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1.
World J Gastroenterol ; 27(28): 4667-4686, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34366628

RESUMO

BACKGROUND: Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown. AIM: To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC. METHODS: The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq). RESULTS: YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance. CONCLUSION: Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proteínas de Transporte , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sorafenibe/farmacologia , Proteína 1 de Ligação a Y-Box
2.
BMC Gastroenterol ; 21(1): 114, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33750308

RESUMO

BACKGROUND: Endoscopic resection has been used for high-grade intraepithelial neoplasia (HGIN) and superficial esophageal squamous cell carcinoma (ESCC) with limited risk of lymph node metastasis. However, some of these lesions cannot be accurately diagnosed based on forceps biopsy prior to treatment. In this study we aimed to investigate how to solve this histological discrepancy and avoid over- and under-treatment. METHODS: The medical records of patients with superficial esophageal squamous cell neoplasia who underwent endoscopic resection at our hospital from January 2012 to December 2019 were reviewed retrospectively. The histological discrepancy between the biopsy and resected specimens was calculated and its association with clinicopathological parameters was analyzed. RESULTS: A total of 137 lesions from 129 patients were included. The discrepancy rate between forceps biopsy and resected specimens was 45.3% (62/137). Histological discrepancy was associated with the histological category of the biopsy (p < 0.001). In addition, 17 of the 30 (56.7%) biopsies that was diagnosed as indefinite/negative for neoplasia or low-grade intraepithelial neoplasia were upgraded to HGIN or ESCC after resection. The upgrade was due to lesion size ≥ 10 mm (p = 0.002) and type B intrapapillary capillary loops (p < 0.001). Moreover, 34 of the 83 biopsies that were diagnosed with HGIN were upgraded to ESCC after resection, which was related to lesion size (p = 0.001), location (p = 0.018), and pink color sign (p = 0.002). CONCLUSIONS: Histological discrepancy between forceps biopsy and resected specimens is common in clinical practice. Recognizing the risk factors for each histological category of biopsy may reduce these discrepancies and improve clinical management.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Biópsia , Células Epiteliais , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Humanos , Estudos Retrospectivos
3.
Clin Exp Med ; 21(3): 479-492, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33677646

RESUMO

REC8 is a member of the cohesin family, and its abnormal activation has been detected in cancer cells. This study explored the role and possible mechanism of REC8 in hepatocellular carcinoma (HCC). A total of 40 pairs of HCC and adjacent tissues were collected, and the clinical significance of REC8 expression in HCC was evaluated. REC8 expression in human HCC tissues and HCC cell lines was investigated by quantitative real-time PCR, Western blotting, immunohistochemistry and immunofluorescence staining. The biological functions of REC8 in HCC cell lines were detected by wound-healing assay, Matrigel invasion assay and tube formation assay. The proteins interacting with REC8 were identified by mass spectrometry after immunoprecipitation screening. There was a correlation between the high expression of REC8 and positive alpha-fetoprotein levels. The expression level of REC8 protein in HCC tissues was higher than that in adjacent tissues. REC8 has mainly located in the nucleus of HCC tissue cells and HCC cell lines, but it was expressed in the cytoplasm of adjacent normal tissue cells and hepatocytes. The results of wound healing, transwell invasion and tubular formation assays indicated that the overexpression of REC8 accelerated the metastasis of HCC in vitro; however, metastasis was suppressed after REC8 was silenced by small interference RNA. A total of 57 differentially expressed proteins were identified by mass spectrometry, and it was found that REC8 and PKA RII-α staining was colocalized in the nucleus. The expression levels of MMP-9 and VEGF-C were decreased after treatment with the PKA inhibitor H89. Overall, REC8 promotes the migration, invasion and angiogenesis of HCC cells through the PKA pathway.

4.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(2): 111-115, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33627202

RESUMO

OBJECTIVE: To explore the reasonable and effective enteral nutrition regimen for children with abdominal Henoch-Schönlein purpura (HSP). METHODS: A retrospective analysis was performed on the medical data of children with abdominal HSP who were hospitalized from August 2013 to August 2018. According to the starting time of enteral nutrition after abdominal pain relief, the children were divided into three groups: < 24 hours (n=68), 24-48 hours (n=64), and 48-72 hours (n=60). According to the type of enteral nutrition, they were divided into another three groups:amino acid-based formula (n=53), extensively hydrolyzed lactoprotein formula (n=67), and normal diet (n=72). The recurrence rate of clinical symptoms and degree of satisfaction among family members were compared between groups. Based on the retrospective analysis, 166 children with abdominal HSP were enrolled in a prospective study. They were given extensively hydrolyzed lactoprotein formula after abdominal pain relief. According to the feeding time after abdominal pain relief, they were divided into three groups: < 24 hours (n=52), 24-48 hours (n=59), and 48-72 hours (n=55). The three groups were compared in terms of the recurrence rates of abdominal pain, rash, and hematochezia, the rate of use of parenteral nutrition and intravenous steroids, and the incidence rate of weight loss at discharge. RESULTS: The retrospective analysis showed that the children who were given extensively hydrolyzed lactoprotein formula for enteral nutrition at 24-48 hours after abdominal pain relief had a lower recurrence rate of clinical symptoms and the highest degree of satisfaction among their family members (P < 0.0167). The prospective study showed that the children who were given extensively hydrolyzed lactoprotein formula for enteral nutrition at 24-48 hours after abdominal pain relief had lower recurrence rates of rash and abdominal pain, a lower rate of use of parenteral nutrition, and a lower incidence rate of weight loss at discharge (P < 0.05). CONCLUSIONS: It is reasonable and effective to start the feeding with extensively hydrolyzed lactoprotein formula at 24-48 hours after abdominal pain relief in children with abdominal HSP.


Assuntos
Nutrição Enteral , Púrpura de Schoenlein-Henoch , Criança , Humanos , Nutrição Parenteral , Estudos Prospectivos , Púrpura de Schoenlein-Henoch/terapia , Estudos Retrospectivos
5.
BMC Med Genomics ; 14(1): 21, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33468134

RESUMO

BACKGROUND: Hirschsprung disease (HSCR) is a hereditary defect, which is characterized by the absence of enteric ganglia and is frequently concurrent with Hirschsprung-associated enterocolitis (HAEC). However, the pathogenesis for HSCR is complicated and remains unclear. Recent studies have shown that pro-inflammatory cytokines such as interleukin-11 (IL-11) are involved in the enteric nervous system's progress. It was found that IL-11 SNPs (rs8104023 and rs4252546) are associated with HSCR in the Korean population waiting for replication in an independent cohort. This study evaluated the relationship between IL-11 and the susceptibility of patients to HSCR by performing subphenotype interaction examination, HAEC pre-/post-surgical patient-only association analysis, and independence testing. METHODS: In this study, a cohort consisting of children from Southern China, comprising 1470 cases and 1473 controls, was chosen to examine the relationship between two polymorphisms (rs8104023 and rs4252546 in IL-11) and susceptibility to HSCR by replication research, subphenotype association analysis, and independence testing. RESULTS: The results showed that IL-11 gene polymorphisms (rs8104023 and rs4252546) are not associated with the risk of HSCR in the Chinese population. The results of both short-segment and long-segment (S-HSCR and L-HSCR) surgery (3.34 ≤ OR ≤ 4.05, 0.02 ≤ P ≤ 0.04) showed that single nucleotide polymorphisms (SNP) rs8104023 is associated with susceptibility to HAEC. CONCLUSIONS: This study explored the relationship between genetic polymorphisms and susceptibility to HAEC in HSCR subtypes for the first time. These findings should be replicated in a larger and multicentre study.

6.
World J Pediatr ; 17(1): 63-70, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32394144

RESUMO

BACKGROUND: There are few approved biomarkers for diagnosis and monitoring of cow's milk protein allergy (CMPA), thus the oral food challenge remains to be the golden diagnostic standard. A potential biomarker is fecal calprotectin, a cytosolic protein, elevating in the presence of intestinal mucosal inflammation. We aimed to undertake a scoping review of the evidence pertaining to the current status of fecal calprotectin used for diagnosis and monitoring CMPA in children, and tried to indicate the aspects needed to be concerned in the future investigations and researches. METHODS: A scoping review was performed using the literature searched from PUBMED, EMBASE, and Web of Science Databases until July 2019 on the studies about the application of fecal calprotectin as a biomarker of CMPA in children. Studies were examined according to the inclusion and exclusion criteria. Data were extracted, and a narrative synthesis was conducted to summarize and analyze. RESULTS: Thirteen studies with different study design embracing 1238 children were included. The age range was from infants to adolescents. Most children with CMPA presented gastrointestinal symptoms, among which hematochezia was most common. Amount of data suggested that infants with CMPA represented elevated levels of fecal calprotectin, particularly with distinct significance in non-IgE-mediated CMPA groups. Decreases of fecal calprotectin after elimination diet were demonstrated in enrolled studies. However, no matter in the CMPA positive or negative groups, the changes of fecal calprotectin before or after challenge showed no significance. Contradictory results were generated from studies on the role of fecal calprotectin in predicting allergic disease. CONCLUSIONS: Available evidence is not sufficient to confirm the utilization of fecal calprotectin both in diagnosis and monitoring of CMPA and predicting for allergic disease. More clinical and bench researches with elaborate design should be conducted and the exact cut-off values of fecal calprotectin in different groups remain to be determined.

7.
Food Chem Toxicol ; 148: 111946, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33359793

RESUMO

Methamphetamine (METH) is an addictive and illegal psychostimulant drug that can cause multiple organ dysfunction, especially in the central nervous system (CNS). Gut microbiota have been implicated in development of various CNS-related diseases, via the gut-brain axis (GBA). However, effect of METH in the alteration of gut microbiota and fecal metabolites is unclear, whereas the relationship with METH-induced neurotoxicity remains unknown. In the current study, we investigated effect of METH on neurotoxicity in striatum and colonic damage by exposing BALB/c mice to an escalating dose-multiple binge regimen, and then analyzed protein expression using Western blot analysis. We further detected and sequenced the 16 S rRNA gene in fecal samples, and performed ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics to analyze gut microbes and fecal metabolites. Exposure to METH significantly downregulated tyrosine hydroxylase (TH) proteins, but upregulated MAOA, Beclin1, Atg5, and LC3-Ⅱ. METH up-regulated inflammation-related factors, such as caspase1, TNF-α and IL-18, by activating the toll-like receptors 4 (TLR4)/myeloid differentiation factor 88 (Myd88)/nuclear factor κB (NF-κB) pathway and reduced occludin protein expression. In addition, METH exposure changed α and ß diversities of gut microbiota. Specifically, METH exposure elevated relative abundances of pathogenic bacteria, but reduced those of probiotics. Metabolomics, combined with enrichment analyses revealed that METH exposure altered fecal metabolites. Our findings suggest that METH exposure induced autophagy in the CNS, elevated intestinal autophagy flora, leading to accumulation of fecal metabolites in the autophagy pathway, and causing enteritis. Moreover, METH promoted intestinal inflammation by increasing the relative abundance of the pathogenic bacteria in the intestinal tract, and reduced intestinal TJ protein expression.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Fezes/química , Microbioma Gastrointestinal/efeitos dos fármacos , Metanfetamina/toxicidade , Síndromes Neurotóxicas/etiologia , Animais , Autofagia/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Enterite/induzido quimicamente , Enterite/metabolismo , Masculino , Metabolômica , Camundongos Endogâmicos BALB C , Monoaminoxidase/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Síndromes Neurotóxicas/metabolismo , Ocludina/metabolismo , Receptor 4 Toll-Like/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
World J Clin Cases ; 8(21): 5467-5473, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33269285

RESUMO

BACKGROUND: Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder caused by mutation of the SLC2A2 gene, which encodes glucose transporter protein 2 (GLUT2). CASE SUMMARY: We report a 7-mo-old girl with cytomegalovirus infection presenting hepatomegaly, jaundice, liver transaminase elevation, fasting hypoglycemia, hyperglycosuria, proteinuria, hypophosphatemia, rickets, and growth retardation. After prescription of ganciclovir, the levels of bilirubin and alanine aminotransferase decreased to normal, while she still had aggravating hepatomegaly and severe hyperglycosuria. Then, whole exome sequencing was conducted and revealed a homozygous c.416delC mutation in exon 4 of SLC2A2 inherited from her parents, which was predicted to change alanine 139 to valine (p.A139Vfs*3), indicating a diagnosis of FBS. During the follow-up, the entire laboratory test returned to normal with extra supplement of vitamin D and corn starch. Her weight increased to normal range at 3 years old without hepatomegaly. However, she still had short stature. Although there was heterogeneity between phenotype and genotype, Chinese children had typical clinical manifestations. No hot spot mutation or association between severity and mutations was found, but nonsense and missense mutations were more common. Data of long-term follow-up were rare, leading to insufficient assessment of the prognosis in Chinese children. CONCLUSION: FBS is a rare genetic metabolic disease causing impaired glucose liver homeostasis and proximal renal tubular dysfunction. Results of urine and blood testing suggesting abnormal glucose metabolism could be the clues for FBS in neonates and infants. Genetic sequencing is indispensable for diagnosis. Since the diversity of disease severity, early identification and long-term follow-up could help improve patients' quality of life and decrease mortality.

9.
PeerJ ; 8: e9720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32864221

RESUMO

Polychlorinated biphenyls (PCBs), particularly low chlorinated congeners in our environment, can induce human hepatotoxicity. However, the mechanisms by which PCBs cause hepatotoxicity remain elusive. Moreover, there are no effective treatments for this condition. In this study, 40 µM PCB52 was administered to rat (Brl-3A) and human hepatocytes (L-02) for 48 h following the N-acetylcysteine (NAC)/saline pretreatment. A significant decrease in cell viability was observed in PCB52-treated cells relative to the control. Besides, PCB52 significantly increased reactive oxygen species (ROS) levels and malondialdehyde (MDA) contents, suggesting induction of oxidative stress. The expression of Traf6, MyD88, and Tnf in Brl-3A cells and that of MYD88, TNF, and IL1B in L-02 cells were significantly upregulated by PCB52. Consistently, overexpression of TLR4, MyD88, Traf6, and NF-κB p65 proteins was observed in PCB52-treated cells, indicating activation of inflammatory responses. Nevertheless, no changes in kelch-like ECH-associated protein 1 (keap1), nuclear factor-erythroid 2-related factor (nrf2), and heme oxygenase-1 proteins were observed in PCB52-treated cells, indicating non-activation of the keap1/nrf2 pathway. Pretreatment with NAC significantly ameliorated PCB52 effects on cell viability, ROS levels, MDA contents and expression of inflammatory elements at both RNA and protein levels. However, no changes in keap1, nrf2 and HO-1 protein levels were detected following NAC pretreatment. Taken together, with non-activated keap1/nrf2 pathway, PCB52-induced oxidative stress and inflammatory responses could be responsible for its hepatotoxicity. These effects were effectively attenuated by NAC pretreatment, which scavenges ROS and dampens inflammatory responses. This study might provide novel strategies for the treatment of the PCBs-associated hepatotoxic effects.

10.
Environ Pollut ; 264: 114715, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32402713

RESUMO

Polychlorinated biphenyls (PCBs) in the air are predominantly the less chlorinated congeners. Non-dioxin-like (NDL) low-chlorinated PCBs are more neurotoxic, and cause neurodevelopmental and neurobehavioral alterations in humans. However, the underlying mechanisms for this neurodevelopmental toxicity remain unknown. In the present study, Wistar rats were treated by gavage with PCB52 (1 mg/kg body weight) or corn oil from gestational day 7 to postnatal day 21. Both the body lengths and weights of the suckling rats at birth were significantly decreased by PCB52 treatment, suggesting developmental toxicity. Although no obvious histopathological changes were observed in the brain, using RNA-sequencing, 208 differentially expressed genes (DEGs) were identified in the striatum of PCB52-treated male offspring, while just 13 DEGs were identified in female offspring, suggesting sex-specific effects. Furthermore, using Gene Ontology enrichment analysis, neurodevelopmental processes, neurobehavioral alterations, and neurotransmission changes were enriched from the 208 DEGs in male offspring. Similarly, using Kyoto Encyclopedia of Genes and Genomes enrichment analysis, neuroactive ligand receptor interactions and multiple synapse pathways were enriched in male offspring, implying dysfunction of the neurotransmission system. Reductions in the protein expressions of these ligand receptors were also identified in the striatum, cerebral cortex, and hippocampus using western blotting methods. Taken together, our findings indicate that PCB52 exposure during gestation and lactation results in the abnormal expression of neurotransmission ligand-receptors in male offspring with a sex bias, and that this may contribute to neurodevelopmental toxicity.


Assuntos
Bifenilos Policlorados , Animais , Encéfalo , Feminino , Humanos , Lactação , Masculino , Ratos , Ratos Wistar , Transmissão Sináptica
11.
Int J Infect Dis ; 96: 710-714, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32389849

RESUMO

INTRODUCTION: Coronaviruses, both SARS-CoV and SARS-CoV-2, first appeared in China. They have certain biological, epidemiological and pathological similarities. To date, research has shown that their genes exhibit 79% of identical sequences and the receptor-binding domain structure is also very similar. There has been extensive research performed on SARS; however, the understanding of the pathophysiological impact of coronavirus disease 2019 (COVID-19) is still limited. METHODS: This review drew upon the lessons learnt from SARS, in terms of epidemiology, clinical characteristics and pathogenesis, to further understand the features of COVID-19. RESULTS: By comparing these two diseases, it found that COVID-19 has quicker and wider transmission, obvious family agglomeration, and higher morbidity and mortality. Newborns, asymptomatic children and normal chest imaging cases emerged in COVID-19 literature. Children starting with gastrointestinal symptoms may progress to severe conditions and newborns whose mothers are infected with COVID-19 could have severe complications. The laboratory test data showed that the percentage of neutrophils and the level of LDH is higher, and the number of CD4+ and CD8+T-cells is decreased in children's COVID-19 cases. CONCLUSION: Based on these early observations, as pediatricians, this review put forward some thoughts on children's COVID-19 and gave some recommendations to contain the disease.


Assuntos
Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Síndrome Respiratória Aguda Grave/diagnóstico , Adolescente , Betacoronavirus/patogenicidade , COVID-19 , Criança , Pré-Escolar , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Humanos , Lactente , Recém-Nascido , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Vírus da SARS/patogenicidade , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/epidemiologia , Síndrome Respiratória Aguda Grave/fisiopatologia
12.
Pediatr Infect Dis J ; 39(7): 645-649, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32433226

RESUMO

Since human coronavirus (HCoV)-like particles were detected in the stool specimens of acute gastroenteritis and necrotizing enterocolitis children with electron microscopy, the relationship between HCoV and the pediatric gastrointestinal illness had been recognized. In recent years, the overall detection rates have been low and have varied by region. HCoVs have not been considered as the major pathogens in pediatric acute gastroenteritis. HCoVs detected in children with acute gastroenteritis have included 229E, OC43, HKU1, NL63, and severe acute respiratory syndrome coronavirus, Middle East Respiratory Syndrome Coronavirus and severe acute respiratory syndrome coronavirus-2 have also been associated with gastrointestinal symptoms in children. Although digestive tract has been recognized as an infection route, it has not been possible to fully investigate the association between HCoVs infection and the gastrointestinal symptoms because of the limited number of pediatric cases. Furthermore, pathologic features have not been clear. Till now, our knowledge of severe acute respiratory syndrome coronavirus-2 is limited. However, diarrhea and vomiting have been seen in pediatric cases, particularly in newborns and infants. It has been necessary to pay more attention on gastrointestinal transmission to identify the infected children early and avoid the children without apparent or mild symptoms becoming the sources of infection.


Assuntos
Infecções por Coronavirus/fisiopatologia , Gastroenterite/virologia , Fatores Etários , Betacoronavirus/isolamento & purificação , COVID-19 , Criança , Infecções por Coronavirus/virologia , Diarreia/virologia , Enterocolite Necrosante/virologia , Gastroenterite/fisiopatologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Pandemias , Pneumonia Viral/virologia , Infecções Respiratórias/virologia , SARS-CoV-2 , Vômito/virologia
13.
Food Chem Toxicol ; 137: 111179, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32035215

RESUMO

Methamphetamine (METH) is a highly addictive stimulant that results in serious and persistent neurotoxic effects. Studies have indicated that luteolin, a flavonoid, may confer neuroprotection against neurotoxicity. Nevertheless, the effects of luteolin on METH-induced neurotoxicity have not been sufficiently verified. In the present study, Sprague Dawley rats were pretreated with luteolin (100 mg/kg) or sodium dodecyl sulfate water, followed by administration of METH (15 mg/kg) or saline. Rat striata were then collected for RNA-sequencing and subsequent analyses. A total of 347 differentially expressed genes (DEGs) were identified in the METH group with 20 pathways, including the phosphoinositol 3 kinase (PI3K)/protein kinase B (Akt), found to be enriched by the KEGG analysis. Seventy-five of the 347 DEGs were modulated in luteolin-pretreated rats, which were enriched into 12 pathways, containing the PI3K/Akt. Results further showed that luteolin pretreatment significantly repressed the METH-induced increases of PI3K, Akt, p-Akt, p53, Bax, caspase 3, normalized the ratio of p-Akt/Akt, and autophagy-related proteins (Beclin1, Atg5 and LC3-II) expression. Taken together, these findings indicate that luteolin attenuates METH-induced apoptosis and autophagy by suppressing the PI3K/Akt pathway. In this case, it exerts protection against METH-induced neurotoxicity. This provides a platform for development of potential therapies for METH treatment.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Luteolina/uso terapêutico , Metanfetamina/toxicidade , Síndromes Neurotóxicas/prevenção & controle , Substâncias Protetoras/uso terapêutico , Animais , Expressão Gênica/efeitos dos fármacos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Análise de Componente Principal , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
14.
Exp Cell Res ; 389(2): 111855, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31978385

RESUMO

Takeda-G-protein-receptor-5 (TGR5) is a G-protein-coupled receptor (GPCR) activated by bile acids, and mortalin is a multipotent chaperone of the HSP70 family. In the present study, TGR5 was detected by immunohistochemistry (IHC) in extrahepatic cholangiocarcinoma (ECC) specimens, and TGR5 expression in ECC tissues and adjacent tissues was compared. In vitro TGR5 was overexpressed and knocked down in human intrahepatic cholangiocarcinoma (ICC) cell line RBE and human extrahepatic cholangiocarcinoma (ECC) cell line QBC-939 to observe its effects on the biological behavior of cholangiocarcinoma (CC) cells, including proliferation, apoptosis and migration. In vivo xenograft model was constructed to explore the role of TGR5 in CC growth. Proteins that interacted with TGR5 were screened using an immunoprecipitation spectrometry approach, and the identified protein was down-regulated to investigate its contribution to CC growth. The present study demonstrated that TGR5 is highly expressed in CC tissues, and strong TGR5 expression may indicate high malignancy in CC. Furthermore, TGR5 promotes CC cell proliferation, migration, and apoptosis resistance. TGR5 boosts CC growth in vivo. In addition, TGR5 combines with mortalin and regulates mortalin expression in the CC cell line. Mortalin participates in the TGR5-induced increase in CC cell proliferation. In conclusion, TGR5 is of clinical significance based on its implications for the degree of malignancy in patients with CC. Mortalin may be a downstream component regulated by TGR5, and TGR5 promotes cholangiocarcinoma at least partially by interacting with mortalin and upregulating its expression. Both TGR5 and mortalin are positive regulators, and may serve as potential therapeutic targets for CC.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/patologia , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas Mitocondriais/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Apoptose , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Biomarcadores Tumorais/genética , Proliferação de Células , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP70/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Prognóstico , Domínios e Motivos de Interação entre Proteínas , Receptores Acoplados a Proteínas G/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Oncol Rep ; 42(1): 263-272, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115555

RESUMO

Piwi­interacting RNAs (piRNAs), a novel class of non­coding RNAs, are enriched in germ cells and implicated in spermatogenesis. Emerging evidence demonstrated deregulated expression of piRNAs in numerous tumor types. However, changes in piRNA expression profiles in colorectal cancer (CRC) have not yet been investigated. In the present study, small RNA sequencing was used to evaluate the differences in piRNA expression profiles between CRC and adjacent non­tumor tissues, as well as to screen for differentially expressed piRNAs. The present results demonstrated that the percentage of unique piRNA reads had no notable difference between the paired CRC and adjacent non­tumor samples (0.12% vs. 0.13%); however, the counts of total piRNA reads in CRC samples were increased, compared with those in adjacent non­tumor samples (0.15% vs. 0.07%). Differential expression analysis identified 33 upregulated piRNAs and 2 downregulated piRNAs in CRC samples, among which piR­18849, piR­19521 and piR­17724 were the top three upregulated piRNAs. Reverse transcription­quantitative polymerase chain reaction further confirmed that the expression levels of piR­18849, piR­19521 and piR­17724 were increased in 80 CRC tissues, compared with paired adjacent non­tumor tissues. Furthermore, the high expression of piR­18849 and piR­19521 was associated with a poor degree of differentiation. The increased expression of piR­18849 was also associated with high lymph node metastasis. However, no associations were determined between piR­17724 expression and clinicopathological characteristics of patients. In summary, the present study is the first to provide an overview of the changes in piRNA expression patterns in CRC, shedding new light on the regulatory roles of piRNAs in colorectal carcinogenesis. piR­18849 and piR­19521 may be prognostic biomarkers for patients with CRC.


Assuntos
Neoplasias Colorretais/genética , Perfilação da Expressão Gênica/métodos , RNA Interferente Pequeno/genética , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sequência de RNA/métodos
16.
Onco Targets Ther ; 12: 2661-2675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040704

RESUMO

Purpose: Gastric cancer (GC) patients display aberrant miRNA expression and defective dendritic cell function. However, the role of cancer cell-derived oncomiR in GC detection and dendritic cell (DC) maturation remains largely elusive. Methods: Candidate miRNAs were selected by deep sequencing (8 GC plasma samples vs 8 control plasma samples; 8 GC tissues vs 8 adjacent normal gastric tissues) and confirmed by PCR with 164 plasma samples and 72 formalin-fixed paraffin-embedded GC tissue samples. Their diagnostic performance was evaluated by receiver operating characteristic curve. Cy3 fluorescence signals in DCs, exposed to conditioned medium obtained from BGC-823 cells pre-transfected with Cy3-miR-17-5p, were determined by flow cytometry and visualized by confocal microscopy. Functional and phenotypical alterations of DCs were assayed when DCs were transfected with miR-17-5p in vitro. Results: Deep sequencing and RT-PCR confirmed that five shared miRNAs were upregulated in plasma and tissue samples of GC patients. Cell-free miR-17-5p was superior to others in GC detection with an area under the curve of 0.82, and correlated with lymphatic metastasis and poor overall survival. GC cell-shuttled miR-17-5p can be delivered to immature DCs, and they significantly inhibited LPS-stimulated phenotypic maturation by diminishing the expression of maturation markers (MHC II, CD80 and CD86 molecules). In line with those alterations in the phenotypic markers, functional experiments demonstrated that miR-17-5p triggered an inhibitory effect on DCs endocytic activity and decreased tumor necrosis factor-α and IL-12 secretion, while enhancing IL-10 production. Mixed lymphocyte reaction showed that miR-17-5p inhibited the T cell stimulating effect of DCs and favored regulatory T cells expansion. Conclusion: GC cell-derived miR-17-5p is a potential biomarker for GC detection. Taken up by DCs, miR-17-5p weakened antitumor immune responses via inhibiting the maturation of dendritic cells.

17.
Chemosphere ; 227: 389-400, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31003123

RESUMO

Polychlorinated biphenyls (PCBs), a kind of persistent organic pollutant, can induce hepatotoxicity in mammals. However, PCB-induced hepatotoxicity in offspring and the underlying mechanisms have been rarely studied. In the present study, Wistar rats were administered with corn oil or PCB52 (1 mg/kg body weight/day, by gavage) from gestational day 7 to postnatal day 21. In the PCB52-treated group, birth body lengths and weights were significantly decreased compared with the control group, suggesting developmental toxicity. Cytoplasmic injury in hepatocytes was observed in PCB52-treated male offspring, while no pathologic change was observed in female offspring, suggesting sex-biased hepatotoxicity. Furthermore, using an RNA-Seq method, coincided with the sexual bias, 454 differential expression genes (DEGs) were screened out in liver tissues of PCB52-treated male offspring, while 10 DEGs were screened out in female offspring. By KEGG annotation analysis, 4 in 12 significant pathways in male offspring were metabolism-related. In the present study, together with cytoplasmic injury of hepatocytes, decreased metabolic enzymes both at RNA and protein levels might aggravate loss of clearance capacity of hepatocytes and induce hepatotoxicity. Moreover, over-expressed peroxisome proliferator-activated receptor delta and mitogen-activated protein kinase 9 might activate apoptosis, which was verified by the augments of cleaved poly ADP-ribose polymerase 1 and caspase 3 in PCB52-treated male offspring. Taken together, PCB52 had developmental toxicity and induced sex-biased hepatotoxicity. The hepatotoxicity in male offspring might be attributed to the aggravated loss of clearance capacity and activation of apoptosis.


Assuntos
Poluentes Ambientais/toxicidade , Bifenilos Policlorados/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caspase 3 , Doença Hepática Induzida por Substâncias e Drogas , Feminino , Hepatócitos/efeitos dos fármacos , Cinética , Masculino , Poli(ADP-Ribose) Polimerase-1 , Ratos , Ratos Wistar , Fatores Sexuais , Testes de Toxicidade
18.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(2): 168-171, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30782281

RESUMO

OBJECTIVE: To study the clinical effect of alanyl-glutamine-enriched nutritional support in the treatment of children with abdominal Henoch-Schönlein purpura. METHODS: Children with abdominal Henoch-Schönlein purpura who needed nutritional support were enrolled and stratified according to age, sex and the severity of disease, and were randomly divided into a control group (n=118) and an enriched nutritional support group (n=107). The control group was given nutritional support without using alanyl-glutamine, while the enriched nutritional support group was given alanyl-glutamine-enriched nutritional support. Intravenous steroids were used according to the severity of disease in both groups. Other therapies were the same in the two groups. The two groups were compared in terms of the length of hospital stay, the rate and duration of use of intravenous steroids, the recurrence rate of symptoms during hospitalization, the rate of total parenteral nutrition (TPN), the rate of weight loss and the rate of fasting for more than 5 days. All patients were followed up for 3 months after discharge to monitor the recurrence of symptoms. RESULTS: There were no significant differences in the length of hospital stay, the rate of TPN and the rate of fasting for more than 5 days between the two groups (P>0.05). Compared with the enriched nutritional support group, the control group showed significant increases in the rate and duration of use of intravenous steroids, the recurrence rate of symptoms and the rate of weight loss (P<0.05). After the 3-month follow-up, all the children resumed normal diet, and the recurrence rate of digestive symptoms was less than 20% in each group. Abdominal pain was the most common symptom (83.33%, 30/36), followed by vomiting and abdominal distention. No digestive hemorrhage was observed. All the symptoms were relieved after symptomatic treatment. No significant difference was found between the two groups in the recurrence rate of digestive symptoms (P=0.693). CONCLUSIONS: Alanyl-glutamine-enriched nutritional support in the treatment of children with abdominal Henoch-Schönlein purpura can reduce the use of intravenous steroids and weight loss, but without impact on the length of hospital stay and post-discharge recurrence.


Assuntos
Púrpura de Schoenlein-Henoch , Criança , Dipeptídeos , Humanos , Nutrição Parenteral Total , Recidiva
19.
Exp Mol Med ; 51(1): 1-13, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635551

RESUMO

The clearance of activated hepatic stellate cells (HSCs) by apoptosis is critical for the reversibility of hepatic fibrosis. Mitochondrial homeostasis is regulated by mitophagy, which is an efficient way of clearing injured mitochondria that plays an important role in apoptosis. However, the role of mitophagy in apoptosis in HSCs and hepatic fibrosis is still unclear. Here, we show that mitophagy is enhanced in parallel with increased apoptosis in hepatic stellate cells during the reversal of hepatic fibrosis. The inhibition of mitophagy suppressed apoptosis in HSCs and aggravated hepatic fibrosis in mice. In contrast, the activation of mitophagy induced apoptosis in HSCs. Furthermore, we confirmed that BCL-B, which is a member of the BCL-2 family, is a regulator mediating mitophagy-related apoptosis. The knockdown of BCL-B resulted in increased apoptosis and mitophagy in HSCs, while the overexpression of BCL-B caused the opposite effects. BCL-B inhibited the phosphorylation of Parkin (a key regulator of mitophagy) and directly bound phospho-Parkin. Altogether, enhanced mitophagy promotes apoptosis in HSCs during the reversal of hepatic fibrosis. BCL-B suppresses mitophagy in HSCs by binding and suppressing phospho-Parkin, thereby inhibiting apoptosis. BCL-B-dependent mitophagy is a new pathway for the regulation of apoptosis in HSCs during the regression of hepatic fibrosis.


Assuntos
Apoptose , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/metabolismo , Mitofagia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Linhagem Celular , Células Cultivadas , Cirrose Hepática/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
20.
Biochem Biophys Res Commun ; 509(2): 395-401, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30594393

RESUMO

Methamphetamine (METH) is a psychostimulant with severe neurotoxicity, which is related to an increase of blood-brain barrier (BBB) permeability. However, the exact mechanisms have not been fully illuminated. In the present study, male Sprague Dawley rats were treated with METH or saline with 8 injections (i.p.) at 12-h intervals and sacrificed 24 h after the last METH injection. To evaluate BBB permeability, 6 rats were administered with Evans blue (EB) by tail vein injection 1 h prior to sacrifice. EB levels significantly increased in both left and right frontal lobes in METH-treated rats, suggesting increase of BBB permeability, which was proved by the rearrangement of F-actin cytoskeleton and decreased expressions of tight junction (TJ) proteins in hippocampus. Over-expressions of RhoA, ROCK, myosin light chain (MLC), cofilin, phosphorylation (p)-MLC, p-cofilin and matrix metalloproteinase (MMP)-9 were observed, indicating activated RhoA/ROCK pathway. Rat brain microvascular endothelial cells (RBMECs) were isolated and treated with inhibitors of RhoA and ROCK followed by METH. Pretreatments of the inhibitors significantly decreased expressions of RhoA, ROCK, MLC, cofilin, p-MLC and p-cofilin, increased expressions of TJ proteins, suppressed F-actin cytoskeleton rearrangement and reduced the permeability of RBMECs. These results suggested that METH increased BBB permeability through activating the RhoA/ROCK pathway, which resulted in F-actin cytoskeleton rearrangement and down-regulation of TJ proteins.


Assuntos
Citoesqueleto de Actina/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/efeitos dos fármacos , Metanfetamina/farmacologia , Junções Íntimas/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestrutura , Actinas/genética , Actinas/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Cofilina 1/genética , Cofilina 1/metabolismo , Corantes/farmacocinética , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Azul Evans/farmacocinética , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Cadeias Leves de Miosina/genética , Cadeias Leves de Miosina/metabolismo , Permeabilidade/efeitos dos fármacos , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo , Junções Íntimas/ultraestrutura , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
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