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2.
Food Chem ; 463(Pt 1): 140844, 2025 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-39236387

RESUMO

Integrating plant proteins into meat products offers a sustainable way to reduce the environmental impact of meat consumption while satisfying the growing flexitarian population. This study explored the effects of textured vegetable proteins (TVPs) on the physico-chemical attributes and flavour profile of hybrid salamis using 4D label-free proteomics. Results showed that hybrid salamis had lower pH, reduced water activity and increased weight loss compared with traditional salamis, along with greater hardness and a slightly rough, porous texture with a filamentous structure. TVPs substantially modified crucial meaty flavour compounds (nitrogen oxides, sulfides and pyrazine), increasing heightening sourness and bitterness while diminishing umami. Proteomic analysis revealed significant upregulation of myosin and actin in hybrid salamis; notably, these proteins were involved in glycerol-3-phosphate dehydrogenase activity and calcineurin-mediated signalling, underscoring their role in flavour enhancement. Therefore, hybrid salamis offer an attractive alternative to traditional salamis by merging meat-like taste and texture with plant protein.


Assuntos
Aromatizantes , Produtos da Carne , Proteínas de Plantas , Proteoma , Paladar , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Proteoma/química , Produtos da Carne/análise , Animais , Aromatizantes/química , Aromatizantes/metabolismo , Humanos , Proteômica
3.
Cancer Discov ; 14(11): 2028-2032, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39485245

RESUMO

The Chinese government has, in recent decades, implemented various administrative laws and regulatory policies to expedite cancer therapeutic development, boosting research and development pipelines for domestic pharmaceutical companies and clinical trials; however, China faces unique challenges given the high prevalence of certain cancer types and distinct disease burdens, some of which are frequently overlooked by international pharmaceutical companies. Given the substantial unmet need for China-specific cancer care, it is crucial to promote the development of innovative pharmaceutical and clinical research in China, with a particular emphasis on addressing tumors most prevalent in its population.


Assuntos
Neoplasias , Pesquisa Translacional Biomédica , Humanos , China/epidemiologia , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Pesquisa Biomédica
4.
Heliyon ; 10(19): e36987, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39435114

RESUMO

Ganoderma lucidum (GL) is a potent source of bioactive compounds with diverse nutritional and pharmacological benefits. Its popularity as a dietary supplement, herbal remedy, and wellness product is steadily on the rise. Furthermore, the standardized advancement of the GL industry has facilitated reliable sourcing of raw materials and quality control measures, enhancing its utilization and endorsement in the realms of nutritional science and pharmaceutical research. This article provides a comprehensive overview of the recent advancements in research pertaining to the bioactive components of GL, particularly polysaccharides (GLP) and triterpenes (GLTs) as well as highlights the latest findings regarding their beneficial effects on human diseases, including anticancer, antidiabetes, liver protection and other aspects (such as regulating gut microbiota, antioxidant, antimicrobial, antiinflammatory and immune regulation). Furthermore, we summarized the potential applications of GL in the food and pharmaceutical sectors, while also examining the current status of standardization throughout the entire industrial chain of GL, both domestically and internationally. These information offer an insight and guidance for the prospects of industrial development and the innovative advancement of GL within the global health industry.

5.
Angew Chem Int Ed Engl ; : e202413181, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39381922

RESUMO

Starting from N-acyl sulfonimidamides, mechanochemically generated rhodium nitrenoids undergo intramolecular N-O couplings to provide unprecedented 1,3,2,4-oxathiadiazole 3-oxides in good to excellent yields. The cyclization proceeds efficiently with a catalyst loading of only 0.5 mol% in the presence of phenyliodine(III) diacetate (PIDA) as oxidant. Neither an inert atmosphere nor additional heating is required in this solvent-free procedure. Under heat or blue light, the newly formed five-membered heterocycles function as nitrene precursors reacting with sulfoxides as exemplified by the imidation of dimethyl sulfoxide.

6.
Food Chem X ; 24: 101854, 2024 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-39398870

RESUMO

Salt-assisted heat treatment is considered an effective way to enhance the bioactivities of flavonoids in Flos Sophorae Immaturus tea (FSIt). Herein, sodium chloride (NaCl)- and potassium chloride (KCl)-assisted heat treatment was employed to process FSIt, the components, xanthine oxidase (XO) inhibitory activity, and degradation or conversion kinetics of FSIt flavonoids were recorded. Results showed that KCl-assisted heat treatment significantly increased the XO inhibition rate of FSIt from 28.05 % to 69.50 %. The de-glycosylation of flavonoids was the crucial reason for enhancing XO inhibitory activity. Notably, KCl exhibited a better catalytic effect on the de-glycosylation reaction than NaCl. Meanwhile, conversion kinetics showed that the generation rate of quercetin, kaempferol, and isorhamnetin reached the maximum at 180, 160, 160 °C, respectively. Furthermore, the established artificial neural network model could accurately predict the changes of FSIt flavonoids during salt-assisted heat treatment. Thus, KCl can be used as a valuable food processing adjuvant to enhance the bioactivities of food materials.

7.
Digit Health ; 10: 20552076241287891, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39398894

RESUMO

Objective: This study aims to develop a prognosis prediction model and visualization system for acute paraquat poisoning based on an improved machine learning model. Methods: 101 patients with acute paraquat poisoning admitted to 6 hospitals from March 2020 to March 2022 were selected for this study. After expiry of the treatment period (one year of follow-up for survivors and up to the time of death for deceased patients) and they were categorized into the survival group (n = 37) and death group (n = 64). The biochemical indexes of the patients were analyzed, and a prognosis prediction model was constructed using HHO-XGBoost, an improved machine-learning algorithm. Multivariate logistic analysis was used to verify the value of the self-screening features in the model. Results: Seven features were selected in the HHO-XGBoost model, including oral dose, serum creatinine, alanine aminotransferase (ALT), white blood cell (WBC) count, neutrophil count, urea nitrogen level, and thrombin time. Univariate analysis showed statistically significant differences between these features' survival and death groups (P < 0.05). Multivariate logistic analysis identified four features significantly associated with prognosis- serum creatinine level, oral dose, ALT level, and WBC count - indicating their critical significance in predicting outcomes. Conclusion: The HHO-XGBoost model based on machine learning is precious in constructing a prognosis prediction model and visualization system for acute paraquat poisoning, which can help clinical prognosis prediction of patients with paraquat poisoning.

8.
Redox Biol ; 77: 103391, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39405981

RESUMO

Post-traumatic stress disorder (PTSD) is characterized by hypermnesia of the trauma and a persistent fear response. The molecular mechanisms underlying the retention of traumatic memories remain largely unknown, which hinders the development of more effective treatments. Utilizing auditory fear conditioning, we demonstrate that a redox-dependent dynamic pathway for dendritic spine morphogenesis in the basolateral amygdala (BLA) is crucial for traumatic memory retention. Exposure to a fear-induced event markedly increased the reduction of oxidized filamentous actin (F-actin) and decreased the expression of the molecule interacting with CasL 1 (MICAL1), a methionine-oxidizing enzyme that directly oxidizes and depolymerizes F-actin, leading to cytoskeletal dynamic abnormalities in the BLA, which impairs dendritic spine morphogenesis and contributes to the persistence of fearful memories. Following fear conditioning, overexpression of MICAL1 in the BLA inhibited freezing behavior during fear memory retrieval via reactivating cytokinesis, whereas overexpression of methionine sulfoxide reductase B 1, a key enzyme that reduces oxidized F-actin monomer, increased freezing behavior during retrieval. Notably, intra-BLA injection of semaphorin 3A, an endogenous activator of MICAL1, rapidly disrupted fear memory within a short time window after conditioning. Collectively, our results indicate that redox modulation of actin cytoskeleton in the BLA is functionally linked to fear memory retention and PTSD-like memory.

9.
Artigo em Inglês | MEDLINE | ID: mdl-39412694

RESUMO

Depression is a serious public health problem that often emerges during adolescence. Many adolescents do not respond to standard treatments, necessitating the development of novel interventions. We conducted a preliminary study to assess the impact of a novel creative arts intervention on depression and well-being in adolescents. In this quasi-experimental study, 69 adolescents 12-17 years completed an 8-day "Creativity Camp" intervention encompassing multiple creative activities. Self-report questionnaires to measure depression, anxiety, and well-being were administered at five time points to allow examination of change across multiple temporal segments: the 2 weeks before the intervention, the 2 weeks during the intervention, the 2 weeks after the intervention, and the 6 months after the intervention. Adolescents were assigned to one of two groups to compare changes observed during the 2 week before-intervention period (Group A) to the changes observed during the intervention period (pre-post intervention) (Group B). According to both parent and child reports, pre-to-post-intervention, mean adolescent depressive symptoms significantly decreased, and these changes were sustained 2 weeks after the intervention and (according to parents) at the 6-month follow-up. There was preliminary evidence for improved well-being at post-intervention. Comparison of Group A's changes during the before-intervention period to Group B's changes pre-post intervention was significant for parent-reported depression. Preliminary evidence suggests that the Creativity Camp intervention may positively impact adolescent depression and well-being. This evidence highlights the importance of investigating and implementing treatment approaches focusing on creative arts for adolescents with depression.

10.
Front Immunol ; 15: 1472772, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39421736

RESUMO

The tumor microenvironment (TME) provides essential conditions for the occurrence, invasion, and spread of cancer cells. Initial research has uncovered immunosuppressive properties of the TME, which include low oxygen levels (hypoxia), acidic conditions (low pH), increased interstitial pressure, heightened permeability of tumor vasculature, and an inflammatory microenvironment. The presence of various immunosuppressive components leads to immune evasion and affects immunotherapy efficacy. This indicates the potential value of targeting the TME in cancer immunotherapy. Therefore, TME remodeling has become an effective method for enhancing host immune responses against tumors. In this study, we elaborate on the characteristics and composition of the TME and how it weakens immune surveillance and summarize targeted therapeutic strategies for regulating the TME.


Assuntos
Imunoterapia , Neoplasias , Microambiente Tumoral , Microambiente Tumoral/imunologia , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia/métodos , Animais , Evasão Tumoral
11.
Materials (Basel) ; 17(19)2024 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-39410359

RESUMO

The Discrete Element Method (DEM) is an important tool for investigating the geotechnical properties of lunar regolith. The accuracy of DEM simulations largely depends on precise particle modeling and the appropriate selection of mesoscopic parameters. To enhance the reliability and accuracy of the DEM in lunar regolith studies, this paper utilized the high-fidelity IRSM-1 lunar regolith simulant to construct a DEM model with realistic particle shapes and conducted an angle of repose (AoR) simulation test. The optimal DEM parameters were calibrated using a combination of the Plackett-Burman test, steepest ascent test, and Box-Behnken design. The results indicate that the sliding friction coefficient, rolling friction coefficient, and surface energy significantly influence the simulation AoR. By optimizing against the measured AoR using a second-order regression model, the optimal parameter values were determined to be 0.633, 0.401, and 0.2, respectively. Under these optimal parameters, the error between the simulation and experimental AoR was 2.1%. Finally, the calibrated mesoscopic parameters were validated through a lifting cylinder test, showing an error of 6.3% between the simulation and experimental results. The high similarity in the shape of the AoR further confirms the accuracy and reliability of the parameter calibration method. This study provides a valuable reference for future DEM-based research on the mechanical and engineering properties of lunar regolith.

12.
bioRxiv ; 2024 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-39416090

RESUMO

Cancer treatment has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, especially those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. Sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 are newly designated glycoimmune checkpoints that are abundantly expressed by tumor-infiltrating myeloid cells. We discovered that T cells express only basal levels of Siglec transcripts; instead, they acquire Siglec-7 and -9 from interacting myeloid cells in the TME via trogocytosis, which impairs their activation and effector function. Mechanistically, Siglec-7 and -9 suppress T cell activity by dephosphorylating T cell receptor (TCR)-related signaling cascades. Using sulfur fluoride exchange (SuFEx) click chemistry, we developed a ligand that binds to Siglec-7 and -9 with high-affinity and exclusive specificity. Using this ligand, we constructed a Siglec-7/9 degrader that targets membrane Siglec-7 and -9 to the lysosome for degradation. Administration of this degrader induced efficient Siglec degradation in both T cells and myeloid cells in the TME. We found that Siglec-7/9 degradation has a negligible effect on macrophage phagocytosis, but significantly enhances T cell anti-tumor immunity. The degrader, particularly when combined with anti-CTLA-4, enhanced macrophage antigen presentation, reshaped the TME, and resulted in long-lasting T cell memory and excellent tumor control in multiple murine tumor models. These findings underscore the need to consider exogenous checkpoints acquired by T cells in the TME when selecting specific checkpoint blockade therapy to enhance T cell immunity.

13.
Biosens Bioelectron ; 267: 116809, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39357495

RESUMO

Anti-double-stranded DNA antibodies (anti-dsDNA) serve as a crucial serological indicator for systemic lupus erythematosus (SLE). Chemiluminescent immunoassay (CIA) is mainly used in clinical diagnosis of SLE, but suffers from low specificity, partially because the use of dsDNA antigens of varied sources in current CIA kits that sometimes led to controversial results. On the basis that anti-dsDNA in healthy individuals tend to selectively bind with dsDNA originating from pathogens, whereas pathogenic anti-dsDNA in SLE patients bind all forms of dsDNA, here we proposed the use of dsDNA fragment derived from human genome as antigen (synthesized via PCR using the human genomic DNA as the template). A magnetic bead-based immunofluorescence assay (IFA) was thus developed for SLE diagnosis, which exhibited improved sensitivity and specificity over CIA using the WHO reference reagent (15/174) as standard. For clinical serum sample analysis (n = 590), IFA exhibited an accuracy of 71.9% that was higher than CIA (65.3%). Crucially, the IFA results exhibited stronger correlations with the activity of SLE, renal involvement, and its prognosis. Besides the improved clinical diagnosis, the proposed IFA also holds great promise in assay standardization due to the high homogeneity of the synthetic dsDNA.

14.
J Environ Manage ; 370: 122754, 2024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39366232

RESUMO

With the escalating global concern for emerging pollutants, particularly antibiotics, microplastics, and nanomaterials, the potential disruption they pose to critical environmental processes like anaerobic ammonia oxidation (anammox) has become a pressing issue. The anammox process, which plays a crucial role in nitrogen removal from wastewater, is particularly sensitive to external pollutants. This paper endeavors to address this knowledge gap by providing a comprehensive overview of the inhibition mechanisms of multi-antibiotic on anaerobic ammonia-oxidizing bacteria, along with insights into their recovery processes. The paper dives deeply into the various ways antibiotics interact with anammox bacteria, focusing specifically on their interference with the bacteria's extracellular polymers (EPS) - crucial components that maintain the structural integrity and functionality of the cells. Additionally, it explores how anammox bacteria utilize quorum sensing (QS) mechanisms to regulate their community structure and respond to antibiotic stress. Moreover, the paper summarizes effective removal methods for these antibiotics from wastewater systems, which is crucial for mitigating their inhibitory effects on anammox bacteria. Finally, the paper offers valuable insights into how anammox communities can recuperate from multi-antibiotic stress. This includes strategies for reintroducing healthy bacteria, optimizing operational conditions, and using bioaugmentation techniques to enhance the resilience of anammox communities. In summary, this paper not only enriches our understanding of the complex interactions between antibiotics and anammox bacteria but also provides theoretical and practical guidance for the treatment of antibiotic pollution in sewage, ensuring the sustainability and effectiveness of wastewater treatment processes.

15.
ChemMedChem ; : e202400547, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39353851

RESUMO

The probing of small molecules with heterocyclic scaffolds covering unexplored chemical space and the evaluation of their biological relevance are essential parts of forward chemical genetics approaches and for the development of potential small-molecule therapeutics. In this study, we profiled sets of chromenopyrazoles (CMPs) and tetrahydroquinolines (THQs), originally developed to target the protein-RNA interaction of LIN28-let-7, in a cell painting assay (CPA) measuring cellular morphological changes. Selected LIN28-inactive CMPs and THQs induced cellular morphological changes to different extents. The most CPA-active CMPs 2 and 3 exhibited high bio-similarity with the LCH and BET clusters, while the most CPA-active THQs 13 and 20 indicated a mechanism of action beyond the currently established biosimilarity clusters. Overall, this work demonstrated that CPA is useful in revealing "hidden" biological targets and mechanisms of action for biologically inactive small molecules, which are CMPs and THQs targeting the RNA-binding protein LIN28 in this case, evaluated in target-based strategies. When compared with annotated reference compounds, CMP 3 exhibited a high biosimilarity with the dual BRD7/9 degrading PROTAC VZ185, suggesting that CPA could potentially function as a new phenotypic approach to identify degrader molecules.

16.
Water Res ; 268(Pt A): 122642, 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39427349

RESUMO

While the multi-coupled anammox system boasts a substantial research foundation, the specific characteristics of its synergistic metabolic response to decreased temperatures, particularly within the range of 13-15 °C, remained elusive. In this study, we delve into the intricate carbon and nitrogen metabolism pathways of mixed-autotrophy/heterotrophy anammox consortia under conditions of temperature reduction. Our macrogenomic analyses reveal a compelling phenomenon: the stimulation of functional genes responsible for complete denitrification, suggesting an enhancement of this process during temperature reduction. This adaptation likely contributes to maintaining system performance amidst environmental challenges. Further metabolic functional recombination analyses highlight a dramatic shift in microbial community composition, with denitrifying MAGs (metagenome-assembled genomes) experiencing a substantial increase in abundance (up to 200 times) compared to autotrophic MAGs. This proliferation underscores the strong stimulatory effect of temperature reduction on denitrifying species. Notably, autotrophic MAGs play a pivotal role in supporting the glycolytic processes of denitrifying MAGs, underscoring the intricate interdependencies within the consortia. Moreover, metabolic variations in amino acid composition among core MAGs emerge as a crucial adaptation mechanism. These differences facilitate the preservation of enzyme activity and enhance the consortia's resilience to low temperatures. Together, these findings offer a comprehensive understanding of the microbial synergistic metabolism within mixed-autotrophy/heterotrophy anammox consortia under temperature reduction, shedding light on their metabolic flexibility and resilience in dynamic environments.

17.
J Am Chem Soc ; 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39436369

RESUMO

Dioxygen (O2) activation by iron-containing enzymes and biomimetic compounds generates iron-oxygen intermediates, such as iron-superoxo, -peroxo, -hydroperoxo, and -oxo, that mediate oxidative reactions in biological and abiological systems. Among the iron-oxygen intermediates, iron(III)-peroxo species are less frequently implicated as active intermediates in oxidation reactions. In this study, we present the combined experimental and theoretical investigations on cis-dihydroxylation reactions mediated by synthetic mononuclear nonheme iron-peroxo intermediates, demonstrating the importance of supporting ligands and metal centers in activating the peroxo ligand toward the O-O bond homolysis for the cis-dihydroxylation reactions. We found a significant ring size effect of the TMC ligand in [FeIII(O2)(n-TMC)]+ (TMC = tetramethylated tetraazacycloalkane; n = 12, 13, and 14) on the cis-dihydroxylation reactivity order: [FeIII(O2)(12-TMC)]+ > [FeIII(O2)(13-TMC)]+ > [FeIII(O2)(14-TMC)]+. Additionally, we found that only [FeIII(O2)(n-TMC)]+, but not other metal-peroxo complexes such as [MIII(O2)(n-TMC)]+ (M = Mn, Co, and Ni), is reactive for the cis-dihydroxylation of olefins. Using density functional theory (DFT) calculations, we revealed that electron transfer from the Fe dxz orbital to the peroxo σ*(O-O) orbital facilitates the O-O bond homolysis, with the O-O bond cleavage barrier well correlated with the energy gap between the frontier molecular orbitals of dxz and σ*(O-O). Further computational studies showed that the reactivity of the synthetic [FeIII(O2)(12-TMC)]+ complex is comparable to that of Rieske dioxygenases in cis-dihydroxylation, providing compelling evidence of the potential involvement of Fe(III)-peroxo species in Rieske dioxygenases. Thus, the present results significantly advance our understanding of the cis-dihydroxylation mechanisms by Rieske dioxygenases and synthetic nonheme iron-peroxo models.

18.
J Adv Res ; 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39357647

RESUMO

INTRODUCTION: Myocardial ischemia-reperfusion injury (MIRI) remains a prevalent clinical challenge globally, lacking an ideal therapeutic strategy. Macrophages play a pivotal role in MIRI pathophysiology, exhibiting dynamic inflammatory and resolutive functions. Macrophage polarization and metabolism are intricately linked to MIRI, presenting potential therapeutic targets. Pubescenoside C (PBC) from Ilex pubescens showed significantly anti-inflammatory effects, however, the effect of PBC on MIRI is unknown. OBJECTIVES: This study aimed to assess the cardioprotective effects of PBC against MIRI and elucidate the underlying mechanisms. METHODS: Sprague-Dawley rats, H9c2 and RAW264.7 macrophages were used to establish the in vitro and in vivo models of MIRI. TTC/Evans blue staining, immunohistochemical staining, metabonomics analysis, chemical probe, surface plasmon resonance (SPR), co-immunoprecipitation (CO-IP) assays were used for pharmacodynamic and mechanism study. RESULTS: PBC administration effectively reduced myocardial infarct size, decreased ST-segment elevation, and lowered CK-MB levels, concurrently promoting macrophage M2 polarization in MIRI. Furthermore, PBC-treated macrophages and their conditioned culture medium attenuated the apoptosis of H9c2 cells induced by oxygen-glucose deprivation/reoxygenation (OGD/R). Metabonomics analysis revealed that PBC increased the production of itaconic acid (ITA) and malic acid (MA) in macrophages, which conferred protection against OGD/R injury in H9c2 cells. Mechanistic investigations indicated that ITA exerted its effects by covalently modifying pyruvate kinase M2 (PKM2) at Cys474, Cys424, and Lys151, thereby facilitating PKM2's mitochondrial translocation and enhancing the PKM2/Bcl2 interaction, subsequently leading to decreased degradation of Bcl2. SPR assays further revealed that PBC bound to HSP90, facilitating the interaction between HSP90 and GSK3ß and resulting in the inactivation of GSK3ß activity and upregulation of key metabolic enzymes for ITA and MA production (Acod1 and Mdh2). CONCLUSION: PBC alleviates MIRI-induced cardiomyocyte apoptosis by modulating the HSP90/ITA/PKM2 axis. Furthermore, pharmacological upregulation of ITA emerges as a promising therapeutic approach for MIRI, hinting at PBC's potential as a candidate drug for MIRI therapy.

19.
J Clin Invest ; 134(20)2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39403921

RESUMO

Parkinson's disease (PD) is characterized by age-dependent neurodegeneration and the accumulation of toxic phosphorylated α-synuclein (pS129-α-syn). The mechanisms underlying these crucial pathological changes remain unclear. Mutations in parkin RBR E3 ubiquitin protein ligase (PARK2), the gene encoding parkin that is phosphorylated by PTEN-induced putative kinase 1 (PINK1) to participate in mitophagy, cause early onset PD. However, current parkin-KO mouse and pig models do not exhibit neurodegeneration. In the current study, we utilized CRISPR/Cas9 technology to establish parkin-deficient monkey models at different ages. We found that parkin deficiency leads to substantia nigra neurodegeneration in adult monkey brains and that parkin phosphorylation decreases with aging, primarily due to increased insolubility of parkin. Phosphorylated parkin is important for neuroprotection and the reduction of pS129-α-syn. Consistently, overexpression of WT parkin, but not a mutant form that cannot be phosphorylated by PINK1, reduced the accumulation of pS129-α-syn. These findings identify parkin phosphorylation as a key factor in PD pathogenesis and suggest it as a promising target for therapeutic interventions.


Assuntos
Modelos Animais de Doenças , Doença de Parkinson , Ubiquitina-Proteína Ligases , alfa-Sinucleína , Animais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/deficiência , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Fosforilação , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Humanos , Substância Negra/metabolismo , Substância Negra/patologia , Macaca fascicularis , Camundongos , Masculino
20.
Acad Radiol ; 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39370312

RESUMO

RATIONALE AND OBJECTIVES: To evaluate amide proton transfer (APT) imaging for assessing Ki-67, p53 and PD-L1 status in bladder cancer (BC) and compare its diagnostic efficacy with that of diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Consecutive patients suspected of BC were recruited for preoperative multiparametric MRI. APT signal was quantified by asymmetric magnetization transfer ratio (MTRasym). MTRasym and apparent diffusion coefficient (ADC) were measured by two radiologists, with interobserver agreement assessed. Spearman's correlation analyzed MTRasym values and molecular markers. The Whitney U test evaluated MTRasym and ADC variation based on molecular marker status. Optimal cutoff points were determined using area under the curve (AUC) analysis. RESULTS: 88 patients (72 ± 10 years; 77 men) with BC were studied. MTRasym values were significantly correlated with Ki-67, p53 and PD-L1 levels (P < 0.05). Higher MTRasym values were found in high Ki-67 expression BCs (1.89% [0.73%] vs. 1.23% ± 0.26%; P < 0.001), high p53 expression BCs (1.63% [0.56%] vs. 1.24% [0.56%]; P < 0.001) and positive PD-L1 expression BCs (2.02% [0.81%] vs. 1.48% [0.38%]; P < 0.001). Lower ADCs were found in high Ki-67 expression BCs (1.06 ×10-3 mm2/s [0.32 ×10-3 mm2/s] vs. 1.38 ×10-3 mm2/s [0.39 ×10-3 mm2/s]; P < 0.001). For p53 status, an MTRasym threshold of 1.27% had 95% sensitivity, 60% specificity, and AUC of 0.781. For PD-L1 status, a 1.90% threshold had 88% sensitivity, 92% specificity, and AUC of 0.859. CONCLUSION: APT may significantly enhance the preoperative assessment of BC aggressiveness and inform targeted immunotherapy decisions, with performance superior to DWI.

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