RESUMO
Impaired clearance of amyloid ß (Aß) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aß clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aß-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes in human cerebrospinal fluid (CSF) and their migration in an APP/PS1 mouse model. The assay reveals macrophage-like Aß-binding monocytes with high phagocytic potential in both the periphery and CNS. We find lower surface Aß levels in mild cognitive impairment (MCI) and AD-dementia patients compared to cognitively unimpaired individuals. Monocyte infiltration from blood to CSF and migration from CNS to peripheral lymph nodes and blood are observed. Here we show that Aß-binding monocytes may play a role in CNS Aß clearance, suggesting their potential as a biomarker for AD diagnosis and monitoring.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Disfunção Cognitiva , Progressão da Doença , Camundongos Transgênicos , Monócitos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Doença de Alzheimer/sangue , Humanos , Monócitos/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Feminino , Idoso , Masculino , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/líquido cefalorraquidiano , Camundongos , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/metabolismo , Citometria de Fluxo , Modelos Animais de Doenças , Fagocitose , Pessoa de Meia-IdadeRESUMO
Background: It is estimated that â¼60% of people with Alzheimer's disease (AD) are undetected or undiagnosed, with higher rates of underdiagnosis in low-to middle-income areas with limited medical resources. To promote health equity, we have developed a web-based tool that utilizes easy-to-collect clinical data to enhance AD detection rate in primary care settings. Methods: This study was leveraged on the data collected from participants of the Australian Imaging, Biomarker & Lifestyle (AIBL) study and the Religious Orders Study and Memory and Aging Project (ROSMAP). The study included three phases: (1) constructing and evaluating a model on retrospective cohort data (1407 AIBL participants), (2) performing simulated trials to assess model accuracy (30 AIBL participants) and missing data tolerability (30 AIBL participants), and (3) external evaluation using a non-Australian dataset (500 ROSMAP participants). The auto-score machine learning algorithm was employed to develop the Florey Dementia Risk Score (FDRS). All the simulated trials and evaluation were performed using a web-based FDRS tool. Findings: FDRS achieved an area under the curve (AUC) of approximately 0.82 [95% CI, 0.75-0.88], with a sensitivity of 0.74 [0.60-0.86] and a specificity of 0.73 [0.70-0.79]. The accuracy of the simulated pilot trial for 30 AIBL participants with complete record was 87% (26/30 correct), while it only slightly decreased (80.0-83.3%, depending on imputation methods) for another 30 AIBL participants with one or two missing data. FDRS achieved an AUC of 0.82 [0.77-0.86] of 500 ROSMAP participants. Interpretation: The FDRS tool offers a potential low-cost solution to AD screening in primary care. The present study warrants future trials of FDRS for optimization and to confirm its generalizability across a more diverse population, especially people in low-income countries. Funding: National Health and Medical Research Council, Australia (GNT2007912) and Alzheimer's Association, USA (23AARF-1020292).
RESUMO
BACKGROUND: Previous clinical and basic studies have revealed that ginseng might have cardioprotective properties against anthracycline-induced cardiotoxicity (AIC). However, the underlying mechanism of ginseng action against AIC remains insufficiently understood. The aim of this study was to explore the related targets and pathways of ginseng against AIC using network pharmacology, molecular docking, cellular thermal shift assay (CETSA) and molecular dynamics (MD) simulations. RESULTS: Fourteen drug-disease common targets were identified. Enrichment analysis showed that the AGE-RAGE in diabetic complications, fluid shear stress and atherosclerosis, and TNF signaling pathway were potentially involved in the action of ginseng against AIC. Molecular docking demonstrated that the core components including Kaempferol, beta-Sitosterol, and Fumarine had notable binding activity with the three core targets CCNA2, STAT1, and ICAM1. Furthermore, the stable complex of STAT1 and Kaempferol with favorable affinity was further confirmed by CETSA and MD simulation. CONCLUSIONS: This study suggested that ginseng might exert their protective effects against AIC through the derived effector compounds beta-Sitosterol, Kaempferol and Fumarine by targeting CCNA2, STAT1, and ICAM1, and modulating AGE-RAGE in diabetic complications, fluid shear stress and atherosclerosis, and TNF signaling pathways.
Assuntos
Antraciclinas , Cardiotoxicidade , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Farmacologia em Rede , Panax , Panax/química , Antraciclinas/efeitos adversos , Antraciclinas/química , Antraciclinas/toxicidade , Humanos , Sitosteroides/farmacologia , Sitosteroides/química , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética , Quempferóis/farmacologia , Quempferóis/química , Transdução de Sinais/efeitos dos fármacosRESUMO
Background: Observational Alzheimer's disease (AD) cohorts including the Australian, Biomarkers, Imaging and Lifestyle (AIBL) Study have enhanced our understanding of AD. The generalizability of findings from AIBL to the general population has yet to be studied. Objective: We aimed to compare characteristics of people with AD dementia in AIBL to 1) the general population of older Australians using pharmacological treatment for AD dementia, and to 2) the general population of older Australians who self-reported a diagnosis of dementia. Methods: Descriptive study comparing people aged 65 years of over (1) in AIBL that had a diagnosis of AD dementia, (2) dispensed with pharmacological treatment for AD in Australia in 2021 linked to the Australian census in 2021 (refer to as PBS/census), (3) self-reported a diagnosis of dementia in the 2021 Australian census (refer to as dementia/census). Baseline characteristics included age, sex, highest education attainment, primary language, and medical co-morbidities. Results: Participants in AIBL were younger, had more years of education, and had a lower culturally and linguistically diverse (CALD) population compared to the PBS/census cohort and dementia/census cohort (mean age±standard deviation - AIBL 79±7 years, PBS/census 81±7, pâ<â0.001, dementia/census 83±8, pâ<â0.001; greater than 12 years of education AIBL 40%, PBS/census 35%, pâ=â0.020, dementia/census 29%, pâ<â0.001; CALD - AIBL 3%, PBS/census 20%, pâ<â0.001, dementia/census 22%, pâ<â0.001). Conclusions: Our findings suggest that care should be taken regarding the generalizability of AIBL in CALD populations and the interpretation of results on the natural history of AD.
Assuntos
Doença de Alzheimer , Humanos , Austrália/epidemiologia , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/diagnóstico , Feminino , Masculino , Idoso , Idoso de 80 Anos ou mais , Estudos Longitudinais , Estudos de CoortesRESUMO
Introduction: Pharmacological management is a vital aspect of dementia care. Suboptimal medication prescribing and adverse drug reactions are major causes for ongoing concerns for the quality of care. This review aims to investigate the existence and comprehensiveness of Australian guidelines dedicated to supporting dementia care in the context of pharmacological management. Methods: Guideline registries and databases (EMBASE and CINAHL) were searched to identify Australian guidelines addressing pharmacological management in dementia care and to uncover barriers and considerations associated with guideline implementation. Results: Seven Australian guidelines were identified. Barriers to effective implementation were identified at individual, provider, and system levels. None of the identified guidelines provided comprehensive guidance on management of multimorbidity and polypharmacy. Discussion: Although Australian guidelines are available to guide pharmacological management in dementia, several barriers impede their effective implementation. There is an urgent need for updated guidelines that address the management of multimorbidity and polypharmacy in people living with dementia.
Assuntos
Demência , Multimorbidade , Polimedicação , Guias de Prática Clínica como Assunto , Humanos , Demência/tratamento farmacológico , AustráliaRESUMO
PURPOSE: Alzheimer's disease (AD) is associated with brain accumulation of amyloid-beta (Aß) and neurofibrillary tangle formation, in addition to reduced brain docosahexaenoic acid (DHA) and increased brain iron levels. DHA requires access across the blood-brain barrier (BBB) to enter the brain, and iron has been shown to affect the expression and function of a number of BBB transporters. Therefore, this study aimed to assess the effect of iron on the expression and function of fatty acid binding protein 5 (FABP5) and fatty acid transport protein 1 (FATP1), both which mediate brain endothelial cell trafficking of DHA. METHODS: The mRNA and protein levels of FABP5 and FATP1 in human cerebral microvascular endothelial (hCMEC/D3) cells was assessed by RT-qPCR and Western blot, respectively following ferric ammonium citrate (FAC) treatment (up to 750 µM, 72 h). The function of FABP5 and FATP1 was assessed via uptake and efflux of radiolabelled 3H-oleic acid and 14C-DHA. RESULTS: FAC (500 µM, 72 h) had no impact on the expression of FABP5 at the protein and mRNA level in hCMEC/D3 cells, which was associated with a lack of effect on the uptake of 14C-DHA. FAC led to a 19.7% reduction in FATP1 protein abundance in hCMEC/D3 cells with no impact on mRNA levels, and this was associated with up to a 32.6% reduction in efflux of 14C-DHA. CONCLUSIONS: These studies demonstrate a role of iron in down-regulating FATP1 protein abundance and function at the BBB, which may have implications on fatty acid access to the brain.
Assuntos
Barreira Hematoencefálica , Encéfalo , Células Endoteliais , Proteínas de Transporte de Ácido Graxo , Proteínas de Ligação a Ácido Graxo , Humanos , Proteínas de Transporte de Ácido Graxo/metabolismo , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Ácidos Graxos/metabolismo , Compostos Férricos , Linhagem Celular , Transporte Biológico/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Ferro/metabolismo , Microvasos/metabolismo , Microvasos/citologia , Microvasos/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Ácidos Docosa-Hexaenoicos/farmacologiaRESUMO
In present study, whey protein isolate fibrils and sodium alginate complexes (WPIFs-SA) were prepared and further used to stabilize Pickering emulsions for lycopene delivery. The optimal interaction between WPIFs and SA occurred at pH 3.0, with a mass ratio of 2:1. Increasing the oil fractions and the content of WPIFs-SA complexes significantly improved Pickering emulsions' stability, concurrently reducing droplet size and increasing viscoelasticity. Meanwhile, it facilitated the formation of a thicker protective layer and a compact network structure around the oil droplets, offering better protection for lycopene against thermal and photo degradation. In vitro digestion studies revealed that as the oil fractions and complex contents increased, the lipolysis degree decreased. The engineered WPIFs-SA Pickering emulsion could be used as an innovative delivery system for the protection and delivery of lycopene.
Assuntos
Alginatos , Emulsões , Licopeno , Proteínas do Soro do Leite , Proteínas do Soro do Leite/química , Alginatos/química , Licopeno/química , Concentração de Íons de Hidrogênio , Digestão , Viscosidade , Tamanho da Partícula , Carotenoides/química , Lipólise , Ácido Glucurônico/química , Ácidos Hexurônicos/químicaRESUMO
Several (inter)national longitudinal dementia observational datasets encompassing demographic information, neuroimaging, biomarkers, neuropsychological evaluations, and muti-omics data, have ushered in a new era of potential for integrating machine learning (ML) into dementia research and clinical practice. ML, with its proficiency in handling multi-modal and high-dimensional data, has emerged as an innovative technique to facilitate early diagnosis, differential diagnosis, and to predict onset and progression of mild cognitive impairment and dementia. In this review, we evaluate current and potential applications of ML, including its history in dementia research, how it compares to traditional statistics, the types of datasets it uses and the general workflow. Moreover, we identify the technical barriers and challenges of ML implementations in clinical practice. Overall, this review provides a comprehensive understanding of ML with non-technical explanations for broader accessibility to biomedical scientists and clinicians.
Assuntos
Demência , Aprendizado de Máquina , Humanos , Demência/diagnóstico , Pesquisa Biomédica/métodos , Neuroimagem/métodosRESUMO
BACKGROUND: The associations between mood disorders (anxiety and depression) and mild cognitive impairment (MCI) or Alzheimer's dementia (AD) remain unclear. METHODS: Data from the Australian Imaging, Biomarker & Lifestyle (AIBL) study were subjected to logistic regression to determine both cross-sectional and longitudinal associations between anxiety/depression and MCI/AD. Effect modification by selected covariates was analysed using the likelihood ratio test. RESULTS: Cross-sectional analysis was performed to explore the association between anxiety/depression and MCI/AD among 2,209 participants with a mean [SD] age of 72.3 [7.4] years, of whom 55.4% were female. After adjusting for confounding variables, we found a significant increase in the odds of AD among participants with two mood disorders (anxiety: OR 1.65 [95% CI 1.04-2.60]; depression: OR 1.73 [1.12-2.69]). Longitudinal analysis was conducted to explore the target associations among 1,379 participants with a mean age of 71.2 [6.6] years, of whom 56.3% were female. During a mean follow-up of 5.0 [4.2] years, 163 participants who developed MCI/AD (refer to as PRO) were identified. Only anxiety was associated with higher odds of PRO after adjusting for covariates (OR 1.56 [1.03-2.39]). However, after additional adjustment for depression, the association became insignificant. Additionally, age, sex, and marital status were identified as effect modifiers for the target associations. CONCLUSION: Our study provides supportive evidence that anxiety and depression impact on the evolution of MCI/AD, which provides valuable epidemiological insights that can inform clinical practice, guiding clinicians in offering targeted dementia prevention and surveillance programs to the at-risk populations.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Depressão , Humanos , Feminino , Masculino , Austrália/epidemiologia , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/psicologia , Estudos Transversais , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Disfunção Cognitiva/etiologia , Depressão/epidemiologia , Ansiedade/epidemiologia , Estilo de Vida , Biomarcadores , Estudos Longitudinais , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
INTRODUCTION: Mounting evidence suggests that certain comorbidities may influence the clinical evolution of Alzheimer's dementia (AD). METHODS: We conducted logistic regression analyses on the medical history and cognitive health diagnoses of participants in the Australian Imaging, Biomarker & Lifestyle study (n = 2443) to investigate cross-sectional associations between various comorbidities and mild cognitive impairment (MCI)/AD. RESULTS: A mixture of associations were observed. Higher comorbidity of anxiety and other neurological disorders was associated with higher odds of AD, while arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD. DISCUSSION: This study underscores the links between specific comorbidities and MCI/AD. Further research is needed to elucidate the longitudinal comorbidity-MCI/AD associations and underlying mechanisms of these associations. Highlights: Comorbidities that significantly increased AD odds included anxiety and other neurological disorders.Arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD.Alcohol consumption had the most significant confounding effect in the study.Visual-AD association was modified by age, sex, and APOE ε4 allele status.Anxiety-AD and depression-AD associations were modified by sex.
RESUMO
BACKGROUND: Lymph node metastasis (LNM) in patients with intrahepatic cholangiocarcinoma (iCCA) affects treatment strategies and prognosis. However, preoperative imaging is not reliable enough for identifying LNM. PURPOSE: To develop and validate a radiomics nomogram based on dynamic contrast enhanced (DCE)-MR images for identifying LNM and prognosis in iCCA. STUDY TYPE: Retrospective. SUBJECTS: Two hundred four patients with pathologically proven iCCA who underwent curative-intent resection and lymphadenectomy (training cohort: N = 107, internal test cohort: N = 46, and external test cohort: N = 51). FIELD STRENGTH/SEQUENCE: T1- and T2-weighted imaging, diffusion-weighted imaging and DCE imaging at 1.5 T or 3.0 T. ASSESSMENT: Radiomics features were extracted from intra- and peri-tumoral regions on preoperative DCE-MR images. Imaging features were evaluated by three radiologists, and significant variables in univariable and multivariable regression analysis were included in clinical model. The best-performing radiomics signature and clinical characteristics (intrahepatic duct dilatation, MRI-reported LNM) were combined to build a nomogram. Patients were divided into high-risk and low-risk groups based on their nomogram scores (cutoff = 0.341). Patients were followed up for 1-102 months (median 12) after surgery, the overall survival (OS) and recurrence-free survival (RFS) were calculated. STATISTICAL TESTS: Receiver operating characteristic (ROC) curve, calibration, decision curve, Delong test, Kaplan-Meier curves, log rank test. Two tailed P < 0.05 was considered statistically significant. RESULTS: The nomogram incorporating intra- and peri-tumoral radiomics features, intrahepatic duct dilatation and MRI-reported LNM obtained the best discrimination for LNM, with areas under the ROC curves of 0.946, 0.913, and 0.859 in the training, internal, and external test cohorts. In the entire cohort, high-risk patients had significantly lower RFS and OS than low-risk patients. High-risk of LNM was an independent factor of unfavorable OS and RFS. DATA CONCLUSION: The nomogram integrating intra- and peri-tumoral radiomics signatures has potential to identify LNM and prognosis in iCCA. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.
RESUMO
INTRODUCTION: Although anthracyclines have demonstrated efficacy in cancer therapy, their utilization is constrained by cardiotoxicity. In contrast, Danshen injection (DSI), derived from Salvia miltiorrhiza, has a longstanding tradition of being employed to ameliorate cardiovascular ailments, including anthracycline- induced cardiotoxicity (AIC). Nonetheless, there is a notable dearth of comprehensive systematic investigation into the molecular mechanisms underlying DSI's effects on AIC. Consequently, this study was undertaken to explore the underlying mechanism by which DSI acted against AIC. METHODS: Employing network pharmacology approach, the current investigation undertook a comprehensive analysis of the impact of DSI on AIC, which was further validated by transcriptome sequencing with in vitro AIC model. Additionally, molecular docking was conducted to evaluate the binding of active ingredients to core targets. A total of 3,404 AIC-related targets and 12 active ingredients in DSI, including chrysophanol, luteolin, tanshinone IIA, isoimperatorin, among others, were collected by differentially expressed analysis and database search, respectively. RESULTS: The network pharmacology and enrichment analysis suggested 102 potential targets and 29 signaling pathways associated with the protective effect of DSI on AIC. Three core targets (CA12, NOS3, and POLH) and calcium signaling pathways were further validated by transcriptomic analysis of the in-vitro model. The high affinity of the active ingredients binding to corresponding targets was confirmed by molecular docking. CONCLUSION: The present study suggested that DSI might exert a cardioprotective effect on AIC via the inhibition of CA12, NOS3, and POLH, as well as the modulation of calcium signaling. Further experiments are warranted to verify the findings.
Assuntos
Cardiotoxicidade , Medicamentos de Ervas Chinesas , Simulação de Acoplamento Molecular , Farmacologia em Rede , Salvia miltiorrhiza , Transcriptoma , Salvia miltiorrhiza/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Transcriptoma/efeitos dos fármacos , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/metabolismo , Humanos , Antraciclinas/química , Antraciclinas/efeitos adversos , AnimaisRESUMO
Despite recent advances in science and medical technology, pancreatic cancer remains associated with high mortality rates due to aggressive growth and no early clinical sign as well as the unique resistance to anti-cancer chemotherapy. Current numerous investigations have suggested that ferroptosis, which is a programed cell death driven by lipid oxidation, is an attractive therapeutic in different tumor types including pancreatic cancer. Here, we first demonstrated that linoleic acid (LA) and α-linolenic acid (αLA) induced cell death with necroptotic morphological change in MIA-Paca2 and Suit 2 cell lines. LA and αLA increased lipid peroxidation and phosphorylation of RIP3 and MLKL in pancreatic cancers, which were negated by ferroptosis inhibitor, ferrostatin-1, restoring back to BSA control levels. Similarly, intraperitoneal administration of LA and αLA suppresses the growth of subcutaneously transplanted Suit-2 cells and ameliorated the decreased survival rate of tumor bearing mice, while co-administration of ferrostatin-1 with LA and αLA negated the anti-cancer effect. We also demonstrated that LA and αLA partially showed ferroptotic effects on the gemcitabine-resistant-PK cells, although its effect was exerted late compared to treatment on normal-PK cells. In addition, the trial to validate the importance of double bonds in PUFAs in ferroptosis revealed that AA and EPA had a marked effect of ferroptosis on pancreatic cancer cells, but DHA showed mild suppression of cancer proliferation. Furthermore, treatment in other tumor cell lines revealed different sensitivity of PUFA-induced ferroptosis; e.g., EPA induced a ferroptotic effect on colorectal adenocarcinoma, but LA or αLA did not. Collectively, these data suggest that PUFAs can have a potential to exert an anti-cancer effect via ferroptosis in both normal and gemcitabine-resistant pancreatic cancer.
Assuntos
Cicloexilaminas , Ferroptose , Neoplasias Pancreáticas , Fenilenodiaminas , Camundongos , Animais , Gencitabina , Ácidos Graxos Insaturados/farmacologia , Ácidos Graxos Insaturados/metabolismo , Ácido Linoleico , Linhagem Celular Tumoral , Neoplasias Pancreáticas/patologiaRESUMO
An inverse association between cancer and Alzheimer's disease (AD) has been demonstrated; however, the association between cancer and mild cognitive impairment (MCI), and the association between cancer and cognitive decline are yet to be clarified. The AIBL dataset was used to address these knowledge gaps. The crude and adjusted odds ratios for MCI/AD and cognitive decline were compared between participants with/without cancer (referred to as C+ and C- participants). A 37% reduction in odds for AD was observed in C+ participants compared to C- participants after adjusting for all confounders. The overall risk for MCI and AD in C+ participants was reduced by 27% and 31%, respectively. The odds of cognitive decline from MCI to AD was reduced by 59% in C+ participants after adjusting for all confounders. The risk of cognitive decline from MCI to AD was halved in C+ participants. The estimated mean change in Clinical Dementia Rating-Sum of boxes (CDR-SOB) score per year was 0.23 units/year higher in C- participants than in C+ participants. Overall, an inverse association between cancer and MCI/AD was observed in AIBL, which is in line with previous reports. Importantly, an inverse association between cancer and cognitive decline has also been identified.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Neoplasias , Humanos , Testes Neuropsicológicos , Austrália/epidemiologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/psicologia , Biomarcadores , Estilo de Vida , Neoplasias/complicações , Neoplasias/epidemiologia , Progressão da DoençaRESUMO
The accumulation of amyloid-ß (Aß) plaques in the brain is considered a hallmark of Alzheimer's disease (AD). Mathematical modeling, capable of predicting the motion and accumulation of Aß, has obtained increasing interest as a potential alternative to aid the diagnosis of AD and predict disease prognosis. These mathematical models have provided insights into the pathogenesis and progression of AD that are difficult to obtain through experimental studies alone. Mathematical modeling can also simulate the effects of therapeutics on brain Aß levels, thereby holding potential for drug efficacy simulation and the optimization of personalized treatment approaches. In this review, we provide an overview of the mathematical models that have been used to simulate brain levels of Aß (oligomers, protofibrils, and/or plaques). We classify the models into five categories: the general ordinary differential equation models, the general partial differential equation models, the network models, the linear optimal ordinary differential equation models, and the modified partial differential equation models (i.e., Smoluchowski equation models). The assumptions, advantages and limitations of these models are discussed. Given the popularity of using the Smoluchowski equation models to simulate brain levels of Aß, our review summarizes the history and major advancements in these models (e.g., their application to predict the onset of AD and their combined use with network models). This review is intended to bring mathematical modeling to the attention of more scientists and clinical researchers working on AD to promote cross-disciplinary research.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Modelos Teóricos , Encéfalo/patologia , Simulação por Computador , Placa Amiloide/patologiaRESUMO
In the present study, flaxseed gum (FG), Arabic gum (GA) and Tween 80 were used to prepare oleogels through an emulsion-templated method, and the obtained oleogels were designed for the partial substitution of pork fat in emulsified sausage. An increment in FG concentrations enhanced the viscoelasticity of emulsions, which resulted in the improved stability of emulsion systems, with smaller droplet sizes. In addition, increased FG concentrations contributed to higher mechanical strength, denser network structure and lower oil loss of oleogels. As a fat substitute, the prepared oleogels improved the textural properties and nutritional quality of emulsified sausages. With the increase in the substitution level of oleogels, the hardness and chewiness of the emulsified sausage increased, and the cooking loss decreased. Meanwhile, the reformulation with oleogels decreased the saturated fat from 57.04 g/100 g lipid to 12.05 g/100 g lipid, while increasing the ratio of omega-6 to omega-3 essential fatty acids from 0.10 to 0.39. The obtained results demonstrated that the flaxseed gum/Arabic gum/Tween 80-based oleogels had huge potential to successfully replace pork fat in emulsified sausage products.
RESUMO
P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), is critical in preventing brain access to substrate drugs and effluxing amyloid beta (Aß), a contributor to Alzheimer's disease (AD). Strategies to regulate P-gp expression therefore may impact central nervous system (CNS) drug delivery and brain Aß levels. As we have demonstrated that the copper complex copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) increases P-gp expression and function in human brain endothelial cells, the present study assessed the impact of Cu(ATSM) on expression and function of P-gp in mouse brain endothelial cells (mBECs) and capillaries in vivo, as well as in peripheral organs. Isolated mBECs treated with Cu(ATSM) (100 nM for 24 h) exhibited a 1.6-fold increase in P-gp expression and a 20% reduction in accumulation of the P-gp substrate rhodamine 123. Oral administration of Cu(ATSM) (30 mg/kg/day) for 28 days led to a 1.5 & 1.3-fold increase in brain microvascular and hepatic expression of P-gp, respectively, and a 20% reduction in BBB transport of [3H]-digoxin. A metallomic analysis showed a 3.5 and 19.9-fold increase in Cu levels in brain microvessels and livers of Cu(ATSM)-treated mice. Our findings demonstrate that Cu(ATSM) increases P-gp expression and function at the BBB in vivo, with implications for CNS drug delivery and clearance of Aß in AD.
RESUMO
Prolonged activation of microglia leads to excessive release of proinflammatory mediators, which are detrimental to brain health. Therefore, there are significant efforts to identify pathways mediating microglial activation. Recent studies have demonstrated that fatty acid-binding protein 4 (FABP4), a lipid binding protein, is a critical player in macrophage-mediated inflammation. Given that we have previously identified FABP4 in microglia, the aim of this study was to assess whether FABP4 activity contributed to inflammation, metabolism and immune function (i.e. immunometabolism) in immortalised mouse microglia (BV-2 cells) using the proinflammatory stimulus lipopolysaccharide (LPS) to induce general microglial activation. Microglial FABP4 expression was significantly increased following exposure to LPS, an outcome associated with a significant increase in microglial proliferation rate. LPS-stimulated BV-2 microglia demonstrated a significant increase in the production of reactive oxygen species (ROS) and tumour necrosis factor-alpha (TNF-α), phosphorylation of c-Jun N-terminal kinase (JNK), increased expression of Toll-like receptor 4 (TLR4), and reduced expression of uncoupling protein 2 (UCP2), all of which were reversed following FABP4 genetic silencing and chemical inhibition with BMS309403. The oxidation rate of 3H-oleic acid and microglial uptake of 3H-2-deoxy-D-glucose were modulated with LPS activation, processes which were restored with genetic and chemical inhibition of FABP4. This is the first study to report on the critical role of FABP4 in mediating the deleterious effects of LPS on microglial immunometabolism, suggesting that FABP4 may present as a novel therapeutic target to alleviate microglia-mediated neuroinflammation, a commonly reported factor in multiple neurodegenerative diseases.
Assuntos
Lipopolissacarídeos , Microglia , Animais , Camundongos , Encéfalo/metabolismo , Proteínas de Ligação a Ácido Graxo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos/toxicidadeRESUMO
Increased expression of the voltage-gated potassium channel Kv1.3 in activated microglia, and the subsequent release of pro-inflammatory mediators, are closely associated with the progression of Alzheimer's disease (AD). Studies have shown that reducing neuroinflammation through the non-selective blockade of microglial Kv1.3 has the potential to improve cognitive function in mouse models of familial AD. We have previously demonstrated that a potent and highly-selective peptide blocker of Kv1.3, HsTX1[R14A], not only entered the brain parenchyma after peripheral administration in a lipopolysaccharide (LPS)-induced mouse model of inflammation, but also significantly reduced pro-inflammatory mediator release from activated microglia. In this study, we show that microglial expression of Kv1.3 is increased in senescence accelerated mice (SAMP8), an animal model of sporadic AD, and that subcutaneous dosing of HsTX1[R14A] (1 mg/kg) every other day for 8 weeks provided a robust improvement in cognitive deficits in SAMP8 mice. The effect of HsTX1[R14A] on the whole brain was assessed using transcriptomics, which revealed that the expression of genes associated with inflammation, neuron differentiation, synapse function, learning and memory were altered by HsTX1[R14A] treatment. Further study is required to investigate whether these changes are downstream effects of microglial Kv1.3 blockade or a result of alternative mechanisms, including any potential effect of Kv1.3 blockade on other brain cell types. Nonetheless, these results collectively demonstrate the cognitive benefits of Kv1.3 blockade with HsTX1[R14A] in a mouse model of sporadic AD, demonstrating its potential as a therapeutic candidate for this neurodegenerative disease.
Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Camundongos , Animais , Peptídeos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Modelos Animais de Doenças , Inflamação , CogniçãoRESUMO
OBJECTIVES: To compare the clinical and MRI features of primary hepatic lymphoepithelioma-like carcinoma (LELC) categorized as LR-M or LR-4/5 using the Liver Imaging Reporting and Data System (LI-RADS) version 2018 and to determine the prognostic factors for recurrence-free survival (RFS). METHODS: In this retrospective study, 37 patients with surgically confirmed LELC were included. Two independent observers evaluated preoperative MRI features according to the LI-RADS version 2018. Clinical and imaging features were compared between two groups. RFS and the associated factors were evaluated using Cox proportional hazards regression analysis, Kaplan-Meier analysis, and log-rank test. RESULTS: In total, 37 patients (mean age, 58.5 ± 10.3 years) were evaluated. Sixteen (43.2%) LELCs were categorized as LR-M and twenty-one (56.8%) LELCs were categorized as LR-4/5. In the multivariate analysis, the LR-M category was an independent factor for RFS (HR 7.908, 95% CI 1.170-53.437; p = 0.033). RFS rates were significantly lower in patients with LR-M LELCs than in patients with LR-4/5 LELCs (5-year RFS rate, 43.8% vs.85.7%; p = 0.002). CONCLUSION: The LI-RADS category was significantly associated with postsurgical prognosis of LELC, with tumor categorized as LR-M having a worse RFS than those categorized as LR-4/5. KEY POINTS: ⢠Lymphoepithelioma-like carcinoma patients categorized as LR-M have worse recurrence-free survival than those categorized as LR-4/5. ⢠MRI-based LI-RADS categorization was an independent factor for postoperative prognosis of primary hepatic lymphoepithelioma-like carcinoma.