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1.
Environ Sci Pollut Res Int ; 30(18): 54022-54034, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36869944

RESUMO

There are growing concerns about the neurodevelopmental toxicity of polybrominated diphenyl ethers (PBDEs), but the toxicological phenotypes and mechanisms are not well elucidated. Here, zebrafish (Danio rerio) were exposed to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) from 4 to 72 h post-fertilization (hpf). The results showed that BDE-47 stimulated the production of dopamine and 5-hydroxytryptamine, but inhibited expression of Nestin, GFAP, Gap43, and PSD95 in 24 hpf embryos. Importantly, we unraveled the inhibitory effects of BDE-47 on neural crest-derived melanocyte differentiation and melanin syntheses process, evidenced by disrupted expression of wnt1, wnt3, sox10, mitfa, tyrp1a, tyrp1b, tryp2, and oca2 gene in 72 hpf embryos and decreased tyrosinase activities in embryos at 48 and 72 hpf. The transcriptional activities of myosin VAa, kif5ba, rab27a, mlpha, and cdc42 genes, which are associated with intracellular transport process, were also disturbed during zebrafish development. Ultimately, these alterations led to fast spontaneous movement and melanin accumulation deficit in zebrafish embryos upon BDE-47 exposure. Our results provide an important extension for understanding the neurodevelopmental effects of PBDEs and facilitate the comprehensive evaluation of neurotoxicity in embryos.


Assuntos
Éteres Difenil Halogenados , Peixe-Zebra , Animais , Éteres Difenil Halogenados/toxicidade , Peixe-Zebra/genética , Melaninas/metabolismo , Éter , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Peixe-Zebra/genética
2.
Am J Hypertens ; 36(6): 348-353, 2023 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-36617224

RESUMO

BACKGROUND: Animals exposed to cold stress develop hypertension; however, the effects of cold-induced hypertension on pregnancy remain unclear. We therefore, aimed to investigate the impacts of cold-stress stimulation on mice pregnancy. METHODS: Four groups of mice were used in the study: non-pregnant control group (NN), non-pregnant cold-stress group (NC), pregnant control group (PN) and pregnant cold-stress group (PC). control groups were kept at 25℃, and the cold-stress groups were kept in a room for cold-stress stimulation (4 ± 2℃) for 4 hours (then back to 25℃) every day from the 1st to the 18th day. RESULTS: The blood pressure of the PC was the highest among the four groups, and the hypertensive percentage of the PC was significantly increased. However, plasma angiotensinⅡ levels of the PC were the lowest. The weights of the foetus and placenta in the PC were significantly decreased compared to the PN. More apparent changes in kidneys and placenta were observed in the PC compared to the PN. The blood pressure of pregnant mice showed no difference between the PN and PC groups 50 days after delivery. CONCLUSIONS: Intermittent cold-stress stimulation had significantly adverse effects on the pregnant mice, leading to maternal hypertension, renal and placental lesions, body weight and placenta reduction in offspring. The study results may offer a non-invasive method to establish an animal model of hypertensive disorders in pregnancy. Cold-stress stimulation may be one of the inducible factors of pregnancy-induced hypertension.Cold-stress stimulation may be one of the inducible factors of pregnancy-induced hypertension.


Assuntos
Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Humanos , Camundongos , Gravidez , Animais , Feminino , Hipertensão Induzida pela Gravidez/etiologia , Placenta/patologia , Resposta ao Choque Frio , Pressão Sanguínea
3.
Anticancer Drugs ; 34(8): 962-966, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36602434

RESUMO

INTRODUCTION: Currently, there are few reports of patients with locally advanced lung cancer achieving a clinical complete response by medical treatment. Preoperative neoadjuvant immunotherapy combined with chemotherapy is an option for patients with unresectable, locally advanced nonsmall cell lung cancer (NSCLC) which is of great potential, and may change traditional treatment paradigms. There are relatively few large-scale, high-quality randomized-controlled trials yet, and limitations such as short postoperative follow-up period and immature disease-free survival and overall survival data still persist. Thus, evidence-based medical evidence is urgently needed. It is worthy to explore the further treatment of patients who achieved complete response after initial treatment, though lacking of evidence by now. CASE PRESENTATION: We report a stage IIIA lung squamous cell carcinoma case who achieved a major pathologic remission after neoadjuvant treatment with tislelizumab and chemotherapy. CONCLUSION: Our case study contributes to the existing evidence on the feasibility, efficacy and safety of neoadjuvant immunotherapy combined with chemotherapy in locally advanced unresectable NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia Neoadjuvante , Carcinoma de Células Escamosas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
4.
Environ Toxicol ; 38(1): 185-192, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36219784

RESUMO

Titanium dioxide nanoparticles (TiO2 NPs) have been shown to induce reproductive system damages in animals. To better underline how TiO2 NPs act in reproductive system, female mice were exposed to 2.5, 5, or 10 mg/kg TiO2 NPs by gavage administration for 60 days, the ovary injuries, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels as well as ovarian follicular development-related molecule expression were investigated. The results showed that TiO2 NPs exposure resulted in reduction of ovary weight and inhibition of ovarian follicular development. Furthermore, the suppression of follicular development was demonstrated to be closely related to higher FSH and LH levels, and higher expression of activin, follistatin, BMP2, BMP4, TGF-ß1, Smad2, Smad3, and Smad4 as well as decreased inhibin-α expression in mouse ovary in a dose-dependent manner. It implies that the impairment of ovarian follicular development caused by TiO2 NPs exposure may be mediated by TGF-ß signal pathway.


Assuntos
Nanopartículas , Titânio , Feminino , Camundongos , Animais , Titânio/toxicidade , Hormônio Foliculoestimulante/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Nanopartículas/toxicidade
6.
NPJ Prim Care Respir Med ; 31(1): 33, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083541

RESUMO

Accurate prediction of the risk of progression of coronavirus disease (COVID-19) is needed at the time of hospitalization. Logistic regression analyses are used to interrogate clinical and laboratory co-variates from every hospital admission from an area of 2 million people with sporadic cases. From a total of 98 subjects, 3 were severe COVID-19 on admission. From the remaining subjects, 24 developed severe/critical symptoms. The predictive model includes four co-variates: age (>60 years; odds ratio [OR] = 12 [2.3, 62]); blood oxygen saturation (<97%; OR = 10.4 [2.04, 53]); C-reactive protein (>5.75 mg/L; OR = 9.3 [1.5, 58]); and prothrombin time (>12.3 s; OR = 6.7 [1.1, 41]). Cutoff value is two factors, and the sensitivity and specificity are 96% and 78% respectively. The area under the receiver-operator characteristic curve is 0.937. This model is suitable in predicting which unselected newly hospitalized persons are at-risk to develop severe/critical COVID-19.


Assuntos
COVID-19/diagnóstico , Hospitalização/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , COVID-19/patologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Prognóstico , Tempo de Protrombina , Curva ROC , Medição de Risco , Sensibilidade e Especificidade , Adulto Jovem
7.
Artigo em Inglês | MEDLINE | ID: mdl-34055015

RESUMO

OBJECTIVE: Systematically evaluate the efficacy of physical ablation combined with TKI in the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: We performed a comprehensive search of databases including OVID, PubMed, EMBASE, the Cochrane Library, and three Chinese databases (China National Knowledge Infrastructure, Wanfang Database, and Chongqing Weipu Database). The aim was to identify randomized controlled trials (RCT) investigating physical ablation as the treatment for advanced NSCLC. We also evaluated the methodological quality of the included studies and summarized the data extracted for meta-analysis with Review Manager 5.3. RESULTS: A total of 9 studies, including 752 patients, were evaluable. The meta-analysis results show that the complete response rate (CRR) (RR: 2.23, 95% CI: 1. 46 to 3.40, P 0.01), partial response rate (PRR) (RR: -2.25, 95% CI: 1.41 to 3.59, P 0.01), and disease control rate (DCR) (RR: -2.80, 95% CI: 1.64 to 4.80, P< 0.01) of patients with advanced NSCLC who received physical ablation combined with TKI therapy were higher than those who did not receive physical ablation therapy. The control groups from seven of the studies had a total of 606 patients with targeted therapies and chemotherapy. The complete response rate was (CRR) (RR: 2.48, 2.4895% CI: 1.55 to 2.47, P 0.01), partial response rate (PRR) (RR: -1.66, 95% CI: 1.20 to 2.31, P< 0.01), and disease control rate (DCR) (RR: -2.68, 95% CI: 1.41 to 5.06, P< 0.01) for patients with advanced NSCLC who had received physical ablation combined with targeted therapies and chemotherapy, compared to patients who had not received physical ablation therapy. This difference was statistically significant. Above all, these results showed that the clinical efficacy of physical ablation combined EGFR-TKIs therapy (regardless of whether it was combined with chemotherapy) was better than that of EGFR-TKIs therapy alone. CONCLUSION: Physical ablation combined with TKI treatment in patients with advanced NSCLC can improve efficacy.

8.
Chemosphere ; 258: 127385, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32947675

RESUMO

2,2,4,4-tetrabromodiphenyl ether (BDE-47) has received considerable attention because of its high detection level in biological samples and potential developmental toxicity. Here, using zebrafish (Danio rerio) as the experimental animal, we investigated developmental effects of BDE-47 and explored the potential mechanism. Zebrafish embryos at 4 h post-fertilization (hpf) were exposed to 0.312, 0.625 and 1.25 mg/L BDE-47 to 74-120 hpf. We found that BDE-47 instigated a dose-related developmental toxicity, evidenced by reduced embryonic survival and hatching rate, shortened body length and increased aberration rate. Meanwhile, higher doses of BDE-47 reduced mitochondrial membrane potential and ATP production but increased apoptosis in zebrafish embryos. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) (ndufb8, sdha, uqcrc1, cox5ab and atp5fal) were negatively related to BDE-47 doses in zebrafish embryos. Moreover, exposure to BDE-47 at 0.625 or 1.25 mg/L impaired mitochondrial biogenesis and mitochondrial dynamics. Our data further showed that BDE- 47 exposure induced excessive reactive oxygen species (ROS) and oxidative stress, which was accompanied by the activation of c-Jun N-terminal Kinase (JNK). Antioxidant NAC and JNK inhibition could mitigate apoptosis in embryos and improve embryonic development in BDE-47-treated zebrafish, suggesting the involvement of ROS/JNK pathway in embryonic developmental changes induced by BDE-47. Altogether, our data suggest here that developmental toxicity of BDE-47 may be associated with mitochondrial ROS-mediated JNK signaling in zebrafish embryo.


Assuntos
Éteres Difenil Halogenados/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Peixe-Zebra/metabolismo
9.
Hematology ; 25(1): 43-47, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31906810

RESUMO

Background: Cytomegalovirus (CMV) infection of the central nervous system (CNS) is a rare but life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Cases presentation: Two patients with drug-resistant CMV encephalitis after allo-HSCT were successfully treated with donor CMV-specific cytotoxic T lymphocytes (CTLs). In the first case, a 27-year-old male who received haploidentical transplantation to treat T-cell acute lymphoblastic leukemia (T-ALL), developed CMV encephalitis during the time of the ganciclovir maintenance treatment. After intravenous foscarnet and donor CMV-specific CTLs, CMV-DNA of CSF became undetectable and the abnormal signs of brain magnetic resonance imaging (MRI) were limited. Another case, a 57-year-old female with acute myeloid leukemia (AML) who underwent haploidentical transplantation, also developed CMV encephalitis during the maintenance treatment of the ganciclovir. After administering donor CMV-specific CTLs intrathecally, the CMV load of the CSF decreased.Conclusions: The intravenous/intratheca administration of donor CMV-specific CTLs may be a safe and effective treatment for CMV encephalitis, especially for patients who suffered from drug-resistant CMV infection.


Assuntos
Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/terapia , Encefalite/etiologia , Encefalite/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfócitos T Citotóxicos/transplante , Adulto , Antivirais/uso terapêutico , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/tratamento farmacológico , Farmacorresistência Viral , Encefalite/tratamento farmacológico , Feminino , Ganciclovir/uso terapêutico , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Doadores de Tecidos , Transplante Homólogo/efeitos adversos
10.
Acta Haematol ; 142(4): 217-223, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597154

RESUMO

Central nervous system complications (CNSCs) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are common and may be a significant source of morbidity and mortality. We performed a retrospective study of 153 pediatric patients who underwent allo-HSCT to determine CNSC type, incidence, and impact on survival. A total of 34 patients (22.2%) developed CNSCs. The cumulative incidence of CNSCs at 100 days and 3 years was 18.30 and 22.73%, respectively. The most common CNSC was calcineurin inhibitor (CNI)-associated neurotoxicity (50.0%). Risk factors for CNSCs were the time from diagnosis to HSCT ≥4.8 months (p = 0.032) and the development of acute graft-versus-host disease (aGVHD) grade III-IV (p = 0.002). CNSCs after allo-HSCT negatively impacted overall survival (hazard ratio [HR] 1.97, p = 0.043) and nonrelapse mortality (HR 4.84, p < 0.001). In conclusion, CNSCs after allo-HSCT are associated with poor outcomes; patients with severe aGVHD and/or late transplantation should be given more attention.


Assuntos
Inibidores de Calcineurina/efeitos adversos , Doenças do Sistema Nervoso Central , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Aguda , Adolescente , Aloenxertos , Inibidores de Calcineurina/administração & dosagem , Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/mortalidade , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Incidência , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
11.
J Biomed Nanotechnol ; 15(3): 571-580, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31165701

RESUMO

Long-term exposure to nanoparticulate titanium dioxide (nano-TiO2) is known to cause reductions of sperm numbers and quality in animals, and the cAMP-dependent signaling pathway has been demonstrated to play a key role in regulating spermatogenesis. However, whether the suppression of spermatogenesis induced by nano-TiO2 is related to regulatory disturbances of the cAMP-CREB/CREM signaling pathway is not well investigated. In the current study, male mice were exposed to nano-TiO2 at doses of 1.25, 2.5, or 5 mg/kgbw via gavage instillation for 90 consecutive days and the molecular mechanisms underlying suppression of spermatogenesis caused by nano-TiO2 were investigated. Our findings showed that nano-TiO2 could cross the blood-testis barrier, and accumulated in mouse testes, thus inducing obvious pathological changes and decreasing sperm concentrations and motility, as well as increasing rate of sperm malformation. Furthermore, nano-TiO2 also induced significant reductions in protein expression including cyclic adenosine monophosphate content, protein kinase A, cAMP-responsive element modulator, p-cAMP-response element binding protein, lactate dehydrogenase-C, testis-specific protein kinase 1, and testicular specific CREM activator, and upregulation of protein expression including protein phosphatase, and transducer of regulated CREB 1, which may be associated with reductions of follicle stimulating hormone and luteinizing hormone levels. Together, the present study indicates that the reductions of FSH and LH concentrations and suppression of spermatogenesis in mice caused by nano-TiO2 may be associated with the dysfunctions of the cAMP-CREB/CREM signaling pathway.


Assuntos
Espermatogênese , Titânio , Animais , Modulador de Elemento de Resposta do AMP Cíclico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Masculino , Nanopartículas Metálicas , Camundongos , Transdução de Sinais
12.
J Biomed Nanotechnol ; 15(4): 839-847, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30841976

RESUMO

Numerous studies have suggested that nano-TiO2 can be translocated to the brain via the placental barrier and blood brain barrier, leading to brain damage and cognitive impairment in both mice and rat offspring. The mechanism of nanoTiO2-induced neurotoxicity is still unclear, as is its role in the inhibition of hippocampal development. In this experiment, nano-TiO2 was employed to investigate whether the inhibition of the hippocampal development of mice offspring involved the alterations in the Rho signaling pathway following consecutive gavage of female mice between 7-21 days postpartum. The results showed that nano-TiO2 particles were concentrated in the hippocampus of offspring, resulting in reduced hippocampal indices and in inhibited axonal and dendritic growth. Furthermore, nano-TiO2 downregulated expression of N-methyl-D-aspartate receptor (NR)1, NR2A, NR2B, RhoGTPase, Ras-related C1 botulinum toxin substrate (Rac1), cell division cycle42 (Cdc42), phosphorylated cAMP response element binding protein (p-CREB), p21-activated kinase (PAK) 3, and PAK1, LIMK (LIM kinase) 1, p-LIMK1, activated Cdc42 kinase (ACK), and myotonic dystrophic kinaseassociated Cdc42-binding kinase (MRCK) and increased expression of RhoA, Rho kinase (ROCK) 1 and cyclin dependent kinase (Cdk) 5 in offspring. In addition, nano-TiO2 disrupted the balance of RhoA/Rac1, RhoA/Cdc42, and Rac1/Cdc42 ratios in the hippocampus of mice offspring. Taken together, these data imply that maternal exposure to nano-TiO2 inhibited development of hippocampal axons and dendrites of offspring may be correlated with the dysfunction of the Rho pathway and that N-methyl-D-aspartate receptors (NMDAR) may also mediate nano-TiO2-Rho pathway interactions.


Assuntos
Exposição Materna , Animais , Feminino , Hipocampo , Camundongos , Gravidez , Ratos , Titânio , Proteína rhoA de Ligação ao GTP
14.
J Nutr Biochem ; 65: 35-45, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30616064

RESUMO

Prevention of obesity-induced cognitive decline is an important public health goal. Purple sweet potato color (PSPC), a class of naturally occurring anthocyanins, has beneficial potentials including antioxidant and neuroprotective activity. Evidence shows that anthocyanins can activate AMP-activated protein kinase (AMPK), a critical mediator of autophagy induction. This study investigated whether PSPC could improve cognitive function through regulating AMPK/autophagy signaling in HFD-fed obese mice. Our results showed that PSPC significantly ameliorated obesity, peripheral insulin resistance and memory impairment in HFD-fed mice. Moreover, enhanced autophagy was observed, along with the decreased levels of protein carbonyls, malondialdehyde and reactive oxygen species (ROS) in the hippocampus of HFD-fed mice due to PSPC administration. PSPC also promoted hippocampal brain-derived neurotrophic factor (BDNF) expression and neuron survival in HFD-fed mouse. These improvements were mediated, at least in part, by the activation of AMPK, which was confirmed by metformin treatment. It is concluded that PSPC has great potential to improve cognitive function in HFD-fed mice via AMPK activation that restores autophagy and protects against hippocampal apoptosis.


Assuntos
Transtornos Cognitivos/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Hipocampo/efeitos dos fármacos , Ipomoea batatas/química , Pigmentos Biológicos/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antocianinas/farmacologia , Autofagia/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/etiologia , Hipocampo/metabolismo , Hipocampo/patologia , Resistência à Insulina , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos ICR , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/psicologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia
15.
IUBMB Life ; 71(1): 81-92, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30296359

RESUMO

Glioma is known to be the most prevalent primary brain tumor. In recent years, there has been evidence indicating myeloid cell leukemia-1 (MCL1) plays a role in brain glioblastoma. Therefore, the present study was conducted with aims of exploring the ability of MCL1 silencing to influence glioma cell senescence and apoptosis through the mediation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Glioma and tumor-adjacent tissues were collected in order to detect the presence of higher levels of MCL1 protein expression. Next, the mRNA and protein expression of MCL1, PI3K, Akt, B cell lymphoma 2 (Bcl2), Bcl2-associated X (Bax), B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1), and phosphatase and tensin homolog (PTEN) were determined. Cell counting kit-8 assay was applied to detect cell proliferation, ß-galactosidase staining for cell senescence, and flow cytometry for cell cycle entry and apoptosis. Initially, the results revealed higher positive expression rate of MCL1 protein, increased mRNA and protein expression of MCL1, PI3K, Akt, Bmi-1, and Bcl-2 and decreased that of Bax and PTEN in human glioma tissues. The silencing of MCL1 resulted in a decrease in mRNA and protein expression of PI3K, Akt, Bmi-1, and Bcl-2 and an increase in Bax and PTEN expressions in glioma cells. Moreover, silencing of MCL1 also inhibited cell proliferation and cell cycle entry in glioma cells, and promoted glioma cell senescence and apoptosis. In conclusion, the aforementioned results collectively suggested that the silencing of MCL1 promotes senescence and apoptosis in glioma cells through inhibiting the PI3K/Akt signaling pathway. Thus, decreasing the expression of MCL1 might have therapeutic functions in glioma. © 2018 IUBMB Life, 71(1):81-92, 2019.


Assuntos
Proliferação de Células/genética , Senescência Celular/genética , Glioma/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Adolescente , Adulto , Apoptose/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Inativação Gênica , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Transdução de Sinais/genética , Adulto Jovem , Proteína X Associada a bcl-2/genética
16.
Am J Physiol Cell Physiol ; 316(1): C70-C80, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30404560

RESUMO

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder, affecting the quality of life of millions of people worldwide. The present study aims to determine the relationship between micro-RNA-143 (miR-143) and C-X-C motif chemokine 13 (CXCL13) and whether it influences the pathogenesis of myasthenia gravis (MG). Thymus specimens were resected from patients with thymic hyperplasia combined with MG and then infused into normal mouse cavities to establish MG mouse models. Immunohistochemistry, reverse transcription-quantitative PCR, in situ hybridization detection, and Western blot analysis were employed to identify the expression of miR-143 and CXCL13 in MG and normal mice. The obtained thymocytes were cultured in vitro and transfected with a series of miR-143 mimic, miR-143 inhibitor, overexpression of CXCL13, or siRNA against CXCL13. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and flow cytometry assays were employed to assess cell viability, cycle entry, and apoptosis of the thymocytes. Dual-luciferase reporter assay provided verification, confirming that CXCL13 was the target gene of miR-143. Low miR-143 expression in the thymus tissues of the MG mice was detected, which presented with a reciprocal relationship with the expression rate of CLCX13. Observations in relation to the interactions between miR-143 mimic or siRNA-CXCL13 exposure showed reduced cell viability, with a greater number of cells arrested at the G0/G1 phase and a greater rate of induced apoptosis. Furthermore, overexpression of CXCL13 rescued miR-143 mimic-induced apoptosis. The findings have identified the potential role of miR-143 as a MG development mediator by targeting CXCL13. The key results obtained provide a promising experimental basis for targeted intervention treatment with miR-143.


Assuntos
Proliferação de Células/fisiologia , Quimiocina CXCL13/biossíntese , Modelos Animais de Doenças , MicroRNAs/biossíntese , Miastenia Gravis/metabolismo , Timócitos/metabolismo , Adolescente , Adulto , Animais , Apoptose/fisiologia , Células Cultivadas , Quimiocina CXCL13/antagonistas & inibidores , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Miastenia Gravis/patologia , Timócitos/patologia , Adulto Jovem
17.
J Cell Physiol ; 234(6): 9033-9044, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30362546

RESUMO

Development of effective therapeutic drugs for Parkinson's disease (PD) is of great importance. Aberrant microRNA (miRNA) expression has been identified in postmortem human PD brain samples, in vitro and in vivo PD models. However, the role of miR-342-3p in PD has been understudied. The study explores the effects of miR-342-3p on expression of glutamate (Glu) transporter, and dopaminergic neuron apoptosis and proliferation by targeting p21-activated kinase 1 (PAK1) through the Wnt signaling pathway in PD mice. After establishment of PD mouse models, gain- or loss-of-function assay was performed to explore the functional role of miR-342-3p in PD. Number of apoptotic neurons and Glu concentration was then determined. Subsequently, PC12 cells were treated with miR-342-3p mimic, miR-342-3p inhibitor, dickkopf-1 (DKK1), and miR-342-3p inhibitor + DKK1. The expression of miR-342-3p, PAK1, the Wnt signaling pathway-related and apoptosis-related genes, Glutamate transporter subtype 1 (GLT-1), l-glutamate/ l-aspartate transporter (GLAST), tyrosine hydroxylase (TH) was measured. Also, cell viability and apoptosis were evaluated. PD mice exhibited increased miR-342-3p, while decreased expression of PAK1, GLT-1, GLAST, TH, and the Wnt signaling pathway-related and antiapoptosis genes. miR-342-3p downregulation could promote expression of PAK1, the Wnt signaling pathway-related and antiapoptosis genes. GLT-1, GLAST, and TH as well as cell viability, but reduce cell apoptosis rate. The results indicated that suppression of miR-342-3p improves expression of Glu transporter and promotes dopaminergic neuron proliferation while suppressing apoptosis through the Wnt signaling pathway by targeting PAK1 in mice with PD.


Assuntos
Apoptose , Encéfalo/enzimologia , Neurônios Dopaminérgicos/enzimologia , Transportador 1 de Aminoácido Excitatório/metabolismo , Transportador 2 de Aminoácido Excitatório/metabolismo , MicroRNAs/metabolismo , Doença de Parkinson/enzimologia , Via de Sinalização Wnt , Quinases Ativadas por p21/metabolismo , Animais , Encéfalo/patologia , Proliferação de Células , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Regulação para Baixo , Transportador 1 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/genética , Regulação Enzimológica da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Células PC12 , Doença de Parkinson/genética , Doença de Parkinson/patologia , Ratos , Quinases Ativadas por p21/genética
18.
J Biomed Mater Res A ; 107(2): 414-422, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30461191

RESUMO

Nanoparticulate titanium dioxide (nano TiO2 ) is extensively applied in biological tissue engineering materials, food additives, cosmetics, and sunscreens. Numerous studies to date have demonstrated that nano TiO2 penetrates through the digestive system and possibly the blood circulation, leading to accumulation in the ovary and consequent reproductive toxicity. However, the mechanisms underlying the toxic effects of nano TiO2 on the female reproductive system remain to be established. In this study, female mice were exposed to different doses of nano TiO2 (1.25, 2.5, or 5 mg/kg body weight) via intragastric administration for 60 consecutive days, followed by investigation of follicular development, regulation of TGF-ß-mediated signaling pathways, and expression of the pathway components. Subchronic exposure to nano TiO2 induced a decrease in the number of primordial, secondary, and antral follicles and corpus luteum and concomitant increase in atretic follicles. Furthermore, follicular development disorder induced by nano TiO2 was associated with upregulation of TGF-ß1, TGF-ßR1, PTEN, and Foxo3a involved in cell growth and apoptosis and downregulation of several growth factors (PI3K, AKT, p-mTOR, p70S6K, p-p70S6K1, rpS6, p-rpS6, TSC1, and TSC2) in mouse ovaries. Our data collectively implied that suppression of ovarian follicle development by nano TiO2 was triggered by dysfunction of the TGF-ß, PI3K/AKT/mTOR, and AKT/p70S6K-rpS6/TSC/mTOR pathways. The adverse effects of nano TiO2 on follicular development highlights the necessity for caution in the use of nanomaterials in the food industry. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 414-422, 2019.


Assuntos
Nanopartículas/toxicidade , Folículo Ovariano/efeitos dos fármacos , Titânio/toxicidade , Fator de Crescimento Transformador beta/metabolismo , Animais , Feminino , Camundongos Endogâmicos ICR , Folículo Ovariano/crescimento & desenvolvimento , Folículo Ovariano/patologia , Transdução de Sinais/efeitos dos fármacos
19.
Cell Physiol Biochem ; 51(4): 1600-1615, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30497067

RESUMO

BACKGROUND/AIMS: Parkinson's disease (PD) is a neurodegenerative movement disease with a high annual incidence. Accumulating evidence demonstrates that microRNAs play important roles in the pathogenesis of multiple neurological disorders, including PD. This study aims to investigate how microRNA-200a (miR-200a) regulates striatal dopamine receptor D2 (DRD2) to affect apoptosis of striatum in rats with PD and to explore the associated mechanism. METHODS: After successfully establishing a PD model by 6-hydroxydopamine injections, PD rats were mainly treated with miR-200a mimics, inhibitors, Forskolin or a combination of miR-200a inhibitors and Forskolin. High-performance liquid chromatography-electrochemical detection (HPLC-ECD) was employed to detect the levels of dopamine, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and chemistry colorimetric methods were applied to detect the levels of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). A TUNEL assay and immunocytochemical staining were performed to observe apoptosis and tyrosine hydroxylase (TH)-positive cells in the striatum. The expression of miR-200a, DRD2, Bad, Bax, Bcl-2, cAMP and PKA was determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot assays. RESULTS: In the cellular experiments, after transfection with the inhibitor of miR-200a, decreased levels of Bax, GSH-Px, SOD, dopamine, DOPAC and HVA but increased levels of MDA and Bcl-2 were found along with a reduced apoptosis rate and increased TH-positive cell number. In addition, downregulating miR-200a resulted in lower expression of AKT, cAMP and PKA but higher expression of DRD2 and CREB, indicating that the downregulation of miR-200a increases DRD2 expression, which blocks the cAMP/PKA signaling pathway. CONCLUSION: This study provides evidence that the inhibition of miR-200a can repress apoptosis in the striatum via inhibition of the cAMP/PKA signaling pathway by upregulating DRD2 expression in PD rats.


Assuntos
Apoptose , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , MicroRNAs/genética , Doença de Parkinson/genética , Receptores de Dopamina D2/genética , Animais , Colforsina/uso terapêutico , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Regulação para Baixo , Terapia Genética , Masculino , MicroRNAs/antagonistas & inibidores , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Ratos Sprague-Dawley , Transdução de Sinais , Regulação para Cima
20.
J Biomed Nanotechnol ; 14(12): 2124-2134, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30305219

RESUMO

Nanosized titanium dioxide (Nano TiO2) has been widely used in daily lives, medicine, industry, and caused the potential reproduction toxicity for animals and human, however, the underlying molecular mechanisms for the reproductive toxicity of nano TiO2 are still largely unclear. In the present study, when primary cultured rat Sertoli cells (SCs) were exposed to nano TiO2, cell injury and alterations in wingless related MMTV integration site (Wnt) pathway-related factors including Wnt1, Wnt3a, Wnt5a, Wnt11, ß-catenin, and p-GSK-3ß expression were investigated. The results suggested that nano TiO2 could be translocated to cytoplasm or nucleus, and decreased cell viability, and impaired morphological structures of SCs, induced apoptosis and dead of primary cultured rat SCs. Furthermore, nano TiO2-induced the toxicity of primary cultured rat SCs was associated with increased expression of Wnt1, Wnt3a, Wnt5a, Wnt11, and ß-catenin and involved with reduced p-GSK-3ß expression. Therefore, this implies that nano TiO2-induced toxic effects on SCs may be associated with Wnt signaling pathways.


Assuntos
Células de Sertoli , Via de Sinalização Wnt , Animais , Células Cultivadas , Glicogênio Sintase Quinase 3 beta , Masculino , Nanoestruturas , Ratos , Titânio
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