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Colonoscopy is an essential method for diagnosing and treating colorectal cancer, relying on effective bowel preparation to thoroughly examine the large intestinal mucosa. Traditional education involves printed instructions and verbal explanations but does not guarantee clear patient understanding. Poor bowel preparation can obscure mucosal visibility, delaying cancer diagnosis and treatment. A mobile medical model using Android devices for bowel preparation education was tested in a single-blind, randomized trial. This trial enrolled outpatients undergoing colonoscopy at the Endoscopy Center for Diagnostic and Treatment between 27 October 2021 and 31 December 2022. This study introduced the ColonClean app alongside traditional methods. After examination, endoscopists rated the preparation quality using the Aronchick scale. A data analysis was conducted using SPSS 25.0 to determine if there was a significant improvement in bowel preparation quality between the control group (traditional method) and the experimental group (traditional method plus the ColonClean app). Forty patients were recruited in each group. In the experimental group, all ratings were "fair", with 75% receiving an "excellent" or "good" rating, showing statistical significance (p = 0.016). The ColonClean app improves bowel preparation quality more effectively than traditional care instructions.
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BACKGROUND: Epidural analgesia is a common technique for managing perioperative and obstetric pain. Patients with cancer who cannot tolerate opioids or not responding to conventional treatment may benefit from epidural analgesia. Therefore, this systematic review aimed to analyze the efficacy and safety of epidural analgesia in patients with intractable cancer pain. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials to identify studies on patients with cancer who received epidural analgesia. We assessed the quality of all included studies using the risk-of-bias tool or Newcastle-Ottawa scale. The primary outcome was pain relief after epidural analgesia, and the secondary outcome was quality of life, analgesic consumption, and adverse events. The studies were grouped based on the medications used for epidural analgesia. A descriptive synthesis was performed following the Synthesis Without Meta-analysis reporting guideline. RESULTS: Our systematic review included nine randomized controlled trials (n = 340) and 15 observational studies (n = 926). Two randomized controlled trials suggested that epidural opioids were not superior to systemic opioids in relieving pain. Epidural opioids combined with local anesthetics or adjuvants, including calcitonin, clonidine, ketamine, neostigmine, methadone, and dexamethasone, offered better analgesic effects. No significant difference in pain relief between an intermittent bolus and a continuous infusion of epidural morphine was observed. Epidural opioids had more analgesic effects on nociceptive pain than neuropathic pain. The methods used to evaluate the quality of life and the corresponding results were heterogeneous among studies. Six observational studies demonstrated that some patients could have decreased opioid consumption after epidural analgesia. Adverse events, including complications and drug-related side effects, were reported in 23 studies. Five serious complications, such as epidural abscess and hematoma, required surgical management. The heterogeneity and methodological limitations of the studies hindered meta-analysis and evidence-level determination. CONCLUSION: Coadministration of epidural opioids, local anesthetics, and adjuvants may provide better pain relief for intractable cancer pain. However, we must assess the patients to ensure that the benefits outweigh the risks before epidural analgesia. Therefore, further high-quality studies are required.
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Analgesia Epidural , Dor do Câncer , Neoplasias , Feminino , Humanos , Gravidez , Analgesia Epidural/efeitos adversos , Analgésicos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Anestésicos Locais , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Qualidade de VidaRESUMO
PURPOSE: The aim of this study was to investigate the factors predictive of clinical outcome in advanced hepatocellular carcinoma patients receiving ramucirumab treatment. METHODS: We conducted a retrospective study using a multi-institutional electronic medical records database in Taiwan. We included advanced HCC patients newly receiving ramucirumab as second-line or beyond systemic therapy between January 2016 and February 2022. The clinical outcomes were median progression-free survival (PFS) based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST), overall survival (OS) and adverse events. We applied Kaplan-Meier methods to estimate median PFS and OS. Uni-variable and multi-variable Cox regression models were applied to identify the prognostic factors. RESULTS: We included 39 ramucirumab naive users with a median age of 65.5 (IQR: 57.0-71.0) years and treatment time of 5.0 (3.0-7.0) cycles, of whom 82.1% were male and 84.6% were Barcelona Clinic Liver Cancer (BCLC) stage C. After median follow-up time of 6.0 months, 33.3% of patients' AFP level had decreased more than 20% within 12 weeks. The median PFS and OS were 4.1 months and non-reach, respectively. Moreover, tumor burden beyond the up-to-11 criteria (HR: 2.95, 95% CI: 1.04-8.38) and a decrease in estimated glomerular filtration rate of more than 10% within 12 weeks (HR: 0.31, 0.11-0.88) were significantly related to PFS in the multi-variable analysis. No patient discontinued ramucirumab during the treatment on account of side effects. CONCLUSION: Ramucirumab was an effective treatment option with good AFP response for advanced HCC patients in real-world experience. Tumor burden beyond the up-to-11 criteria and a decrease in estimated glomerular filtration rate were independent predictive factors for progression-free survival.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , alfa-Fetoproteínas/análise , Estimativa de Kaplan-Meier , Resultado do Tratamento , RamucirumabRESUMO
This is a retrospective cohort study by analyzing a multi-institutional electronic medical records database in Taiwan to compare long-term effectiveness and risk of major adverse cardiac events (MACE) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate-specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63-1.17) and OS (0.68: 0.41-1.14) between the use of ENZ and AA in chemotherapy-naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07-0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy-naïve mCRPC patients with high CV risk profile.
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Doenças Cardiovasculares , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Nitrilas/uso terapêutico , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Fixed doses at 200 mg of pembrolizumab or 2 mg/kg every 3 weeks are the standard dosages for first- and second-line treatment of non-small-cell lung cancer (NSCLC); however, in clinical practice, patients with NSCLC may receive lower doses of pembrolizumab due to drug product availability or economic factors. To date, the comparative effectiveness and safety of the standard dose and lower doses of pembrolizumab in these patients still remains limited. We conducted a retrospective cohort study by analyzing electronic medical records data from the largest multi-institutional hospital system in Taiwan. Advanced NSCLC patients newly receiving pembrolizumab with or without chemotherapy were included. Patients were classified into: (1) the standard-dose group (≥2 mg/kg), and (2) the low-dose group (<2 mg/kg). We applied inverse probability of treatment weighting (IPTW) to compare the overall survival (OS) and immune-related adverse events (irAEs) between the two treatment groups, and to evaluate the minimum clinically effective dose of pembrolizumab. We included a total of 147 NSCLC patients receiving standard-dose pembrolizumab (mean [range] age: 63.7 [58.0−73.0] years; male: 62.6%; mean [range] body weight: 60.5 [58.0−73.0] kg) and 95 patients receiving low-dose pembrolizumab (mean [range] age: 62.0 [50.0−68.8] years; male: 64.2%; mean [range] body weight: 63.9 [55.0−73.8] kg). After IPTW adjustments, the median OS was similar for both the standard-dose and low-dose pembrolizumab groups (19.3 vs. 14.3 months, log-rank p = 0.15). Also, the rate for all classes of irAEs was similar for both groups. We found that patients with a pembrolizumab dose ≥1.8 mg/kg were associated with better OS than those receiving <1.8 mg/kg. Our findings suggested no significant difference in OS and irAEs between patients receiving pembrolizumab ≥2 mg/kg and <2 mg/kg in clinical practice. A pembrolizumab dose ≥1.8 mg/kg may be the clinically most efficient dose.
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BACKGROUND: Head-to-head comparison of clinical effectiveness between dulaglutide and liraglutide in Asia is limited. This study was aimed to assess the real-world comparative effectiveness of dulaglutide versus liraglutide. METHODS: We conducted a retrospective cohort study by utilizing multi-institutional electronic medical records to identify real-world type 2 diabetes patients treated with dulaglutide or liraglutide during 2016-2018 in Taiwan and followed up until 2019. Effectiveness outcomes were assessed at every 3 months in the 1-year follow-up. Propensity score techniques were applied to enhance between-group comparability. Significant differences in changes of effectiveness outcomes between treatment groups during the follow-up were examined and further analyzed using mixed-model repeated-measures approaches. RESULTS: A total of 1512 subjects receiving dulaglutide and 1513 subjects receiving liraglutide were identified. At 12 months, significant HbA1c changes from baseline were found in both treatments (dulaglutide: - 1.06%, p < 0.001; liraglutide: - 0.83%, p < 0.001), with a significant between-group difference (- 0.23%, 95% confidence interval - 0.38 to - 0.08%, p < 0.01). Both treatments yielded significant declines in weight, alanine aminotransferase level, and estimated glomerular filtration rate from baseline (dulaglutide: - 1.14 kg, - 3.08 U/L and - 2.08 mL/min/1.73 m2, p < 0.01; liraglutide: - 1.64 kg, - 3.65 U/L and - 2.33 mL/min/1.73 m2, p < 0.001), whereas only dulaglutide yielded a significant systolic blood pressure reduction (- 2.47 mmHg, p < 0.001). Between-group differences in changes of weight, blood pressure, and liver and renal functions at 12 months were not statistically significant. CONCLUSIONS: In real-world T2D patients, dulaglutide versus liraglutide was associated with better glycemic control and comparable effects on changes of weight, blood pressure, and liver and renal functions.
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Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Controle Glicêmico , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Liraglutida/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Idoso , Povo Asiático , Biomarcadores/sangue , Glicemia/metabolismo , Pesquisa Comparativa da Efetividade , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnologia , Feminino , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hemoglobinas Glicadas/metabolismo , Controle Glicêmico/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Estudos Retrospectivos , Taiwan/epidemiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Increasing nitrogen use efficiency (NUE) is critical to improve crop yield, reduce N fertilizer demand and alleviate environmental pollution. N remobilization is a key component of NUE. The nitrate transporter NRT1.7 is responsible for loading excess nitrate stored in source leaves into phloem and facilitates nitrate allocation to sink leaves. Under N starvation, the nrt1.7 mutant exhibits growth retardation, indicating that NRT1.7-mediated source-to-sink remobilization of stored nitrate is important for sustaining growth in plants. To energize NRT1.7-mediated nitrate recycling, we introduced a hyperactive chimeric nitrate transporter NC4N driven by the NRT1.7 promoter into the nrt1.7 mutant. NRT1.7p::NC4N::3' transgenic plants accumulated more nitrate in younger leaves, and 15NO3- tracing analysis revealed that more 15N was remobilized into sink tissues. Consistently, transgenic Arabidopsis, tobacco and rice plants showed improved growth or yield. Our study suggests that enhancing source-to-sink nitrate remobilization represents a new strategy for enhancing NUE and crop production.
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Proteínas de Arabidopsis/metabolismo , Nitrogênio/metabolismo , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Plantas/genéticaRESUMO
The T cell Ig and mucin domain (TIM) proteins inhibit release of HIV-1 and other enveloped viruses by interacting with cell- and virion-associated phosphatidylserine (PS). Here, we show that the Nef proteins of HIV-1 and other lentiviruses antagonize TIM-mediated restriction. TIM-1 more potently inhibits the release of Nef-deficient relative to Nef-expressing HIV-1, and ectopic expression of Nef relieves restriction. HIV-1 Nef does not down-regulate the overall level of TIM-1 expression, but promotes its internalization from the plasma membrane and sequesters its expression in intracellular compartments. Notably, Nef mutants defective in modulating membrane protein endocytic trafficking are incapable of antagonizing TIM-mediated inhibition of HIV-1 release. Intriguingly, depletion of SERINC3 or SERINC5 proteins in human peripheral blood mononuclear cells (PBMCs) attenuates TIM-1 restriction of HIV-1 release, in particular that of Nef-deficient viruses. In contrast, coexpression of SERINC3 or SERINC5 increases the expression of TIM-1 on the plasma membrane and potentiates TIM-mediated inhibition of HIV-1 production. Pulse-chase metabolic labeling reveals that the half-life of TIM-1 is extended by SERINC5 from <2 to â¼6 hours, suggesting that SERINC5 stabilizes the expression of TIM-1. Consistent with a role for SERINC protein in potentiating TIM-1 restriction, we find that MLV glycoGag and EIAV S2 proteins, which, like Nef, antagonize SERINC-mediated diminishment of HIV-1 infectivity, also effectively counteract TIM-mediated inhibition of HIV-1 release. Collectively, our work reveals a role of Nef in antagonizing TIM-1 and highlights the complex interplay between Nef and HIV-1 restriction by TIMs and SERINCs.
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Infecções por HIV/metabolismo , Receptor Celular 1 do Vírus da Hepatite A/fisiologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/fisiologia , Membrana Celular/metabolismo , Regulação para Baixo , Células HEK293 , Soropositividade para HIV , HIV-1/metabolismo , HIV-1/patogenicidade , Receptor Celular 1 do Vírus da Hepatite A/antagonistas & inibidores , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Leucócitos Mononucleares/metabolismo , Glicoproteínas de Membrana , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Transporte Proteico , Receptores de Superfície Celular/metabolismo , Vírion/metabolismo , Replicação Viral/efeitos dos fármacos , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismoRESUMO
Medication errors substantially threaten patient safety, and their prevention requires clinical vigilance. We present a case of taking the wrong drug due to a dispensing error by pharmacists involving medication packaging confusion, and we report how we prevent similar dispensing errors by thorough investigation and intervention. This case emphasizes the need for constant attention by hospital, medical industry, and regulatory authorities to avoid look-alike medication packaging in the interest of medication safety.
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Embalagem de Medicamentos/métodos , Erros Médicos/tendências , Segurança do Paciente/normas , Idoso , Humanos , MasculinoRESUMO
Lung fibroblasts play critical roles in fibrotic procedures and contribute to lung fibrosis. Several studies indicated that thrombin, a disintegrin and metalloproteinase 17 (ADAM17), and connective tissue growth factor (CTGF) participate in the formation of pulmonary fibrosis. In this study, we examined the involvement of the ADAM17/epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) pathway in thrombin-stimulated CTGF manifestation in human lung fibroblasts (WI-38). We found that cells treated with thrombin significantly increased ADAM17 expression, ADAM17 and c-Jun phosphorylation in time-dependent manners. Thrombin-stimulated CTGF expression, ERK and c-Jun phosphorylation were inhibited by TAPI-0 (an ADAM17 inhibitor). Moreover, U0126 (an ERK inhibitor) inhibited thrombin-stimulated CTGF expression and c-Jun phosphorylation. Cells transfected with small interfering RNA of the EGFR attenuated thrombin-stimulated ERK phosphorylation, c-Jun phosphorylation, and CTGF expression. Thus, these results suggested that ADAM17/EGFR-dependent ERK activation mediated thrombin-stimulated CTGF expression in human lung fibroblasts.
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Proteína ADAM17/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fibroblastos/metabolismo , Linhagem Celular , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Pulmão , Fosforilação/fisiologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fibrose Pulmonar/metabolismo , Transdução de Sinais/fisiologia , Trombina/metabolismoRESUMO
Cantharidin, a natural toxin from blister beetles, has shown potent anticancer activities on many solid tumor cells. Recently, cantharidin and its analogue, norcantharidin, were also shown to suppress nonsolid tumors such as chronic myeloid leukemia, acute myeloid leukemia (AML), and leukemic stem cells. However, there is no available information to address the effects of cantharidic acid (CAC), a hydrolysis product of cantharidin, on human AML cells. The present study showed that CAC, at a range of concentrations (0-20 µM), concentration-dependently inhibited cell proliferation in the HL-60 AML cell line. Western blot and flow cytometric assays demonstrated that CAC induced several features of apoptosis such as sub G1-phase cell increase, phosphatidylserine (PS) externalization, and significantly activated proapoptotic signaling including caspase-8, -9, and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in HL-60 AML cells. Moreover, treatment of HL-60 cells with CAC induced concentration- and time- dependent activation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK). Only JNK-, but not p38 MAPK-specific inhibitor can reverse the CAC-induced activation of the caspase-8, -9, and -3. We concluded that CAC can induce apoptosis in human leukemic HL-60 cells via a caspases-dependent pathway, and that the apoptosis-inducing effect of CAC can be regulated by JNK activation signaling.
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Cantaridina/farmacologia , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática , Fase G1 , Células HL-60 , Humanos , Sistema de Sinalização das MAP Quinases , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Tricetin is a dietary flavonoid with cytostatic properties and antimetastatic activities in various solid tumors. The anticancer effect of tricetin in nonsolid tumors remains unclear. Herein, the molecular mechanisms by which tricetin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. Results showed that tricetin inhibited cell viability in various types of AML cell lines. Tricetin induced morphological features of apoptosis such as chromatin condensation and phosphatidylserine (PS) externalization, and significantly activated proapoptotic signaling including caspase-8, -9, and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in HL-60 AML cells. Of note, tricetin-induced cell growth inhibition was dramatically reversed by a pan caspase and caspase-8- and -9-specific inhibitors, suggesting that this compound mainly acts through a caspase-dependent pathway. Moreover, treatment of HL-60 cells with tricetin induced sustained activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), and inhibition of ERK and JNK by their specific inhibitors respectively promoted and abolished tricetin-induced cell apoptosis. Dichlorofluorescein (DCF) staining showed that intracellular reactive oxygen species (ROS) levels were higher in tricetin-treated HL-60 cells compared to the control group. Moreover, an ROS scavenger, N-acetylcysteine (NAC), reversed tricetin-induced JNK activation and subsequent cell apoptosis. In conclusion, our results indicated that tricetin induced cell death of leukemic HL-60 cells through induction of intracellular oxidative stress following activation of a JNK-mediated apoptosis pathway. A combination of tricetin and an ERK inhibitor may be a better strategy to enhance the anticancer activities of tricetin in AML.
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Cromonas/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Apoptose , Caspases/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células HL-60 , HumanosRESUMO
Viral-encoded ATPase can act as a part of molecular motor in genome packaging of DNA viruses, such as vaccinia virus and adenovirus, by ATP hydrolysis and interaction with DNA. Poxviral ATPase (also called A32) is involved in genomic double-stranded DNA (dsDNA) encapsidation, and inhibition of the expression of A32 causes formation of immature virions lacking viral DNA. However, the role of A32 in goatpoxvirus genome packaging and its dsDNA binding property are not known. In this study, purified recombinant goatpoxvirus A32 protein (rA32) was examined for its dsDNA binding property as well as the effect of dsDNA on ATP hydrolysis. We found that rA32 could bind dsDNA, and its ATPase activity was significant increased with dsDNA binding. Effects of magnesium and calcium ions on ATP hydrolysis were investigated also. The ATPase activity was dramatically enhanced by dsDNA in the presence of Mg(2+); in contrast, ATPase function was not altered by Ca(2+). Furthermore, the enzyme activity of rA32 was completely blocked by Zn(2+). Regarding DNA-protein interaction, the rA32-ATP-Mg(2+) showed lower dsDNA binding affinity than that of rA32-ATP-Ca(2+). The DNA-protein binding was stronger in the presence of zinc ion. Our results implied that A32 may play a role in viral genome encapsidation and DNA condensation.
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Adenosina Trifosfatases/metabolismo , Capripoxvirus/metabolismo , Vírus de DNA/genética , DNA Viral/metabolismo , DNA/genética , Proteínas Virais/metabolismo , Zinco/metabolismo , Trifosfato de Adenosina/metabolismo , Cálcio/metabolismo , Capripoxvirus/genética , Empacotamento do DNA/genética , Proteínas de Ligação a DNA/metabolismo , Genoma Viral/genética , Vaccinia virus/genética , Vaccinia virus/metabolismo , Montagem de Vírus/genéticaRESUMO
Amphipods are commonly parasitized by acanthocephalans and microsporidians and co-infections are found frequently. Both groups of parasites are known to have severe effects on their host. For example, microsporidians can modify host sex ratio and acanthocephalans can manipulate the behavior of the amphipod to promote transmission to the final host. These effects influence host metabolism in general and will also affect the ability of amphipods to cope with additional stressors such as environmental pollution, e.g., by toxic metals. Here we tested the effects of sub-lethal concentrations of cadmium on glycogen and lipid levels, as well as on the 70kDa heat shock protein (hsp70) response of field collected Gammarus fossarum, which were naturally infected with microsporidians and the acanthocephalan Polymorphus minutus. Infected and uninfected G. fossarum were exposed to a nominal Cd concentration of 4 µg/L, which resembled measured aqueous Cd concentration of 2.9 µg/L in reconstituted water for 7 d at 15 °C in parallel to an unexposed control. After exposure gammarids were snap frozen, weighed, sexed and tested for microsporidian infection by PCR. Only individuals containing the microsporidian Dictyocoela duebenum were used for the further biochemical and metal analyses. P. minutus infected amphipods were significantly smaller than their uninfected conspecifics. Mortality was insignificantly increased due to cadmium exposure, but not due to parasite infection. Microsporidian infection in combination with cadmium exposure led to increased glycogen levels in female gammarids. An increase of glycogen was also found due to interaction of acanthocephalan and microsporidian infection. Elevated lipid levels were observed in all groups infected with microsporidians, while acanthocephalans had the opposite effect. A positive correlation of lipid and glycogen levels was observed. The general stress response measured in form of hsp70 was significantly increased in microsporidian infected gammarids exposed to cadmium. P. minutus did not affect the stress response of its host. Lipid levels were correlated negatively with hsp70 response, and indicated a possible increased stress susceptibility of individuals with depleted energy reserves. The results of our study clearly demonstrate the importance of parasitic infections, especially of microsporidians, for ecotoxicological research.
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Conventional chemotherapy is commonly used to treat advanced non-resectable hepatocellular carcinoma (HCC) but this treatment modality has not demonstrated convincing survival benefit in HCC patients. Our previous studies indicated that targeted expression of therapeutic BikDD driven by a liver cancer-specific α-fetoprotein promoter/enhancer (eAFP) in the VISA backbone (eAFP-VISA-BikDD) significantly and specifically kills HCC cells in multiple orthotopic animal models. To enhance its therapeutic efficacy, we combined eAFP-VISA-BikDD with chemotherapeutic agents and found that eAFP-VISA-BikDD plus doxorubicin (Dox) or 5-fluorouracil (5-FU) demonstrated synergistic cytotoxicity in HCC cells. Specifically, the combination of eAFP-VISA-BikDD plus Dox markedly induced apoptosis via increased Bax mitochondrial translocation and cytoplasmic cytochrome c release. Compared with either agent alone, a low dose of Dox combined with eAFP-VISA-BikDD induced better antitumor effect and prolonged longer survival of mice in two orthotopic liver cancer xenograft models. Our findings provide strong preclinical support for evaluating the combined therapy of eAFP-VISA-BikDD and Dox in a clinical setting as a treatment option for HCC.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/tratamento farmacológico , Doxorrubicina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Membrana/genética , alfa-Fetoproteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Ativação Enzimática , Fluoruracila/farmacologia , Humanos , Marcação In Situ das Extremidades Cortadas , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Proteínas Mitocondriais , Regiões Promotoras Genéticas/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismoRESUMO
A home-made combustion and sampling apparatus was used to burn green leaves under flaming and smoldering conditions and to collect the smoke generated. The smoke was measured with Organic/Elemental Carbon (OC/EC) Analyzer using IMPROVE thermal-optical reflectance (TOR) method, to investigate the mass fractions and the distribution of OC, EC and eight carbon fractions in foliar smoke. The results showed that in smoldering condition, the mean OC, EC mass fractions of ten foliar smokes were 48.9% and 4.5%, respectively. The mean mass fraction of char-EC (EC1 - POC) was 4.4%. The average emission factors (EF) of particulate matters, OC and EC in smoldering foliar smoke were 102.4 g x kg(-1), 50.0 g x kg(-1) and 4.7 g x kg(-1), respectively. The mean ratios of OC/EC, OC1/OC2 and char-EC/soot-EC (EC1 - POC/EC2 + EC3) in this condition were 11.5, 1.9 and 48.1, respectively. For the foliar smoke emitted in flaming condition, the mean mass fractions of OC, EC and char-EC were 44.9%, 10.9% and 10.7%, respectively. The average EF of PM, OC and EC in flaming smoke were 59.2 g x kg(-1), 26.6 g x kg(-1) and 6.0 g x kg(-1). And the three ratios mentioned above in this condition were 4.8, 1.1 and 133.0, respectively. In conclusion, foliar smoke had higher OC1 mass fractions and OC1/OC2 values in smoldering condition. While flaming foliar smoke had higher char-EC mass fractions and char-EC/soot-EC values. The compositions of OC, EC in foliar smoke varied between different tree species and different combustion conditions. The composition was also obviously different from those of other biomass smoke.
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Carbono/análise , Folhas de Planta , Fumaça/análise , Biomassa , Material Particulado , FuligemRESUMO
Timosaponin AIII (TAIII) is a steroidal saponin isolated from Anemarrhena asphodeloides that has been shown to inhibit cell growth and induce apoptosis in cancer. However, the effect of TAIII on acute myeloid leukemia (AML) remains unclear. Here, the molecular mechanism by which TAIII-induced apoptosis affects human AML cells was investigated. The results showed that TAIII significantly inhibited cell proliferation of four AML cell lines (MV4-11, U937, THP-1, and HL-60). Furthermore, TAIII induced apoptosis of HL-60 cells through caspase-3, caspase-8, and caspase-9 activations and PARP cleavage in a dose- and time-dependent manner. Moreover, Western blot analysis also showed that TAIII increased phosphorylation of JNK1/2 and p38 MAPK in a dose-dependent manner. Inhibition of JNK1/2 by specific inhibitors significantly abolished the TAIII-induced activation of the caspase-8. Taken together, our results suggest that TAIII induces HL-60 cell apoptosis through JNK1/2 pathways and could serve as a potential additional chemotherapeutic agent for treating AML.
Assuntos
Apoptose/efeitos dos fármacos , Caspases/biossíntese , Leucemia Promielocítica Aguda/tratamento farmacológico , Saponinas/administração & dosagem , Esteroides/administração & dosagem , Caspases/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/biossínteseRESUMO
Nobiletin, a compound isolated from citrus fruits, is a polymethoxylated flavone derivative that was shown to have anti-inflammatory and anticancer activities in various solid tumors. The anticancer effect of nobiletin on nonsolid tumor remains unclear. Herein, the molecular mechanisms by which nobiletin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. The results showed that nobiletin suppressed cell proliferation in various types of AML cell lines. Moreover, nobiletin induced cell-cycle arrest of HL-60 AML cells at the G0/G1 phase by suppressing extracellular signal-regulated kinase (ERK) activity. Furthermore, nobiletin effectively induced apoptosis of HL-60 cells through caspase-8, caspase-9, and caspases-3 activation concomitantly with a marked induction of p38 mitogen-activated protein kinase (MAPK) activation, but without affecting expression levels of Bcl-2, Bax, or Bid. Taken together, our results suggest that nobiletin inhibited HL-60 cell proliferation through inducing cell-cycle arrest and apoptosis and could serve as a potential additional chemotherapeutic agent for treating AML.
Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Flavonas/farmacologia , Leucemia Mieloide Aguda/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/genéticaRESUMO
BACKGROUND: Pterostilbene (PTER) is a dimethylated analog of the phenolic phytoalexin, resveratrol, with higher anticancer activity in various tumors. Herein, the molecular mechanisms by which PTER exerts its anticancer effects against acute myeloid leukemia (AML) cells were investigated. METHODOLOGY AND PRINCIPAL FINDINGS: Results showed that PTER suppressed cell proliferation in various AML cell lines. PTER-induced G0/G1-phase arrest occurred when expressions of cyclin D3 and cyclin-dependent kinase (CDK)2/6 were inhibited. PTER-induced cell apoptosis occurred through activation of caspases-8-9/-3, and a mitochondrial membrane permeabilization (MMP)-dependent pathway. Moreover, treatment of HL-60 cells with PTER induced sustained activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2, and inhibition of both MAPKs by their specific inhibitors significantly abolished the PTER-induced activation of caspases-8/-9/-3. Of note, PTER-induced cell growth inhibition was only partially reversed by the caspase-3-specific inhibitor, Z-DEVE-FMK, suggesting that this compound may also act through a caspase-independent pathway. Interestingly, we also found that PTER promoted disruption of lysosomal membrane permeabilization (LMP) and release of activated cathepsin B. CONCLUSION: Taken together, our results suggest that PTER induced HL-60 cell death via MAPKs-mediated mitochondria apoptosis pathway and loss of LMP might be another cause for cell apoptosis induced by PTER.
Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Leucemia Mieloide Aguda/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estilbenos/farmacologia , Caspases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HL-60 , Humanos , Membranas Intracelulares/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lisossomos/metabolismo , Metaloproteinases da Matriz/metabolismoRESUMO
Posttranslational modifications of histones play fundamental roles in many biological functions. Specifically, histone H4-K20 methylation is critical for DNA synthesis and repair. However, little is known about how these functions are regulated by the upstream stimuli. Here, we identify a tyrosine phosphorylation site at Y72 of histone H4, which facilitates recruitment of histone methyltransferases (HMTases), SET8 and SUV4-20H, to enhance its K20 methylation, thereby promoting DNA synthesis and repair. Phosphorylation-defective histone H4 mutant is deficient in K20 methylation, leading to reduced DNA synthesis, delayed cell cycle progression, and decreased DNA repair ability. Disrupting the interaction between epidermal growth factor receptor (EGFR) and histone H4 by Y72 peptide significantly reduced tumor growth. Furthermore, EGFR expression clinically correlates with histone H4-Y72 phosphorylation, H4-K20 monomethylation, and the Ki-67 proliferation marker. These findings uncover a mechanism by which EGFR transduces signal to chromatin to regulate DNA synthesis and repair.