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1.
ChemSusChem ; : e202401365, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39289157

RESUMO

Lithium-ion capacitors (LICs) have attracted considerable interest because of their excellent power and energy densities. However, the development of LICs is limited by the low capacity of the cathode and the kinetics mismatch between the cathode and anode. In this work, mesoporous carbon materials (MCs) with uniform pore sizes were prepared using magnesium citrate as the raw material through a self-templating method. During the carbonization process, MgO nanoparticles generated from magnesium citrate act as a template, resulting in a more orderly pore structure. The resultant MCs demonstrate a high specific surface area of 1673 m2 g-1 and an abundance of small mesopores, which significantly accelerated ion migration within the electrolyte and expedited the formation of electric double layers. Benefiting from these advantages, the MCs cathode demonstrates a high reversible specific capacity, excellent cycling stability, and rate performance. The assembled MCs-based LIC provides a high energy density of 152.2 Wh kg-1 and a high power density of 14.3 kW kg-1. After 5000 cycles, a capacity retention rate of 80% at the current density of 1 A g-1 is obtained. These results highlight the excellent potential of MCs as a cathode material for LICs.

2.
Psychol Res Behav Manag ; 17: 3181-3195, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39301575

RESUMO

Background: : Family coping, as an essential part of family management of patients with chronic heart failure (CHF), is an important component of CHF interventions, affecting the health of patients, family members, and the whole family. It is necessary to understand the current situation of family coping in patients with CHF to facilitate the development of family interventions for patients with CHF. This study aims to develop and validate a tool for assessing the family coping scale for patients with CHF. Methods: The semi-structured interviews, expert consensus meetings, expert consultations, and item analysis were used to develop the initial scale. We employed classical test theory and exploratory factor analysis to scrutinize and refine the items in the scale. To validate the scale, we used confirmatory factor analysis to assess structural validity. We assessed internal consistency, and split-half reliability to ensure the scale's robustness and accuracy. Results: The FCS-CHF consisted of 24 items, including six dimensions: strategies for better management of CHF, psychological coping, substantial support by family members, emergency coping, overall heart failure awareness, and patients' health behavior. The results of confirmatory factor analysis showed that the scale fitted the data with well construct validity. The results of the confirmatory factor analysis for the overall goodness of fit indices for the fitted model were found to be acceptable for the scale. The scale demonstrates good reliability and validity, meeting the requirements of psychometrics. Conclusions: The FCS-CHF developed in this study is considered reliable and valid, which can measure family coping in patients with CHF and provide a basis for developing family coping enhancement strategies.

3.
iScience ; 27(9): 110741, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39280604

RESUMO

Osteoarthritis (OA) is a progressive degenerative joint disease, and the underlying molecular mechanisms of OA remain poorly understood. This study aimed to elucidate the relationship between mitochondrial autophagy and OA by identifying key regulatory genes and their biological functions. Utilizing bioinformatics analyses of RNA expression profiles from the GSE55235 dataset, we identified 2,136 differentially expressed genes, leading to the discovery of hub genes associated with mitochondrial autophagy and OA. Gene set enrichment analysis (GSEA) revealed their involvement in critical pathways, highlighting their potential roles in OA pathogenesis. Furthermore, our study explored the immunological landscape of OA, identifying distinct immune cell infiltration patterns that contribute to the disease's inflammatory profile. We also evaluated the therapeutic potential of drugs targeting these hub genes, suggesting potential approaches for OA treatment. Collectively, this study advances our knowledge of mitochondrial autophagy in OA and proposes promising biomarkers and therapeutic targets.

4.
Langmuir ; 2024 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-39321402

RESUMO

Ionic conductive cellulose hydrogels are some of the most promising candidates for flexible sensors. However, it is difficult to simultaneously prepare cellulose hydrogels with high mechanical strength, good ionic conductivity, and antifreeze performance. In this work, a natural clay (attapulgite)-reinforced cellulose hydrogel was fabricated. Through a one-pot method, cellulose and attapulgite were dispersed in a concentrated ZnCl2 solution. The obtained hydrogel exhibited a dual network of hydrogen bonds and Zn2+-induced ionic interactions. Attapulgite serves as an inorganic filler that can regulate the hydrogen-bonding density among cellulose molecules and provides abundant channels for fast ion transport. By optimizing the attapulgite loading, a mechanically strong (compressive strength up to 1.10 MPa), tough (fracture energy up to 0.36 MJ m-3), highly ionic conductive (4.15 S m-1), and freezing-tolerant hydrogel was prepared. These hydrogels can be used for sensitive and stable human motion sensing, demonstrating their great potential for healthcare applications.

5.
Front Hum Neurosci ; 18: 1464152, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39296915

RESUMO

Introduction: Freezing of gait (FOG) is a disabling and heterogeneous symptom in patients with Parkinson's disease (PD). Among them, dopamine-induced FOG is rare and difficult to identify. The treatment of dopamine-induced FOG is complex. Case presentation: We herein presented a case of PD patient who complicated with refractory FOG. It was identified as dopamine-induced FOG during levodopa challenge test. Her symptoms were alleviated after we reduced the total equivalent dosage of levodopa. Conclusion: Our report emphasizes the importance of levodopa challenge test in identifying different types of FOG, which is very important for further adjusting treatment.

6.
Small ; : e2402668, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39235584

RESUMO

Photodetectors are one of the most critical components for future optoelectronic systems and it undergoes significant advancements to meet the growing demands of diverse applications spanning the spectrum from ultraviolet (UV) to terahertz (THz). 2D materials are very attractive for photodetector applications because of their distinct optical and electrical properties. The atomic-thin structure, high carrier mobility, low van der Waals (vdWs) interaction between layers, relatively narrower bandgap engineered through engineering, and significant absorption coefficient significantly benefit the chip-scale production and integration of 2D materials-based photodetectors. The extremely sensitive detection at ambient temperature with ultra-fast capabilities is made possible with the adaptability of 2D materials. Here, the recent progress of photodetectors based on 2D materials, covering the spectrum from UV to THz is reported. In this report, the interaction of light with 2D materials is first deliberated on in terms of optical physics. Then, various mechanisms on which detectors work, important performance parameters, important and fruitful fabrication methods, fundamental optical properties of 2D materials, various types of 2D materials-based detectors, different strategies to improve performance, and important applications of photodetectors are discussed.

7.
Chem Biol Interact ; 403: 111230, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39244186

RESUMO

Vascular endothelial injury is closely related to the progression of various cardio-cerebrovascular diseases. Whether Human Urinary Kallidinogenase (HUK) has a protective effect on endothelial injury remains unclear. This study established an in vivo model of rat common carotid artery intima injury and an in vitro model of human umbilical vein endothelial cell (HUVECs) injury induced by hydrogen peroxide (H2O2). To explore the protective effect and mechanism of HUK on endothelial injury. In vivo, HUK can reduce the hyperplasia and lumen stenosis of rat common carotid artery after intimal injury, and promote the fluorescence expression of vWF in the common carotid artery. HUK also activated the Nrf2/HO-1 signaling pathway in rat common carotid artery tissue to reduce endothelial damage. In vitro, HUK can inhibit the H2O2-induced decline in HUVECs activity, improve the migration ability of HUVECs induced by H2O2, inhibit the apoptosis and necrosis of HUVECs and the generation of ROS, and regulate the expression of VEGFA, ET-1 and eNOS proteins related to endothelial function in cells. The Nrf2/HO-1 signaling pathway is activated, and the HO-1 specific inhibitor zinc porphyrin (ZnPP) can partially reverse the protective effect of HUK on H2O2-induced HUVECs injury in terms of cell migration, necrosis and oxidative stress. The Nrf2/HO-1 signaling pathway plays an important role in the regulation of migration, necrosis and oxidative stress of HUVECs cells. HUK has a protective effect on vascular endothelial injury. HUK can inhibit oxidative stress and apoptotic necrosis by activating Nrf2/HO-1 signaling pathway.

8.
Small ; : e2403078, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39221641

RESUMO

Ti3C2Tx (MXene) is widely acknowledged as an excellent substrate for constructing heterogeneous structures with transition metal chalcogenides (TMCs) for boosting the electrochemical performance of lithium-ion storage. However, conventional synthesis strategies inevitably lead to poor electrochemical charge transfer due to Ti3C2Tx-derived TiO2 at the heterogeneous interface between Ti3C2Tx and TMCs. Here, an innovative in situ selenization strategy is proposed to replace the originally generated TiO2 on Ti3C2Tx with metallic TiSe2 interphase, clearing the bottleneck of slow charge transfer barrier caused by MXene oxidation. The construction of bimetallic selenide formed by CoSe2 and TiSe2 generates intrinsic electric fields to guide the fast ion diffusion kinetics in a heterogeneous interface. Additionally, the CoSe2/TiSe2/Ti3C2Tx heterogeneous structure with enhanced structural stability and improved rate performance is confirmed by both experiments and theoretical calculations. The engineered heterogeneous structure exhibits an ultra-high pseudocapacitance contribution (73.1% at 0.1 mV s-1), rendering it well-suited to offset the kinetics differences between double-layer materials. The assembled lithium-ion capacitor based on CoSe2/TiSe2/Ti3C2Tx possesses a high energy density and an ultralong life span (89.5% after 10 000 times at 2 A g-1). This devised strategy provides a feasible solution for utilizing the performance advantages of MXene substrates in lithium storage with ultrafast charge transfer kinetics.

11.
Xenotransplantation ; 31(4): e12881, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39185796

RESUMO

BACKGROUND: The number of multigene-modified donor pigs for xenotransplantation is increasing with the advent of gene-editing technologies. However, it remains unclear which gene combination is suitable for specific organ transplantation. METHODS: In this study, we utilized CRISPR/Cas9 gene editing technology, piggyBac transposon system, and somatic cell cloning to construct GTKO/hCD55/hTBM/hCD39 four-gene-edited cloned (GEC) pigs and performed kidney transplantation from pig to rhesus monkey to evaluate the effectiveness of these GEC pigs. RESULTS: First, 107 cell colonies were obtained through drug selection, of which seven were 4-GE colonies. Two colonies were selected for somatic cell nuclear transfer (SCNT), resulting in seven fetuses, of which four were GGTA1 biallelic knockout. Out of these four, two fetuses had higher expression of hCD55, hTBM, and hCD39. Therefore, these two fetuses were selected for two consecutive rounds of cloning, resulting in 97 live piglets. After phenotype identification, the GGTA1 gene of these pigs was inactivated, and hCD55, hTBM, and hCD39 were expressed in cells and multiple tissues. Furthermore, the numbers of monkey IgM and IgG binding to the peripheral blood mononuclear cells (PBMCs) of the 4-GEC pigs were markedly reduced. Moreover, 4-GEC porcine PBMCs had greater survival rates than those from wild-type pigs through complement-mediated cytolysis assays. In pig-to-monkey kidney xenotransplantation, the kidney xenograft successfully survived for 11 days. All physiological and biochemical indicators were normal, and no hyperacute rejection or coagulation abnormalities were found after transplantation. CONCLUSION: These results indicate that the GTKO/hCD55/hTBM/hCD39 four-gene modification effectively alleviates immune rejection, and the pig kidney can functionally support the recipient monkey's life.


Assuntos
Animais Geneticamente Modificados , Galactosiltransferases , Edição de Genes , Transplante de Rim , Transplante Heterólogo , Animais , Transplante Heterólogo/métodos , Transplante de Rim/métodos , Suínos , Edição de Genes/métodos , Galactosiltransferases/genética , Sistemas CRISPR-Cas , Macaca mulatta , Técnicas de Transferência Nuclear , Xenoenxertos , Humanos , Sobrevivência de Enxerto/imunologia , Rejeição de Enxerto/imunologia , Apirase , Antígenos CD
12.
J Am Chem Soc ; 146(35): 24368-24376, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39166377

RESUMO

Effective design and engineering of catalysts for an optimal performance depend extensively on a profound understanding of the intricate catalytic dynamics under reaction conditions. In this work, we showcase rapid freeze-quench (RFQ) Mössbauer spectroscopy as a powerful technique for quantitatively monitoring the catalytic dynamics of single-Cu-atom-modified SnS2 (Cu1/SnS2) in the electrochemical CO2 reduction reaction (CO2RR). Utilizing the newly established RFQ 119Sn Mössbauer methodology, we clearly identified the dynamic transformation of Cu1/SnS2 to Cu1/SnS and Cu1/Sn during the CO2RR, resulting in an outstanding Faradaic efficiency for formate production (∼90.9%) with a partial current density of 158 mA cm-2. Results from operando Raman spectroscopy, operando attenuated total reflection surface-enhanced infrared absorption spectroscopy (ATR-SEIRAS), quasi in situ electron microscopy, and quasi in situ X-ray photoelectron spectroscopy (XPS) measurements indicate that the anchored single Cu atom in Cu1/SnS2 can accelerate the reduction of SnS with in situ formation of Cu1/Sn under CO2RR conditions, which effectively promote the generation of *CO2-/*OCHO intermediates. Theoretical calculations further support that in situ formed Cu1/Sn works as active sites catalyzing the CO2RR, which reduces the energy barrier for the CO2 activation and formation of the *OCHO intermediate, thereby facilitating the conversion of CO2 to formate. The results of this work provide a thorough understanding of the dynamic evolution of Sn-based catalytic sites in the CO2RR and shed light for engineering single atoms with an optimized catalytic performance. We anticipate that RFQ Mössbauer spectroscopy will emerge as an advanced spectroscopic technique for enabling a genuine visualization of catalytic dynamics across various reaction systems.

14.
Nat Commun ; 15(1): 6626, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39103353

RESUMO

N-Myc is a key driver of neuroblastoma and neuroendocrine prostate cancer (NEPC). One potential way to circumvent the challenge of undruggable N-Myc is to target the protein homeostasis (proteostasis) system that maintains N-Myc levels. Here, we identify heat shock protein 70 (HSP70) as a top partner of N-Myc, which binds a conserved "SELILKR" motif and prevents the access of E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1 (STUB1), possibly through steric hindrance. When HSP70's dwell time on N-Myc is increased by treatment with the HSP70 allosteric inhibitor, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites and forms polyubiquitination chains linked by the K11 and K63 sites. Notably, HSP70 inhibition significantly suppressed NEPC tumor growth, increased the efficacy of aurora kinase A (AURKA) inhibitors, and limited the expression of neuroendocrine-related pathways.


Assuntos
Proteínas de Choque Térmico HSP70 , Neoplasias da Próstata , Proteostase , Ubiquitina-Proteína Ligases , Ubiquitinação , Masculino , Humanos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Proteínas de Choque Térmico HSP70/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , Aurora Quinase A/metabolismo , Aurora Quinase A/genética , Aurora Quinase A/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Camundongos , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia
15.
Neurochem Res ; 49(10): 2957-2971, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39088164

RESUMO

Depression and anxiety disorders are prevalent stress-related neuropsychiatric disorders and involve multiple molecular changes and dysfunctions across various brain regions. However, the specific and shared pathophysiological mechanisms occurring in these regions remain unclear. Previous research used a rat model of chronic mild stress (CMS) to segregate and identify depression-susceptible, anxiety-susceptible, and insusceptible groups; then the proteomes of six distinct brain regions (the hippocampus, prefrontal cortex, hypothalamus, pituitary, olfactory bulb, and striatum) were separately and quantitatively analyzed. To gain a comprehensive and systematic understanding of the molecular abnormalities, this study aimed to investigate and compare differential proteomics data from the six regions. Differentially expressed proteins (DEPs) were identified in between specific regions and across all regions and subjected to a series of bioinformatics analyses. Regional comparisons showed that stress-induced proteomic changes and corresponding gene ontology and pathway enrichments were largely distinct, attributable to differences in cell populations, protein compositions, and brain functions of these areas. Additionally, a notable degree of overlap in the significantly enriched terms was identified, potentially suggesting strong connections in the enrichment across different regions. Furthermore, intra-regional and inter-regional protein-protein interaction networks and drug-target-DEP networks were constructed. Integrated analysis of the three association networks in the six regions, along with the DisGeNET database, identified ten DEPs as potential targets for anti-depression/anxiety drugs. Collectively, these findings revealed commonalities and differences across different brain regions at the protein level induced by CMS, and identified several novel protein targets for the development of new therapeutics for depression and anxiety.


Assuntos
Ansiolíticos , Encéfalo , Proteoma , Ratos Sprague-Dawley , Estresse Psicológico , Animais , Estresse Psicológico/metabolismo , Estresse Psicológico/tratamento farmacológico , Proteoma/metabolismo , Masculino , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/metabolismo , Ansiedade/tratamento farmacológico , Depressão/metabolismo , Depressão/tratamento farmacológico , Mapas de Interação de Proteínas , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ratos , Proteômica
16.
Neuroscience ; 553: 172-184, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-38964454

RESUMO

Genetic variants in genes encoding subunits of the γ-aminobutyric acid-A receptor (GABAAR) have been found to cause neurodevelopmental disorders and epileptic encephalopathy. In a patient with epilepsy and developmental delay, a de novo heterozygous missense mutation c.671 T > C (p.F224S) was discovered in the GABRB2 gene, which encodes the ß2 subunit of GABAAR. Based on previous studies on GABRB2 variants, this new GABRB2 variant (F224S) would be pathogenic. To confirm and investigate the effects of this GABRB2 mutation on GABAAR channel function, we conducted transient expression experiments using GABAAR subunits in HEK293T cells. The GABAARs containing mutant ß2 (F224S) subunit showed poor trafficking to the cell membrane, while the expression and distribution of the normal α1 and γ2 subunits were unaffected. Furthermore, the peak current amplitude of the GABAAR containing the ß2 (F224S) subunit was significantly smaller compared to the wild type GABAAR. We propose that GABRB2 variant F224S is pathogenic and GABAARs containing this ß2 mutant reduce response to GABA under physiological conditions, which could potentially disrupt the excitation/inhibition balance in the brain, leading to epilepsy.


Assuntos
Deficiências do Desenvolvimento , Epilepsia , Mutação de Sentido Incorreto , Receptores de GABA-A , Humanos , Receptores de GABA-A/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Células HEK293 , Epilepsia/genética , Epilepsia/fisiopatologia , Masculino , Feminino
17.
J Med Chem ; 67(14): 11789-11813, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38990190

RESUMO

The exploration of novel anticancer compounds based on natural cyclopeptides has emerged as a pivotal paradigm in the contemporary advancement of macrocyclic pharmaceuticals. Phakellistatin 13 is a cycloheptapeptide derived from the brown snubby sponge and exhibits remarkable antitumor activity. In this study, we have designed and synthesized a series of chiral cyclopeptides incorporating the rigid isoindolinone moiety at various sites within the natural cycloheptapeptide Phakellistatin 13, with the aim of investigating conformationally constrained cyclopeptides as potential antitumor agents. Cyclopeptide 3, comprising alternating l-/d-amino acid residues, exhibited promising antihepatocellular carcinoma effects. Detailed biological experiments have revealed that Phakellistatin 13 analogs effectively inhibit the proliferation of tumor cells and induce apoptosis and autophagy, while also causing cell cycle arrest through the modulation of the p53 and mitogen-activated protein kinase (MAPK) signaling pathway. This study not only provides valuable insights into chemical structural modifications but also contributes to a deeper understanding of the biological mechanisms underlying the development of natural cyclopeptide-based drugs.


Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Peptídeos Cíclicos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Humanos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais
18.
Eur Spine J ; 33(8): 3191-3212, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38965088

RESUMO

OBJECTIVE: To compare the efficacy and safety of vertebroplasty through different pedicle approaches in the treatment of osteoporotic vertebral compression fracture osteoporotic vertebral compression fractures (OVCF) by network meta-analysis. METHODS: Pubmed, Embase, Cochrane Library, Web of Science. Database for literature retrieval, retrieval time from the establishment of the database to April 2023, the randomized controlled trials of unilateral vertebroplasty (UVP), bilateral vertebroplasty (BVP), unilateral kyphoplasty (UKP), bilateral kyphoplasty (BKP), curved vertebroplasty (CVP) and curved kyphoplasty (CKP) were screened, evaluated and the data were extracted and included in the analysis. STATA 15.0 and ReMan 5.3 were used for data analysis. This study was registered in the National Institute for Health Research (NIHR) with the registration number CRD42023405181. RESULTS: This study included 16 articles with a total of 1712 patients. The order of visual analogue scale (VAS) improvement from good to bad is CVP > BVP > UVP > CKP > BKP > UKP. The order of kyphotic angles improvement from good to bad is CKP > UKP > UKP > UVP > BVP > CVP. The order of bone cement injection from less to more is UVP > CVP > UKP > CKP > BVP > BKP. The order of bone cement leakage rate from less to more is CKP > CVP > UKP > BKP > UVP > BVP. The order of X-ray exposure time from less to more is CKP > CVP > UVP > BVP > UKP > BKP. The order of operation time from less to more is CVP > UVP > UKP > CKP > BVP > BKP. CONCLUSION: For patients with kyphotic angles, kyphoplasty has unique advantages in improving kyphotic angles. But generally speaking, curved approach can optimize the distribution of bone cement through unilateral approach to achieve the orthopedic effect of bilateral approach, which is a minimally invasive technique with better curative effect and higher safety in the treatment of OVCF.


Assuntos
Fraturas por Compressão , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Vertebroplastia , Humanos , Vertebroplastia/métodos , Fraturas por Osteoporose/cirurgia , Fraturas da Coluna Vertebral/cirurgia , Fraturas por Compressão/cirurgia , Resultado do Tratamento , Cifoplastia/métodos , Metanálise em Rede
19.
Int Immunopharmacol ; 139: 112619, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39024748

RESUMO

BACKGROUND: Osteoarthritis (OA) is a prevalent age-related disease characterized by the gradual deterioration of cartilage. The involvement of chondrocyte senescence is crucial in the pathogenesis of OA. Desferoxamine (DFO) is an iron chelator with therapeutic potential in various diseases. However, the relationship of chondrocyte senescence and iron homeostasis is largely unknown. METHODS: Chondrocyte senescence was induced using tert-butyl hydroperoxide (TBHP), and the impact of DFO on chondrocyte senescence and iron metabolism was assessed through techniques such as western blotting, qRT-PCR, and ß-Galactosidase staining. To assess the impact of DFO on chondrocyte senescence and the progression of osteoarthritis (OA), the surgical destabilization of the medial meniscus model was established. RESULTS: In chondrocytes, TBHP administration resulted in elevated expression of P16, P21, and P53, as well as alterations in SA-ß-gal staining. Nevertheless, DFO effectively mitigated chondrocyte senescence induced by TBHP, and reversed the decrease in collagen II expression and increase in MMP13 expression caused by TBHP. Mechanismly, TBHP induced NCOA4 expression and iron release in chondrocytes. Excessive iron could induce chondrocyte senescence, whereas, DFO could inhibit NCOA4 expression and restore ferritin level, and chelate excessive iron. Importantly, intra-articular injection of DFO enhanced collagen II expression and reduced expression of P16, P21, and MMP13 of cartilage in OA mice, and delayed cartilage degeneration. CONCLUSIONS: Overall, this study provides evidence that DFO has the potential to alleviate chondrocyte senescence induced by TBHP and slow down the progression of osteoarthritis (OA) by effectively chelating excessive iron. These findings suggest that iron chelation could be a promising therapeutic strategy for treating OA.


Assuntos
Senescência Celular , Condrócitos , Desferroxamina , Homeostase , Ferro , Osteoartrite , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Desferroxamina/farmacologia , Desferroxamina/uso terapêutico , Animais , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Osteoartrite/metabolismo , Ferro/metabolismo , Senescência Celular/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Camundongos , Células Cultivadas , Masculino , Camundongos Endogâmicos C57BL , Progressão da Doença , terc-Butil Hidroperóxido , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Cartilagem Articular/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/genética , Humanos , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Modelos Animais de Doenças
20.
Int Immunopharmacol ; 139: 112715, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39032471

RESUMO

Citalopram and escitalopram are structurally close-related antidepressants and both forms are widely used in the world. We aimed to comparatively evaluate the anti-neuroinflammatory and neuroprotective effects of escitalopram and citalopram in Parkinson's disease (PD) mouse model. Mice were randomly divided into six groups and received 6-hydroxydopamine (6-OHDA) or vehicle administration. The mice were then treated with escitalopram, citalopram or saline for consecutive 7 days. Behaviors, neuroinflammation, neurotransmitters, and neurotoxicity were assessed. Results showed that citalopram but not escitalopram worsened body weight loss and increased freezing time in the PD mice. Both drugs had no impact on the anxiety-like behaviors but ameliorated the depressive-like behaviors as in elevated plus maze and sucrose splash tests. Escitalopram but not citalopram ameliorated motor discoordination in the PD mice as in rotarod test. In accordance, escitalopram but not citalopram attenuated the 6-OHDA-induced nigrostriatal dopaminergic loss. Further mechanistic investigations showed that both drugs mitigated activations of microglia and astrocytes and/or levels of pro-inflammatory cytokines in the PD mice, but escitalopram showed appreciably better effects in the substantia nigra. Neurotransmitter examination in the prefrontal cortex suggested that the two drugs had comparable effects on the disturbed neurotransmitters in the PD mice, but citalopram was prone to disrupt certain normal homeostasis. In conclusion, escitalopram is moderately superior than citalopram to suppress neuroinflammation and to protect against dopaminergic neuronal death and motor discoordination in the 6-OHDA-induced PD mice. Our findings imply that escitalopram shall be prescribed with priority over citalopram to treat PD patients with depression as escitalopram may meanwhile provide greater additional benefits to the patients.


Assuntos
Citalopram , Modelos Animais de Doenças , Escitalopram , Fármacos Neuroprotetores , Oxidopamina , Animais , Citalopram/farmacologia , Citalopram/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Masculino , Camundongos , Escitalopram/uso terapêutico , Escitalopram/farmacologia , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/imunologia , Camundongos Endogâmicos C57BL , Citocinas/metabolismo , Doença de Parkinson/tratamento farmacológico , Humanos , Comportamento Animal/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/induzido quimicamente
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