, 1.0 ng mL-1 for 2 % human serum samples. SIGNIFICANCE: This one-step P-III-NP detection method provides both qualitative and quantitative outcomes within a concise 5-min timeframe. Furthermore, its application can be expanded using a 96-well platform and human serum, making it a high-throughput and sensitive method for testing fibrotic biomarkers.


Assuntos
Biomarcadores , Fibrose , Corantes Fluorescentes , Fragmentos de Peptídeos , Pró-Colágeno , Biomarcadores/sangue , Biomarcadores/análise , Humanos , Corantes Fluorescentes/química , Pró-Colágeno/sangue , Pró-Colágeno/química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Anticorpos de Cadeia Única/química , Anticorpos de Cadeia Única/imunologia , Técnicas Biossensoriais , Imunoensaio/métodos
20.
Bioorg Chem ; 150: 107584, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38964146

RESUMO

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Cinamatos , Triazóis , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Cinamatos/química , Cinamatos/farmacologia , Cinamatos/síntese química , Humanos , Camundongos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Relação Estrutura-Atividade , Estrutura Molecular , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química , Relação Dose-Resposta a Droga , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Descoberta de Drogas , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Masculino
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