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1.
Mol Cell Endocrinol ; : 112292, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38830447

RESUMO

RESEARCH QUESTION: Granulosa cells (GCs) dysfunction plays a crucial role in the pathogenesis of polycystic ovary syndrome (PCOS). It is reported that YTH domain-containing family protein 2 (YTHDF2) is upregulated in mural GCs of PCOS patients. What effect does the differential expression of YTHDF2 have in PCOS patients? DESIGN: Mural GCs and cumulus GCs from 15 patients with PCOS and 15 ovulatory controls and 4 cases of pathological sections in each group were collected. Real-time PCR, Western Blot, immunohistochemistry, and immunofluorescence experiments were conducted to detect gene and protein expression. RNA immunoprecipitation assay was performed to evaluate the binding relationship between YTHDF2 and MSS51. Mitochondrial morphology, cellular ATP and ROS levels and glycolysis-related gene expression were detected after YTHDF2 overexpression or MSS51 inhibition. RESULTS: In the present study, we found that YTHDF2 was upregulated in GCs of PCOS patients while MSS51 was downregulated. YTHDF2 protein can bind to MSS51 mRNA and affect MSS51 expression. The reduction of MSS51 expression or the increase in YTHDF2 expression can lead to mitochondrial damage, reduced ATP levels, increased ROS levels and reduced expression of LDHA, PFKP and PKM. CONCLUSIONS: YTHDF2 may regulate the expression of MSS51, affecting the structure and function of mitochondria in GCs and interfering with cellular glycolysis, which may disturb the normal biological processes of GCs and follicle development in PCOS patients.

2.
Int Immunopharmacol ; 136: 112386, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38850794

RESUMO

Epilepsy is a severe central nervous system disorder characterized by an imbalance between neuronal excitation and inhibition, resulting in heightened neuronal excitability, particularly within the hippocampus. About one-third of individuals with epilepsy experience difficult-to-manage seizures, known as refractory epilepsy. Epilepsy is closely linked to inflammatory immune response, with elevated levels of inflammatory mediators observed in individuals with this condition. This inflammation of the brain can lead to seizures of various types and is further exacerbated by the release of inflammatory factors, which heighten the excitability of peripheral neurons and worsen the progression of epilepsy. Pyroptosis is an inflammatory programmed cell death which has been shown to be involved in the pathological process of epilepsy. Inflammatory factors released during pyroptosis increase neuronal excitability and promote abnormal discharge in epilepsy, increasing susceptibility to epilepsy. This article provides an overview of the current knowledge on cell pyroptosis and its potential mechanisms, including both canonical and noncanonical pathways. Additionally, we discuss the potential mechanisms of pyroptosis occurrence in epilepsy and the potential therapeutic drugs targeting pyroptosis as a treatment strategy. In summary, this review highlights the promising potential of pyroptosis as a target for developing innovative therapies for epilepsy.

3.
Molecules ; 29(9)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38731553

RESUMO

One-step carbonization was explored to prepare biochar using the residue of a traditional Chinese herbal medicine, Atropa belladonna L. (ABL), as the raw material. The resulting biochar, known as ABLB4, was evaluated for its potential as a sustainable material for norfloxacin (NOR) adsorption in water. Subsequently, a comprehensive analysis of adsorption isotherms, kinetics, and thermodynamics was conducted through batch adsorption experiments. The maximum calculated NOR adsorption capacity was 252.0 mg/g at 298 K, and the spontaneous and exothermic adsorption of NOR on ABLB4 could be better suited to a pseudo-first-order kinetic model and Langmuir model. The adsorption process observed is influenced by pore diffusion, π-π interaction, electrostatic interaction, and hydrogen bonding between ABLB4 and NOR molecules. Moreover, the utilization of response surface modeling (RSM) facilitated the optimization of the removal efficiency of NOR, yielding a maximum removal rate of 97.4% at a temperature of 304.8 K, an initial concentration of 67.1 mg/L, and a pH of 7.4. Furthermore, the biochar demonstrated favorable economic advantages, with a payback of 852.5 USD/t. More importantly, even after undergoing five cycles, ABLB4 exhibited a consistently high NOR removal rate, indicating its significant potential for application in NOR adsorption.


Assuntos
Carvão Vegetal , Medicamentos de Ervas Chinesas , Norfloxacino , Poluentes Químicos da Água , Norfloxacino/química , Carvão Vegetal/química , Adsorção , Medicamentos de Ervas Chinesas/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/isolamento & purificação , Cinética , Termodinâmica , Purificação da Água/métodos , Concentração de Íons de Hidrogênio
4.
BMC Pediatr ; 24(1): 299, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702595

RESUMO

PURPOSE: We aimed to investigated the influencing risk factors of voriconazole-induced liver injury in Uygur pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: This was a prospective cohort design study. High-performance liquid chromatography-mass spectrometry was employed to monitor voriconazole concentration. First-generation sequencing was performed to detect gene polymorphisms. Indicators of liver function were detected at least once before and after voriconazole therapy. RESULTS: Forty-one patients were included in this study, among which, 15 patients (36.6%) had voriconazole-induced liver injury. The proportion of voriconazole trough concentration > 5.5 µg·mL-1 patients within the DILI group (40.0%) was significantly higher compared to the control group (15.4%) (p < 0.05). After administration of voriconazole, the values of ALT (103.3 ± 80.3 U/L) and AST (79.9 ± 60.6 U/L) in the DILI group were higher than that in the control group (24.3 ± 24.8 and 30.4 ± 8.6 U/L) (p < 0.05). There was no significant difference between the two groups in genotype and allele frequencies of CYP2C19*2, CYP2C19*3, CYP2C19*17, and UGT1A4 (rs2011425) (p > 0.05). CONCLUSION: There was a significant correlation between voriconazole-induced liver injury and voriconazole trough concentration in high-risk Uygur pediatric patients with allogeneic HSCT.


Assuntos
Antifúngicos , Doença Hepática Induzida por Substâncias e Drogas , Transplante de Células-Tronco Hematopoéticas , Voriconazol , Humanos , Voriconazol/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Criança , Masculino , Feminino , Estudos Prospectivos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Fatores de Risco , Antifúngicos/efeitos adversos , Pré-Escolar , China , Adolescente , Citocromo P-450 CYP2C19/genética , Transplante Homólogo/efeitos adversos
5.
Inorg Chem ; 63(20): 9265-9274, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38724113

RESUMO

Creating affordable electrocatalysts and understanding the real-time catalytic process of the urea oxidation reaction (UOR) are crucial for advancing urea-based technologies. Herein, a Cu-Ni based selenide electrocatalyst (CuSey/NiSex/NF) was created using a hydrothermal technique and selenization treatment, featuring a heterogeneous interface rich in Cu2-xSe, Cu3Se2, Ni3Se4, and NiSe2. This catalyst demonstrated outstanding urea electrooxidation performance, achieving 10 mA cm-2 with just 1.31 V and sustaining stability for 96 h. Through in-situ Raman spectroscopy and ex-situ characterizations, it is discovered that NiOOH is formed through surface reconstruction in the UOR process, with high-valence Ni serving as the key site for effective urea oxidation. Moreover, the electrochemical analysis revealed that CuSey had dual effects. An analysis of XPS and electrochemical tests revealed that electron transfer from CuSey to NiSex within the CuSey/NiSex/NF heterostructure enhanced the UOR kinetics of the catalyst. Additionally, according to the in-situ Raman spectroscopy findings, the existence of CuSey facilitates a easier and faster surface reconstruction of NiSex, leading to the creation of additional active sites for urea oxidation. More significantly, this work provides an excellent "precatalyst" for highly efficient UOR, along with an in-depth understanding of the mechanism behind the structural changes in electrocatalysts and the discovery of their true active sites.

6.
bioRxiv ; 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38766073

RESUMO

Stereotyped dendritic arbors are shaped by dynamic and stochastic growth during neuronal development. It remains unclear how guidance receptors and ligands coordinate branch dynamic growth, retraction, and stabilization to specify dendritic arbors. We previously showed that extracellular ligand SAX-7/LICAM dictates the shape of the PVD sensory neuron via binding to the dendritic guidance receptor DMA-1, a single transmembrane adhesion molecule. Here, we perform structure-function analyses of DMA-1 and unexpectedly find that robust, stochastic dendritic growth does not require ligand-binding. Instead, ligand-binding inhibits growth, prevents retraction, and specifies arbor shape. Furthermore, we demonstrate that dendritic growth requires a pool of ligand-free DMA-1, which is maintained by receptor endocytosis and reinsertion to the plasma membrane via recycling endosomes. Mutants defective of DMA-1 endocytosis show severely truncated dendritic arbors. We present a model in which ligand-free guidance receptor mediates intrinsic, stochastic dendritic growth, while extracellular ligands instruct dendrite shape by inhibiting growth.

7.
BMC Biol ; 22(1): 110, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38735918

RESUMO

BACKGROUND: Plants differ more than threefold in seed oil contents (SOCs). Soybean (Glycine max), cotton (Gossypium hirsutum), rapeseed (Brassica napus), and sesame (Sesamum indicum) are four important oil crops with markedly different SOCs and fatty acid compositions. RESULTS: Compared to grain crops like maize and rice, expanded acyl-lipid metabolism genes and relatively higher expression levels of genes involved in seed oil synthesis (SOS) in the oil crops contributed to the oil accumulation in seeds. Here, we conducted comparative transcriptomics on oil crops with two different SOC materials. In common, DIHYDROLIPOAMIDE DEHYDROGENASE, STEAROYL-ACYL CARRIER PROTEIN DESATURASE, PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE, and oil-body protein genes were both differentially expressed between the high- and low-oil materials of each crop. By comparing functional components of SOS networks, we found that the strong correlations between genes in "glycolysis/gluconeogenesis" and "fatty acid synthesis" were conserved in both grain and oil crops, with PYRUVATE KINASE being the common factor affecting starch and lipid accumulation. Network alignment also found a conserved clique among oil crops affecting seed oil accumulation, which has been validated in Arabidopsis. Differently, secondary and protein metabolism affected oil synthesis to different degrees in different crops, and high SOC was due to less competition of the same precursors. The comparison of Arabidopsis mutants and wild type showed that CINNAMYL ALCOHOL DEHYDROGENASE 9, the conserved regulator we identified, was a factor resulting in different relative contents of lignins to oil in seeds. The interconnection of lipids and proteins was common but in different ways among crops, which partly led to differential oil production. CONCLUSIONS: This study goes beyond the observations made in studies of individual species to provide new insights into which genes and networks may be fundamental to seed oil accumulation from a multispecies perspective.


Assuntos
Produtos Agrícolas , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Óleos de Plantas , Produtos Agrícolas/genética , Produtos Agrícolas/metabolismo , Óleos de Plantas/metabolismo , Perfilação da Expressão Gênica/métodos , Transcriptoma , Sementes/genética , Sementes/metabolismo , Regulação da Expressão Gênica de Plantas
8.
Front Public Health ; 12: 1309673, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38774050

RESUMO

Objectives: Sarcopenia and disability represent significant concerns impacting the health of older people. This study aimed to explore the bidirectional relationship between sarcopenia and disability in Chinese older people. Methods: This study recruited older people ≥60 years old from the China Health and Retirement Longitudinal Study. In phase I, the study analyzed the relation between disability and subsequent sarcopenia using multinomial logistic regression models. Conversely, in phase II, the study assessed whether sarcopenia was associated with future disability using binary logistic regression models. Results: In phase I, 65 (16.80%) new cases of possible sarcopenia, 18 (4.65%) cases of sarcopenia, and 9 (2.33%) cases of severe sarcopenia were observed in the disabled older people and 282 (10.96%) new cases of possible sarcopenia, 97 (3.77%) cases of sarcopenia, 35 (1.36%) cases of severe sarcopenia were observed in the older people without disability. The OR (95% CI) for sarcopenia in older disabled individuals compared to those without disability was 1.61 (1.25-2.07). Adjusting for all covariates in 2011, the OR (95% CI) value for disabled individuals vs. those without disability was 1.35 (1.02-1.79). Subgroup analyses showed that disabled participants aged < 80 years were more likely to have sarcopenia (OR = 1.42, 95% CI: 1.07-1.89), and the risk of sarcopenia did not differ significantly between sex subgroups. In phase II, 114 cases (33.83%) in the possible sarcopenia patients, 85 cases (28.91%) in the sarcopenia patients, 23 cases (35.94%) in the severe sarcopenia patients, and 501 cases (16.10%) in the individuals without sarcopenia showed symptoms of disability. The OR (95% CI) for disability was 2.66 (2.08-3.40) in the possible sarcopenia patients, 2.12 (1.62-2.77) in the sarcopenia patients, and 2.92 (1.74-4.91) in the severe sarcopenia patients compared with the no sarcopenia patients. After adjusting for all covariates in 2011, the OR (95% CI) values were 2.21 (1.70-2.85) in the possible sarcopenia patients, 1.58 (1.14-2.19) in the sarcopenia patients, and 1.99 (1.14-3.49) in the severe sarcopenia patients, as compared to the older people without sarcopenia. Subgroup analyses showed that compared with men, women with possible sarcopenia had a higher risk of disability (OR = 2.80, 95% CI: 1.98-3.97). In addition, participants aged < 80 years with sarcopenia or severe sarcopenia s were more likely to have disability (OR = 2.13, 95% CI: 1.52-2.98; OR = 2.98, 95% CI: 1.60-5.54). Conclusion: The occurrence of disability increase the risk of sarcopenia in the older people, and baseline sarcopenia predicts the future disability in older people.


Assuntos
Pessoas com Deficiência , Sarcopenia , Humanos , Sarcopenia/epidemiologia , Sarcopenia/complicações , Masculino , Estudos Longitudinais , China/epidemiologia , Feminino , Idoso , Pessoas com Deficiência/estatística & dados numéricos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Fatores de Risco , Modelos Logísticos
9.
Asian J Surg ; 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38734559
10.
Asian J Surg ; 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38729880
11.
Artigo em Inglês | MEDLINE | ID: mdl-38728170

RESUMO

PURPOSE: This study was the first to evaluate the effect of CYP3A5*3 gene polymorphisms on plasma concentration of perampanel (PER) in Chinese pediatric patients with epilepsy. METHODS: We enrolled 98 patients for this investigation. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final checkup. RESULTS: The plasma concentration showed a linear correlation with the daily dose taken ( r  = 0.17; P  < 0.05). The ineffective group showed a significantly lower plasma concentration of PER (490.5 ±â€…297.1 vs. 633.8 ±â€…305.5 µg/ml; P  = 0.019). For the mean concentration-to-dose (C/D) ratio, the ineffective group showed a significantly lower C/D ratio of PER (3.2 ±â€…1.7 vs. 3.8 ±â€…2.0; P  = 0.040). The CYP3A5*3 CC genotype exhibited the highest average plasma concentration of PER at 562.8 ±â€…293.9 ng/ml, in contrast to the CT and TT genotypes at 421.1 ±â€…165.6 ng/ml and 260.0 ±â€…36.1 ng/ml. The mean plasma PER concentration was significantly higher in the adverse events group (540.8 ±â€…285.6 vs. 433.0 ±â€…227.2 ng/ml; P  = 0.042). CONCLUSION: The CYP3A5*3 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A5*3 genetic genotype should be factored in when prescribing PER to patients with epilepsy.

12.
Environ Toxicol ; 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38808594

RESUMO

Decabrominated diphenyl ether (BDE-209) is a typical persistent organic pollutant that can cross the placental barrier, increasing the exposure risk for offspring. Norepinephrine (NE) from nerve terminals and acetylcholine (Ach) can bind to specific receptors on immune cells, inhibit the immune function of the body then cause immunotoxicity. However, whether maternal exposure to BDE-209 could lead to immunotoxicity in the offspring by acting on the sympathetic and parasympathetic nervous systems remains unclear. In view of this, the pregnancy and lactation rat BDE-209 exposure model was established and the results demonstrated that pregnancy and lactation BDE-209 exposure could induce immunotoxicity to female offspring via affecting immunopathology (hematological and biochemical parameters, organ indices, and spleen histopathological), decreasing humoral immunity (serum hemolysin, immunoglobulins, and cytokine productions), damaging cellular immunity (splenic lymphocytes and spleen cytokine productions), and restraining nonspecific immunity. Moreover, a dramatically significant correlation was observed between spleen nerve indices and immunity indices. Additionally, the mechanism revealed that maternal BDE-209 exposure caused offspring immunotoxicity through (1) activating MHC/PKCθ/NF-κB pathway; (2) promoting sympathetic nervous pathway, by upregulating the expression of ß2AR protein, which in turn elevating cAMP, following activate PKA and phosphorylate CREB, ultimately leading to immunotoxicity;(3) activating parasympathetic nerve pathway by reducing the binding with Ach and α7nAchR, upregulating the expression of JAK2 and phosphorylating STAT3, induced immunotoxicity of female offspring.

13.
Zhongguo Zhong Yao Za Zhi ; 49(9): 2393-2401, 2024 May.
Artigo em Chinês | MEDLINE | ID: mdl-38812140

RESUMO

Rhei Radix et Rhizoma is common traditional Chinese medicine with multiple original plants. The content and proportion of the active components in Rhei Radix et Rhizoma from different plant species were compared to accurately evaluate the medicine qua-lity and provide a theoretical basis for precise use of this medicine in clinical practice. In this study, fresh Rhei Radix et Rhizoma samples were collected from the four-year-old plants of Rheum palmatum, R. tanguticum, and R. officinale. The relative content of 220 anthraquinones, anthrones, and tannins in the samples were determined by pseudo-targeted metabolomics, and the differential components were screened by multivariate statistical methods. The principal component analysis classified the samples into three clusters according to the original plants. The orthogonal partial least squares-discriminant analysis(OPLS-DA) screened out 117 differential components, including 8 free anthraquinones, 18 anthraquinone glycosides, 80 anthrones, and 11 tannins. Twenty-eight components had the highest content in R. tanguticum, mainly including sennosides, anthraquinone glycosides, and procyanidins. Thirty-five components showed the highest content in R. officinale, mainly including free anthraquinones and catechines. Fifty-four components showed the highest content in R. palmatum, mainly including dianthrones, while the structures of most of them cannot be determined temporarily. The content distribution of differential components in the three original plants indicates that R. tanguticum has the strongest effect of purging, while R. officinale has the strongest effect of clearing heat and purging fire, and both have stronger effects of resolvong stasis and dredging meridians than R. palmatum.


Assuntos
Medicamentos de Ervas Chinesas , Metabolômica , Rheum , Rizoma , Rheum/química , Rizoma/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Antraquinonas/química , Antraquinonas/análise , Cromatografia Líquida de Alta Pressão
14.
Cell Mol Life Sci ; 81(1): 221, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38763964

RESUMO

In females, the pathophysiological mechanism of poor ovarian response (POR) is not fully understood. Considering the expression level of p62 was significantly reduced in the granulosa cells (GCs) of POR patients, this study focused on identifying the role of the selective autophagy receptor p62 in conducting the effect of follicle-stimulating hormone (FSH) on antral follicles (AFs) formation in female mice. The results showed that p62 in GCs was FSH responsive and that its level increased to a peak and then decreased time-dependently either in ovaries or in GCs after gonadotropin induction in vivo. GC-specific deletion of p62 resulted in subfertility, a significantly reduced number of AFs and irregular estrous cycles, which were same as pathophysiological symptom of POR. By conducting mass spectrum analysis, we found the ubiquitination of proteins was decreased, and autophagic flux was blocked in GCs. Specifically, the level of nonubiquitinated Wilms tumor 1 homolog (WT1), a transcription factor and negative controller of GC differentiation, increased steadily. Co-IP results showed that p62 deletion increased the level of ubiquitin-specific peptidase 5 (USP5), which blocked the ubiquitination of WT1. Furthermore, a joint analysis of RNA-seq and the spatial transcriptome sequencing data showed the expression of steroid metabolic genes and FSH receptors pivotal for GCs differentiation decreased unanimously. Accordingly, the accumulation of WT1 in GCs deficient of p62 decreased steroid hormone levels and reduced FSH responsiveness, while the availability of p62 in GCs simultaneously ensured the degradation of WT1 through the ubiquitin‒proteasome system and autophagolysosomal system. Therefore, p62 in GCs participates in GC differentiation and AF formation in FSH induction by dynamically controlling the degradation of WT1. The findings of the study contributes to further study the pathology of POR.


Assuntos
Hormônio Foliculoestimulante , Células da Granulosa , Folículo Ovariano , Proteína Sequestossoma-1 , Ubiquitinação , Proteínas WT1 , Animais , Hormônio Foliculoestimulante/metabolismo , Hormônio Foliculoestimulante/farmacologia , Feminino , Proteínas WT1/metabolismo , Proteínas WT1/genética , Camundongos , Folículo Ovariano/metabolismo , Folículo Ovariano/efeitos dos fármacos , Células da Granulosa/metabolismo , Células da Granulosa/efeitos dos fármacos , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , Camundongos Endogâmicos C57BL , Autofagia/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Humanos , Camundongos Knockout
15.
J Am Soc Mass Spectrom ; 35(6): 1310-1319, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38780475

RESUMO

The accumulation of amyloid beta (Aß1-42) results in neurotoxicity and is strongly related to neurodegenerative disorders, especially Alzheimer's disease (AD), but the underlying molecular mechanism is still poorly understood. Therefore, there is an urgent need for researchers to discover the proteins that interact with Aß1-42 to determine the molecular basis. Previously, we developed peptide-ligand-induced changes in the abundance of proTeinS (PACTS)-assisted thermal proteome profiling (TPP) to identify proteins that interact with peptide ligands. In the present study, we applied this technique to analyze clinical samples to identify Aß1-42-interacting proteins. We detected 115 proteins that interact with Aß1-42 in human frontal lobe tissue. Pathway enrichment analysis revealed that the differentially expressed proteins were involved mainly in neurodegenerative diseases. Further orthogonal validation revealed that Aß1-42 interacted with the AD-associated protein mitogen-activated protein kinase 3 (MAPK3), and knockdown of the Aß1-42 amyloid precursor protein (APP) inhibited the MAPK signaling pathway, suggesting potential functional roles for Aß1-42 in interacting with MAPK3. Overall, this study demonstrated the application of the PACTS-TPP in clinical samples and provided a valuable data source for research on neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Fragmentos de Peptídeos , Proteômica , Humanos , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/análise , Proteômica/métodos , Doença de Alzheimer/metabolismo , Proteoma/análise , Proteoma/metabolismo , Lobo Frontal/metabolismo , Lobo Frontal/química , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/química , Ligação Proteica
16.
Clin Neurol Neurosurg ; 241: 108291, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38701547

RESUMO

OBJECTIVE: Acute cerebral infarction (ACI) contributes to disability and death accross the globe. Remote ischemic preconditioning (RIPC) reduces cerebral infarct size and improves neurological function in ACI. We conducted this research to reveal the effects of RIPC intervention on serum levels of microRNA-582-5p (miR-582-5p)/high mobility group box-1 protein (HMGB1), inflammation, oxidative stress and neurological function in patients with ACI. METHODS: In this study, 158 patients with ACI were prospectively selected and randomized into the control (administered symptomatic medication alone) and the RIPC (underwent RIPC of the limbs based on medication) groups, with their clinical baseline data documented. Serum levels of miR-582-5p, and HMGB1 and inflammatory factors [tumor necrosis factor alpha (TNF-α)/interleukin-1beta (IL-1ß)/IL-10] were assessed by RT-qPCR/ELISA, followed by comparisons of oxidative stress indices [glutathione-peroxidase (GSH-Px)/catalase (CAT)/superoxide dismutase (SOD)] using a fully automatic biochemical analyzer. Correlations between serum miR-582-5p with serum HMGB1, and between their levels with TNF-α/IL-1ß/IL-10 were analyzed by Pearson analysis. The NIHSS score/Barthel Index scale were used to assess neurological function/daily living ability. Intervention safety for ACI patients was evaluated. RESULTS: RIPC intervention increased serum miR-582-5p levels and decreased serum HMGB1 levels in ACI patients. RIPC intervention significantly reduced inflammation (diminished TNF-α/IL-1ß levels, increased IL-10 level) and oxidative stress (elevated GSH-Px/CAT/SOD levels) in ACI patients. Serum miR-582-5p was negatively correlated with TNF-α and IL-1ß levels, while positively correlated with IL-10 level, while HMGB1 was positively correlated with TNF-α and IL-1ß levels, while negatively correlated with IL-10 level. miR-582-5p was negatively correlated with HMGB1. RIPC intervention improved neurological function (reduced NIHSS, increased Barthel scores) in ACI patients to some extent. RIPC had certain effectiveness and safety in the treatment of ACI. CONCLUSION: After RIPC intervention, serum miR-582-5p levels were increased, HMGB1 levels were decreased, and inflammation and oxidative stress were reduced in ACI patients, which mitigated neurological deficits, improved patients' ability to perform life activities, and exerted neuroprotective effects to some extent.


Assuntos
Infarto Cerebral , Proteína HMGB1 , Precondicionamento Isquêmico , MicroRNAs , Estresse Oxidativo , Humanos , Masculino , Proteína HMGB1/sangue , Feminino , Precondicionamento Isquêmico/métodos , MicroRNAs/sangue , Pessoa de Meia-Idade , Idoso , Infarto Cerebral/sangue , Infarto Cerebral/terapia , Estresse Oxidativo/fisiologia
17.
Adv Sci (Weinh) ; : e2306294, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38757379

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social communication disability and stereotypic behavior. This study aims to investigate the impact of prenatal exposure to 1-nitropyrene (1-NP), a key component of motor vehicle exhaust, on autism-like behaviors in a mouse model. Three-chamber test finds that prenatal 1-NP exposure causes autism-like behaviors during the weaning period. Patch clamp shows that inhibitory synaptic transmission is reduced in medial prefrontal cortex of 1-NP-exposed weaning pups. Immunofluorescence finds that prenatal 1-NP exposure reduces the number of prefrontal glutamate decarboxylase 67 (GAD67) positive interneurons in fetuses and weaning pups. Moreover, prenatal 1-NP exposure retards tangential migration of GAD67-positive interneurons and downregulates interneuron migration-related genes, such as Nrg1, Erbb4, and Sema3F, in fetal forebrain. Mechanistically, prenatal 1-NP exposure reduces hydroxymethylation of interneuron migration-related genes through inhibiting ten-eleven translocation (TET) activity in fetal forebrain. Supplement with alpha-ketoglutarate (α-KG), a cofactor of TET enzyme, reverses 1-NP-induced hypohydroxymethylation at specific sites of interneuron migration-related genes. Moreover, α-KG supplement alleviates 1-NP-induced migration retardation of interneurons in fetal forebrain. Finally, maternal α-KG supplement improves 1-NP-induced autism-like behaviors in weaning offspring. In conclusion, prenatal 1-NP exposure causes autism-like behavior partially by altering DNA hydroxymethylation of interneuron migration-related genes in developing brain.

18.
Front Oncol ; 14: 1381250, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38756658

RESUMO

Objective: Endocrinopathies are the most common immune-related adverse events (irAEs) observed during therapy with PD-1 inhibitors. In this study, we conducted a comprehensive systematic review and meta-analysis to evaluate the risk of immune-related endocrinopathies in patients treated with PD-1 inhibitors. Methods: We performed a systematic search in the PubMed, Embase, and Cochrane Library databases to retrieve all randomized controlled trials (RCTs) involving PD-1 inhibitors, spanning from their inception to November 24, 2023. The comparative analysis encompassed patients undergoing chemotherapy, targeted therapy, or receiving placebo as control treatments. This study protocol has been registered with PROSPERO (CRD42023488303). Results: A total of 48 clinical trials comprising 24,514 patients were included. Compared with control groups, patients treated with PD-1 inhibitors showed an increased risk of immune-related adverse events, including hypothyroidism, hyperthyroidism, hypophysitis, thyroiditis, diabetes mellitus, and adrenal insufficiency. Pembrolizumab was associated with an increased risk of all aforementioned endocrinopathies (hypothyroidism: RR=4.76, 95%CI: 3.55-6.39; hyperthyroidism: RR=9.69, 95%CI: 6.95-13.52; hypophysitis: RR=5.47, 95%CI: 2.73-10.97; thyroiditis: RR=5.95, 95%CI: 3.02-11.72; diabetes mellitus: RR=3.60, 95%CI: 1.65-7.88; adrenal insufficiency: RR=4.80, 95%CI: 2.60-8.88). Nivolumab was associated with an increased risk of hypothyroidism (RR=7.67, 95%CI: 5.00-11.75) and hyperthyroidism (RR=9.22, 95%CI: 4.71-18.04). Tislelizumab and sintilimab were associated with an increased risk of hypothyroidism (RR=19.07, 95%CI: 5.46-66.69 for tislelizumab and RR=18.36, 95%CI: 3.58-94.21 for sintilimab). For different tumor types, both hypothyroidism and hyperthyroidism were at high risks. Besides, patients with non-small cell lung cancer were at a higher risk of thyroiditis and adrenal insufficiency. Patients with melanoma were at a higher risk of hypophysitis and diabetes mellitus. Both low- and high-dose group increased risks of hypothyroidism and hyperthyroidism. Conclusion: Risk of endocrine irAEs may vary in different PD-1 inhibitors and different tumor types. Increased awareness and understanding of the risk features of endocrine irAEs associated with PD-1 inhibitors is critical for clinicians. Systematic review registration: crd.york.ac.uk/prospero, identifier PROSPERO (CRD42023488303).

19.
Mol Med Rep ; 30(1)2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38757346

RESUMO

Ovarian cancer is a multifactorial and deadly disease. Despite significant advancements in ovarian cancer therapy, its incidence is on the rise and the molecular mechanisms underlying ovarian cancer invasiveness, metastasis and drug resistance remain largely elusive, resulting in poor prognosis. Oncolytic viruses armed with therapeutic transgenes of interest offer an attractive alternative to chemical drugs, which often face innate and acquired drug resistance. The present study constructed a novel oncolytic adenovirus carrying ERCC1 short interfering (si)RNA, regulated by hTERT and HIF promoters, termed Ad­siERCC1. The findings demonstrated that this oncolytic adenovirus effectively inhibits the proliferation, migration and invasion of ovarian cancer cells. Furthermore, the downregulation of ERCC1 expression by siRNA ameliorates drug resistance to cisplatin (DDP) chemotherapy. It was found that Ad­siERCC1 blocks the cell cycle in the G1 phase and enhances apoptosis through the PI3K/AKT­caspase­3 signaling pathways in SKOV3 cells. The results of the present study highlighted the critical effect of oncolytic virus Ad­siERCC1 in inhibiting the survival of ovarian cancer cells and increasing chemotherapy sensitivity to DDP. These findings underscore the potent antitumor effect of Ad­siERCC1 on ovarian cancers in vivo.


Assuntos
Adenoviridae , Apoptose , Proliferação de Células , Cisplatino , Proteínas de Ligação a DNA , Endonucleases , Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias Ovarianas , RNA Interferente Pequeno , Humanos , Feminino , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Adenoviridae/genética , Linhagem Celular Tumoral , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Endonucleases/genética , Endonucleases/metabolismo , Apoptose/genética , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Movimento Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Vetores Genéticos/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
20.
Int Immunopharmacol ; 134: 112247, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38759374

RESUMO

BACKGROUND: Epilepsy is a chronic disabling disease poorly controlled by available antiseizure medications. Oridonin, a bioactive alkaloid with anti-inflammatory properties and neuroprotective effects, can inhibit the increased excitability of neurons caused by glutamate accumulation at the cellular level. However, whether oridonin affects neuronal excitability and whether it has antiepileptic potential has not been reported in animal models or clinical studies. METHOD: Pentylenetetrazol was injected into mice to create a model of chronic epilepsy. Seizure severity was assessed using the Racine scale, and the duration and latency of seizures were observed. Abnormal neuronal discharge was detected using electroencephalography, and neuronal excitability was assessed using calcium imaging. Damage to hippocampal neurons was evaluated using Hematoxylin-Eosin and Nissl staining. The expression of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and other pyroptosis-related proteins was determined using western blotting and immunofluorescence. A neuronal pyroptosis model was established using the supernatant of BV2 cells treated with lipopolysaccharide and adenosine triphosphate to stimulate hippocampal neurons. RESULTS: Oridonin (1 and 5 mg/kg) reduced neuronal damage, increased the latency of seizures, and shortened the duration of fully kindled seizures in chronic epilepsy model mice. Oridonin decreased abnormal discharge during epileptic episodes and suppressed increased neuronal excitability. In vitro experiments showed that oridonin alleviated pyroptosis in hippocampal HT22 neurons. CONCLUSION: Oridonin exerts neuroprotective effects by inhibiting pyroptosis through the NLRP3/caspase-1 pathway in chronic epilepsy model mice. It also reduces pyroptosis in hippocampal neurons in vitro, suggesting its potential as a therapy for epilepsy.


Assuntos
Anticonvulsivantes , Modelos Animais de Doenças , Diterpenos do Tipo Caurano , Epilepsia , Hipocampo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Neurônios , Fármacos Neuroprotetores , Piroptose , Animais , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Epilepsia/tratamento farmacológico , Piroptose/efeitos dos fármacos , Camundongos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Masculino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Pentilenotetrazol , Camundongos Endogâmicos C57BL , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Linhagem Celular , Convulsões/tratamento farmacológico
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