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1.
Front Psychiatry ; 15: 1423008, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38962058

RESUMO

Introduction: Chronic schizophrenia has a course of 5 years or more and has a widespread abnormalities in brain functional connectivity. This study aimed to find characteristic functional and structural changes in a long illness duration chronic schizophrenia (10 years or more). Methods: Thirty-six patients with a long illness duration chronic schizophrenia and 38 healthy controls were analyzed by independent component analysis of brain network functional connectivity. Correlation analysis with clinical duration was performed on six resting state networks: auditory network, default mode network, dorsal attention network, fronto-parietal network, somatomotor network, and visual network. Results: The differences in the resting state network between the two groups revealed that patients exhibited enhanced inter-network connections between default mode network and multiple brain networks, while the inter-network connections between somatomotor network, default mode network and visual network were reduced. In patients, functional connectivity of Cuneus_L was negatively correlated with illness duration. Furthermore, receiver operating characteristic curve of functional connectivity showed that changes in Thalamus_L, Rectus_L, Frontal_Mid_R, and Cerebelum_9_L may indicate a longer illness duration chronic schizophrenia. Discussion: In our study, we also confirmed that the course of disease is significantly associated with specific brain regions, and the changes in specific brain regions may indicate that chronic schizophrenia has a course of 10 years or more.

2.
Int J Biol Macromol ; 259(Pt 1): 129172, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38176496

RESUMO

Varieties of plant species may affect the composition and structures of the polysaccharides, thus have an impact on their chemical properties and biological activities. Herein, the present study comparatively evaluated the differences in the chemical composition, morphological structures, antioxidant activity, and anti-inflammatory activity of the stem and peel polysaccharides from different varieties of pitaya. The FT-IR and NMR spectra indicated that the six polysaccharides had similar structural features, whereas the physicochemical characterization showed that they differed significantly in terms of the monosaccharide composition, molecular weight, and surface morphology. In addition, different varieties of pitaya polysaccharides exhibited different antioxidant activities and similar anti-inflammatory activities. These data suggested that varietal differences resulted in pitaya stem and peel polysaccharides with different monosaccharide compositions and molecular weights, thus led to different antioxidant activities and protection against oxidative damage, while similar structural features were closely related to their similar anti-inflammatory activities. Therefore, the study of the stem and peel polysaccharides from different varieties of pitaya can help us to better understand the relationship between their composition and structure and their biological activities. In addition, pitaya stem and peel polysaccharides have the potential to act as antioxidants or to treat inflammatory damage.


Assuntos
Antioxidantes , Cactaceae , Antioxidantes/farmacologia , Antioxidantes/química , Espectroscopia de Infravermelho com Transformada de Fourier , Polissacarídeos/farmacologia , Polissacarídeos/química , Monossacarídeos , Anti-Inflamatórios/farmacologia
3.
Expert Opin Drug Discov ; 18(12): 1367-1377, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37676052

RESUMO

INTRODUCTION: Computer-aided drug design (CADD) is a computational approach used to discover, develop, and analyze drugs and active molecules with similar biochemical properties. Molecular simulation technology has significantly accelerated drug research and reduced manufacturing costs. It is an optimized drug discovery method that greatly improves the efficiency of novel drug development processes. AREASCOVERED: This review discusses the development of molecular simulations of effective cancer inhibitors and traces the main outcomes of in silico studies by introducing representative categories of six important anticancer targets. The authors provide views on this topic from the perspective of both medicinal chemistry and artificial intelligence, indicating the major challenges and predicting trends. EXPERT OPINION: The goal of introducing CADD into cancer treatment is to realize a highly efficient, accurate, and desired approach with a high success rate for identifying potent drug candidates. However, the major challenge is the lack of a sophisticated data-filtering mechanism to verify bottom data from mixed-quality references. Consequently, despite the continuous development of algorithms, computer power, and interface optimization, specific data filtering mechanisms will become an urgent and crucial issue in the future.


Assuntos
Desenho Assistido por Computador , Neoplasias , Humanos , Inteligência Artificial , Desenho de Fármacos , Descoberta de Drogas/métodos , Neoplasias/tratamento farmacológico
4.
J Ethnopharmacol ; 317: 116743, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37331452

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiovascular disease (CVD) is a serious disease with a high incidence rate and mortality. Inflammation is closely related to the occurrence of CVDs. As an essential medicine of promoting blood circulation and removing blood stasis in China, Salvia miltiorrhiza Bunge (Danshen) is widely used to treat CVDs due to its anti-inflammatory and cardiovascular protective effects. Salvianolic acids are the most abundant component in the water extract of S. miltiorrhiza, which has a significant effect on the treatment of CVDs. However, due to the complex composition of salvianolic acids, the active molecules and their underlying mechanisms have not been fully explored. AIM OF THIS STUDY: The present study aims to isolate and identify salvianolic acids from Danshen with anti-inflammatory activity and explore the potential mechanisms of isolates. METHODS: The structures of isolated salvianolic acids were elucidated by UV, IR, NMR, MS and electronic circular dichroism (ECD) calculations. Then anti-inflammatory activities of isolates were screened out by the zebrafish inflammation models. The most active compound was further used to explore the anti-inflammatory mechanisms on LPS-stimulated RAW 264.7 cells. The key inflammatory cytokines IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). The protein expression levels of STAT3, p-STAT3 (Tyr705), NF-κB p65, IκBα, p-IκBα (Ser32) and α7nAchR were determined by Western blotting. The nuclear translocation of p-STAT3 (Tyr705) and NF-κB p65 was evaluated by immunofluorescence assays. Finally, the in vivo anti-inflammatory mechanisms were investigated by observation of neutrophil migration, H&E staining, survival analysis and quantitative PCR (Q-PCR) in LPS-microinjected zebrafish. RESULTS: Two new and four known compounds were isolated from Danshen. Among them, isosalvianolic acid A-1 (C1) and ethyl lithospermate (C5) inhibited neutrophil migrations in three zebrafish inflammation models and C1 with the best activities decreased the secretion of IL-6 and TNF-α and inhibited the expression level of p-IκBα (Ser32) in LPS stimulated RAW 264.7 cells. In addition, C1 also reduced the nuclear translocation of NF-κB p65 and p-STAT3 (Tyr705). Moreover, C1 significantly upregulated the protein expression of α7nAchR, and the knockdown of α7nAchR counteracted the effects of C1 on the production of IL-6 and TNF-α and the expression levels of p-STAT3 (Tyr705), NF-κB p65 and p-IκBα (Ser32). In vivo experiments, C1 decreased the migration and infiltration of inflammatory cells, increased the survival ratio and inhibited the mRNA level of IL-6, TNF-α, STAT3, NF-κB and IκBα in LPS-microinjected zebrafish. CONCLUSION: Two new and four known compounds were isolated from Danshen. Among them, C1 exerted anti-inflammatory activities by activating α7nAchR signaling and subsequently inhibiting STAT3 and NF-κB pathways. This study provided evidence for the clinical application of Danshen and contributed to the development of C1 as a novel in the treatment of cardiovascular disease.


Assuntos
Doenças Cardiovasculares , Salvia miltiorrhiza , Animais , Camundongos , NF-kappa B/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Peixe-Zebra , Receptor Nicotínico de Acetilcolina alfa7 , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Células RAW 264.7
5.
Drug Dev Res ; 84(1): 110-120, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36433708

RESUMO

In this work, a series of indole-containing pyrazole-carbohydrazide derivatives A1-A25 were synthesized, and their biological activity on tubulin polymerization inhibition and mitotic catastrophe was evaluated. For introducing indole group to CA-4 pattern, the carbohydrazide linker was used for the first time. As the top hit, A18 suggested notable antiproliferation efficacy and tubulin polymerization inhibitory activity. Inferring comparable antitubulin effect with the positive control Colchicine, A18 indicated obviously lower cyto-toxicity. The cell scratch test showed that A18 could block the cell migration, while the confocal imaging depicted that A18 could induce the mitotic catastrophe via a Colchicine-like approach. The docking simulation visualized the probable binding pattern of A18. With the information in this work, some new hints on modification might be involved in further tubulin-related investigations.


Assuntos
Antineoplásicos , Moduladores de Tubulina , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/metabolismo , Tubulina (Proteína)/metabolismo , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Colchicina/farmacologia , Indóis/farmacologia , Pirazóis/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Relação Estrutura-Atividade
6.
Am J Transl Res ; 14(11): 8390-8397, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36505336

RESUMO

OBJECTIVE: To validate a response surface model for the inhibition of somatic motor response at corrected body weight (CBW) doses of remifentanil plus propofol in elderly patients and to analyze the dose-effect relationship and optimal dosing range for total intravenous anesthesia (TIVA) induction in painless gastroscopy. METHODS: We designed a prospective, open-ended, randomized, parallel group study. A total of 300 elderly patients undergoing painless gastroscopy were randomized to receive remifentanil (0-0.5 µg/kg) and propofol (0.8-2.2 mg/kg) dosing based on CBW. Gastroscopy was performed at the drug's peak effect time. The somatic motor response to gastroscopic stimulation and the adverse reactions at different points were recorded. The somatic motor response was used as the basic element in the subsequent RSM analysis. Model parameters and 95% confidence intervals were fitted by MATLAB software. RESULTS: The CBW doses of remifentanil and propofol showed synergistic inhibitory effects on motor response to noxious stimulation and attenuated adverse reactions. The 50% effective doses of remifentanil and propofol for inhibiting the motor response were 1.754 µg/kg and 2.048 mg/kg, respectively. CONCLUSION: Remifentanil or propofol alone could not inhibit the somatic motor response at weight-adjusted doses among elderly patients. A combination of remifentanil and propofol showed a synergistic interaction in suppressing the motor response and adverse reactions in elderly patients. Preinjection of remifentanil could reduce the needed dose of propofol.

7.
Radiol Case Rep ; 17(11): 4302-4307, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36132067

RESUMO

Adenomatoid tumor is a kind of benign tumor, accounts for a low percentage of scrotal tumors. It usually locates in epididymis, less commonly, arises from the tunica albuginea, spermatic cord or tunica vaginalis of male's urogenital tract system. Here, we report a case of a 32-year-old male, which presented as a 6-month history of left scrotal swelling pain with a scrotal mass, and it had progressively enlarged over the last 1 month. The ultrasonography (US) described a giant well-defined hypoechoic mass in the left scrotum, a thick pedicle connected the mass and the left scrotal wall, and the pedicle had large blood vessels in it. Enhanced CT showed an irregular solid mass in the left scrotum, the left testicular artery was thickened to supply blood for the mass, and the radiologist mentioned it could not be excluded as a malignant lesion. The patient underwent left radical orchiectomy, the mass was diagnosed as an adenomatoid tumor of the tunica vaginalis by pathology. We review literature regarding adenomatoid tumors originating in the tunica vaginalis, summarize the ultrasonographic presentations, provide the idea of diagnosis and differential diagnosis to improve diagnostic accuracy and avoid unnecessary orchiectomy.

9.
J Clin Lab Anal ; 35(9): e23907, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34268792

RESUMO

BACKGROUND: The miRNAs play critical roles in the progression of various tumors. Our study aimed to screen and identify miRNAs to investigate their diagnostic and prognostic value for papillary thyroid carcinoma (PTC). METHODS: miRNAs were evaluated in PTC (n = 30) tissues, A-PTC (n = 30), benign nodules (n = 35) and A-benign nodules (n = 35). The expression levels of five miRNAs were quantified using real-time, quantitative PCR. ROC analysis was used to evaluate the miRNA diagnostic value. RESULTS: The expression of miR-1296-5p, miR-1301-3p, and miR-532-5p was significantly downregulated (p = 0.0001, p = 0.0006, p = 0.0024, respectively), while miR-551b-3p and miR-455-3p were significantly upregulated in PTC tissues compared to A-PTC tissues (p = 0.0005, p = 0.0046, respectively). Interestingly, the expression of miR-1296-5p was downregulated, while miR-551b-3p and miR-455-3p were upregulated in the A-PTC group compared to the A-benign group. Moreover, the miR-1296-5p expression level was associated with tumor size, the number of foci and the TNM stage; the miR-455-3p expression level was correlated with patient age, tumor size, and TNM stage; and the miR-532-5p expression level was correlated with patient age, lymph node metastasis and TNM stage correspondingly. ROC analysis revealed that the AUCs for miR-1301-3p, miR-1296-5p, miR-455-3p, miR-532-5p, and miR-551b-3p were 0.773, 0.790, 0.783, 0.744, and 0.650, respectively. CONCLUSIONS: Our results indicated that miR-1296-5p, miR-1301-3p, miR-532-5p, miR-551b-3p, and miR-455-3p are aberrantly expressed in papillary thyroid carcinomas and correlated with clinicopathological features. ROC curve analysis indicated that these five miRNAs have a potential diagnostic value. Consequently, we speculate that the five altered miRNAs may serve as potential diagnostic and prognostic biomarkers for PTC.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia
10.
BMC Anesthesiol ; 21(1): 174, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34157985

RESUMO

BACKGROUND: The number of caesarean deliveries has been increasing. Although intrathecal morphine (ITM) can relieve pain and is widely applied in caesarean deliveries, it is associated with many side effects. Transversus abdominis plane block (TAPB), a new analgesic technology, has also began playing a certain role after caesarean delivery, with fewer adverse effects. This study mainly compares the analgesic and adverse effects of ITM and TAPB in caesarean delivery. METHODS: We systematically searched PubMed, Cochrane Library, EMBASE, and Web of Science, for randomised controlled trials (RCTs) published before 9 October, 2020 to compare the effects of ITM and TAPB. Primary outcome of the study was the pain score at rest 24 h after caesarean delivery, whereas the secondary outcomes were the pain score at movement 24 h after operation, postoperative nausea and vomiting (PONV), itching, and morphine consumption. For the outcome assessment, we conducted a sensitivity analysis. RESULT: Six RCTs involving 563 patients and meeting the study inclusion criteria were included in this study. Results indicated no significant difference in the pain score between ITM and TAPB at 24 h of rest or movement. The sensitivity analysis results indicated that the resting pain score (95% CI = - 1.27 to - 0.28; P = 0.002) and 24-h moving pain score (95% CI = - 1.8 to - 0.07; P = 0.03) of the ITM group were lower than those of the TAPB group. The consumption of morphine in the ITM group was lower than in the TAPB group (95% CI = 1.92 to 4.87; P < 0.00001); however, in terms of adverse reactions, the incidence of pruritus (95% CI = 1.17 to 8.26; P = 0.02) and PONV (95% CI = 1.92 to 4.87, P < 0.00001) in the ITM group was higher than in the TAPB group. CONCLUSION: Parturients in the ITM and TAPB groups exhibited similar analgesic effects. However, in the sensitivity analysis performed by eliminating the studies causing heterogeneity, the ITM group was found to have superior analgesic effects compared with the TAPB group, with less morphine consumption. Differently, the TAPB group displayed less side effects such as PONV. Therefore, TAPB is still a valuable analgesia option for patients who cannot use ITM for analgesia after caesarean delivery or those having a high risk of PONV. TRIAL REGISTRATION: Registration number: Registered on Prospero with the registration number of CRD42020210135 .


Assuntos
Cesárea/métodos , Morfina/administração & dosagem , Bloqueio Nervoso/métodos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Feminino , Humanos , Injeções Espinhais , Morfina/efeitos adversos , Bloqueio Nervoso/efeitos adversos , Dor Pós-Operatória/prevenção & controle , Náusea e Vômito Pós-Operatórios/epidemiologia , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
BMC Cancer ; 21(1): 559, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001062

RESUMO

BACKGROUND: As an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression, KDM6B has been implicated in the development and malignant progression in various types of cancers. However, its potential roles in esophageal squamous cell carcinoma (ESCC) have not been explored. METHODS: The expression of KDM6B in human ESCC tissues and cell lines was examined using RT-qPCR, immunohistochemical staining and immunoblotting. The effects of KDM6B on the proliferation and metastasis of ESCC were examined using in vitro and in vivo functional tests. RNA-seq and ChIP-seq assay were used to demonstrate the molecular biological mechanism of KDM6B in ESCC. RESULTS: We show that the expression level of KDM6B increased significantly in patients with lymph node metastasis. Furthermore, we confirmed that KDM6B knockdown reduces proliferation and metastasis of ESCC cells, while KDM6B overexpression has the opposite effects. Mechanistically, KDM6B regulates TNFA_SIGNALING_VIA_NFκB signalling pathways, and H3K27me3 binds to the promoter region of C/EBPß, leading to the promotion of C/EBPß transcription. Besides, we show that GSK-J4, a chemical inhibitor of KDM6B, markedly inhibits proliferation and metastasis of ESCC cells. CONCLUSIONS: The present study demonstrated that KDM6B promotes ESCC progression by increasing the transcriptional activity of C/EBPß depending on its H3K27 demethylase activity.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Animais , Benzazepinas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sequenciamento de Cromatina por Imunoprecipitação , Desmetilação do DNA , Conjuntos de Dados como Assunto , Progressão da Doença , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Camundongos , Regiões Promotoras Genéticas , Pirimidinas/farmacologia , RNA-Seq , Ativação Transcricional , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Carbohydr Polym ; 260: 117811, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33712156

RESUMO

Novel pectin/poly(m-phenylenediamine) (P/PmPDA) microspheres with different content of PmPDA were prepared by assembling PmPDA on the surface of pectin microsphere. The successful preparation was confirmed by the results of Fourier Transform Infrared spectra (FTIR), scanning electron microscopy (SEM) and elemental analysis. Compared with pectin microsphere, the Pb2+ adsorption performance of P/PmPDA microspheres was significantly improved. The results of batch adsorption experiments were in good agreement with the Langmuir isotherm model for Pb2+ adsorption, indicating the adsorption was monolayer. The maximum adsorption capacity of Pb2+ was found to be 390.9 mg/g. The kinetic adsorption process was well described by the pseudo-second-order model and chemical adsorption dominated the adsorption process. The potential mechanisms of Pb2+ adsorption were speculated as ion exchange and chelation, which were supported by X-ray photoelectron spectroscopy (XPS). The P/PmPDA microspheres showed good recyclability after five adsorption/desorption cycles. All these results indicated the potential of P/PmPDA microspheres for removing Pb2+.


Assuntos
Chumbo/química , Microesferas , Pectinas/química , Fenilenodiaminas/química , Adsorção , Concentração de Íons de Hidrogênio , Íons/química , Cinética , Chumbo/isolamento & purificação , Espectroscopia Fotoeletrônica , Propriedades de Superfície
13.
Am J Otolaryngol ; 42(2): 102920, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33454555

RESUMO

OBJECTIVE: Thyroid carcinoma is the most common endocrine tumor, and thyroid papillary carcinoma is the most common form. Although thyroid papillary carcinoma presents a good prognosis, some patients still exhibit recurrence or distant metastasis. miR-1301-3p has been found involved in the occurrence and development of some special tumors. Our study aims to investigate the miR-1301-3p expression in thyroid papillary carcinoma, to explore its biological function, and to provide a potential marker for diagnosis and treatment of thyroid papillary carcinoma. MATERIALS AND METHODS: The tissue samples from 70 patients with PTC (n = 35) and benign tumors (n = 35) were collected respectively. miR-1301-3p expression were detected by qPCR. Diagnostic value of miR-1301-3p was analyzed by ROC curve. CCK-8 assays and flow cytometry were performed to detect the effect of miR-1301-3p on TPC-1 function. PCNA expression of protein was detected by WB. RESULTS: Compared with the normal group, the expression of miR-1301-3p was obviously decreased in both benign group and PTC group. With the higher T and N grades, the lower expression of miR-1301-3p. ROC curve analysis showed that the diagnostic values of miR-1301-3p for benign tumor and PTC were 0.766 and 0.881, respectively. Vitro experiments showed that miR-1301-3p was decreased in TPC-1 cells, then, upregulated miR-1301-3p blocked the TPC-1 cell cycle in G1/S phase, and inhibited the proliferation. PCNA expression was significantly increased in TPC-1 cells and significantly decreased after upregulation of miR-1301-3p. CONCLUSION: The present study showed that the expression of miR-1301-3p in PTC was significantly decreased, which was related to T and N grade. Upregulation of miR-1301-3p could inhibit cell proliferation and cell migration. miR-1301-3p may serve as a potential biomarker for the early diagnosis and treatment of PTC.


Assuntos
Biomarcadores Tumorais/genética , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , MicroRNAs/genética , MicroRNAs/fisiologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Câncer Papilífero da Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Adulto Jovem
14.
Oxid Med Cell Longev ; 2020: 2963540, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33294118

RESUMO

Neuroinflammation plays a crucial role in the pathological process of Parkinson's disease (PD). Nod-like receptor protein 3 (NLRP3) inflammasome was highly located in microglia and involved in the process of neuroinflammation. Activation of the NLRP3 inflammasome has been confirmed to contribute to the progression of PD. Thus, inhibition of NLRP3 inflammasome activation could be an important breakthrough point on PD therapy. Ellagic acid (EA) is a natural polyphenol that has been widely found in soft fruits, nuts, and other plant tissues with anti-inflammatory, antioxidant, and neuroprotective properties. However, the mechanisms underlying EA-mediated anti-inflammation and neuroprotection have not been fully elucidated. In this study, a lipopolysaccharide- (LPS-) induced rat dopamine (DA) neuronal damage model was performed to determine the effects of EA on the protection of DA neurons. In addition, the DA neuronal MN9D cell line and microglial BV-2 cell line were employed to explore whether EA-mediated neuroprotection was through an NLRP3-dependent mechanism. Results indicated that EA ameliorated LPS-induced DA neuronal loss in the rat substantia nigra. Further, inhibition of microglial NLRP3 inflammasome signaling activation was involved in EA-generated neuroprotection, as evidenced by the following observations. First, EA reduced NLRP3 inflammasome signaling activation in microglia and subsequent proinflammatory cytokines' excretion. Second, EA-mediated antineuroinflammation and further DA neuroprotection from LPS-induced neurotoxicity were not shown upon microglial NLRP3 siRNA treatment. In conclusion, this study demonstrated that EA has a profound effect on protecting DA neurons against LPS-induced neurotoxicity via the suppression of microglial NLRP3 inflammasome activation.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Ácido Elágico/farmacologia , Inflamassomos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Inflamassomos/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
15.
Ecotoxicol Environ Saf ; 189: 109937, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31785945

RESUMO

Growing epidemiological evidence has shown that exposure to polychlorinated biphenyls (PCBs) is harmful to the cardiovascular system. However, how PCB 118-induced oxidative stress mediates endothelial dysfunction is not fully understood. Here, we explored whether and how PCB 118 exposure-induced oxidative stress leads to NLRP3 inflammasome-dependent pyroptosis in endothelial cells. As expected, PCB 118 was cytotoxic to HUVECs and induced caspase-1 activation and cell membrane disruption, which are characteristics of pyroptosis. Moreover, PCB 118-induced pyroptosis may have been due to the activation of the NLRP3 infammasomes. PCB 118 also induced excessive reactive oxygen species (ROS) in HUVECs. The ROS scavenger (±)-α-tocopherol and the NFκB inhibitor BAY11-7082 reversed the upregulation of NLRP3 expression and the increase in NLRP3 inflammasome activation induced by PCB 118 exposure in HUVECs. Additionally, PCB 118-induced oxidative stress and pyroptosis were dependent on Aryl hydrocarbon receptor (AhR) activation and subsequent cytochrome P450 1A1 upregulation, which we confirmed by using the AhR selective antagonist CH 223191. These data suggest that PCB 118 exposure induces NLRP3 inflammasome activation and subsequently leads to pyroptosis in endothelial cells in vitro and in vivo. AhR-mediated ROS production play a central role in PCB 118-induced pyroptosis by priming NFκB-dependent NLRP3 expression and promoting inflammasome activation.


Assuntos
Poluentes Ambientais/toxicidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Bifenilos Policlorados/toxicidade , Piroptose , Espécies Reativas de Oxigênio/metabolismo , Citocromo P-450 CYP1A1 , Células Endoteliais/metabolismo , Humanos , Inflamassomos/metabolismo , NF-kappa B/metabolismo , Bifenilos Policlorados/metabolismo
16.
J Exp Clin Cancer Res ; 38(1): 321, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324197

RESUMO

BACKGROUND: Recurrence and metastasis are the leading causes of tumour-related death in patients with oesophageal squamous cell carcinoma (ESCC). Tumour-infiltrating natural killer cells (NK cells) display powerful cytotoxicity to tumour cells and play a pivotal role in tumour therapy. However, the phenotype and functional regulation of NK cells in oesophageal squamous cell carcinoma (ESCC) remains largely unknown. METHODS: Single cell suspensions from blood and tissue samples were isolated by physical dissociation and filtering through a 70 µm cell strainer. Flow cytometry was applied to profile the activity and function of NK cells, and an antibody chip experiment was used to identify and quantitate cytokine levels. We studied IL-6 and IL-8 function in primary oesophageal squamous carcinoma and NK cell co-cultures in vitro and by a xenograft tumour model in vivo. Western blotting was used to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Finally, we performed an IHC array to analyse IL-6/IL-8 (interleukin 6/interleukin 8) expression in 103 pairs of tumours and matched adjacent tissues of patients with ESCC to elucidate the correlation between IL-6 or IL-8 and clinical characteristics. RESULTS: The percentages of NK cells in both peripheral blood and tumour tissues from patients with ESCC were significantly increased in comparison with those in the controls and correlated with the clinical characteristics. Furthermore, the decrease in activating receptors and increase in inhibitory receptors on the surface of tumour-infiltrating NK cells was confirmed by flow cytometry. The level of granzyme B, the effector molecule of tumour-infiltrating NK cells, was also decreased. Mechanistically, primary ESCC cells activated the STAT3 signalling pathway on NK cells through IL-6 and IL-8 secretion, leading to the downregulation of activating receptors (NKp30 and NKG2D) on the surface of NK cells. An ex vivo study showed that blockade of STAT3 attenuated the IL-6/IL-8-mediated impairment of NK cell function. Moreover, the expression of IL-6 or IL-8 in tumour tissues was validated by immunohistochemistry to be positively correlated with tumour progression and poor survival, respectively. CONCLUSIONS: Tumour cell-secreted IL-6 and IL-8 impair the activity and function of NK cells via STAT3 signalling and contribute to oesophageal squamous cell carcinoma malignancy.


Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Interleucina-6/genética , Interleucina-8/genética , Fator de Transcrição STAT3/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Transdução de Sinais/genética , Análise de Célula Única , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Biotechnol Appl Biochem ; 66(5): 738-743, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31210367

RESUMO

Astroglia support neuron by providing substrates for neuronal metabolism, glutamate clearance, and antioxidative protection. Nuclear factor erythroid 2-related factor 2 (Nrf2) participates in the antioxidative defense response. Also, Nrf2 signaling is recognized to activate the neurotrophic pathway to replace/protect damaged organelles. Ellagic acid (EA), an extraction component of fruits and nuts, presents many pharmacological activities such as anti-inflammation, antioxidation, and neuroprotection. However, few studies have been focused on the neurotrophic properties of EA. Our study investigated whether EA could increase neuronal survival and the target cells. Thus, primary neuron-enriched cultures and primary astroglia-enriched cultures were applied to detect whether EA-elicited neurotrophic effects were mediated by astroglia Nrf2. This study indicated that EA promoted neuronal survival. Further, astroglia Nrf2 participate in EA-elicited neuronal survival with the following scenarios. First, EA elicited astroglia proliferation, glial cell line-derived neurotrophic factor (GDNF) release, and Nrf2 activation. Second, after silencing astroglia Nrf2, EA-induced astrogliosis, GDNF release, and neuronal survival disappeared. Thus, EA-mediated astroglia Nrf2 activation is important to enhance neurotrophic effects on neurons, which might provide new insights for neurodegenerative disease.


Assuntos
Ácido Elágico/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Animais , Células Cultivadas , Inativação Gênica/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real
18.
Front Immunol ; 10: 936, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118933

RESUMO

Background: Parkinson's disease (PD) is the second most prevalent central nervous system (CNS) degenerative disease and characterized by slow and progressive loss of dopamine (DA) neurons in the midbrain substantia nigra. Microglia-mediated neuroinflammation has been considered as the major central event in the process of DA neuronal loss. Thus, inhibition of neuroinflammation could possess a more viable strategy for PD treatment. Naringenin (NAR), a natural flavanoid contained in citrus fruit and grapefruits, possesses amounts of pharmacological activities. Recent studies indicated that NAR produced neuroprotection against several neurological disorders. However, the mechanisms underlying NAR-generated neuroprotection are not fully illuminated. Methods: In the present study, rat nigral stereotaxic injection of lipopolysaccharide (LPS)-induced DA neuronal loss was performed to investigate NAR-mediated neuroprotection. In addition, BV-2 and MN9D cell lines were applied to explore the underlying mechanisms. Results: NAR protected DA neurons against LPS-induced neurotoxicity. Also, NAR suppressed microglial nod-like receptor protein 3 (NLRP3) inflammasome signaling activation and the subsequent pro-inflammatory factors release. In addition, NAR-mediated DA neuroprotection was dependent on the inhibition of microglial NLRP3 inflammasome activation, as evidenced by the observations that NAR-reduced pro-inflammatory factors production and further NAR-exerted DA neuroprotection against LPS-induced neuronal damage was not discerned after microglial NLRP3 siRNA treatment. Conclusions: This study demonstrated that NAR targeted microglial NLRP3 inflammasome to protect DA neurons against LPS-induced neurotoxicity. These findings suggest NAR might hold a promising therapeutic potential for PD.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Flavanonas/farmacologia , Inflamassomos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Lipopolissacarídeos/toxicidade , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Doença de Parkinson , Ratos , Ratos Sprague-Dawley
19.
Molecules ; 24(6)2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917573

RESUMO

The longan industry produces a large amount of byproducts such as pericarp and seed, resulting in environmental pollution and resource wastage. The present study was performed to systematically evaluate functional components, i.e., polyphenols (phenolics and flavonoids) and alkaloids, in longan byproducts and their bioactivities, including antioxidant activities, nitrite scavenging activities in simulated gastric fluid and anti-hyperglycemic activities in vitro. Total phenolic and total flavonoid contents in pericarp were slightly higher than those in seeds, but seeds possessed higher alkaloid content than pericarp. Four polyphenolic substances, i.e., gallic acid, ethyl gallate, corilagin and ellagic acid, were identified and quantified using high-performance liquid chromatography. Among these polyphenolic components, corilagin was the major one in both pericarp and seed. Alkaloid extract in seed showed the highest DPPH radical scavenging activity and oxygen radical absorbance capacity. Nitrite scavenging activities were improved with extract concentration and reaction time increasing. Flavonoids in seed and alkaloids in pericarp had potential to be developed as anti-hyperglycemic agents. The research result was a good reference for exploring longan byproducts into various valuable health-care products.


Assuntos
Alcaloides/análise , Polifenóis/análise , Sapindaceae/química , Alcaloides/farmacologia , Antioxidantes/análise , Antioxidantes/farmacologia , Cromatografia Líquida de Alta Pressão , Hipoglicemiantes/análise , Hipoglicemiantes/farmacologia , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Sementes/química
20.
Reprod Sci ; 26(1): 26-34, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29277146

RESUMO

Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare disease that causes primary infertility. However, the genetic causes for approximately half of MMAF cases are unknown. Whole exome sequencing analysis of the 27 patients with MMAF identified several CFAP44 mutations (3 homozygous: c.2935_2944del: p.D979*, c.T1769A: p.L590Q, c.2005_2006del: p.M669Vfs*13; and putative compound heterozygous: c.G3262A: p.G1088S and c.C1718A: p.P573H.) and CFAP43 acceptor splice-site deletion (c.3661-2A>-) mutations in 5 and 1 patients, respectively. Real-time quantitative polymerase chain reaction assays also demonstrated that CFAP44 expression was very weak in patient (P)1 and P3, and CFAP43 expression was lower in P6 than in the control. Immunofluorescence analysis of CFAP43 showed lower CFAP43 protein expression levels in P6 than in the normal control. This study demonstrated that biallelic mutations in CFAP44 and CFAP43 cause MMAF. These results provide researchers with a new insight to understand the genetic etiology of MMAF and to identify new loci for genetic counselling of MMAF.


Assuntos
Infertilidade Masculina/genética , Proteínas dos Microtúbulos/genética , Proteínas Nucleares/genética , Peptídeo Hidrolases/genética , Cauda do Espermatozoide/patologia , Adulto , Proteínas do Citoesqueleto , Humanos , Infertilidade Masculina/patologia , Masculino , Mutação , Sequenciamento do Exoma
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