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OBJECTIVES: About 20% of stage I lung adenocarcinoma (LUAD) patients suffer a relapse after surgical resection. While finer substages have been defined and refined in the AJCC staging system, clinical investigations on the tumor molecular landscape are lacking. MATERIALS AND METHODS: We performed whole exome sequencing, DNA copy number and microRNA profiling on paired tumor-normal samples from a cohort of 113 treatment-naïve stage I Taiwanese LUAD patients. We searched for molecular features associated with relapse-free survival (RFS) of stage I or its substages and validated the findings with an independent Caucasian LUAD cohort. RESULTS: We found sixteen nonsynonymous mutations harbored at EGFR, KRAS, TP53, CTNNB1 and six other genes associated with poor RFS in a dose-dependent manner via variant allele fraction (VAF). An index, maxVAF, was constructed to quantify the overall mutation load from genes other than EGFR. High maxVAF scores discriminated a small group of high-risk LUAD at stage I (median RFS: 4.5 versus 69.5 months; HR = 10.5, 95% CI = 4.22-26.12, P < 0.001). At the substage level, higher risk was found for patients with high maxVAF or high miR-31; IA (median RFS: 32.1 versus 122.8 months, P = 0.005) and IB (median RFS: 7.1 versus 26.2, P = 0.049). MicroRNAs, miR-182, miR-183 and miR-196a were found correlated with EGFR mutation and poor RFS in stage IB patients. CONCLUSION: Distinctive features of somatic gene mutation and microRNA expression of stage I LUAD are characterized to complement the survival prognosis by substaging. The findings open up more options for precision management of stage I LUAD patients.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , MicroRNAs , Humanos , Sequenciamento do Exoma , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/genética , MicroRNAs/genética , Receptores ErbB/genéticaRESUMO
We investigated factors associated with postoperative lipiduria and hypoxemia in patients undergoing surgery for orthopedic fractures. We enrolled patients who presented to our emergency department due to traumatic fractures between 2016 and 2017. We collected urine samples within 24â h after the patients had undergone surgery to determine the presence of lipiduria. Hypoxemia was defined as an SpO2 <95% determined with a pulse oximeter during the hospitalization. Patients' anthropometric data, medical history, and laboratory test results were collected from the electronic medical record. Logistic regression analyses were used to determine the associations of clinical factors with postoperative lipiduria and hypoxemia with multivariate adjustments. A total of 144 patients were analyzed (mean age 51.3 ± 22.9 years, male 50.7%). Diabetes (odd ratio 3.684, 95% CI, 1.256-10.810, p = 0.018) and operation time (odd ratio 1.005, 95% CI, 1.000-1.009, p = 0.029) were independently associated with postoperative lipiduria, while age (odd ratio 1.034, 95% CI, 1.003-1.066, p = 0.029), body mass index (odd ratio 1.100, 95% CI, 1.007-1.203, p = 0.035), and operation time (odd ratio 1.005, 95% CI, 1.000-1.010, p = 0.033) were independently associated with postoperative hypoxemia. We identified several factors independently associated with postoperative lipiduria and hypoxemia in patients with fracture undergoing surgical intervention. Operation time was associated with both postoperative lipiduria and hypoxemia, and we recommend that patients with prolonged operation for fractures should be carefully monitored for clinical signs related to fat embolism syndrome.
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Growing evidence suggested that energy deficiency might be involved in the pathophysiological mechanism of depression. Energy deficiency, mainly results from mitochondrial damage, can lead to the dysfunction of synaptic neurotransmission, and further cause depressive-like behavior. The antidepressant effect of resveratrol had been widely demonstrated in previous studies; however, the underlying mechanism remains poorly understood. The present study aimed to investigate whether the antidepressant effects of resveratrol involved in the energy levels and neurotransmission in the hippocampus. We found that resveratrol and fluoxetine significantly attenuated depressive-like behaviors induced by chronic unpredictable mild stress (CUMS), which evidenced by the increased sucrose preference and the reduced immobility time in a forced swimming test. In addition, resveratrol increased hippocampal ATP levels, decreased Na+-K+-ATPase and pyruvate levels, and upregulated the levels of mitochondrial DNA (mtDNA), mRNA expression of sirtuin (SIRT)1 and peroxisome proliferator-activated receptor γ coactivator (PGC)1α. Furthermore, resveratrol and fluoxetine increased serotonin (5-HT) levels and downregulated the mRNA expression of 5-HT transporter (SERT) in the hippocampus. The decreased protein expression of growth-associated protein (GAP)-43 induced by CUMS was also ameliorated by resveratrol and fluoxetine. These findings demonstrated the antidepressant effects of resveratrol and suggested that resveratrol was able to promote mitochondrial biogenesis, enhance ATP and 5-HT levels, as well as upregulate GAP-43 expression in the hippocampus.
Assuntos
Trifosfato de Adenosina/biossíntese , Proteína GAP-43/biossíntese , Hipocampo/metabolismo , Resveratrol/uso terapêutico , Serotonina/biossíntese , Estresse Psicológico/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Doença Crônica , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Resveratrol/farmacologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/psicologia , Resultado do TratamentoRESUMO
Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93-28.32, p < 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine.
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Liver injury is one of the main toxic effect of sulfasalazine (SASP). However, the toxicological mechanism of SASP-induced liver injury remains unclear. In the present study, the liver injury was induced by orally treatment with SASP for 4 weeks in mice. The hepatic mRNA profiles were detected by RNA sequencing and the differentially expressed genes (DEGs) were analyzed by bioinformatics methods. The elevated serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TBIL), combined with the hepatic histopathological features verified that liver injury was successfully caused by SASP. Transcriptomic results showed that 187 genes (fold change > 1.5 and P < 0.05) were differentially expressed, of which 106 genes were up-regulated and 81 genes were down-regulated in SASP-treated group. Moreover, the further analysis showed that these 187 differentially expressed genes (DEGs) were enriched in 123 GO terms, which mainly including oxidation-reduction process, oxidoreductase activity and epoxygenase P450 pathway. KEGG pathway analysis showed 30 pathways including chemical carcinogenesis, retinol metabolism, arachidonic acid metabolism, linoleic acid metabolism and glutathione metabolism. Among these 187 DEGs, the top 22 hub genes were screened from network of protein-protein interaction (PPI) and verified by qRT-PCR. The results showed that the mRNA levels of hepatic drug-metabolizing enzymes, including cyp2b50, cyp2c50, cyp2c39, cyp2c38, cyp2c29, cyp2c54, cyp2c55, cyp2a5, gsta1, gsta2, gstt2, gstm2 and ephx1, were significantly up-regulated, while egfr and egr1 were down-regulated in SASP-treated group. Moreover, the mRNA levels of egfr and cyp2c55 exhibited a dose-dependent changes in SASP groups. Western blotting verified that the changes of protein levels of EGFR and CYP2C55 were consistent with mRNA levels. Considering that egfr has the highest score in PPI degree and cyp2c55 has the largest fold change in qPCR analysis, our present results suggested that the toxicological mechanisms of SASP-induced liver injury might be related to multi-biological processes and pathways, and egfr and cyp2c55 may play important roles in SASP-induced liver injury. The present study would be helpful for better understanding the hepatotoxic mechanism of SASP. However, the precise mechanism still needs further research.
Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/genética , Perfilação da Expressão Gênica , Fígado/efeitos dos fármacos , Sulfassalazina/toxicidade , Transcriptoma/efeitos dos fármacos , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos ICR , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de TempoRESUMO
The present study was envisaged to investigate the chemical constituents and the intervention effects of Portulaca oleracea extract (POE) on acute alcoholic liver injury of rats. The chemical composition of POE was detected by high performance liquid chromatography (HPLC). Sixty male Wistar rats were divided into 6 groups: Normal control (NC) group, acute alcoholic liver injury model group (ALI), low, medium and high dose of POE (25, 50, 100 mg/kg) groups and bifendate (BF, 3.75 mg/kg) group. Each group was given by intragastrical administration for 7 days. Alcoholic liver injury was induced in the experimental model by administering 50% ethanol at 8 mL/kg and repeated administration after 6 h, for a period of 7 days. The results showed that pretreatment with POE significantly reduced the ethanol-elevated serum level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and triglyceride (TG). The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in liver were enhanced followed by administration of POE, while the content of nitric oxide (NO) and malondialdehyde (MDA) was found to decrease. Hepatic content of tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was also reduced by POE treatment. These results indicated that POE could increase the antioxidant capacity and relieve the inflammatory injury of the liver cells induced by ethanol. Meanwhile, in our study, POE reduced the expression of miR-122, acetyl coenzyme A carboxylase (ACC) 1 mRNA and protein and increased the expression of lipoprotein lipase (LPL) mRNA and protein in liver, which indicated that POE could improve the lipid metabolism disorder induced by ethanol. Our findings suggested that POE had protective effects on acute alcoholic liver injury of rats.
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Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Extratos Vegetais/farmacologia , Portulaca/química , Animais , Biomarcadores , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RatosRESUMO
Lung cancer is the leading cause of cancer death worldwide and cancer relapse accounts for the majority of cancer mortality. The mechanism is still unknown, especially in hereditary lung cancer without known actionable mutations. To identify genetic alternations involved in hereditary lung cancer and relapse is urgently needed. We collected genetic materials from a unique hereditary lung cancer patient's blood, first cancer tissue (T1), adjacent normal tissue (N1), relapse cancer tissue (T2), and adjacent normal tissue (N2) for whole genome sequencing. We identified specific mutations in T1 and T2, and attributed them to tumorigenesis and recurrence. These tumor specific variants were enriched in antigen presentation pathway. In addition, a lung adenocarcinoma cohort from the TCGA dataset was used to confirm our findings. Patients with high mutation burdens in tumor specific genes had decreased relapse-free survival (P = 0.017, n = 186). Our study may provide important insight for designing immunotherapeutic treatment for hereditary lung cancer.
Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia/genética , Sequenciamento Completo do Genoma/métodos , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Apresentação de Antígeno , Biomarcadores Tumorais/genética , Estudos de Coortes , Feminino , Redes Reguladoras de Genes , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Recidiva Local de Neoplasia/mortalidade , Análise de SobrevidaRESUMO
The present study aimed to evaluate the effects of paeoniflorin on insulin resistance and hepatic steatosis induced by fructose. Male Sprague-Dawley rats were fed 20% fructose drink for eight weeks. The insulin sensitivity, serum lipid profiles, and hepatic lipids contents were measured. The results showed that paeoniflorin significantly decreased serum insulin and glucagon levels, improved insulin sensitivity and serum lipids profiles, and alleviated hepatic steatosis in fructose-fed rats. Moreover, paeoniflorin enhanced the phosphorylation level of AMP-activated protein kinase (AMPK) and protein kinase B (PKB/AKT) and inhibited the phosphorylation of acetyl coenzyme A carboxylase (ACC)1 in liver. Paeoniflorin also increased the hepatic carnitine palmitoyltransferase (CPT)-1 mRNA and protein expression and decreased the mRNA expression of sterol regulatory element-binding protein (SREBP)1c, stearyl coenzyme A decarboxylase (SCD)-1 and fatty acid synthetase (FAS). Furthermore, we found that paeoniflorin significantly increased the heptatic protein expression of tumor suppressor serine/threonine kinase (LKB)1 but not Ca2+/CaM-dependent protein kinase kinase (CaMKK)ß. These results suggest that the protective effects of paeoniflorin might be involved in the activation of LKB1/AMPK and insulin signaling, which resulted in the inhibition of lipogenesis, as well as the activation of ß-oxidation and glycogenesis, thus ameliorated the insulin resistance and hepatic steatosis. The present study may provide evidence for the beneficial effects of paeoniflorin in the treatment of insulin resistance and non-alcoholic fatty liver.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Frutose , Glucosídeos/farmacologia , Resistência à Insulina , Fígado/efeitos dos fármacos , Monoterpenos/farmacologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Quinases Proteína-Quinases Ativadas por AMP , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Glicogênio/metabolismo , Insulina/sangue , Lipídeos/sangue , Lipogênese/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos Sprague-DawleyRESUMO
Berberine, the major constituent alkaloid originally from the famous Chinese herb Huanglian (Coptis chinensis), has been shown to exert antidepressant-like effects in rodents. However, it is still not clear the involvement of neuro-inflammation suppression in the effects of berberine. The purpose of this study was to determine whether berberine affects the neuro-inflammation system in mice induced by chronic unpredictable mild stress (CUMS). Berberine was orally administrated in normal or CUMS mice for successive four weeks. Behavioral evaluation showed that berberine prevented the depressive deficits both in sucrose preference test and novelty-suppressed feeding test. The elevation of hippocampal pro-inflammatory cytokines such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), as well as the activation of microglia were decreased by berberine. In addition, chronic berberine treatment inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway as the phosphorylated proteins of NF-κB, IκB kinase (IKK)α and IKKß in the hippocampus were suppressed after berberine administration. Furthermore, inducible nitric oxide synthase (iNOS), one downstream target of NF-κB signaling pathway was also inhibited by berberine. In conclusion, these findings suggest that administration of berberine could prevent depressive-like behaviors in CUMS mice by suppressing neuro-inflammation in the hippocampus.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antidepressivos/farmacologia , Berberina/farmacologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/imunologia , Animais , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Quinase I-kappa B/metabolismo , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Ferulic acid is a hydroxycinnamic acid that widely presents in plant cell wall components. It has been demonstrated that ferulic acid can attenuate depressive-like behaviors in both forced swimming test and tail suspension test. Considering that depression is an inflammatory related mental disease, our present study was aimed to investigate the role of ferulic acid in the regulation of microglia activation, pro-inflammatory cytokines, nuclear factor kappa B (NF-κB) and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in mice exposed to chronic unpredictable mild stress (CUMS). Our results firstly showed that decreased sucrose preference and increased immobility time were completely reversed by administration with ferulic acid and fluoxetine for four weeks. Then, we found that CUMS significantly caused interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) up-regulation, microglia, NF-κB signaling and NLRP3 inflammasome activation in the prefrontal cortex. On the contrary, these activated inflammatory response induced by CUMS were reversed by ferulic acid and fluoxetine as well, suggesting that anti-inflammatory related mechanism was involved in the antidepressant-like effects of ferulic acid in stressed mice.
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Anti-Inflamatórios/uso terapêutico , Antidepressivos/uso terapêutico , Ácidos Cumáricos/uso terapêutico , Depressão/tratamento farmacológico , Microglia/efeitos dos fármacos , Inflamação Neurogênica/tratamento farmacológico , Estresse Psicológico/tratamento farmacológico , Animais , Citocinas/metabolismo , Fluoxetina/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microglia/imunologia , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
RATIONALE: Gypenosides have been reported to produce neuroprotective effects and increase monoamine neurotransmitter levels in the brain. OBJECTIVE: Considering that depression is involved in monoamine reduction, this study evaluated the antidepressant-like effects of gypenosides in mice exposed to chronic unpredictable mild stress (CUMS). METHODS: The sucrose preference test and forced swimming test were performed after administration of gypenosides (at 25, 50, or 100 mg/kg) for 4 weeks. Hippocampal brain-derived neurotrophic factor (BDNF) and its downstream targets were analyzed by western blot. Additionally, hippocampal neuronal proliferation was measured by immunohistochemistry. RESULTS: Four-week treatment with fluoxetine (20 mg/kg) and gypenosides (at either 50 or 100 mg/kg) increased sucrose preference and decreased the immobility time in mice exposed to CUMS. In addition, gypenosides (at either 50 or 100 mg/kg) also increased BDNF expression and neuronal proliferation in the hippocampus of CUMS animals. Further, we showed that treating CUMS mice with K252a, which is an inhibitor of the BDNF receptor TrkB, blocked the effects of gypenosides (100 mg/kg), including behavioral improvements, neuronal proliferation, and up-regulation of p-TrkB, p-ERK, and p-Akt proteins. CONCLUSIONS: This study demonstrates that gypenosides exhibit antidepressant-like effects in mice, which may be mediated by activation of the BDNF-ERK/Akt signaling pathway in the hippocampus.
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Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Estresse Psicológico/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carbazóis/farmacologia , Depressão , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fluoxetina/farmacologia , Gynostemma , Hipocampo/metabolismo , Alcaloides Indólicos/farmacologia , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor trkB/antagonistas & inibidores , Receptor trkB/efeitos dos fármacos , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/psicologia , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem , Natação , Regulação para Cima/efeitos dos fármacosRESUMO
PURPOSE: To investigate the potential protective effects of Proanthocyanidins(PAs) on intestinal motility disturbance following intestinal ischemia/reperfusion (I/R). MATERIALS AND METHODS: Male rats were divided into four groups: Sham, I/R, I/R+PA100 and I/R+PA200. Sham group underwent laparotomy without ligation, the others were subjected to intestinal ischemia for 1 h and reperfusion 4 h. Rats in the I/R+PA100 group received PAs (100 mg/kg/d) for 5 days prior to I/R, while rats in the I/R+PA200 group received PAs (200 mg/kg/d). After reperfusion, using an electrophysiology instrument measured ileal slow wave. Ileal specimens were obtained to determine contractility, tissue levels of Bax, Bcl-2, and Caspase-3 and evaluate histopathological changes. In addition, blood sample was obtained to determine serum superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. RESULTS: Intestinal I/R caused severe histopathological injury including mucosal erosions, inflammatory cell infiltration, necrosis, and hemorrhage. Both PAs treatment decreased mucosal pathological impairment in comparison with the I/R group (p < .05) in light microscopic evaluations. In both PAs-treated groups, Bax and Caspase-3 expression were decreased compared to I/R group, while the Bcl-2 expression increased (p < .05), which was similarly the case for serum SOD activity demonstrated significant enhance (p < .05) and decline in MDA levels in comparison with I/R group (both p < .05). Moreover, PAs treatment was more efficient in attenuating serum MDA levels of intestinal I/R (both p < .05). And the contractile amplitude and frequency of slow wave in I/R+PA100 and I/R+PA200 groups were higher than I/R group (both p < .05). CONCLUSIONS: PAs improve intestinal motility disturbance following intestinal I/R by alleviating oxidative stress and apoptosis.
Assuntos
Motilidade Gastrointestinal/efeitos dos fármacos , Íleo/efeitos dos fármacos , Proantocianidinas/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Caspase 3/metabolismo , Avaliação Pré-Clínica de Medicamentos , Íleo/irrigação sanguínea , Íleo/metabolismo , Íleo/patologia , Masculino , Malondialdeído/sangue , Proantocianidinas/farmacologia , Distribuição Aleatória , Ratos Sprague-Dawley , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Circulação Esplâncnica , Superóxido Dismutase/sangue , Proteína X Associada a bcl-2/metabolismoRESUMO
The objective of the present study was to examine the expression of Silent information regulator 1 (Sirt1) in colorectal cancer and peritumoral normal mucosa tissue, and therefore analyze the role and molecular mechanism of Sirt1 in the pathogenesis of colorectal cancer. Colorectal cancer tissue specimens were employed as the experimental group, and adjacent normal mucosa tissues >5 cm from tumor lesions were used as the control group. The expression of Sirt1 was detected by the immunohistochemical streptavidin peroxidase detection method in paraffin-embedded sections, whilst Sirt1 protein expression was examined by western blot analysis in the fresh tissues. Sirt1 protein was primarily expressed in the nuclei of the tumor cells, and positive staining was brownish-yellow in color. The relative expression quantities of Sirt1 in the peritumoral normal rectal mucosa and rectal carcinoma were 1.15 and 2.62, and the differences between the two groups were statistically significant (P<0.05). The expression level of Sirt1 in colorectal carcinoma was significantly associated with the depth of tumor invasion, differentiation and tumor size (P<0.05). Sirt1 expression was also found to be associated with tumor tissue type, lymph node metastasis, Duke's stage and patient age. These characteristics combined may therefore be used as markers for the early diagnosis of colorectal cancer pathogenesis.
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In this study, EGFR-activating mutation status and DNA copy number abundances of members of ErbB family were measured in 261 lung adenocarcinomas. The associations between DNA copy number abundances of ErbB family, EGFR-activating mutation status, and prognosis were explored. Results showed that DNA copy number abundances of EGFR, ERBB2, ERBB3, and ERBB4 had associations with overall survival in lung adenocarcinoma with EGFR-activating mutations. In the stratification analysis, only ERBB2 showed significant discrepancy in patients carrying wild type EGFR and other members of ErbB family in patients carrying EGFR-activating mutation. This indicated that CNAs of ErbB family had effect modifications of EGFR-activating mutation status. Findings of this study demonstrate potential molecular guidance of patient management of lung adenocarcinoma with or without EGFR-activating mutations.
Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Receptores ErbB/genética , Dosagem de Genes/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Receptor ErbB-2/genética , Receptor ErbB-3/genética , Receptor ErbB-4/genética , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Ativação Enzimática/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/genética , MasculinoRESUMO
PURPOSE: Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. PATIENTS AND METHODS: Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluated for lung abnormalities. RESULTS: YAP1 R331W missense mutation from the original family was identified and validated in the external controls and the cohort with lung adenocarcinoma. The YAP1 mutant-allele carrier frequency was 1.1% in patients with lung adenocarcinoma compared with 0.18% in controls (P = .0095), yielding an odds ratio (adjusted for age, sex, and smoking status) of 5.9. Among the relatives, YAP1-mutant carriers have overwhelmingly higher frequencies of developing lung adenocarcinoma or ground-glass opacity lung lesions than those who do not carry the mutation (10:0 v 1:7; P < .001). YAP1 mutation was shown to increase the colony formation ability and invasion potential of lung cancer cells. CONCLUSION: These results implicated YAP1 R331W as an allele predisposed for lung adenocarcinoma with high familial penetrance. Low-dose computed tomography scans may be recommended to this subpopulation, which is at high risk for lung cancer, for personalized prevention and health management.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Mutação em Linhagem Germinativa , Neoplasias Pulmonares/genética , Mutação de Sentido Incorreto , Fosfoproteínas/genética , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Biologia Computacional , Análise Mutacional de DNA/métodos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Lactente , Modelos Logísticos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Linhagem , Penetrância , Fenótipo , Medicina de Precisão , Fatores de Risco , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Taiwan , Tomografia Computadorizada por Raios X , Fatores de Transcrição , Proteínas de Sinalização YAPRESUMO
BACKGROUND: Contralateral C7 nerve transfer to the median nerve has been used in an attempt to restore finger flexion in patients with total brachial plexus avulsion injury. However, the results have not been satisfactory mainly because of the requirement to use a long bridging nerve graft, which causes an extended nerve regeneration process and irreversible muscle atrophy. A new procedure involving contralateral C7 nerve transfer via a modified prespinal route and direct coaptation with the injured lower trunk is presented here. METHODS: Contralateral C7 nerve transfer via the modified prespinal route and direct coaptation with the injured lower trunk was performed in seventy-five patients with total brachial plexus avulsion injury. Thirty-five required humeral shortening osteotomy (3 to 4.5 cm) in order to accomplish the direct coaptation. The contralateral C7 nerve was also transferred to the musculocutaneous nerve through the bridging medial antebrachial cutaneous nerve arising from the lower trunk in forty-seven of the seventy-five patients. Recovery of finger, wrist, and elbow flexion was evaluated with use of the modified British Medical Research Council muscle grading system. RESULTS: The mean follow-up period (and standard deviation) was 57 ± 6 months (range, forty-eight to seventy-eight months). Motor function with a grade of M3+ or greater was attained in 60% of the patients for elbow flexion, 64% of the patients for finger flexion, 53% of the patients for thumb flexion, and 72% of the patients for wrist flexion. CONCLUSIONS: Contralateral C7 nerve transfer via a modified prespinal route and direct coaptation with the injured lower trunk decreases the distance for nerve regeneration in patients with total brachial plexus avulsion injury. There was satisfactory recovery of finger flexion and wrist flexion in this series. In addition, contralateral C7 nerve transfer was successfully used to repair two different target nerves: the lower trunk and the musculocutaneous nerve.
Assuntos
Neuropatias do Plexo Braquial/cirurgia , Plexo Braquial/lesões , Plexo Braquial/cirurgia , Nervo Mediano/cirurgia , Transferência de Nervo/métodos , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Adulto JovemRESUMO
AIM: To investigate different methods of creating incomplete intestinal obstruction in a rat model and to compare their electrophysiologic, morphologic and histologic characteristics. METHODS: Rat ileum was partially obstructed by the respective application of: braided silk (penetrated the mesentery and surrounded intestine); half ligation (penetrated directly and ligated 1/2 cross-section of the intestine); wide pipe (6 mm in width, surrounded the intestine); narrow pipe (2 mm in width, surrounded the intestine). A control was also included (no obstruction). Various behavioral and electrophysiologic variables, as well as morphologic and immunohistochemical observations were recorded by blinded investigators at different time points (12, 24, 48, 72 h), including daily general condition, ileal wet weight and circumference, macromorphous and micromorphous intestine, bowel movement capability in vivo and in vitro, slow wave and neural electrical activity, and the number of c-Kit positive interstitial cells of Cajal (ICC). RESULTS: Despite being of a similar general condition, these methods resulted in different levels of obstruction in each group compared with the control at different time points (12, 24, 48, 72 h). However, these fields of the wide pipe rat showed significantly differences when compared with the other three obstructed groups at 12 to 72 h, including macroscopic and histological presentation, intestinal transit ratio and contractility, circumference and wet weight, amplitude and frequency of nerve electrical discharge and slow wave, and ICC numbers (all P < 0.01). CONCLUSION: The wide pipe rat method is significantly more reliable and stable than the other methods of obstruction, demonstrating that use of the wide pipe method can be a useful model of incomplete intestinal obstruction.
Assuntos
Doenças do Íleo/etiologia , Íleo/cirurgia , Obstrução Intestinal/etiologia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Feminino , Trânsito Gastrointestinal , Doenças do Íleo/metabolismo , Doenças do Íleo/patologia , Doenças do Íleo/fisiopatologia , Íleo/inervação , Íleo/patologia , Íleo/fisiopatologia , Células Intersticiais de Cajal/metabolismo , Obstrução Intestinal/metabolismo , Obstrução Intestinal/patologia , Obstrução Intestinal/fisiopatologia , Ligadura , Masculino , Complexo Mioelétrico Migratório , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
The aim of this study was to explore the possibility that Microcystis phycocyanin (MC-PC) functions as a photosensitizer and to investigate the mechanism for the apoptosis induced by Microcystis phycocyanin-mediated photodynamic therapy (MC-PC-PDT) in human hepatocellular carcinoma cells (HepG2). After incubation with MC-PC, HepG2 cells were exposed to a He-Ne Laser beam and the cell survival rate was detected by MTT and Colony forming assay. The mechanism of apoptosis was determined by ultrastructural observation, reactive oxygen species (ROS) and mitochondrial membrane potential (Δψm) assay, activity detection of caspase-3 and cytosol cytochrome c and flow cytometry (FCM) for cell cycle analysis. Our results demonstrated that MC-PC-PDT effectively inhibits HepG2 proliferation with a half-lethal dose of 100 µg/mL and induces apoptosis at 24h with a dose of 200 µg/mL MC-PC. MC-PC was found to localized in mitochondria, it could induce a high level of ROS accumulation at 16 h after PDT treatment, cause mitochondrial damage and the release of mitochondrial cytochrome c into the cytosol. These cellular changes are accompanied by a reduction of the Δψm, activation of caspase-3 and G2/M phase arrest, finally leading to apoptosis through a mitochondria-dependent pathway after 24h. Meanwhile, necrosis was also contributed to cell death in MC-PC PDT process. The present study also identified a new source of phycocyanin from Microcystis as a safe and effective photosensitizer.
Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Microcystis/química , Mitocôndrias/efeitos dos fármacos , Ficocianina/isolamento & purificação , Ficocianina/farmacologia , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos da radiação , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Fármacos Fotossensibilizantes/isolamento & purificação , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
The NOD-like receptor 3 (NLRP3) inflammasome-mediated inflammation is recently recognized in the development of renal injury. However, the mechanisms of the inflammasome-mediated inflammation and lipid accumulation in renal injury and the actions of lowing urate agents remain unclear. The present study used fructose to induce hyperuricemia and dyslipidemia, which caused renal NLRP3 inflammasome activation characterized by over-expression of the NLRP3, apoptosis-associated speck-like protein (ASC) and caspase-1, resulting in overproduction of interleukin (IL)-1ß and IL-18, as well as IL-6 and tumor necrosis factor α (TNF-α) in rats. The elevated levels of these pro-inflammatory cytokines impaired renal janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3)/peroxisome proliferator-activated receptor α (PAPR-α), and insulin receptor (IR)/insulin receptor substrate 1 (IRS1)/protein kinase B (Akt)/extracellular signal-regulated kinase1/2 (ERK1/2) signaling pathways with over-expression of suppressor of cytokine signaling 3 (SOCS3), exacerbating renal lipid accumulation and injury in fructose-fed rats. The restoration of fructose-induced hyperuricemia and dyslipidemia by the treatment of allopurinol, quercetin and rutin blocked the NLRP3 inflammasome activation to improve the signaling impairments and reduce lipid accumulation in the kidney of rats. These results suggest that the activation of renal NLRP3 inflammasome may play an important role in the link among renal inflammation, JAK2/STAT3/PAPR-α and IR/IRS1/Akt/ERK1/2 signaling impairment, and lipid accumulation driven by fructose. The NLRP3 inflammasome may be the target mediating the improvement of urate-lowering agents allopurinol, quercetin and rutin on fructose-induced renal lipid accumulation and injury.
Assuntos
Alopurinol/farmacologia , Frutose/farmacologia , Inflamassomos/metabolismo , Rim/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Quercetina/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Rutina/farmacologia , Alopurinol/uso terapêutico , Animais , Western Blotting , Proteínas de Transporte , Colesterol/sangue , Creatinina/sangue , Dislipidemias/sangue , Dislipidemias/imunologia , Dislipidemias/prevenção & controle , Frutose/administração & dosagem , Teste de Tolerância a Glucose , Hiperuricemia/sangue , Hiperuricemia/imunologia , Hiperuricemia/prevenção & controle , Resistência à Insulina , Rim/imunologia , Rim/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR , Quercetina/uso terapêutico , Ratos , Ratos Sprague-Dawley , Rutina/uso terapêutico , Ácido Úrico/sangueRESUMO
UNLABELLED: High consumption of dietary fructose is an important contributory factor in the development of hepatic steatosis in insulin or leptin resistance. We investigated the effects of curcumin on fructose-induced hypertriglyceridemia and liver steatosis and explored its preventive mechanisms in rats. Curcumin reduced serum insulin and leptin levels in fructose-fed rats. This compound could increase phosphorylation of insulin receptor and insulin receptor substrate 1 to enhance Akt and extracellular signal-regulated kinase1/2 (ERK1/2) activation in the liver of fructose-fed rats. Moreover, curcumin increased phosphorylation of hepatic janus-activated kinase-signal transducer 2 and subsequently also stimulated Akt and ERK1/2 activation in this model. Suppression of curcumin on leptin signaling overstimulation in tyrosine1138 phosphorylation of the long form of leptin receptor and signal transducer and activator of transcription 3 resulted in down-regulation of suppressor of cytokine signaling 3 in the liver of fructose-fed rats. Thus, improvement of insulin and leptin signaling transduction and subsequently elevation of peroxisome proliferator-activated receptor alpha expression by curcumin led to reduction of very-low-density lipoprotein overproduction and triglyceride hypersynthesis. Furthermore, overexpression and hyperactivity of hepatic protein tyrosine phosphatase 1B (PTP1B) associated with defective insulin and leptin signaling were observed in fructose-fed rats. Additionally, curcumin was found to significantly reduce hepatic PTP1B expression and activity in this model. CONCLUSION: Our data indicate that the mechanisms by which curcumin protects against fructose-induced hypertriglyceridemia and hepatic steatosis are its inhibition on PTP1B and subsequently improvement of insulin and leptin sensitivity in the liver of rats. This PTP1B inhibitory property may be a promising therapeutic strategy for curcumin to treat fructose-induced hepatic steatosis driven by hepatic insulin and leptin resistance.