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1.
Mol Pain ; : 1744806920908474, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024434

RESUMO

This cross-sectional study investigated whether the Catechol-O-methyltransferase (COMT) gene acts as a significant regulator of pain signaling pathways, regulates ß-endorphin, and contributes to ethnic differences in pain sensitivity. One-hundred-sixty healthy subjects were enrolled in this study, with Han and Uyghur groups each consisting of 80 participants. Subjects went through six pain threshold experiments. From venous blood, COMT polymorphisms were genotyped, and serum ß-endorphin levels were measured. Bivariate correlation analysis and multiple linear regression were used to identify the relationships among genotypes or ß-endorphin levels and different types of pain thresholds. Han and Uyghur ethnic differences were determined in terms of acute-pressure pain-perception thresholds, blunt-pressure pain-perception thresholds, blunt-pressure pain-tolerance thresholds, electric pain-tolerance thresholds, ß-endorphin levels, and distributions of rs4680 and rs4633 COMT polymorphisms. ß-endorphin levels did not correlate with COMT rs4680 or rs4633 genotypes in both Han and Uyghur. Statistical predictors for a lower pain-threshold performance included being young, Uyghur, female, and having a low BMI, low ß-endorphin level, and the rs4680 GA or GG allele. There is the significant difference in pain sensitivity between healthy Han and Uyghur. COMT gene variants and ß-endorphin levels contribute to ethnic differences in pain sensitivity.

2.
Psychoneuroendocrinology ; 114: 104594, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-32007669

RESUMO

Second generation antipsychotics, particularly olanzapine, induce severe obesity, which is associated with their antagonistic effect on the histamine H1 receptor (H1R). We have previously demonstrated that oral administration of olanzapine increases the concentration of neuropeptide Y (NPY) in the hypothalamus of rats, accompanied by hyperphagia and weight gain. However, it is unclear if the increased NPY after olanzapine administration is due to its direct effect on hypothalamic neurons and its H1R antagonistic property. In the present study, we showed that with an inverted U-shape dose-response curve, olanzapine increased NPY expression in the NPY-GFP hypothalamic neurons; however, this was not the case in the hypothalamic neurons of H1R knockout mice. Olanzapine inhibited the interaction of H1R and GHSR1a (ghrelin receptor) in the primary mouse hypothalamic neurons and NPY-GFP neurons examined by confocal fluorescence resonance energy transfer (FRET) technology. Furthermore, an H1R agonist, FMPH inhibited olanzapine activation of GHSR1a downstream signaling pAMPK and transcription factors of NPY (pFOXO1 and pCREB) in the hypothalamic NPY-GFP cell. However, an olanzapine analogue (E-Olan) with lower affinity to H1R presented negligible enhancement of pCREB within the nucleus of NPY neurons. These findings suggest that the H1R antagonist property of olanzapine inhibits the interaction of H1R and GHSR1a, activates GHSR1a downstream signaling pAMPK-FOXO1/pCREB and increases hypothalamic NPY: this could be one of the important molecular mechanisms of H1R antagonism of olanzapine-induced obesity in antipsychotic management of psychiatric disorders.

3.
Radiother Oncol ; 145: 186-192, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32044531

RESUMO

BACKGROUND AND PURPOSE: Manual delineation of clinical target volumes (CTVs) and organs at risk (OARs) is time-consuming, and automatic contouring tools lack clinical validation. We aimed to construct and validate the use of convolutional neural networks (CNNs) to set better contouring standards for rectal cancer radiotherapy. MATERIALS AND METHODS: We retrospectively collected and evaluated computed tomography (CT) scans of 199 rectal cancer patients treated at our hospital from February 2018 to April 2019. Two CNNs-DeepLabv3+ for extracting high-level semantic information and ResUNet for extracting low-level visual features-were used for the CTV and small intestine contouring, and bladder and femoral head contouring, respectively. Contouring quality was compared using the paired t test. Five-point objective grading was performed independently by two experienced radiation oncologists and verified by a third. The CNN manual correction time was recorded. RESULTS: CTVs calculated using DeepLabv3+ (CTVDeepLabv3+) had significant quantitative parameter advantages over CTVResUNet (volumetric Dice coefficient, 0.88 vs 0.87, P = 0.0005; surface Dice coefficient, 0.79 vs 0.78, P = 0.008). Among 315 graded cases, DeepLabv3+ obtained the highest scores with 284 cases, consistent with the objective criteria, whereas CTVResUNet had the minimum mean manual correction time (7.29 min). DeepLabv3+ performed better than ResUNet for small intestine contouring and ResUNet performed better for bladder and femoral head contouring. The manual correction time for OARs was <4 min for both models. CONCLUSION: CNNs at various feature resolution levels well delineate rectal cancer CTVs and OARs, displaying high quality and requiring shorter computation and manual correction time.

4.
Blood Purif ; : 1-6, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32018249

RESUMO

BACKGROUND/AIMS: Continuous renal replacement therapy (CRRT) has been used widely in the treatment of critically ill children for its continuity. However, sometimes we have to interrupt the continuity for necessary surgeries or blood transfusions. Our objective was to demonstrate a feasible self-circulation anticoagulation protocol based on citrate (CSAP) to address discontinuity during CRRT. METHODS: We conducted a prospective observational study of 57 pediatric patients undergoing 88 CRRT sessions that were receiving CSAP during the treatment discontinuity period by using an anticoagulation regimen containing 5 mL 4% sodium citrate in 50 mL of saline to maintain the continuity. We documented the reasons for CSAP and the total duration of the treatment. We assessed the in-line pressure recordings, blood routine examination, blood electrolytes, and blood gas analysis before, throughout, and after the period of CSAP. RESULTS: The average duration of CSAP was 118.5 ± 45.3 min. There was no significant increase in arterial pressures, venous pressures, and transmembrane pressures and no significant decreases in blood cell counts observed at the end of the CSAP, compared to the data recorded at the beginning of the CSAP. Compared to before the CSAP, there was no significant change in the ratio of total to ionized calcium, Na+, HCO3-, and pH value after CSAP. CONCLUSIONS: CSAP might be a safe, effective, and easy approach for use during the treatment discontinuity of CRRT in children.

5.
Oncol Rep ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-32020210

RESUMO

Glioblastoma (GBM) is the most common type of primary central nervous system tumor in adults, which has high mortality and morbidity rates, and short survival time, namely <15 months after the diagnosis and application of standard therapy, which includes surgery, radiation therapy and chemotherapy; thus, novel therapeutic strategies are imperative. The activation of the PI3K/AKT signaling pathway plays an important role in GBM. In the present study, U87 and U251 GBM cells were treated with the PI3K/mTORC1/2 inhibitor PQR309, and its effect on glioma cells was investigated. Cell Counting Kit­8 assay, 5­ethynyl­2'­deoxyuridine and colony formation assays revealed dose­ and time­dependent cytotoxicity in glioma cells that were treated with PQR309. Flow cytometry and western blotting revealed that PQR309 can significantly induce tumor cell apoptosis and arrest the cell cycle in the G1 phase. Furthermore, the expression levels of AKT, phosphorylated (p)­AKT, Bcl­2, Bcl­xL, Bad, Bax, cyclin D1, cleaved caspase­3, MMP­9 and MMP­2 were altered. In addition, the migration and invasion of glioma cells, as detected by wound healing, migration and Transwell invasion assays, exhibited a marked suppression after treating the cells with PQR309. These results indicated that PQR309 exerts an antitumor effect by inhibiting proliferation, inducing apoptosis, inducing G1 cell cycle arrest, and inhibiting invasion and migration in human glioma cells. The present study provides evidence supportive of further development of PQR309 for adjuvant therapy of GBM.

6.
J Cell Physiol ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32020590

RESUMO

Atherosclerosis is one of the leading causes of morbidity and mortality, mainly due to the immune response triggered by the recruitment of monocytes/macrophages in the artery wall. Accumulating evidence have shown that matrix stiffness and oxidized low-density lipoproteins (ox-LDL) play important roles in atherosclerosis through modulating cellular behaviors. However, whether there is a synergistic effect for ox-LDL and matrix stiffness on macrophages behavior has not been explored yet. In this study, we developed a model system to investigate the synergistic role of ox-LDL and matrix stiffness on macrophage behaviors, such as migration, inflammatory and apoptosis. We found that there was a matrix stiffness-dependent behavior of monocyte-derived macrophages stimulated with ox-LDL. What's more, macrophages were more sensitive to ox-LDL on the stiff matrices compared to cells cultured on the soft matrices. Through next-generation sequencing, we identified miRNAs in response to matrix stiffness and ox-LDL and predicted pathways that showed the capability of miRNAs in directing macrophages fates. Our study provides a novel understanding of the important synergistic role of ox-LDL and matrix stiffness in modulating macrophages behaviors, especially through miRNAs signaling pathways, which could be potential key regulators in atherosclerosis and immune-targeted therapies.

7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 101-105, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034731

RESUMO

OBJECTIVE: To explore the clinical feature, genetic variant and clinical outcome of patients with cblA-type methylmalonic acidemia (MMA). METHODS: Clinical manifestations, therapeutic schedule and prognosis of 12 patients with cblA type MMA were analyzed. MMAA gene variants were analyzed for all patients and their parents. RESULTS: Vomiting, dyspnea and drowsiness were the major clinical features of cblA-type MMA. Eleven patients were vitamin B12-responsive. After treatment, the blood level of propionylcarnitine, ratio of propionylcarnitine/acetylcarnitine, urine level of methylmalonic acid and methylcitric acid have decreased significantly (P< 0.05). Follow-up study showed that 8 patients (66.7%) had normal development, while the rest (33.3%) remained to have various level of mental or movement delay. Fourteen MMAA gene variants were detected, with c.365T>C (p.L122P) being the most common (29.2%). Six novel variants, including c.54delA (p.A19Hfs*43), c.275G>A (p.G92V), c.456delT (p.G153Vfs*8), c.667dupA (p.T223Nfs*4), c.1114C>T (p.Q372X) and c.1137_1138delCA (p.F379Lfs*27) were found. CONCLUSION: The main clinical manifestations of patients with cblA-type of MMA include vomiting, dyspnea and drowsiness. Most patients are vitamin B12-responsive. c.365T>C is a potential hot spot variant of MMAA gene in China.

8.
Int J Mol Sci ; 21(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012921

RESUMO

Cerebral amyloid angiopathy (CAA) is the deposition of amyloid protein in the cerebral vasculature, a common feature in both aging and Alzheimer's disease (AD). However, the effects of environmental factors, particularly cognitive stimulation, social stimulation, and physical activity, on CAA pathology are poorly understood. These factors, delivered in the form of the environmental enrichment (EE) paradigm in rodents, have been shown to have beneficial effects on the brain and behavior in healthy aging and AD models. However, the relative importance of these subcomponents on CAA pathology has not been investigated. Therefore, we assessed the effects of EE, social enrichment (SOC), and cognitive enrichment (COG) compared to a control group that was single housed without enrichment (SIN) from 4 to 8 months of age in wild-type mice (WT) and Tg-SwDI mice, a transgenic mouse model of CAA that exhibits cognitive/behavioral deficits. The results show that individual facets of enrichment can affect an animal model of CAA, though the SOC and combined EE conditions are generally the most effective at producing physiological, cognitive/behavioral, and neuropathological changes, adding to a growing literature supporting the benefits of lifestyle interventions.

9.
Surg Endosc ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32016520

RESUMO

BACKGROUND: Laparoscopic splenectomy (LS) has been proven to be a safe and advantageous procedure. To ensure that resections of appropriate difficulty are selected, an objective preoperative grading of difficulty is required. We aimed to develop a predictive difficulty grading of LS based on intraoperative complications. METHODS: A total of 272 non-traumatic patients who underwent LS were identified from a regional medical center. Patients were randomized into a training cohort (n = 222) and a validation cohort (n = 50). Data on demographics, medical and surgical history, operative and pathological characteristics, and postoperative outcome details were collected. Univariate and multivariate analyses of risk factors for intraoperative complications were performed to develop a difficulty scoring system. The Spearman correlation coefficient was used to evaluate the relationship between the difficulty grading score and intraoperative outcomes. Receiver operating characteristic (ROC) curve was used to evaluate the discriminatory power of this scoring system. RESULTS: Three preoperative factors (spleen weight, esophagogastric varices, and INR) had a significant effect on operative time, bleeding, and conversion to open surgery. We created a difficulty grading score with three levels of difficulty: low (≤ 4 points), medium (5-6 points), and high (≥ 7 points), based on the three preoperative parameters. The correlation was highly significant (P < 0.01) according to Spearman's correlation. The area under the ROC curve was 0.695 (95% CI 0.630-0.755). The external validation showed significant correlations with the present model, with an AUC of 0.725 (95% CI 0.580-0.842). The comparison between our difficulty score and the previous grading system in the 272-patient cohort presented a significant difference in the AUC (0.701, 95% CI 0.643-0.755 vs. 0.644, 95% CI 0.584-0.701, P = 0.0452). CONCLUSION: The present difficulty scoring system, based on preoperative factors, has good performance in predicting the risk of intraoperative complications of LS and could be helpful for enabling appropriate case selection with respect to the current experience of a surgeon.

10.
Sci Rep ; 10(1): 1990, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029859

RESUMO

The glymphatic system (GS) hypothesis states that advective driven cerebrospinal fluid (CSF) influx from the perivascular spaces into the interstitial fluid space rapidly transport solutes and clear waste from brain. However, the presence of advection in neuropil is contested and solutes are claimed to be transported by diffusion only. To address this controversy, we implemented a regularized version of the optimal mass transport (rOMT) problem, wherein the advection/diffusion equation is the only a priori assumption required. rOMT analysis with a Lagrangian perspective of GS transport revealed that solute speed was faster in CSF compared to grey and white matter. Further, rOMT analysis also demonstrated 2-fold differences in regional solute speed within the brain. Collectively, these results imply that advective transport dominates in CSF while diffusion and advection both contribute to GS transport in parenchyma. In a rat model of cerebral small vessel disease (cSVD), solute transport in the perivascular spaces (PVS) and PVS-to-tissue transfer was slower compared to normal rats. Thus, the analytical framework of rOMT provides novel insights in the local dynamics of GS transport that may have implications for neurodegenerative diseases. Future studies should apply the rOMT analysis approach to confirm GS transport reductions in humans with cSVD.

11.
J Chromatogr A ; : 460845, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31924329

RESUMO

Posaconazole represents a triazole antifungal agent which is used to treat various fungal infections. It contains four chiral centers leading to 16 stereoisomers. With the convergent synthesis route, only 11 related stereoisomeric impurities may potentially exist in the active pharmaceutical ingredient (API). It is a challenge to separate all the stereoisomers in one run. To address this problem, a multiple heart-cutting chiral-chiral two-dimensional liquid chromatography (2D-LC) method was developed. The multiple heart-cutting 2D-LC separation was implemented on 2D-LC system with three chiral columns with immobilized polysaccharide chiral stationary phases, namely Chiralpak IB, IC and IF3. In the system, the column Chiralpak IB was used as the 1D separation column and IC and IF3 columns were used parallelly for the 2D separation. The twelve stereoisomers were all well separated in one run by the multiple heart-cutting chiral-chiral 2D-LC system.

12.
Zhongguo Fei Ai Za Zhi ; 23(1): 50-54, 2020 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-31948538

RESUMO

BACKGROUND: Da Vinci robotic system is currently widely used in thoracic surgery. The ports employment and procedures vary in different medical center in China. Usually, a small incision was used for assistant. METHODS: Based on clinical practice, we summarized domestic and foreign experience, combined with the characteristics of the Chinese body anatomy, employ portal technique and artificial pneumothorax, summarized a set of simplified and easier surgical method. RESULTS: Port-only artificial pneumothorax robot-assisted lobectomy has further improvement in anatomical safety, hemostatic effect and aesthetic appearance of the wound. CONCLUSIONS: This study optimizes the procedure of port-only artificial pneumothorax robot-assisted lobectomy in order to serve lung cancer patients better.

13.
J Pineal Res ; : e12631, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31943334

RESUMO

In the elderly with atherosclerosis, hypertension and diabetes, vascular calcification and ageing are ubiquitous. Melatonin (MT) has been demonstrated to impact the cardiovascular system. In this study, we have shown that MT alleviates vascular calcification and ageing, and the underlying mechanism involved. We found that both osteogenic differentiation and senescence of vascular smooth muscle cells (VSMCs) were attenuated by MT in a MT membrane receptor-dependent manner. Moreover, exosomes isolated from VSMCs or calcifying vascular smooth muscle cells (CVSMCs) treated with MT could be uptaken by VSMCs and attenuated the osteogenic differentiation and senescence of VSMCs or CVSMCs, respectively. Moreover, we used conditional medium from MT-treated VSMCs and Transwell assay to confirm exosomes secreted by MT-treated VSMCs attenuated the osteogenic differentiation and senescence of VSMCs through paracrine mechanism. We also found exosomal miR-204/miR-211 mediated the paracrine effect of exosomes secreted by VSMCs. A potential target of these two miRs was revealed to be BMP2. Furthermore, treatment of MT alleviated vascular calcification and ageing in 5/6-nephrectomy plus high-phosphate diet-treated (5/6 NTP) mice, while these effects were partially reversed by GW4869. Exosomes derived from MT-treated VSMCs were internalised into mouse artery detected by in vivo fluorescence image, and these exosomes reduced vascular calcification and ageing of 5/6 NTP mice, but both effects were largely abolished by inhibition of exosomal miR-204 or miR-211. In summary, our present study revealed that exosomes from MT-treated VSMCs could attenuate vascular calcification and ageing in a paracrine manner through an exosomal miR-204/miR-211.

14.
Sci Rep ; 10(1): 826, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964915

RESUMO

MDS development is a dynamic process during which the accumulation of somatic mutations leads to specific malignant evolution. To elucidate the differential roles of gene mutations in typical MDS, we used targeted sequencing to investigate clonal patterns from 563 patients and focused on cases (199/563 cases) with initial mutations (ASXL1, DNMT3A and TET2) at MDS diagnosis. The consistency of frequency and distribution in patients with or without aberrant chromosomes suggested early events of these initial mutations. Some additional driver mutations (SF3B1, U2AF1 or RUNX1) played roles to keep the basic disease features, or give rise to different phenotypes (BCOR, EZH2 or TP53) in individual patients. Notably, analysis in paired samples before and after MDS progression showed that the mutations identified as last events (involving active signaling, myeloid transcription or tumor suppressor) seemed necessary for MDS development to be AML. Last mutations can exist at MDS diagnosis, or emerge at AML transformation, and involve a small group of genes. Single-allele CEBPA mutations and diverse TP53 mutations were checked as the most common last event mutations. Considering the necessity of last event mutations and limited gene involvement in AML transformations, it is possible to validate a small group of last events involved mutations to develop some new strategies to block MDS progression.

15.
Nanotechnology ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31986500

RESUMO

Polyaniline-coated multi-walled carbon nanotube conductive polymer precursors (MWCNTs@PANI) were prepared by an in situ microemulsion oxidation polymerization of aniline in the case of multi-walled carbon nanotubes (MWCNTs), and then hydroxyl-terminated polybutadiene polyurethane conductive polymer nanocomposites based on MWCNTs@PANI (MWCNTs@PANI/HTPB PUs) were prepared through an in situ stepwise polymerization of HTPB and diisocyanates. The chemical structure was characterized by Fourier transform infrared spectroscopy (FTIR), Raman, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and thermogravimetric analysis (TGA). The morphologies and dispersion behavior were examined by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and UV-vis transmittance. The MWCNTs@PANI/HTPB PUs nanocomposites were fabricated into film sensors for detection of volatile organic compound (VOC) vapors, and displayed an evident response to trichloromethane vapor (CHCl3). The effect of MWCNTs on the conductivity and the responsivity of conductive polymer nanocomposite films to trichloromethane were studied, finding that the conductive composite films have fast and strong response, good repeatability and recoverability, and long-term stability. Consequently, they can be potentially applied for supervision and detection of interior and outdoor environmental gases or vapors.

16.
HPB (Oxford) ; 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31987739

RESUMO

BACKGROUND: To define the chronological changes of long-term survival among patients with non-hepatitis-related hepatocellular carcinoma (Non-Hep-HCC) versus hepatitis C-related HCC (HCV-HCC) over the last two decades. METHODS: Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. Overall (OS) and recurrence-free survival (RFS) were analyzed and compared among Non-Hep-HCC versus HCV-HCC patients. Propensity score matching (PSM) was utilized to mitigate residual bias. RESULTS: Among 617 patients, 196 (31.8%) patients had HCV-HCC, whereas 421 (68.2%) patients had Non-Hep-HCC. While patients with HCV-HCC had an improvement in OS over time (5-year OS, 2000-2009 55% vs. 2010-2017 67%, p = 0.034), OS among patients with Non-Hep-HCC remain unchanged (5-year OS, 2000-2009 53% vs. 2010-2017 52%, p = 0.905). In the matched cohort, patients with HCV-HCC had a worse OS versus patients with Non-Hep-HCC during 2000 and 2009 (5-year OS, 12% vs. 63%, p = 0.029), but significantly better OS from 2010 to 2017 than patients with Non-Hep-HCC (5-year OS, 86% vs. 73%, p = 0.035). The recurrence timing, patterns and re-treatments were comparable among Non-Hep-HCC and HCV-HCC patients. CONCLUSION: While OS of patients with HCV-HCC improved over time, the long-term survival of patients with Non-Hep-HCC patients remained unchanged and was more unfavorable.

18.
J Hazard Mater ; 387: 122004, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31901844

RESUMO

The effect of Ca modification on the Ni/ZSM-5 catalyst for efficient toluene oxidation was studied in a plasma-catalytic system. The Ni/ZSM-5 and Ca-Ni/ZSM-5 catalysts were prepared by a wet impregnation method and characterized by X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET), Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), Pyridine-FTIR spectroscopy and temperature programmed desorption of ammonia (NH3-TPD). Among the catalysts tested, the Ca-Ni/ZSM-5 sample showed the best potential for toluene conversion (90.2%) and CO2 selectivity (70.7%). Pyridine-FTIR spectra and NH3-TPD results proved that the introduction of Ca and Ni onto ZSM-5 caused a decrease in the strong and weak acidic sites. In addition, gas chromatography/mass spectrometry (GC-MS) result showed that the Ca-Ni/ZSM-5 catalyst reduced the production of undesirable byproducts (such as p-nitrotoluene and methyl benzoate). Calcium in the Ni/ZSM-5 system influenced the acidity and other surface characteristic of the catalyst, as well as directly impacting the reactive plasma species and the intermediates. Finally, possible reaction mechanisms in the plasma catalysis of toluene were also proposed.

19.
Int J Mol Sci ; 21(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31906317

RESUMO

The accumulation of fibrillar amyloid ß-protein (Aß) in blood vessels of the brain, the condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease that promotes cognitive impairment and is strongly associated with Alzheimer's disease. Presently, the clinical diagnosis of this condition relies on neuroimaging markers largely associated with cerebral macro/microbleeds. However, these are markers of late-stage disease detected after extensive cerebral vascular amyloid accumulation has become chronic. Recently, we generated a novel transgenic rat model of CAA (rTg-DI) that recapitulates multiple aspects of human CAA disease with the progressive accumulation of cerebral vascular amyloid, largely composed of Aß40, and the consistent emergence of subsequent microbleeds. Here, we investigated the levels of Aß40 in the cerebrospinal fluid (CSF) and plasma of rTg-DI rats as CAA progressed from inception to late stage disease. The levels of Aß40 in CSF and plasma precipitously dropped at the early onset of CAA accumulation at three months of age and continued to decrease with the progression of disease. Notably, the reduction in CSF/plasma Aß40 levels preceded the emergence of cerebral microbleeds, which first occurred at about six months of age, as detected by in vivo magnetic resonance imaging and histological staining of brain tissue. These findings support the concept that reduced CSF/plasma levels of Aß40 could serve as a biomarker for early stage CAA disease prior to the onset of cerebral microbleeds for future therapeutic intervention.

20.
Appl Microbiol Biotechnol ; 104(5): 2163-2178, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31980918

RESUMO

Tea tree oil (TTO) and its two characteristic components (terpinen-4-ol and 1,8-cineole) have been shown to inhibit Botrytis cinerea growth. In this study, we conducted a transcriptome analysis to determine the effects of TTO and its characteristic components, alone and in combination, against B. cinerea. Most differentially expressed genes (DEGs) from B. cinerea cells treated with terpinen-4-ol participated in the biosynthesis of secondary metabolites, and the metabolism of amino acids, carbohydrates, and lipids. All treatments containing terpinen-4-ol potentially induced mitochondrial dysfunction and oxidative stress. These were further confirmed by the decreased activities of several enzymes (e.g., succinate dehydrogenase (SDH), malate dehydrogenase (MDH), α-ketoglutarate dehydrogenase (α-KGDH), isocitrate dehydrogenase (ICDH)), the increased activities of certain enzymes (e.g., catalase (CAT), peroxidase (POD), superoxide dismutase (SOD)), and increased content of hydrogen peroxide (H2O2). 1,8-Cineole mainly affected DEGs involved in genetic information processing, resulting in cell death. This study provides insight into the molecular mechanism of B. cinerea inhibition by TTO, and explains the synergistic effect of terpinen-4-ol and 1,8-cineole on B. cinerea.

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