Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Resultados 1 - 20 de 79
Filtrar
1.
Cell Mol Life Sci ; 81(1): 382, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39223418

RESUMEN

In orchestrating cell signaling, facilitating plasma membrane repair, supervising protein secretion, managing waste elimination, and regulating energy consumption, lysosomes are indispensable guardians that play a crucial role in preserving intracellular homeostasis. Neurons are terminally differentiated post-mitotic cells. Neuronal function and waste elimination depend on normal lysosomal function. Converging data suggest that lysosomal dysfunction is a critical event in the etiology of Parkinson's disease (PD). Mutations in Glucosylceramidase Beta 1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) confer an increased risk for the development of parkinsonism. Furthermore, lysosomal dysfunction has been observed in the affected neurons of sporadic PD (sPD) patients. Given that lysosomal hydrolases actively contribute to the breakdown of impaired organelles and misfolded proteins, any compromise in lysosomal integrity could incite abnormal accumulation of proteins, including α-synuclein, the major component of Lewy bodies in PD. Clinical observations have shown that lysosomal protein levels in cerebrospinal fluid may serve as potential biomarkers for PD diagnosis and as signs of lysosomal dysfunction. In this review, we summarize the current evidence regarding lysosomal dysfunction in PD and discuss the intimate relationship between lysosomal dysfunction and pathological α-synuclein. In addition, we discuss therapeutic strategies that target lysosomes to treat PD.


Asunto(s)
Lisosomas , Enfermedad de Parkinson , alfa-Sinucleína , Humanos , Lisosomas/metabolismo , alfa-Sinucleína/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/genética , Animales , Mutación
2.
Environ Geochem Health ; 46(9): 341, 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39073467

RESUMEN

Selenium (Se) has a dual nature, with beneficial and harmful effects on plants, essential for both humans and animals, playing a crucial role in ecosystem regulation. Insufficient Se in specific terrestrial environments raises concerns due to its potential to cause diseases, while excess Se can lead to severe toxicity. Thus, maintaining an optimal Se level is essential for living organisms. This review focuses first on Se transformation, speciation, and geochemical properties in soil, and then provides a concise overview of Se distribution in Chinese soil and crops, with a focus on the relationship between soil Se levels and parent materials. Additionally, this paper explores Se bioavailability, considering parent materials and soil physicochemical properties, using partial least squares path modeling for analysis. This paper aimed to be a valuable resource for effectively managing Se-enriched soil resources, contributing to a better understanding of Se role in ecosystems.


Asunto(s)
Disponibilidad Biológica , Selenio , Suelo , Selenio/metabolismo , China , Suelo/química , Contaminantes del Suelo/metabolismo , Plantas/metabolismo , Productos Agrícolas/metabolismo , Monitoreo del Ambiente/métodos , Ecosistema
3.
Phys Rev Lett ; 131(13): 134002, 2023 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-37832000

RESUMEN

Active colloids in a bath of inert particles of smaller size cause anisotropic depletion. The active hydrodynamics of this nonequilibrium phenomenon, which is fundamentally different from its equilibrium counterpart and passive particles in an active bath, remains scarcely understood. Here we combine mesoscale hydrodynamic simulation as well as theoretical analysis to examine the physical origin for the active depletion around a self-propelled noninteractive colloid. Our results elucidate that the variable hydrodynamic effect critically governs the microstructure of the depletion zone. Three characteristic states of anisotropic depletion are identified, depending on the strength and stress of activity. This yields a state diagram of depletion in the two-parameter space, captured by developing a theoretical model with the continuum kinetic theory and leading to a mechanistic interpretation of the hydrodynamic anisotropy of depletion. Furthermore, we demonstrate that such depletion in nonequilibrium results in various clusters with ordered organization of squirmers, which follows a distinct principle contrary to that of the entropy scenario of depletion in equilibrium. The findings might be of immediate interest to tune the hydrodynamics-mediated anisotropic interactions and active nonequilibrium organizations in the self-propulsion systems.

4.
Mov Disord ; 38(11): 2005-2018, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37593929

RESUMEN

BACKGROUND: The accumulation and aggregation of α-synuclein (α-Syn) are characteristic of Parkinson's disease (PD). Epidemiological evidence indicates that hyperlipidemia is associated with an increased risk of PD. The levels of 27-hydroxycholesterol (27-OHC), a cholesterol oxidation derivative, are increased in the brain and cerebrospinal fluid of patients with PD. However, whether 27-OHC plays a role in α-Syn aggregation and propagation remains elusive. OBJECTIVE: The aim of this study was to determine whether 27-OHC regulates α-Syn aggregation and propagation. METHODS: Purified recombinant α-Syn, neuronal cultures, and α-Syn fibril-injected mouse model of PD were treated with 27-OHC. In addition, CYP27A1 knockout mice were used to investigate the effect of lowering 27-OHC on α-Syn pathology in vivo. RESULTS: 27-OHC accelerates the aggregation of α-Syn and enhances the seeding activity of α-Syn fibrils. Furthermore, the 27-OHC-modified α-Syn fibrils localize to the mitochondria and induce mitochondrial dysfunction and neurotoxicity. Injection of 27-OHC-modified α-Syn fibrils induces enhanced spread of α-Syn pathology and dopaminergic neurodegeneration compared with pure α-Syn fibrils. Similarly, subcutaneous administration of 27-OHC facilitates the seeding of α-Syn pathology. Genetic deletion of cytochrome P450 27A1 (CYP27A1), the enzyme that converts cholesterol to 27-OHC, ameliorates the spread of pathologic α-Syn, degeneration of the nigrostriatal dopaminergic pathway, and motor impairments. These results indicate that the cholesterol metabolite 27-OHC plays an important role in the pathogenesis of PD. CONCLUSIONS: 27-OHC promotes the aggregation and spread of α-Syn. Strategies aimed at inhibiting the CYP27A1-27-OHC axis may hold promise as a disease-modifying therapy to halt the progression of α-Syn pathology in PD. © 2023 International Parkinson and Movement Disorder Society.


Asunto(s)
Enfermedad de Parkinson , Humanos , Ratones , Animales , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Hidroxicolesteroles/farmacología , Colesterol
5.
Biochem Biophys Res Commun ; 529(4): 1053-1060, 2020 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-32819564

RESUMEN

The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is the major component. Converging evidence supports the prion-like transmission of α-synuclein aggregates in the onset and progression of PD. Intracellular α-synuclein aggregates into pathological fibrils, which can be transferred from aggregate-producing cells to aggregate-free cells, triggering neuronal injury and the progression of pathology. However, the specific mechanisms mediating the aggregation and transmission of pathological α-synuclein remain unknown. Here we show that cofilin 1 binds to α-synuclein and promotes its aggregation. The mixed fibrils consist of cofilin 1 and α-synuclein are more compact and more potent than pure α-synuclein fibrils in seeding α-synuclein aggregation. Cofilin 1 also facilitates the uptake of α-synuclein fibrils and finally induces neuronal dysfunction. Together, these observations indicate that cofilin 1 acts as a crucial mediator in the aggregation and propagation of pathological α-synuclein, contributing to the pathogenesis of PD.


Asunto(s)
Cofilina 1/metabolismo , Enfermedad de Parkinson/metabolismo , Agregado de Proteínas , alfa-Sinucleína/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Células HEK293 , Humanos , Ratones Transgénicos , Unión Proteica , alfa-Sinucleína/toxicidad
6.
J Chem Phys ; 150(18): 184903, 2019 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-31091923

RESUMEN

We present a systematic investigation on the effect of adding nanoparticles on the dynamics of polymer chains by using coarse-grained molecular dynamics simulation. The dynamics is characterized by three aspects: molecular motion, relaxation at different length scales, and dynamical heterogeneity. It is found that the motion of polymer chains slows down and the deviation from Gaussian distribution becomes more pronounced with increasing nanoparticle volume fractions. For polymer nanocomposites with R ≤ Rg, the relaxation at the wave vector q = 7.0 displays multistep decay, consistent with the previous reports in strongly interacting polymer nanocomposites. Moreover, a qualitatively universal law is established that dynamic heterogeneity at whole chain's scale follows a nonmonotonic increase with increasing nanoparticle loadings, where the volume fraction of the maximum dynamic heterogeneity corresponds to the particle loading when the average distance between nanoparticles is equal to the Kuhn length of polymer chains. We show that the decoupling between whole chain's dynamics and segment dynamics is responsible for the nonmonotonic behavior of dynamic heterogeneity of whole chains.

7.
Bioorg Med Chem Lett ; 28(4): 547-551, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29422390

RESUMEN

α1-Adrenoceptor (α1-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2-17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH3, 2-CH3 or 2, 5-CH3, respectively, exhibited potent α1-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (-)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α1A), spleen (α1B) and thoracic aorta (α1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α1D/1A subtype selectivity, especially improved α1A subtype selectivity, and the ratios pA2 (α1D)/pA2 (α1B) and pA2 (α1A)/pA2 (α1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.


Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Naftalenos/farmacología , Fenilacetatos/farmacología , Piperazinas/farmacología , Vasodilatadores/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/síntesis química , Antagonistas de Receptores Adrenérgicos alfa 1/química , Animales , Aorta/efectos de los fármacos , Masculino , Contracción Muscular/efectos de los fármacos , Naftalenos/síntesis química , Naftalenos/química , Fenilacetatos/síntesis química , Fenilacetatos/química , Piperazinas/síntesis química , Piperazinas/química , Prazosina/análogos & derivados , Prazosina/farmacología , Conejos , Ratas Sprague-Dawley , Bazo/efectos de los fármacos , Estereoisomerismo , Conducto Deferente/efectos de los fármacos , Vasodilatadores/síntesis química , Vasodilatadores/química
8.
Blood ; 119(20): 4608-13, 2012 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-22451423

RESUMEN

This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m(2) (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/administración & dosificación , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina , Dexametasona/efectos adversos , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/efectos de los fármacos , Estudios de Factibilidad , Femenino , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Compuestos de Mostaza Nitrogenada/efectos adversos , Recurrencia , Talidomida/administración & dosificación , Talidomida/efectos adversos , Resultado del Tratamiento
9.
Cell Biochem Biophys ; 2024 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-39187743

RESUMEN

Sepsis patients are highly prone to sepsis-associated encephalopathy (SAE) complications, resulting in a high mortality rate. Recently, there has been no specific treatment for long-term improvement of cerebral function. Ginsenoside Rh2 is a form of steroidal saponins isolated from plant ginseng and has been shown to possess anti-inflammatory as well as neuroprotective characteristics; yet, the effect of ginsenoside Rh2 on SAE treatment is obscure. Accordingly, we proposed to investigate the effect of ginsenoside Rh2 in alleviating SAE damage. We established and utilized the SAE mouse model to determine the effect of Rh2 treatment on alleviating SAE. We determined the expression levels of Heme oxygenase-1(HO-1) and Nuclear factor erythroid 2-related factor 2 (Nrf2) as well as measured neural apoptosis by flow cytometry. Also, we quantified the levels of caspase-3, malondialdehyde (MDA), GSH-Px superoxide dismutase (SOD) and evaluated the animals' neural reflex function. First, used Rh2 to treat microglia BV2 and mouse neuron MN-c whether LPS exist or not, and then measured expression level of Iba-1, apoptotic rate, and ROS content applying flow cytometry. Also, we quantified the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). In comparison with the Sham group, the SAE model exhibited an elevated MDA content, caspase-3 activity, and cell apoptosis. On the other hand, the GSH-Px activity and SOD level were decreased along with a decreased neural reflex score. Our investigation concluded that Rh2 treatment significantly alleviated SAE damage and inhibited LPS-induced response via up-regulation of the Nrf2/HO-1 pathway to promote anti-oxidative stress capacity and inhibit neural cell apoptosis.

10.
Mol Neurobiol ; 61(4): 2446-2458, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37897633

RESUMEN

The 2019 novel coronavirus disease (COVID-19) is an infectious disease that began to spread globally since 2019. Some COVID-19 patients have neurological complications, such as olfactory disorders and movement disorders, which coincide with the symptoms of Parkinson's disease (PD). Increasing imaging and autopsy evidence supports that the density of dopaminergic neurons in the nigrostriatal pathway is damaged in some COVID-19 patients. However, the underlying mechanism that causes PD-like symptoms remains unclear. PD is an age-related neurodegenerative disease with Lewy bodies (LBs) as its histopathologic feature. The main component of LBs is abnormally aggregated α-synuclein (α-syn). The prion-like propagation of α-syn aggregates plays a key role in the onset and progression of PD. The spike protein (S protein) of SARS-CoV-2 is a heparin-binding protein that mediates the entry of the virus into host cells. Here we found that the S1 domain interacts with α-syn and promotes α-syn aggregation. The S1 domain induces mitochondrial dysfunction, oxidative stress, and cytotoxicity. The S1-seeded α-syn fibrils show enhanced seeding activity and induce synaptic damage and cytotoxicity. Thus, the S1 domain of SARS-CoV-2 promotes the aggregation of α-syn in the cellular model of synucleinopathy and may contribute to the pathogenesis of PD.


Asunto(s)
COVID-19 , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Sinucleinopatías , Humanos , alfa-Sinucleína/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Fosforilación , SARS-CoV-2 , Enfermedad de Parkinson/patología
11.
Trends Neurosci ; 47(3): 209-226, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38355325

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies (LBs). The main proteinaceous component of LBs is aggregated α-synuclein (α-syn). However, the mechanisms underlying α-syn aggregation are not yet fully understood. Converging lines of evidence indicate that, under certain pathological conditions, various proteins can interact with α-syn and regulate its aggregation. Understanding these protein-protein interactions is crucial for unraveling the molecular mechanisms contributing to PD pathogenesis. In this review we provide an overview of the current knowledge on protein-protein interactions that regulate α-syn aggregation. Additionally, we briefly summarize the methods used to investigate the influence of protein-protein interactions on α-syn aggregation and propagation.


Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , alfa-Sinucleína/metabolismo , Neuronas Dopaminérgicas/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedad de Parkinson/metabolismo
12.
Biomater Adv ; 166: 214041, 2024 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-39278037

RESUMEN

In the realm of skin injury management, the expedited closure of wounds, prevention of scar formation, and enhancement of the healing process are of critical significance. The creation of economical dressings that effectively facilitate swift wound sealing in the initial phase of skin trauma while curbing scar development represents a promising avenue for clinical utility. Within the context of this investigation, we synthesized a novel hydrogel composed of chitosan (CS), carboxylated poly(vinyl alcohol) (PVA-COOH) via a Schiff base reaction between carboxylated PVA and chitosan, yielding networks abundant in amide bonds. Following this, a chitosan/carboxylated PVA/poly(N-isopropylacrylamide) hydrogel (CNP) was engineered by incorporating poly-N-isopropylacrylamide chains for interpenetration at ambient temperature. Our findings indicate that the CNP hydrogel exhibits favorable degradability and swelling characteristics. Moreover, it possesses favorable antimicrobial efficacy and biocompatibility. In a murine full-thickness skin injury model, the hydrogel was found to expedite wound healing by augmenting granulation tissue formation, mitigating wound inflammation, and promoting angiogenesis.

13.
J Inflamm Res ; 17: 2383-2397, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38660574

RESUMEN

Objective: Keratoconus is a commonly progressive and blinding corneal disorder. Iron metabolism and oxidative stress play crucial roles in both keratoconus and ferroptosis. However, the association between keratoconus and ferroptosis is currently unclear. This study aimed to analyze and verify the role of ferroptosis-related genes (FRGs) in the pathogenesis of keratoconus through bioinformatics. Methods: We first obtained keratoconus-related datasets and FRGs. Then, the differentially expressed FRGs (DE-FRGs) associated with keratoconus were screened through analysis, followed by analysis of their biological functions. Subsequently, the LASSO and SVM-RFE algorithms were used to screen for diagnostic biomarkers. GSEA was performed to explore the potential functions of the marker genes. Finally, the associations between these biomarkers and immune cells were analyzed. qRT‒PCR was used to detect the expression of these biomarkers in corneal tissues. Results: A total of 39 DE-FRGs were screened, and functional enrichment analysis revealed that the DE-FRGs were closely related to apoptosis, oxidative stress, and the immune response. Then, using multiple algorithms, 6 diagnostic biomarkers were selected, and the ROC curve was used to verify their risk prediction ability. In addition, based on CIBERSORT analysis, alterations in the immune microenvironment of keratoconus patients might be associated with H19, GCH1, CHAC1, and CDKN1A. Finally, qRT‒PCR confirmed that the expression of H19 and CHAC1 was elevated in the keratoconus group. Conclusion: This study identified 6 DE-FRGs, 4 of which were associated with immune infiltrating cells, and established a diagnostic model with predictive value for keratoconus.

14.
Sci Total Environ ; 916: 170260, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38253105

RESUMEN

Mercury (Hg) contamination in aquatic environments presents a significant ecological and human health concern. This study explored the relationship between catchment land use and Hg concentrations within Qinghai Lake sediment, the largest lake in China, situated on the Qinghai-Tibet plateau. The study entailed detailed mapping of Hg sediment concentrations and a subsequent environmental risk assessment. Considering the complex nature of the plateau landform and surface vegetation, the study area was delineated at a 100 km radius centered on Qinghai Lake, which was divided into 30 sectors to quantify relationships between land use and the sediment Hg concentration. The results revealed a mean sediment Hg concentration of 29.91 µg/kg, which was elevated above the background level. Kendall's correlation analysis revealed significant but weak associations between sediment Hg concentrations and three land use types: grassland (rangeland and trees) (rs = 0.27, p < 0.05), crops (rs = -0.37, p < 0.05), and bare ground (rs = -0.25, p < 0.1), suggesting that growing areas of grassland correlated with higher Hg levels in the lake sediment, in contrast to bare ground or crops area, which correlated with lower Hg concentrations. Multiple linear regression models also observed weak negative relationships between bare ground and crops with sediment Hg concentration. This research methodology enhances our understanding of the impact of land use on Hg accumulation in lake sediments and underscores the need for integrated watershed management strategies to mitigate Hg pollution in Qinghai Lake.

15.
Int J Biol Macromol ; 271(Pt 2): 132632, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38797298

RESUMEN

Current limitations in mechanical performance and foreign body reactions (FBR) often lead to implant failure, restricting the application of bioceramic scaffolds. This study presents a novel 3D-printed scaffold that combines the release of anti-inflammatory drugs with osteogenic stimulation. Initially, the inorganic and organic phases were integrated to ensure the scaffold's mechanical integrity through catechol chemistry and the electrostatic interactions between tannic acid and quaternary ammonium chitosan. Subsequently, layers of polydopamine-encapsulated puerarin-loaded zeolitic imidazolate framework-8 (ZIF-8) were self-assembled onto the stent's surface, creating the drug-loaded scaffold that improved drug release without altering the scaffold's structure. Compared with unloaded scaffolds, the puerarin-loaded scaffold demonstrated excellent osteogenic differentiation properties along with superior anti-inflammatory and osteogenic effects in a range of in vitro and in vivo studies. RNA sequencing clarified the role of the TNF and NF/κB signaling pathways in these effects, further supporting the scaffold's osteogenic potential. This study introduces a novel approach for creating drug-loaded scaffolds, providing a unique method for treating cancellous bone defects.


Asunto(s)
Alginatos , Fosfatos de Calcio , Quitosano , Isoflavonas , Osteogénesis , Taninos , Ingeniería de Tejidos , Andamios del Tejido , Quitosano/química , Andamios del Tejido/química , Ingeniería de Tejidos/métodos , Isoflavonas/química , Isoflavonas/farmacología , Osteogénesis/efectos de los fármacos , Animales , Alginatos/química , Fosfatos de Calcio/química , Fosfatos de Calcio/farmacología , Taninos/química , Taninos/farmacología , Huesos/efectos de los fármacos , Ratones , Regeneración Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Humanos , Polifenoles
16.
Cell Death Differ ; 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39174646

RESUMEN

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (α-Syn) aggregates. However, the molecular mechanisms regulating α-Syn aggregation and neuronal degeneration remain poorly understood. The peptidase M20 domain containing 1 (PM20D1) gene lies within the PARK16 locus genetically linked to PD. Single nucleotide polymorphisms regulating PM20D1 expression are associated with changed risk of PD. Dopamine (DA) metabolism and DA metabolites have been reported to regulate α-Syn pathology. Here we report that PM20D1 catalyzes the conversion of DA to N-arachidonoyl dopamine (NADA), which interacts with α-Syn and inhibits its aggregation. Simultaneously, NADA competes with α-Syn fibrils to regulate TRPV4-mediated calcium influx and downstream phosphatases, thus alleviating α-Syn phosphorylation. The expression of PM20D1 decreases during aging. Overexpression of PM20D1 or the administration of NADA in a mouse model of synucleinopathy alleviated α-Syn pathology, dopaminergic neurodegeneration, and motor impairments. These observations support the protective effect of the PM20D1-NADA pathway against the progression of α-Syn pathology in PD.

17.
Nat Commun ; 15(1): 3700, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38697989

RESUMEN

Detecting early-stage esophageal squamous cell carcinoma (ESCC) and precancerous lesions is critical for improving survival. Here, we conduct whole-genome bisulfite sequencing (WGBS) on 460 cfDNA samples from patients with non-metastatic ESCC or precancerous lesions and matched healthy controls. We develop an expanded multimodal analysis (EMMA) framework to simultaneously identify cfDNA methylation, copy number variants (CNVs), and fragmentation markers in cfDNA WGBS data. cfDNA methylation markers are the earliest and most sensitive, detectable in 70% of ESCCs and 50% of precancerous lesions, and associated with molecular subtypes and tumor microenvironments. CNVs and fragmentation features show high specificity but are linked to late-stage disease. EMMA significantly improves detection rates, increasing AUCs from 0.90 to 0.99, and detects 87% of ESCCs and 62% of precancerous lesions with >95% specificity in validation cohorts. Our findings demonstrate the potential of multimodal analysis of cfDNA methylome for early detection and monitoring of molecular characteristics in ESCC.


Asunto(s)
Biomarcadores de Tumor , Variaciones en el Número de Copia de ADN , Metilación de ADN , Detección Precoz del Cáncer , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Lesiones Precancerosas , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/diagnóstico , Lesiones Precancerosas/genética , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/patología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patología , Masculino , Detección Precoz del Cáncer/métodos , Femenino , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Anciano , Epigenoma , Ácidos Nucleicos Libres de Células/genética , Ácidos Nucleicos Libres de Células/sangre , Secuenciación Completa del Genoma/métodos , Microambiente Tumoral/genética
18.
J Nanosci Nanotechnol ; 13(6): 3832-40, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23862415

RESUMEN

Cross-linked chitosan (CS) nanohydrogels were successfully prepared via cross-linking CS nanodroplets in inverse miniemulsions. The cross-linker was transferred to the CS nanodroplets via the evaporation from its aqueous solution and diffusion through the continuous phase. The formation of cross-linked CS nanohydrogels was confirmed by the morphological investigation during the reaction and the successful preparation of acidic aqueous dispersion of CS nanohydrogels. The size and size distribution of the CS nanodroplets and nanohydrogels were characterized by dynamic light scattering (DLS). The particle morphology of CS nanohydrogels was observed by transmission electron microscopy (TEM). The influence of the synthetic parameters on the particle properties and colloidal stability was investigated with respect to sonication time, surfactant type and amount, type of low polarity solvent, and concentration of CS solution. The cross-linked CS nanohydrogels could be easily re-dispersed in water, and showed a pH sensitivity.


Asunto(s)
Quitosano/química , Emulsiones , Hidrogeles , Nanotecnología , Microscopía Electrónica de Transmisión
19.
Neurosciences (Riyadh) ; 18(4): 356-62, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24141459

RESUMEN

OBJECTIVE: To investigate whether lithium modifies open-field and elevated plus maze behavior, and brain phospho-glycogen synthase kinase 3 (P-GSK3beta) expression in Fmr1 knockout mice. METHODS: One hundred and eighty FVB mice, including knockout and wild type, with an age of 30 days were used. An open-field and elevated plus maze was utilized to test behavior, while western blot was used to measure the P-GSK3beta expression. Six groups were formed: control (saline), lithium chloride 30, 60, 90, 120, and 200 mg/kg. The experiments were carried out in the Institute of Neuroscience, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China between January and June 2012. RESULTS: Lithium significantly decreased total distance, crossing, central area time, and center entry in the open-field test (p<0.05), and significantly reduced open-arm tracking, open-arm entry, and open-arm time in the elevated plus maze (p<0.05) in knockout mice. In wild type mice, significant changes were observed in both behavior tests in some treatment groups. Lithium ameliorated P-GSK3beta expression in the hippocampus of all the treatment groups in knockout mice (p<0.05). However, lithium did not modify either GSK3beta expression in tissues of knockout mice, or P-GSK3beta or GSK3beta expression in tissues of wild type mice. CONCLUSION: Lithium ameliorated open-field and elevated plus maze behaviors of Fmr1 knockout mice. This effect may be related to its enhancement of P-GSK3beta expression. Our findings suggest that lithium might have a therapeutic effect in fragile X syndrome.


Asunto(s)
Antimaníacos/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Síndrome del Cromosoma X Frágil/enzimología , Glucógeno Sintasa Quinasa 3/biosíntesis , Cloruro de Litio/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Animales , Western Blotting , Encéfalo/enzimología , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta , Inmunohistoquímica , Ratones , Ratones Noqueados
20.
Environ Pollut ; 337: 122614, 2023 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-37748639

RESUMEN

The presence of trace metals (TMs) in agricultural soil has garnered considerable attention due to their potential migration into crops, posing a significant risk to human health. In this study, we examined the concentrations of eight trace metals (Cd, Cr, Cu, Hg, Mn, Ni, Pb, and Zn) in the soil and investigated various soil physicochemical characteristics in the Three Rivers Plain region, China. The assessment of the geoaccumulation index (Igeo) for the mean concentration of all trace metals indicated that the soils were generally free from significant TM pollution. However, a noteworthy finding emerged in relation to Hg, where the maximum Igeo value suggested moderate pollution levels. Kriging prediction results further indicated that approximately 1.55% of the study area might be impacted by Hg pollution. Moreover, it is prudent to direct attention towards Cd, Cr, Cu, Mn, and Ni, as their Igeo values revealed that the region with the highest concentrations of these metals ranged from unpolluted to moderately polluted. This study employed a comprehensive approach, utilizing the Self-Organizing Map (SOM), Kriging spatial distribution, and the Positive Matrix Factorization (PMF) model to identify the sources of TMs in agricultural soil. The results unveiled that the primary contributors to TM presence were the natural parental materials, alongside industrial activities such as coal mining and coal plant operations, as well as agricultural practices. These findings provide foundational insights for future management strategies in the Three Rivers Plain, aiming to enhance agricultural productivity and promote sustainability.


Asunto(s)
Mercurio , Metales Pesados , Contaminantes del Suelo , Oligoelementos , Humanos , Suelo , Granjas , Metales Pesados/análisis , Cadmio , Monitoreo del Ambiente/métodos , Contaminantes del Suelo/análisis , Medición de Riesgo , China
SELECCIÓN DE REFERENCIAS
Detalles de la búsqueda