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Obesity is a global health challenge that causes metabolic dysregulation and increases the risk of various chronic diseases. The gut microbiome is crucial in modulating host energy metabolism, immunity, and inflammation and is influenced by dietary factors. Gac fruit (Momordica cochinchinensis), widely consumed in Southeast Asia, has been proven to have various biological activities. However, the composition and effect of crude gac aril polysaccharides (GAP) on obesity and gut microbiota disturbed by high-fat diet (HFD) remain to be elucidated. Compositional analysis showed that GAP contains high oligosaccharides, with an average of 7-8 saccharide units. To mimic clinical obesity, mice were first made obese by feeding HFD for eight weeks. GAP intervention was performed from week 9 to week 20 in HFD-fed mice. Our results showed that GAP inhibited body weight gain, eWAT adipocyte hypertrophy, adipokine derangement, and hyperlipidemia in HFD-induced obese mice. GAP improved insulin sensitivity, impaired glucose tolerance, and hepatic steatosis. GAP modulated the gut microbiota composition and reversed the HFD-induced dysbiosis of at least 20 genera. Taken together, GAP improves metabolic health and modulates the gut microbiome to relieve obesity risk factors, demonstrating the potential of dietary GAP for treating obesity-associated disorders.
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Dieta Alta en Grasa , Microbioma Gastrointestinal , Obesidad , Polisacáridos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Obesidad/tratamiento farmacológico , Obesidad/etiología , Obesidad/microbiología , Dieta Alta en Grasa/efectos adversos , Polisacáridos/farmacología , Ratones , Masculino , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/etiología , Disbiosis , Ratones Endogámicos C57BL , Resistencia a la InsulinaRESUMEN
Care aides in long-term care (LTC) institutions care for older disabled residents at high risk for COVID-19. However, they experienced many stressors during the COVID-19 pandemic. This study aims to explore the working experiences of care aides in LTC institutions following the relaxation of COVID-19 regulations in Taiwan. This qualitative descriptive study included 20 care aides who had cared for residents with COVID-19. Data were obtained via semi-structured interviews. Caring for residents with COVID-19 and the difficulties, resources and teamwork, and impact of care aides' work on their lives were discussed. Consequently, four themes were identified. First, difficulties in care, which included physical limitations by protection, workload, and impact of work schedule on the lives of the care aides. Second, psychological impact, such as worry, social isolation, and burnout. Third, interpersonal relationships with supervisors, colleagues, residents, and their families. Fourth, infection control policy from the institution and government. When infection control policies were relaxed, care aides had difficulties in caring for residents; furthermore, their family and social lives were also affected. They were required to learn knowledge of and skills for COVID-19 management. Institutions were required to provide support in materials, care processes, environment, and management.
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Glioblastoma multiforme (GBM) is the most aggressive type of malignant brain tumor. Currently, the predominant clinical treatment is the combination of surgical resection with concurrent radiotherapy and chemotherapy, using temozolomide (TMZ) as the primary chemotherapy drug. Lidocaine, a widely used amidebased local anesthetic, has been found to have a significant anticancer effect. It has been reported that aberrant hepatocyte growth factor (HGF)/mesenchymalepithelial transition factor (MET) signaling plays a role in the progression of brain tumors. However, it remains unclear whether lidocaine can regulate the MET pathway in GBM. In the present study, the clinical importance of the HGF/MET pathway was analyzed using bioinformatics. By establishing TMZresistant cell lines, the impact of combined treatment with lidocaine and TMZ was investigated. Additionally, the effects of lidocaine on cellular function were also examined and confirmed using knockdown techniques. The current findings revealed that the HGF/MET pathway played a key role in brain cancer, and its activation in GBM was associated with increased malignancy and poorer patient outcomes. Elevated HGF levels and activation of its receptor were found to be associated with TMZ resistance in GBM cells. Lidocaine effectively suppressed the HGF/MET pathway, thereby restoring TMZ sensitivity in TMZresistant cells. Furthermore, lidocaine also inhibited cell migration. Overall, these results indicated that inhibiting the HGF/MET pathway using lidocaine can enhance the sensitivity of GBM cells to TMZ and reduce cell migration, providing a potential basis for developing novel therapeutic strategies for GBM.
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Neoplasias Encefálicas , Resistencia a Antineoplásicos , Glioblastoma , Lidocaína , Humanos , Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Lidocaína/farmacología , Lidocaína/uso terapéutico , Transducción de Señal , Temozolomida/uso terapéuticoRESUMEN
α-Viniferin, a natural stilbene compound found in plants and a polymer of resveratrol, had demonstrated potential anti-cancer and anti-inflammatory effects. However, the specific mechanisms underlying its anti-cancer activity were not yet fully understood and required further investigation. This study evaluated the effectiveness of α-viniferin and ε-viniferin using MTT assay. Results showed that α-viniferin was more effective than ε-viniferin in reducing the viability of NCI-H460 cells, a type of non-small cell lung cancer. Annexin V/7AAD assay results provided further evidence that the decrease in cell viability observed in response to α-viniferin treatment was due to the induction of apoptosis in NCI-H460 cells. The present findings indicated that treatment with α-viniferin could stimulate apoptosis in cells by cleaving caspase 3 and PARP. Moreover, the treatment reduced the expression of SIRT1, vimentin, and phosphorylated AKT, and also induced AIF nuclear translocation. Furthermore, this research provided additional evidence for the effectiveness of α-viniferin as an anti-tumor agent in nude mice with NCI-H460 cell xenografts. As demonstrated by the TUNEL assay results, α-viniferin promoted apoptosis in NCI-H460 cells in nude mice.
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Glioblastoma (GBM) is a malignant brain tumor, commonly treated with temozolomide (TMZ). Upregulation of A disintegrin and metalloproteinases (ADAMs) is correlated to malignancy; however, whether ADAMs modulate TMZ sensitivity in GBM cells remains unclear. To explore the role of ADAMs in TMZ resistance, we analyzed changes in ADAM expression following TMZ treatment using RNA sequencing and noted that ADAM17 was markedly upregulated. Hence, we established TMZ-resistant cell lines to elucidate the role of ADAM17. Furthermore, we evaluated the impact of ADAM17 knockdown on TMZ sensitivity in vitro and in vivo. Moreover, we predicted microRNAs upstream of ADAM17 and transfected miRNA mimics into cells to verify their effects on TMZ sensitivity. Additionally, the clinical significance of ADAM17 and miRNAs in GBM was analyzed. ADAM17 was upregulated in GBM cells under serum starvation and TMZ treatment and was overexpressed in TMZ-resistant cells. In in vitro and in vivo models, ADAM17 knockdown conferred greater TMZ sensitivity. miR-145 overexpression suppressed ADAM17 and sensitized cells to TMZ. ADAM17 upregulation and miR-145 downregulation in clinical specimens are associated with disease progression and poor prognosis. Thus, miR-145 enhances TMZ sensitivity by inhibiting ADAM17. These findings offer insights into the development of therapeutic approaches to overcome TMZ resistance.
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Neoplasias Encefálicas , Glioblastoma , MicroARNs , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Línea Celular Tumoral , MicroARNs/metabolismo , Regulación hacia Abajo , Neoplasias Encefálicas/patología , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Proteína ADAM17/genética , Proteína ADAM17/metabolismoRESUMEN
BACKGROUND: Serum albumin level is a crucial nutritional indicator for patients on dialysis. Approximately one-third of patients on hemodialysis (HD) have protein malnutrition. Therefore, the serum albumin level of patients on HD is strongly correlated with mortality. METHODS: In study, the data sets were obtained from the longitudinal electronic health records of the largest HD center in Taiwan from July 2011 to December 2015, included 1,567 new patients on HD who met the inclusion criteria. Multivariate logistic regression was performed to evaluate the association of clinical factors with low serum albumin, and the grasshopper optimization algorithm (GOA) was used for feature selection. The quantile g-computation method was used to calculate the weight ratio of each factor. Machine learning and deep learning (DL) methods were used to predict the low serum albumin. The area under the curve (AUC) and accuracy were calculated to determine the model performance. RESULTS: Age, gender, hypertension, hemoglobin, iron, ferritin, sodium, potassium, calcium, creatinine, alkaline phosphatase, and triglyceride levels were significantly associated with low serum albumin. The AUC and accuracy of the GOA quantile g-computation weight model combined with the Bi-LSTM method were 98% and 95%, respectively. CONCLUSION: The GOA method was able to rapidly identify the optimal combination of factors associated with serum albumin in patients on HD, and the quantile g-computation with DL methods could determine the most effective GOA quantile g-computation weight prediction model. The serum albumin status of patients on HD can be predicted by the proposed model and accordingly provide patients with better a prognostic care and treatment.
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Colorectal cancer is a leading cause of cancer mortality worldwide, with an increasing incidence rate in developing countries. Integration of genetic information with cancer therapy guidance has shown promise in cancer treatment, indicating its potential as an essential tool in translation oncology. However, the high-throughput analysis and variability of genomic data poses a major challenge to conventional analytic approaches. In this study, we propose an advanced analytic approach, named "Fuzzy-based RNNCoxPH," incorporated fuzzy logic, recurrent neural networks (RNNs), and Cox proportional hazards regression (CoxPH) for detecting missense variants associated with high-risk of all-cause mortality in rectum adenocarcinoma. The test data set was downloaded from "Rectum adenocarcinoma, TCGA-READ" the Genomic Data Commons (GDC) portal. In this study, four model-based risk score models were derived using RNN, CoxPH, RNNCoxPHAddition, and RNNCoxPHMultiplication. The RNNCoxPHAddition and RNNCoxPHMultiplication models were obtained as the sum and product of the RNN risk degree matrix and the CoxPH risk degree matrix, respectively. Moreover, the fuzzy logic system was used to calculate the survival risk values of missense variants and classified their membership grade to improve the identification of high-risk gene variation locations associated with cancer mortality. The four models were integrated to develop an advanced risk estimation model. There were 20 028 variants associated with survival status, amongst 17 638 variants were associated with survival and 2390 variants associated with mortality. The proposed Fuzzy-based RNNCoxPH model obtained a balanced accuracy of 93.7%, which was significantly higher than that of the other four test methods. In particular, the CoxPH model is commonly used in medical researches and the XGBoost model is famous for its high accuracy in machine learning. The results suggest that the Fuzzy-based RNNCoxPH model exhibits a higher efficacy in identifying and classifying the missense variants related to mortality risk in rectum adenocarcinoma.
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Adenocarcinoma , Aprendizaje Profundo , Neoplasias del Recto , Humanos , Algoritmos , Medición de Riesgo , Neoplasias del Recto/genéticaRESUMEN
Chondrosarcoma is the second most common type of bone cancer. Surgical resection is the best choice for clinical treatment. High-grade chondrosarcoma is destructive and is more possible to metastasis, which is difficult to remove using surgery. Doxorubicin (Dox) is the most commonly used chemotherapy drug in the clinical setting; however, drug resistance is a major obstacle to effective treatment. In the present study, we compared Dox-resistant SW1353 cells to their parental cells using RNA sequencing (RNA-Seq). We found that the apelin (APLN) pathway was highly activated in resistant cells. In addition, tissue array analysis also showed that APLN was higher in high-grade tissues compared to low-grade tissues. APLN is a member of the adipokine family, which is a novel secreted peptide with multifunctional and biological activities. Previously, studies have shown that inhibition of the APLN axis may have a therapeutic benefit in cancers. However, the role of APLN in chondrosarcoma is completely unclear, and no related studies have been reported. During in vitro experiments, APLN was also observed to be highly expressed and secreted in Dox-resistant cells. Once APLN was knocked down, it could effectively improve its sensitivity to Dox. We also explored possible upstream regulatory microRNAs (miRNAs) of APLN through bioinformatics tools and the results disclosed that miR-631 was the most likely regulator of APLN. Furthermore, the expression of miR-631 was lower in the resistant cells, but overexpression of miR-631 in the Dox-resistant cell lines significantly increased the Dox sensitivity. These results were also observed in another chondrosarcoma cell line, JJ012 cells. Taken together, these findings will provide rationale for the development of drug resistance biomarkers and therapeutic strategies for APLN pathway inhibitors to improve the survival of patients with chondrosarcoma.
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Apelina , Neoplasias Óseas , Condrosarcoma , Doxorrubicina , Resistencia a Antineoplásicos , MicroARNs , Humanos , Apelina/genética , Apelina/metabolismo , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Condrosarcoma/tratamiento farmacológico , Condrosarcoma/genética , Condrosarcoma/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , MicroARNs/genética , MicroARNs/uso terapéuticoRESUMEN
BACKGROUND: Cancer screening can improve outcomes in patients with cancer. Accordingly, under the direction of the National Health Insurance program, the Taiwan government conducts screenings for breast cancer, cervical cancer, oral cancer, and colorectal cancer. OBJECTIVE: The aim of this study was to identify the primary predictors of cancer screening intention and behavior at 1 and 6 months after patients are provided information and an invitation by telephone to attend cancer screenings. METHODS: In this prospective longitudinal study, 339 participants meeting the screening criteria were recruited. At baseline, telephone interviews were used to collect information on demographic characteristics, exercise and smoking habits, family cancer history, screening beliefs, and screening intention. Screening behavior was followed up at 1 and 6 months after the telephone interviews. RESULTS: At baseline, 87.02% of the participants intended to undergo screening, and 31.86% and 63.42% had undergone screening after 1 and 6 months, respectively. The predictors of screening intention were awareness of the screening policy, willingness to learn about screening, and believing in the health benefits of screening. The predictor of screening behavior after 1 month was screening intention at baseline, and the predictors of behavior after 6 months were screening intention, marital status, and belief that cancer is a hereditary disease. CONCLUSION: Adults with screening intention tended to undergo cancer screenings. IMPLICATIONS FOR PRACTICE: The use of strategies based on screening intention, beliefs, and information can be used to improve participation in cancer screening in Taiwan.
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Neoplasias de la Mama , Neoplasias Colorrectales , Neoplasias de la Boca , Neoplasias del Cuello Uterino , Adulto , Femenino , Humanos , Detección Precoz del Cáncer , Intención , Taiwán , Estudios Prospectivos , Estudios Longitudinales , Neoplasias de la Mama/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/prevención & control , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/prevención & control , Neoplasias Colorrectales/diagnóstico , Tamizaje MasivoRESUMEN
Epistasis detection is vital for understanding disease susceptibility in genetics. Multiobjective multifactor dimensionality reduction (MOMDR) was previously proposed to detect epistasis. MOMDR was performed using binary classification to distinguish the high-risk (H) and low-risk (L) groups to reduce multifactor dimensionality. However, the binary classification does not reflect the uncertainty of the H and L classification. In this study, we proposed an empirical fuzzy MOMDR (EFMOMDR) to address the limitations of binary classification using the degree of membership through an empirical fuzzy approach. The EFMOMDR can simultaneously consider two incorporated fuzzy-based measures, including correct classification rate and likelihood rate, and does not require parameter tuning. Simulation studies revealed that EFMOMDR has higher 7.14% detection success rates than MOMDR, indicating that the limitations of binary classification of MOMDR have been successfully improved by empirical fuzzy. Moreover, EFMOMDR was used to analyze coronary artery disease in the Wellcome Trust Case Control Consortium dataset.
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Enfermedad de la Arteria Coronaria , Epistasis Genética , Humanos , Epistasis Genética/genética , Reducción de Dimensionalidad Multifactorial , Modelos Genéticos , Simulación por Computador , Enfermedad de la Arteria Coronaria/genética , Polimorfismo de Nucleótido Simple , AlgoritmosRESUMEN
Obesity is a chronic disease that may lead to the development of metabolic diseases, cardiovascular diseases, and cancers and has been predicted to affect one billion adults by 2030. Owing to the pivotal role of the gut microbiota in health, including metabolism and energy homeostasis, dietary fiber, the primary energy resource for the gut microbiota, not only helps reduce appetite and short-term food intake but also modulates the structure of the gut microbiota. In this study, we investigated whether high-amylose maize (HAM), with a particular amount of dietary fiber, improves dysmetabolism and gut microbiota dysbiosis in diet-induced obese mice. Promisingly, the HAM dietary intervention not only reduced body weight gain, adipocyte hypertrophy, and dyslipidemia but also mitigated non-alcoholic fatty liver disease, insulin resistance, impaired glucose tolerance, and inflammation in the liver and epididymal white adipose tissues in high-fat diet (HFD)-fed obese mice. In addition, the HAM dietary intervention ameliorated gut microbiota dysbiosis in HFD-fed mice. Changes in families, genera, and species of gut biota that have a relative abundance of 0.01% in at least one group were scrutinized. At the species level, HAM dietary intervention increased Bifidobacterium pseudolongum, Bifidobacterium animalis, Bifidobacterium bifidum, and Lactobacillus paraplantarum and decreased Streptococcus agalactiae, Mucispirillum schaedleri, and Alistipes indistinctus. This change in the gut microbiota driven by the HAM diet was strongly associated with obesity-related indices, highlighting the nutraceutical potential of HAM for improving overall metabolic health. Taken together, this study demonstrates the potential of the HAM diet for mediating metabolic syndrome and gut microbiota dysbiosis.
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Microbioma Gastrointestinal , Amilosa , Animales , Dieta Alta en Grasa/efectos adversos , Fibras de la Dieta , Disbiosis/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/metabolismo , Zea maysRESUMEN
Resveratrol has well-known anticancer properties; however, its oligomers, including α-viniferin, ε-viniferin, and kobophenol A, have not yet been well investigated. This is the first study examining the anti-epithelial-mesenchymal transition (EMT) effects of α-viniferin and ε-viniferin on A549, NCI-H460, NCI-H520, MCF-7, HOS, and U2OS cells. The results showed that α-viniferin and ε-viniferin significantly inhibited EMT, invasion and migration in TGF-ß1- or IL-1ß-induced non-small cell lung cancer. α-Viniferin and ε-viniferin also reversed TGF-ß1-induced reactive oxygen species (ROS), MMP2, vimentin, Zeb1, Snail, p-SMAD2, p-SMAD3, and ABCG2 expression in A549 cells. Furthermore, ε-viniferin was found to significantly inhibit lung metastasis in A549 cell xenograft metastatic mouse models. In view of these findings, α-viniferin and ε-viniferin may play an important role in the prevention of EMT and cancer metastasis in lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Benzofuranos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Movimiento Celular , Regulación hacia Abajo , Transición Epitelial-Mesenquimal , Humanos , Neoplasias Pulmonares/patología , Ratones , Estilbenos , Factor de Crecimiento Transformador beta1/metabolismo , Vimentina/genética , Vimentina/metabolismoRESUMEN
This study investigated the effects and molecular mechanisms of ε-viniferin and α-viniferin in non-small cell lung cancer cell line A549, melanoma cell line A2058, and osteosarcoma cell lines HOS and U2OS. Results showed ε-viniferin having antiproliferative effects on HOS, U2OS, and A549 cells. Compared with ε-viniferin at the same concentration, α-viniferin had higher antiproliferative effects on HOS cells, but not the same effect on U2OS and A549 cells. Lower dose combination of α-viniferin and ε-viniferin had more synergistic effects on A549 cells than either drug alone. α-Viniferin induced apoptosis in HOS cells by decreasing expression of phospho-c-Jun-N-terminal kinase 1/2 (p-JNK1/2) and increasing expression of cleaved Poly (ADP-ribose) polymerase (PARP), whereas α-viniferin in combination with ε-viniferin induced apoptosis in A549 cells by decreasing expression of phospho-protein kinase B (p-AKT) and increasing expression of cleaved PARP and cleaved caspase-3. ε-Viniferin and α-viniferin have not been studied using in vivo tumor models for cancer. This research is the first showing that ε-viniferin treatment resulted in significant inhibition of tumor growth in A549-cell xenograft-bearing nude mice compared with the control group. Consequently, ε-viniferin and α-viniferin may prove to be new approaches and effective therapeutic agents for osteosarcoma and lung cancer treatment.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzofuranos/farmacología , Necrosis/metabolismo , Estilbenos/farmacología , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Osteosarcoma/metabolismoRESUMEN
Melanoma is a type of skin cancer that often leads to poor prognostic responses and survival rates. Melanoma usually develops in the limbs, including in fingers, palms, and the margins of the nails. When melanoma is detected early, surgical treatment may achieve a higher cure rate. The early diagnosis of melanoma depends on the manual segmentation of suspected lesions. However, manual segmentation can lead to problems, including misclassification and low efficiency. Therefore, it is essential to devise a method for automatic image segmentation that overcomes the aforementioned issues. In this study, an improved algorithm is proposed, termed EfficientUNet++, which is developed from the U-Net model. In EfficientUNet++, the pretrained EfficientNet model is added to the UNet++ model to accelerate segmentation process, leading to more reliable and precise results in skin cancer image segmentation. Two skin lesion datasets were used to compare the performance of the proposed EfficientUNet++ algorithm with other common models. In the PH2 dataset, EfficientUNet++ achieved a better Dice coefficient (93% vs. 76%-91%), Intersection over Union (IoU, 96% vs. 74%-95%), and loss value (30% vs. 44%-32%) compared with other models. In the International Skin Imaging Collaboration dataset, EfficientUNet++ obtained a similar Dice coefficient (96% vs. 94%-96%) but a better IoU (94% vs. 89%-93%) and loss value (11% vs. 13%-11%) than other models. In conclusion, the EfficientUNet++ model efficiently detects skin lesions by improving composite coefficients and structurally expanding the size of the convolution network. Moreover, the use of residual units deepens the network to further improve performance.
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Melanoma , Enfermedades de la Piel , Neoplasias Cutáneas , Humanos , Procesamiento de Imagen Asistido por Computador , Melanoma/diagnóstico por imagen , Redes Neurales de la Computación , Neoplasias Cutáneas/diagnóstico por imagenRESUMEN
Hepatitis B virus (HBV) infection leads to severe liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). More than 257 million individuals are chronically infected, particularly in the Western Pacific region and Africa. Although nucleotide and nucleoside analogues (NUCs) and interferons (IFNs) are the standard therapeutics for HBV infection, none eradicates HBV covalently closed circular DNA (cccDNA) from the infected hepatocytes. In addition, long-term treatment with NUCs increases the risk of developing drug resistance and IFNs may cause severe side effects in patients. Thus, a novel HBV therapy that can achieve a functional cure, or even complete elimination of the virus, is highly desirable. Regarding the HBV life cycle, agents targeting the entry step of HBV infection reduce the intrahepatic cccDNA pool preemptively. The initial entry step in HBV infection involves interaction between the pre-S1 domain of the large hepatitis B surface protein (LHBsAg) and the sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor for HBV. In this study, ergosterol peroxide (EP) was identified as a new inhibitor of HBV entry. EP inhibits an early step of HBV entry into DMSO-differentiated immortalized primary human hepatocytes HuS-E/2 cells, which were overexpressed NTCP. Also, EP interfered directly with the NTCP-LHBsAg interaction by acting on the NTCP. In addition, EP had no effect on HBV genome replication, virion integrity or virion secretion. Finally, the activity of EP against infection with HBV genotypes A-D highlights the therapeutic potential of EP for fighting HBV infection.
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Ergosterol/análogos & derivados , Virus de la Hepatitis B/fisiología , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Simportadores/metabolismo , Internalización del Virus/efectos de los fármacos , ADN Circular/metabolismo , Ergosterol/farmacología , Células Hep G2 , Hepatitis B/patología , Hepatitis B/virología , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Humanos , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Simportadores/genética , Replicación ViralRESUMEN
Drug resistance and disease recurrence are important contributors for the poor prognosis of glioblastoma multiforme (GBM). Temozolomide (TMZ), the standard chemotherapy for GBM treatment, can methylate DNA and cause the formation of double-strand breaks (DSBs). X-ray repair cross complementing 5 (XRCC5), also known as Ku80 or Ku86, is required for the repair of DSBs. The present study identified novel determinants that sensitize cells to TMZ, using an array-based short hairpin (sh)RNA library. Then, cBioportal, Oncomine, and R2 databases were used to analyze the association between gene expression levels and clinical characteristics. Subsequently, lentiviral shRNA or pCMV was used to knockdown or overexpress the gene of interest, and the effects on TMZ sensitivity were determined using a MTT assay and western blot analysis. TMZ-resistant cells were also established and were used in in vitro and in vivo experiments to analyze the role of the gene of interest in TMZ resistance. The results indicated that XRCC5 was effective in enhancing TMZ cytotoxicity. The results from the bioinformatics analysis revealed that XRCC5 mRNA expression levels were associated with clinical deterioration and lower overall survival rates. In addition, XRCC5 knockdown could significantly increase TMZ sensitivity in GBM cells, while XRCC5 overexpression caused the cancer cells to be resistant to TMZ. Both the in vivo and in vitro experiments showed that TMZ treatment could induce expression of XRCC5 in TMZ-resistant cells. Taken together these findings suggested that XRCC5 could be a promising target for GBM treatment and could also be used as a diagnostic marker for refractory GBM.
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Obesity and its associated conditions, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), are a particular worldwide health problem at present. Momordica cochinchinensis (MC) is consumed widely in Southeast Asia. However, whether it has functional effects on fat-induced metabolic syndrome remains unclear. This study was conducted to examine the prevention effect of Momordica cochinchinensis aril (MCA) on obesity, non-alcoholic fatty liver and insulin resistance in mice. MCA protected the mice against high-fat diet (HFD)-induced body weight gain, hyperlipidemia and hyperglycemia, compared with mice that were not treated. MCA inhibited the expansion of adipose tissue and adipocyte hypertrophy. In addition, the insulin sensitivity-associated index that evaluates insulin function was also significantly restored. MCA also regulated the secretion of adipokines in HFD-induced obese mice. Moreover, hepatic fat accumulation and liver damage were reduced, which suggested that fatty liver was prevented by MCA. Furthermore, MCA supplementation suppressed hepatic lipid accumulation by activation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) signaling pathway in the human fatty liver HuS-E/2 cell model. Our data indicate that MCA altered the microbial contents of the gut and modulated microbial dysbiosis in the host, and consequently is involved in the prevention of HFD-induced adiposity, insulin resistance and non-alcoholic fatty liver disease.
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Frutas/química , Microbioma Gastrointestinal/efectos de los fármacos , Momordica/química , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/inducido químicamente , Obesidad/metabolismo , Obesidad/patología , Extractos Vegetales/químicaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19). Since its emergence, the COVID-19 pandemic has not only distressed medical services but also caused economic upheavals, marking urgent the need for effective therapeutics. The experience of combating SARS-CoV and MERS-CoV has shown that inhibiting the 3-chymotrypsin-like protease (3CLpro) blocks the replication of the virus. Given the well-studied properties of FDA-approved drugs, identification of SARS-CoV-2 3CLpro inhibitors in an FDA-approved drug library would be of great therapeutic value. Here, we screened a library consisting of 774 FDA-approved drugs for potent SARS-CoV-2 3CLpro inhibitors, using an intramolecularly quenched fluorescence (IQF) peptide substrate. Ethacrynic acid, naproxen, allopurinol, butenafine hydrochloride, raloxifene hydrochloride, tranylcypromine hydrochloride, and saquinavir mesylate have been found to block the proteolytic activity of SARS-CoV-2 3CLpro. The inhibitory activity of these repurposing drugs against SARS-CoV-2 3CLpro highlights their therapeutic potential for treating COVID-19 and other Betacoronavirus infections.
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Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , COVID-19/virología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Reposicionamiento de Medicamentos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Dominio Catalítico , Proteasas 3C de Coronavirus/química , Evaluación Preclínica de Medicamentos , Colorantes Fluorescentes , Humanos , Simulación del Acoplamiento Molecular , Especificidad por SustratoRESUMEN
Closely associated with visceral obesity, hepatic steatosis resulting from non-alcoholic fatty liver disease (NAFLD) exacerbates insulin resistance. Developing effective drugs to treat NAFLD is imperative. Here, we investigated the pharmacological mechanism of ugonin J (UJ) in controlling metabolic disorder and ameliorating NAFLD pathophysiology in diet-induced obese mice. The effects of UJ were assessed in 5-week-old C57BL/6 J mice fed a high-fat diet (HFD) for 12 weeks. UJ treatment averted HFD-induced body weight gain by reducing fat deposition in adipose tissues and reduced HFD-induced hyperlipidemia and hepatic inflammation. UJ also improved HFD-induced glucose tolerance and insulin resistance. Moreover, the mode of action of UJ was analyzed in palmitate (PA)-induced steatotic human HuS-E/2 hepatocytes and in hyperglycemia-simulating rat BRIN-BD11 pancreatic ß cells. In PA-induced steatotic human hepatocytes, UJ treatment promoted lipid clearance via pAMPK, pACC and CPT-1 upregulation and SREBP-1c downregulation. Interestingly, UJ upregulated Akt activity in hepatocytes and increased insulin secretion from ß cells in acute insulin secretion tests. Taken together, UJ improved adipocyte hypertrophy, hyperinsulinemia, hyperglycemia, hyperlipidemia and fat deposition in livers. UJ also reduced fatty acid accumulation by modulating key metabolic regulators. Our findings demonstrated the therapeutic potential of UJ for the treatment of NAFLD and diet-induced metabolic disorders.
Asunto(s)
Enfermedades Metabólicas/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Adipoquinas/sangre , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Animales , Línea Celular , Células Cultivadas , Dieta Alta en Grasa , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Enfermedades Metabólicas/metabolismo , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Ratas , Aumento de Peso/efectos de los fármacosRESUMEN
BACKGROUND: Obesity and its associated diseases have become a major world-wide health problem. Purple-leaf Tea (Camellia sinensis L.) (PLT), that is rich of anthocyanins, has been shown to have preventive effects on obesity and metabolic disorders. The intestinal microbiota has been shown to contribute to inflammation, obesity, and several metabolic disorders. However, whether PLT consumption could prevent obesity and diet-induced metabolic diseases by modulating the gut microbiota, is not clearly understood. METHODS: In this study, six-week-old male C57BL/6 J mice were fed a normal diet (ND) or a high fat diet (HFD) without or with PLT for 10 weeks. RESULTS: PLT modulated the gut microbiota in mice and alleviated the symptoms of HFD-induced metabolic disorders, such as insulin resistance, adipocyte hypertrophy, and hepatic steatosis. PLT increased the diversity of the microbiota and the ratio of Firmicutes to Bacteroidetes. f_Barnesiellaceae, g_Barnesiella, f_Ruminococcaceae, and f_Lachnospiraceae were discriminating faecal bacterial communities of the PLT mice that differed from the HFD mice. CONCLUSIONS: These data indicate that PLT altered the microbial contents of the gut and prevented microbial dysbiosis in the host, and consequently is involved in the modulation of susceptibility to insulin resistance, hepatic diseases, and obesity that are linked to an HFD.