RESUMO
The receptor for advanced glycation end-products (RAGE) has been implicated in tumorigenesis, whereas epidermal growth factor receptor (EGFR) signaling plays a vital role in lung cancer progression. Both RAGE and EGFR are transmembrane receptors that transmit intracellular signals through ligand binding, and their downstream signaling cascades show substantial overlap. However, the interplay between these two molecules remains poorly understood. In the present study, we evaluated the correlation between RAGE and EGFR in the tumorigenesis of non-small cell lung cancer (NSCLC) and evaluated the impact of RAGE on the response of NSCLC cells to gefitinib, an EGFR-tyrosine kinase inhibitor (TKI). The expression and activation of EGFR and the phosphorylation of its downstream molecules, signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (Erk), were increased in RAGE-overexpressed A549 (A549-RAGE) cells. Notably, ligand-triggered activation of EGFR signaling was significantly greater in A549-RAGE compared with A549-parental cells. In addition, gefitinib had less effect on the inhibition of EGFR signaling in A549-RAGE cells. These findings were validated in other NSCLC cell lines, H1299 and H1975. Furthermore, upon gefitinib administration, the antiapoptotic marker B-cell lymphoma 2 (Bcl-2) expression was upregulated in A549-RAGE cells, whereas the apoptotic markers Bcl-2 associated X protein (Bax) and Bcl-2 interacting mediator (Bim) remained at lower levels compared with A549-parental cells. Importantly, our findings provide evidence that RAGE interferes with the anticancer effect of gefitinib by modulating the activation of EGFR-STAT3 and EGFR-Erk pathways. Overall, these significant findings deepen our understanding of the intricate relationship between RAGE and EGFR signaling in NSCLC tumorigenesis and provide new considerations for the clinical treatment of NSCLC.NEW & NOTEWORTHY This study represents a pioneering endeavor in comprehending the intricate interplay between RAGE and EGFR signaling within NSCLC. The findings reveal that RAGE serves to enhance EGFR phosphorylation and activation, consequently modulating apoptosis regulators through the EGFR-STAT3 and EGFR-Erk1/2 signaling pathways. Through this mechanism, RAGE potentially imparts resistance to the toxicity induced by EGFR-TKIs in NSCLC cells.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor para Produtos Finais de Glicação Avançada , Ligantes , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , CarcinogêneseRESUMO
Chemotherapy, in combination with immune checkpoint blockade (ICB) targeting to programmed death-1 (PD-1) or its ligand PD-L1, is one of the first-line treatments for patients with advanced non-small-cell lung cancer (NSCLC). However, a large proportion of patients, especially those with PD-L1 negative tumors, do not benefit from this treatment. This may be due to the existence of multiple immunosuppressive mechanisms other than the PD-1/PD-L1 axis. Human leukocyte antigen-G (HLA-G) has been identified as an immune checkpoint protein (ICP) and a neoexpressed tumor-associated antigen (TAA) in a large proportion of solid tumors. In this study, we evaluated the induction of HLA-G as well as PD-L1 using sublethal doses of chemotherapeutics including pemetrexed in different NSCLC cell lines. Except for gefitinib, most of the chemotherapeutic agents enhanced HLA-G and PD-L1 expression in a dose-dependent manner, whereas pemetrexed and carboplatin treatments showed the most consistent upregulation of PD-L1 and HLA-G in each cell line. In addition to protein levels, a novel finding of this study is that pemetrexed enhanced the glycosylation of HLA-G and PD-L1. Pemetrexed potentiated the cytotoxicity of cytotoxic T lymphocytes (CTLs) to treat NSCLC. Both in vitro and in vivo experiments revealed that CTL-mediated cytotoxicity was most pronounced when both anti-PD-L1 and anti-HLA-G ICBs were combined with pemetrexed treatment. In conclusion, anti-HLA-G could be an intervention strategy in addition to the anti-PD-1/PD-L1 pathway for NSCLC. Moreover, dual targeting of PD-L1 and HLA-G combined with pemetrexed might have a better extent of CTL-based immunotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linfócitos T Citotóxicos , Pemetrexede/farmacologia , Pemetrexede/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno B7-H1/metabolismoRESUMO
Antrodia salmonea (AS) is a fungus, which belongs to a fungal family of Taiwanofungus salmoneus with the features of anti-oxidant, anti-inflammatory, and anticancer. Recent studies have shown that AS has anti-cancer functions in ovarian and breast cancer. However, the effects of AS on prostate cancer (PCa) proliferation remain unknown. Therefore, we investigated the role of AS in PCa proliferation through apoptosis, and cell cycle regulation in PCa cell lines. Our results showed that Antrodia salmonea extract (ASE) inhibited PCa cells growth with a dose-dependent manner. In addition, ASE decreased the anchorage-independent growth formation ability in PC3 cells. Moreover, ASE-induced cell growth inhibition in PCa cells (DU145, PC3) was correlated to decreased cell cycle-related proteins such as cyclin A/B and cyclin-dependent kinase CDK1/2/4, and increased cell cycle inhibitor proteins p21. Besides, ASE decreased the total protein level of epidermal growth factor receptor and its downstream signaling pathways Akt and Erk in both PCa cells. We found that apoptotic markers such as cleaved-PARP protein levels increased significantly in DU145 cells indicating ASE might induce apoptosis. In conclusion, our results suggest that ASE may have the ability to induce PCa cell death through regulating cell cycle arrest and apoptosis pathways.
Assuntos
Apoptose , Neoplasias da Próstata , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Extratos Vegetais/farmacologia , Polyporales , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismoRESUMO
BACKGROUND: The combination of diabetes mellitus (DM) and chronic kidney disease (CKD) is associated with a high risk of mortality. Annual assessment of the estimated glomerular filtration rate (eGFR) is recommended for patients with DM. We investigated the effect of variability in annual eGFR values on all-cause mortality in patients with type 2 DM. METHODS: In this retrospective cohort study, we enrolled patients with eGFR data between 01 Aug 2017 and 31 July 2018. We defined the index eGFR as the first available eGFR value within the enrollment year and collected additional annual eGFR data from the previous three years. A total of 3592 patients with type 2 DM were enrolled, including 959 patients with CKD (index eGFR < 60 mL/min/1.73 m2) and 2633 patients without CKD. We assessed eGFR variability by using the standard deviation (SD) of the three annual eGFR and index eGFR values. We divided patients into subgroups according to the median SD of their annual eGFR (7.62 mL/min/1.73 m2). The primary endpoint was all-cause mortality after the index eGFR was assessed. RESULTS: During a median follow-up of 19 months (interquartile range: 18â20 months), 127 (3.5%) deaths occurred among all 3592 enrolled patients. The highest mortality risk was observed in the high SD with CKD group, with a hazard ratio (HR) of 2.382 [95% confidence interval (CI) 1.346â4.215] in comparison to the low SD without CKD group after adjusting for the associated factors. In patients without CKD, a high SD was an independent risk factor for mortality (HR = 2.105, 95% CI 1.256â3.528). According to the C-index, the mortality prediction ability was better for the index eGFR + SD model than for the index eGFR alone model (0.671 vs. 0.629, P < 0.001). CONCLUSION: There was a synergistic effect of eGFR variability with single-measured eGFR for the prediction of mortality in patients with type 2 DM. The SD of the annual eGFR values was also an independent predictor of mortality in patients with an eGFR > 60 mL/min/1.73 m2.
Assuntos
Diabetes Mellitus Tipo 2/mortalidade , Rim/fisiopatologia , Insuficiência Renal Crônica/mortalidade , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Causas de Morte , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Taxa de Filtração Glomerular , Hemoglobinas Glicadas/metabolismo , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC50 inhibition abilities by enzyme kinetics and Kd values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.
Assuntos
Antineoplásicos/farmacologia , Enzimas Reparadoras do DNA/antagonistas & inibidores , Diaminas/farmacologia , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Enzimas Reparadoras do DNA/metabolismo , Diaminas/síntese química , Diaminas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Monoéster Fosfórico Hidrolases/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , TermodinâmicaRESUMO
BACKGROUND: Peripheral artery disease (PAD) in the lower extremities is a common complication of type 2 diabetes and has been shown to be associated with mortality. The ankle-brachial index (ABI) is a simple noninvasive method to screen PAD, but this method has limited sensitivity. We hypothesized that using the percentage of mean arterial pressure (%MAP) in combination with the ABI would improve the prediction of mortality. METHODS: We retrospectively collected data from patients with type 2 diabetes who had undergone ABI and %MAP measurements at our hospital. We separated the cohort into four groups according to their ABI and %MAP values, and we examined whether these indices were associated with mortality. RESULTS: A total of 5569 patients (mean age, 65 ± 11 years) were enrolled. During the follow-up period (median, 22.9 months), 266 (4.8%) of the enrolled patients died. The combination of ABI and %MAP was significantly more effective than ABI alone for predicting mortality (C index of 0.62, 95% confidence interval [CI] of 0.57 to 0.65 vs. C index of 0.57, 95% CI of 0.53 to 0.62; P = 0.038). In multivariate analysis (with a reference group defined by ABI > 0.90 and %MAP ≤ 45%), the highest risk of mortality was seen in patients with ABI ≤ 0.90 and %MAP > 45% (hazard ratio = 2.045 [95% CI 1.420, 2.945], P < 0.001). CONCLUSIONS: The use of %MAP alongside ABI appears to significantly improve the prediction of all-cause mortality in patients with type 2 diabetes.
Assuntos
Índice Tornozelo-Braço , Pressão Arterial , Determinação da Pressão Arterial , Diabetes Mellitus Tipo 2/diagnóstico , Doença Arterial Periférica/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/mortalidade , Doença Arterial Periférica/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
We investigated if brain-derived neurotrophic factor (BDNF) accumulation after glucose intake could predict cardiovascular outcomes. We enrolled patients admitted for angiography due to angina. After their conditions stabilized, serum BDNF levels were detected at 0, 30, and 120 min during oral glucose tolerance test (OGTT). Area under the curve (AUC) of BDNF was calculated. The first occurrence of nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality served as the primary composite endpoint. Of 480 enrolled patients, 428 completed the follow-up, and 36 primary endpoint events occurred during a median follow-up of 4.4 years. The area under the receiver operating characteristic curve significantly increased from 0.61 (95% confidence interval (CI): 0.52-0.73) for the Framingham risk score (FRS) alone model to 0.72 (95%CI: 0.63-0.81) for the AUC of BDNF plus FRS model (p = 0.016) for predicting the primary endpoint, but not to 0.65 (95%CI: 0.55-0.75) for the fasting BDNF plus FRS model (p = 0.160). Grouped by median AUC of BDNF of 38.0 (ng/mL) × h, the low BDNF group had a significantly higher risk of the endpoint than the high BDNF group (hazard ratio = 3.410, 95%CI: 1.520-7.653, p = 0.003). In conclusion, AUC of BDNF during OGTT could be superior to fasting BDNF for predicting a low cardiovascular risk.
Assuntos
Angina Pectoris/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Teste de Tolerância a Glucose , Idoso , Idoso de 80 Anos ou mais , Angina Pectoris/diagnóstico , Área Sob a Curva , Glicemia/análise , Jejum/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
OBJECTIVES: This study investigated the clinical effectiveness of intervention with an open-mouth exercise device designed to facilitate maximal interincisal opening (MIO) and improve quality of life in patients with head and neck (H&N) cancer and oral submucous fibrosis (OSF). MATERIALS AND METHODS: Sixty patients with H&N cancer, OSF, and trismus (MIO < 35 mm) participated in the functional rehabilitation program. An open-mouth exercise device intervention group and conventional group, each consisting of 20 patients, underwent a 12-week training and exercising program and follow-up. For the control group, an additional 20 patients were randomly selected to match the demographic characteristics of the aforementioned two groups. RESULTS: The patients' MIO improvements in the aforementioned three groups were 14.0, 10.5, and 1.3 mm, respectively. CONCLUSION: Results of this study confirm the significant improvement in average mouth-opening range. In addition, according to patient feedback, significant improvements in health-related quality of life and reductions in trismus symptoms occurred in the open-mouth exercise device group. CLINICAL RELEVANCE: This newly designed open-mouth exercise device can facilitate trismus patients with H&N cancer and OSF and improve mouth-opening range and quality of life.
Assuntos
Terapia por Exercício/instrumentação , Neoplasias de Cabeça e Pescoço/complicações , Fibrose Oral Submucosa/complicações , Trismo/etiologia , Trismo/reabilitação , Adulto , Idoso , Avaliação da Deficiência , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Resultado do TratamentoRESUMO
OBJECTIVES: Autofluorescence imaging is gaining popularity as an adjunctive test for oral potentially malignant disorders (OPMD). This study evaluated the efficacy of autofluorescence imaging based on the current standard oral mucosal disorder checklist in Taiwan. MATERIALS AND METHODS: In total, 126 patients suspected to have mucosal disorders at the Division of Oral and Maxillofacial Surgery, Tri-Service General Hospital, Taipei, Taiwan, were enrolled. Following a conventional oral examination by using the oral mucosal disorder checklist and an autofluorescence imaging examination, all participants underwent histopathological examination to access epithelial dysplasia. RESULTS: Among 126 patients, 68 patients were diagnosis as having an OPMD and 63 having epithelial dysplasia. Autofluorescence imaging exhibited a sensitivity, specificity, positivity predictive value (PPV), negative predictive value (NPV), and accuracy of 77.94%, 35.42%, 63.10%, 53.13%, and 60.34%, respectively, for OPMD and of 88.89%, 43.86%, 63.64%, 78.13%, and 67.50%, respectively, for epithelial dysplasia. After the exclusion of 48 non-OPMD cases according to the checklist, the sensitivity, specificity, PPV, NPV, and accuracy of autofluorescence imaging became 87.50%, 72.73%, 94.23%, 53.33%, and 85.07%, respectively, for epithelial dysplasia. CONCLUSION: The efficacy of epithelial dysplasia identification and OPMD risk assessment can be increased after the exclusion of the non-OPMD cases through autofluorescence imaging. CLINICAL RELEVANCE: Autofluorescence imaging is a useful adjunct that can assist specialists in assessing OPMD patients prone to dysplasia without compromising patient care.
Assuntos
Neoplasias Bucais/diagnóstico por imagem , Imagem Óptica , Lesões Pré-Cancerosas/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/diagnóstico por imagem , Mucosa Bucal/patologia , Sensibilidade e Especificidade , TaiwanRESUMO
Correction for '2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition' by Kunal Nepali et al., Org. Biomol. Chem., 2016, 14, 716-723.
RESUMO
BACKGROUND: The oral glucose tolerance test (OGTT) is recommended to screen for diabetes in patients with coronary artery disease. We hypothesized that testing for glycated hemoglobin (HbA1c), in addition to the OGTT, in screening for abnormal glucose regulation may help to reveal patients with ß-cell function impairment. METHODS: Patients with no history of diabetes who were admitted for coronary angiography were recruited to undergo an OGTT and HbA1c test 2-4 weeks after hospital discharge. ß-cell function and insulin resistance were assessed using the homeostasis model assessment (HOMA-ß and HOMA-IR, respectively). For patients with normal glucose tolerance (NGT) based on the OGTT, we compared HOMA-ß between two subgroups of patients using an HbA1c cutoff of 39 mmol/mol or 42 mmol/mol. For patients with prediabetes based on an OGTT, we compared the HOMA-ß between two subgroups of patients using an HbA1c cutoff of 48 mmol/mol. RESULTS: A total of 1044 patients were analyzed. In patients with NGT by OGTT (n=432), those with an HbA1c ≥42 mmol/mol had a lower HOMA-ß compared to those with an HbA1c <42 mmol/mol (107±82 vs. 132±96, p=0.018). In patients with prediabetes by OGTT (n=423), those with an HbA1c ≥48 mmol/mol had a lower HOMA-ß compared to those with an HbA1c <48 mmol/mol (91±52 vs. 120±88, p=0.003). No significant between-group difference in HOMA-IR was noted. CONCLUSIONS: The use of HbA1c in addition to the OGTT in screening for abnormal glucose regulation helped to reveal patients with early ß-cell function impairment.
Assuntos
Diabetes Mellitus/diagnóstico , Hemoglobinas Glicadas/análise , Estado Pré-Diabético/diagnóstico , Idoso , Análise Química do Sangue , Diabetes Mellitus/fisiopatologia , Feminino , Teste de Tolerância a Glucose , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Estado Pré-Diabético/fisiopatologiaRESUMO
This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11-23) on the basis of scaffold hopping. The presence of a methoxy group at C6 assists the highly regioselective incorporation with various amines, and simplifies the structural identification process. Among the synthetic compounds, 6-dimethylamino-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (12) and 7-pyrrolidin-1-yl-2-(3,4,5-trimethoxybenzoyl)-quinoline-5,8-dione (23) exhibit remarkable anti-proliferative activity against the cancer cell lines tested with mean IC50 values of 0.14 and 0.27 µM, respectively. Compound 23 showed moderate inhibitory activity against tubulin polymerization with an IC50 value of 5.9 µM. In a western blot analysis, 23 caused induction of HSP70 and degradation of Akt, revealing that it possesses HSP90 inhibitory activity.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Quinolonas/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Proteínas de Choque Térmico HSP72/biossíntese , Humanos , Células KB , Proteínas Proto-Oncogênicas c-akt/biossíntese , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
This study focused on the substitution effect at position C7 of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines. Compound 9, (E)-3-(7-amino-1-(4-methoxyphenylsulfonyl)indolin-5-yl)-N-hydroxyacrylamide, displayed 4- to 14-fold more potent antiproliferative activity than vorinostat (SAHA, 1). Notably, 9 possessed specific histone deacetylase (HDAC) inhibitory activity toward HDAC1 and HDAC2, but had no effect on HDAC6, indicating that 9 has the potential to be developed as a class I HDAC inhibitor. In a xenograft tumor model, 9 suppressed the growth of HCT116 cells at 100 mg kg(−1), which led to a TGI (tumor growth inhibition) of 40.3%. Taken together, the C7 substitutions have a crucial effect on class I HDACs, which is beneficial for synthesizing efficient anticancer agents.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HeLa , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Hepatitis C virus (HCV) infection is prevalent in patients with type 2 diabetes mellitus (DM). We aimed to investigate whether HCV antibody (Ab) seropositivity is associated with diabetic micro- and macro-vascular diseases. In this hospital-based cross-sectional study, we retrospectively collected data from patients who participated in the diabetes pay-for-performance program and underwent HCV Ab screening in the annual comprehensive assessment between January 2021 and March 2022. We examined the relationships of HCV Ab seropositivity with the spot urinary albumin-to-creatinine ratio (UACR) and ankle-brachial index (ABI) in patients aged ≥ 50 years with type 2 DM. A total of 1758 patients were enrolled, and 85 (4.83%) of the enrolled patients had HCV Ab seropositivity. Multivariable regression analyses revealed that albuminuria showed a dose-dependent association with HCV Ab seropositivity (UACR [30-299 mg/g]: odds ratio [OR] = 1.463, 95% confidence interval [CI] 0.872â2.456); UACR [≥ 300 mg/g]: OR = 2.300, 95% CI 1.160â4.562; P for trend = 0.015) when compared with normal albuminuria (UACR < 30 mg/g). However, the proportion of patients with peripheral arterial disease, defined as an ABI ≤ 0.9, was not significantly different between the groups with and without HCV Ab seropositivity (3.5% vs. 3.9%, P = 0.999). In conclusion, severely increased albuminuria, but not the ABI, showed a significant association with HCV Ab seropositivity in patients aged ≥ 50 years with type 2 DM.
Assuntos
Diabetes Mellitus Tipo 2 , Hepatite C , Doença Arterial Periférica , Humanos , Diabetes Mellitus Tipo 2/complicações , Hepacivirus , Estudos Retrospectivos , Albuminúria/complicações , Estudos Transversais , Reembolso de Incentivo , Doença Arterial Periférica/complicações , Hepatite C/complicações , Artérias , CreatininaRESUMO
Metformin, the most commonly prescribed drug for the treatment of diabetes, is increasingly used during pregnancy to address various disorders such as diabetes, obesity, preeclampsia, and metabolic diseases. However, its impact on neocortex development remains unclear. Here, we investigated the direct effects of metformin on neocortex development, focusing on ERK and p35/CDK5 regulation. Using a pregnant rat model, we found that metformin treatment during pregnancy induces small for gestational age (SGA) and reduces relative cortical thickness in embryos and neonates. Additionally, we discovered that metformin inhibits neural progenitor cell proliferation in the sub-ventricular zone (SVZ)/ventricular zone (VZ) of the developing neocortex, a process possibly mediated by ERK inactivation. Furthermore, metformin induces neuronal apoptosis in the SVZ/VZ area of the developing neocortex. Moreover, metformin retards neuronal migration, cortical lamination, and differentiation, potentially through p35/CDK5 inhibition in the developing neocortex. Remarkably, compensating for p35 through in utero electroporation partially rescues metformin-impaired neuronal migration and development. In summary, our study reveals that metformin disrupts neocortex development by inhibiting neuronal progenitor proliferation, neuronal migration, cortical layering, and cortical neuron maturation, likely via ERK and p35/CDK5 inhibition. Consequently, our findings advocate for caution in metformin usage during pregnancy, given its potential adverse effects on fetal brain development.
Assuntos
Proliferação de Células , Quinase 5 Dependente de Ciclina , Metformina , Neocórtex , Metformina/farmacologia , Animais , Feminino , Gravidez , Neocórtex/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/metabolismo , Ratos , Proliferação de Células/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ratos Sprague-Dawley , Diferenciação Celular/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
A series of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines (7-15) has been developed; the compounds exhibited potent histone deacetylase (HDAC) inhibitory activities. Notably, almost all of this series exhibited better HDAC-inhibitory and antiproliferative activities than 3-(1-benzenesulfonyl-1H-indol-5-yl)-N-hydroxyacrylamide (6), as reported in a previous study. Among these compounds, 3-[1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]-N-hydroxyacrylamide (9) showed a two- to tenfold increase in activity compared to SAHA (1) in the suppression of lipopolysaccharide-induced cytokine production. Compound 9 also caused a marked reduction in carrageenan-induced acute inflammation in a rat model. Taken together, these data indicated that 1-arylsulfonyl-5-(N-hydroxyacrylamide)indolines HDAC inhibitors exhibit potent anti-inflammatory activity.
Assuntos
Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Indóis/farmacologia , Acrilamidas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Células HeLa , Humanos , Masculino , Camundongos , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
This retrospective cohort study aimed to assess the mortality risk in patients with type 2 diabetes mellitus (DM) by screening for depressive symptoms and peripheral artery disease (PAD). We enrolled patients aged ≥60 years who had undergone assessments of both the ankle-brachial index (ABI) and the five-item Geriatric Depression Scale (GDS-5). PAD and depression were defined as ABI ≤ 0.90 and GDS-5 ≥ 1, respectively. The primary endpoint was total mortality. In 1673 enrolled patients, the prevalence of PAD was higher in those with depression than in those without depression (8.9% vs. 5.7%, p = 0.021). After a median follow-up of 56.6 months (interquartile range: 47.0-62.3 months), a total of 168 (10.0%) deaths occurred. The patients in the depression and PAD subgroup had the highest hazard ratio of mortality, followed by the PAD without depression subgroup and the depression without PAD subgroup (2.209, 95%CI: 1.158-4.217; 1.958, 95%CI: 1.060-3.618; and 1.576, 95%CI: 1.131-2.196; respectively) in comparison to the patients without depression and PAD after adjustment for associated factors. In conclusion, a combination of depression and PAD predicted the highest mortality risk. Screening for depression and PAD is recommended in patients aged ≥60 years with type 2 DM.
RESUMO
Glycemic control in patients with type 2 diabetes may be disrupted due to restricted medical service access and lifestyle changes during COVID-19 lockdown period. This retrospective cohort study examined changes of HbA1c levels in adults with type 2 diabetes 12 weeks before and after May 19 in 2021, the date that COVID-19 lockdown began in Taiwan. The mean levels of HbA1c-after were significantly lower than HbA1c-before in 2019 (7.27 ± 1.27% vs 7.43 ± 1.38%, p < 0.001), 2020 (7.27 ± 1.28% vs 7.37 ± 1.34%, p < 0.001), and 2021 (7.03 ± 1.22% vs 7.17 ± 1.29%, p < 0.001). Considering the seasonal variation of HbA1c, ΔHbA1c values (HbA1c-after minus HbA1c-before) in 2020 (with sporadic COVID-19 cases and no lockdown) were not significantly different from 2021 (regression coefficient [95% CI] = 0.01% [-0.02%, 0.03%]), while seasonal HbA1c variation in 2019 (no COVID-19) was significantly more obvious than in 2021 (-0.05% [-0.07, -0.02%]). In conclusion, HbA1c level did not deteriorate after a lockdown measure during the COVID-19 pandemic in Taiwan. However, the absolute seasonal reduction in HbA1c was slightly less during the COVID-19 pandemic compared with the year without COVID-19.
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BACKGROUND: Epicardial adipose tissue (EAT) is a type of ectopic fat with endocrine and paracrine functions. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that responds to environmental stimuli. AhR expression is associated with obesity. In this cross-sectional study, we aimed to determine the relationship between circulating AhR concentrations and EAT. METHODS: A total of 30 men with obesity and 23 age-matched men as healthy controls were enrolled. Plasma AhR concentrations were determined at fasting. The EAT thickness was measured on the free wall of the right ventricle from the basal short-axis plane by magnetic resonance imaging. RESULTS: The participants with obesity had a higher plasma AhR level than the controls (81.0 ± 24.5 vs. 65.1 ± 16.4 pg/mL, P = 0.010). The plasma AhR level was positively correlated with EAT thickness (correlation coefficient = 0.380, P = 0.005). After adjusting for fasting glucose levels, plasma AhR levels were still significantly associated with EAT thickness (95% CI 0.458â5.357, P = 0.021) but not with body mass index (P = 0.168). CONCLUSION: Plasma AhR concentrations were positively correlated with EAT thickness on the free wall of the right ventricle in men. Further investigations are needed to evaluate the causal effects and underlying mechanisms between AhR and EAT.
RESUMO
The canonical ß-catenin-dependent wingless (Wnt) pathway is associated with endothelial function. We examined the effect of plasma dickkopf-1 (DKK-1), an inhibitor of the Wnt pathway, on the prediction of major adverse cardiac events (MACEs). We enrolled patients who had undergone selective coronary angiography for angina. DKK-1 levels were determined using plasma collected at the outpatient visit after fasting. MACEs served as the primary endpoint. All 470 enrolled patients were divided into four groups according to their median plasma DKK-1 levels and the presence of obstructive coronary artery disease (CAD). Forty-eight patients reached the primary endpoint during a median follow-up time of 4.8 years. Kaplan-Meier survival analysis indicated that the group with high DKK-1 and obstructive CAD had a significantly higher mortality rate than the other three groups (log-rank test p = 0.001). Compared with the low plasma DKK-1 without significant coronary obstruction group, the high DKK-1 with obstructive CAD group had a hazard ratio of 10.640 (95% confidence interval: 1.350-83.874) for MACEs, as determined by multivariable Cox proportional hazard regression analysis. In conclusion, we observed a synergistic effect between high plasma DKK-1 and obstructive CAD on the prediction of MACEs in patients with angina.