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As one of the main pathmechanisms of Alzheimer's disease (AD), amyloid-ß (Aß) is widely considered to be the prime target for the development of AD therapy. Recently, imidazolylacetophenone oxime ethers or esters (IOEs) have shown neuroprotective effects against neuronal cells damage, suggesting their potential use in the prevention and treatment of AD. Thirty IOEs compounds from our lab in-house library were constructed and screened for the inhibitory effects on Aß42-induced cytotoxicity. Among them, TJ1, as a new IOEs hit, preliminarily showed the effect on inhibiting Aß42-induced cytotoxicity. Furthermore, the inhibitory effects of TJ1 on Aß42 aggregation were tested by ThT assays and TEM. The neuroprotective effects of TJ1 were evaluated in Aß42-stimulated SH-SY5Y cells, LPS-stimulated BV-2 cells, and H2O2- and RSL3-stimulated PC12 cells. The cognitive improvement of TJ1 was assessed in 5xFAD (C57BL/6J) transgenic mouse. These results showed that TJ1 had strong neuroprotective effects and high blood-brain barrier (BBB) permeability without obvious cytotoxicity. TJ1 impeded the self-accumulation process of Aß42 by acting on Aß oligomerization and fibrilization. Besides, TJ1 reversed Aß-, H2O2- and RSL3-induced neuronal cell damage and decreased neuroinflammation. In 5xFAD mice, TJ1 improved cognitive impairment, increased GSH level, reduced the level of Aß42 and Aß plaques, and attenuated the glia reactivation and inflammatory response in the brain,. Taken together, our results demonstrate that TJ1 improves cognitive impairments as a new neuroprotective candidate via targeting amyloidogenesis, which suggests the potential of TJ1 as a treatment for AD.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Barreira Hematoencefálica , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fármacos Neuroprotetores , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Humanos , Camundongos , Ratos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Fragmentos de Peptídeos/metabolismo , Células PC12 , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Oximas/farmacologia , Oximas/uso terapêutico , Linhagem Celular Tumoral , MasculinoRESUMO
Objective: The prostate-specific membrane antigen (PSMA) PET/CT is potentially identifying patients with oligo-metastasis who would be deemed to only have localized disease in the traditional approaches. However, the best selected oligo-metastasis prostate cancer (PCa) patients most likely to benefit from system androgen deprivation therapy (ADT) are still unknown. The aim of this study was to explore the potential 18F-PSMA-1007 PET/CT parameters and clinicopathologic characteristics for oligo-metastasis PCa discrimination and follow-up evaluation. Materials and methods: A total of 180 retrospective patients with different metastasis burdens (PCa of none-metastases, oligo-metastases, and poly-metastases), different metastasis status (untreated and recurrent oligo-metastases), and follow-up ADT were included respectively. A one-way analysis of variance was used to evaluate whether PET/CT parameters and clinicopathologic characteristics were different and univariate/multivariate logistic regression models were applied to assess independent predictors in the metastasis burdens group (89/180). Selected predictors were further compared between different metastasis statuses to test the diagnostic accuracy (69/180). The predictor efficiency was evaluated by the ROC and the cut-off value was used to test the ADT response-to-treatment with a longitudinal cohort (22/180) from untreated baseline to 3-15 months. Results: The significant group differences were observed on SUVmax (P = 0.012), International Society of Urologic Pathologists (ISUP, P<0.001) and Gleason Score (P<0.001). Poly-Metastases patients had higher SUVmax, ISUP and Gleason Score compared to Non-Metastases and Oligo-Metastases patients, respectively (P<0.05, all), and no difference between Non-Metastases and Oligo-Metastases. The SUVmax, ISUP and Gleason Score were independent predictors for metastasis burdens discrimination. The untreated and recurrent oligo-metastases lesions SUVmax were also different (P = 0.036). The AUC of ROC for oligo-metastasis prediction was 0.658 (P = 0.039) when the primary prostatic carcinoma focus SUVmax was higher than 28.22, ADT response-to-treatment patients (5/5 in 22) were all progress in a follow-up test. Conclusion: The SUVmax can discriminate PCa metastasis degree and oligo-metastasis status. The ADT-treated oligo-metastasis patient may still have disease progression when the primary prostatic carcinoma focus SUVmax is greater than 28.22.
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OBJECTIVE: Given the limitation of biomarkers to predict the renal function progression in diabetic nephropathy, N-(6-[18F]Fluoropyridin-3-yl)glycine (6-[18F]FPyGly) was used to evaluate renal function progression in a rat model of diabetic nephropathy. METHODS: Twenty male Sprague-Dawley rats were randomly divided into four groups, including the healthy control group (HC group), diabetic nephropathy group (DNM group), routine diet treated diabetic nephropathy group (RDNM group), and high fat/high sucrose -diet-fed diabetic nephropathy group (HDNM group). All renal function parameters were determined from animal PET renograms. P and Tmax represent the curve peak counts and the time to the curve peak counts of 6-[18F]FPyGly in kidneys after injection, C1/2 and the 15 min/Peak ratio represent the time from peak to 1/2 peak in the clearance phase, and the ratio of the curve counts at 15 min to the curve peak counts. RESULTS: P, Tmax, C1/2, and 15 min/peak ratio of each rat were significantly correlated with S-Cr, BUN. There were significant differences in Tmax, P, serum creatinine (SCr), and blood urea nitrogen (BUN) levels between HC and DNM groups. P and the 15 min/Peak ratio were significantly different among DNM, RDNM, and HDNM groups, while Tmax and C1/2 were only significantly different between DNM and RDNM or HDNM groups. There only was a significant difference in BUN between the DNM and HDNM groups. CONCLUSION: The renal function parameters P, Tmax, C1/2 and 15 min/peak value obtained by dynamic renal imaging based on 6-[18F]FPyGly could reflect changes of renal function in rats, which had a good correlation with SCr and BUN, and showed more efficient in the diagnosis of diabetic nephropathy and renal function classification than SCr and BUN.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Biomarcadores , Creatinina , Nefropatias Diabéticas/diagnóstico por imagem , Glicina , Rim/diagnóstico por imagem , Rim/fisiologia , Masculino , Tomografia por Emissão de Pósitrons , Renografia por Radioisótopo , Ratos , Ratos Sprague-Dawley , SacaroseRESUMO
OBJECTIVE: To evaluate the prediction performance of 18F-PSMA-1007 PET/CT and clinicopathologic characteristics on prostate cancer (PCa) risk stratification and distant metastatic prediction. MATERIALS AND METHODS: A retrospective analysis was performed on 101 consecutively patients with biopsy or radical prostatectomy proved PCa who underwent 18F-PSMA-1007 PET/CT. The semi-quantitative analysis provided minimum, maximum and mean standardized uptake (SUVmin, SUVmax and SUVmean) of PCa. Association between clinicopathologic characteristics (total prostate-specific antigen, tPSA and Gleason Score, GS) and PET/CT indexes were analyzed. The diagnostic performance of distant metastatic on PET/CT parameters, tPSA and GS was evaluated using logistic regression analyses. A path analysis was conducted to evaluate the mediating effect of tPSA level on the relation between semi-quantitative parameters of primary tumors and metastatic lesions. RESULTS: The PET/CT parameters were all higher in high risk stratification subgroups (tPSA>20 ng/mL, GS ≥ 8, and tPSA>20 ng/mL and/or GS ≥ 8, respectively) with high sensitivity (86.89%, 90.16% and 83.61%, respectively). The SUVmax, tPSA and GS could effectively predict distant metastatic with high sensitivity of SUVmax (90.50%) compared with tPSA (57.14%) and GS (55.61%). With a cutoff value of 29.01ng/mL for tPSA, the detection rate of distant metastasis between low and high prediction tPSA group had statistical differences (50.00% vs. 76.60%, respectively; P = 0.006) which was not found on guideline tPSA level (P>0.05). 6/15 (40%) patients tPSA between 20ng/mL to 29.01ng/mL without distant metastases may change the risk stratification. Finally, tPSA had a partial mediating effect on SUVmax of primary tumors and metastases lesions. CONCLUSION: The 18F-PSMA-1007 PET/CT SUVmax has a higher sensitivity and can be an "imaging biomarker" for primary PCa risk stratification. The prediction tPSA level (29.01 ng/mL) is more conducive to the assessment of distant metastasis and avoid unnecessary biopsy.
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Photoassisted electrocatalysis (P-EC) emerges as a rising star for hydrogen production by embedding photoactive species in electrocatalysts, for which the interfacial structure design and charge transfer kinetics of the multifunctional catalysts remain a great challenge. Herein, Zn-AgIn5S8 quantum dots (ZAIS QDs) were embedded into 2D NiFe layered double hydroxide nanosheets through a simple hydrothermal treatment to form 0D/2D composite catalysts for P-EC. With evidence from transient photovoltage spectroscopy, we acquired a clear and fundamental understanding on the kinetics of charge extraction time and extraction amount in the 0D/2D heterojunctions that was proved to play a key role in P-EC. Upon light illumination, for HER, the optimized NiFe-ZAIS exhibits obviously reduced overpotentials of 129 and 242 mV at current densities of 10 and 50 mA cm-2, which are 22 and 33 mV lower than those of dark electrocatalysis, respectively. For OER, the NiFe-ZAIS electrode also shows low overpotentials of 220 and 268 mV at current densities of 10 and 50 mA cm-2, respectively, under light illumination, which were able to almost double the intrinsic activity. Finally, with NF@NiFe-ZAIS as both the cathode and the anode, the assembled electrolyzer only requires 1.62 V to reach the overall water splitting current density of 10 mA cm-2 under P-EC. This work provides a useful example for the profound understanding of the design and the kinetics study of multifunctional P-EC catalysts.
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OBJECTIVE: Studies have confirmed that tumorigenesis is related to an imbalance of polyamine metabolism and over-expression of oncogenes resulting in the up-regulation of ornithine decarboxylase (ODC, the first rate-limiting enzyme for regulating intracellular polyamines biosynthesis), which has become a target for anti-tumor therapy. In this study, an ornithine derivative, N5-(2-[18F]fluoropropionyl) ornithine (N5-[18F]FPO), has been prepared and its potential utility for tumor PET imaging evaluated. METHODS: N5-[18F]FPO was successfully prepared via a nucleophilic fluorination reaction and a subsequent efficient deprotection step. The in vitro and in vivo stability were determined by HPLC conducted in fetal bovine serum, saline and rat urine. Cellular uptake studies were conducted in HepG2 cells and the biodistribution and micro-PET/CT imaging performed in normal ICR mice and three tumor-bearing mice models, respectively. RESULTS: Total synthesis time of N5-[18F]FPO was about 80 min with a radiochemical yield of 15% ± 6% (uncorrected, based on 18F-, n = 6) and a high radiochemical stability can be seen in vitro and vivo. The N5-[18F]FPO exhibited fast uptake in HepG2 cells and the cellular uptake ability of N5-[18F]FPO can be inhibited by L-ornithine and DFMO, which indicated that the transport pathway of N5-[18F]FPO is similar to that of L-ornithine, interacting with ODC after being transported into the cell. The biodistribution and micro-PET/CT images demonstrate that N5-[18F]FPO was excreted by the urinary system, and excellent tumor visualization with high tumor-to-background ratios can be observed in the three tumor-bearing mice models studied. CONCLUSION: All the above results suggest that N5-[18F]FPO has the potential to be a novel radiotracer for imaging ODC expression in solid tumors.
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Radioisótopos de Flúor/química , Ornitina/química , Ornitina/síntese química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Animais , Linhagem Celular Tumoral , Camundongos , Ornitina/farmacocinética , Radioquímica , Ratos , Distribuição TecidualRESUMO
A challenge in photocatalysis consists in improving the efficiency by harnessing a large portion of the solar spectrum. We report the design and realization of a robust molecular-semiconductor photocatalytic system (MSPS) consisting of an earth-abundant phytic acid nickel (PA-Ni) biomimetic complex and polymeric carbon nitride (PCN). The MSPS exhibits an outstanding activity at λ=940â nm with high apparent quantum efficiency (AQE) of 2.8 %, particularly λ>900â nm, as it outperforms all reported state-of-the-art near-infrared (NIR) hybrid photocatalysts without adding any noble metals. The optimum hydrogen (H2 ) production activity was about 52 and 64 times higher with respect to its pristine counterpart under the AMâ 1.5 G and visible irradiation, respectively, being equivalent to the platinum-assisted PCN. This work sheds light on feasible avenues to prepare highly active, stable, cheap NIR-harvesting photosystems toward sustainable and scalable solar-to-H2 production.
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OBJECTIVE: Given the requirements of high sensitivity and spatial resolution, the development of new positron emission tomography (PET) agents is required for PET renography. The objective of this study was to investigate a new fluorine-18 labeled hippurate analogue of picolinamide, N-(6-[18F]Fluoropyridin-3-yl)glycine, as a new renal PET agent for evaluating renal function. METHODS: N-(6-[18F]Fluoropyridin-3-yl)glycine was prepared via a two-step reaction, including the nucleophilic substitution reaction of Br with 18F using methyl 2-(6-bromonicotinamido)acetate as a precursor followed the hydrolysis with sodium hydroxide and purification by preparative-HPLC. The in vitro and in vivo stability were determined using HPLC, and the plasma protein binding (PPB) and erythrocyte uptake of N-(6-[18F]Fluoropyridin-3-yl)glycine were determined using blood collected from healthy rats at 5â¯min post-injection. Biodistribution and dynamic micro-PET/CT imaging studies were conducted in healthy rats. RESULTS: N-(6-[18F]Fluoropyridin-3-yl)glycine was prepared within 45â¯min with an uncorrected radiochemical yield of 24.5⯱â¯6.7% (nâ¯=â¯6, based on [18F]F-) and a radiochemical purity of >98%. N-(6-[18F]Fluoropyridin-3-yl)glycine demonstrated good stability both in vitro and in vivo. The results of the biodistribution and dynamic micro-PET/CT imaging studies in normal rats indicated that N-(6-[18F]Fluoropyridin-3-yl)glycine was rapidly and exclusively excreted via the renal-urinary pathway. CONCLUSION: N-(6-[18F]Fluoropyridin-3-yl)glycine is has been shown to be a promising renal PET agent and warrants further evaluation of renal function.