Adipose and endothelial dysfunction is associated with cardiovascular disease. Perivascular adipose tissue (PVAT) directly surrounds vessels and influences vessel function via a paracrine effect, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) modulates the metabolic pathway, thus, the present study hypothesized that activation of AMPK in PVAT may regulate endothelial function in pathological settings. The present study investigated the effect of methotrexate (MTX) on adipocytokine expression in PVAT with an emphasis on the regulation of endothelial function. The effects of MTX and the mechanisms involved were investigated using a relaxation assay and western blot analysis. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to detect the mRNA and protein expression levels. ELISA assay was used to quantify the level of TNF‑α and IL‑6. Palmitic acid (PA) stimulation induced inflammation and dysregulation of adipocytokine expression in PVAT. MTX treatment inhibited nuclear factor‑κB p65 phosphorylation and downregulated expression of pro‑inflammatory cytokines, including tumor necrosis factor‑α and interleukin-6, whereas adiponectin expression increased. MTX increased AMPK phosphorylation under basal and inflammatory conditions in PVAT, whereas knockdown of AMPK via small interfering RNA diminished its modulatory effect, indicating that MTX inhibits inflammation in an AMPK‑dependent manner. The present study prepared conditioned medium from PA‑stimulated PVAT to induce endothelial dysfunction and observed that pre‑treatment of PVAT with MTX effectively restored the loss of acetylcholine‑induced vasodilation and increased endothelial nitric oxide synthase phosphorylation in the rat aorta. The results of the present study demonstrated that MTX ameliorated inflammation-associated adipocytokine dysregulation and thus prevented endothelial dysfunction. These data provide further pharmacological evidence regarding the beneficial effects of MTX in cardiovascular diseases.
Background: It has limitations in predicting patient survival to use of the traditional American Joint Committee on Cancer (AJCC) staging system alone.Objectives: We aimed to establish and evaluate a comprehensive prognostic nomogram and compare its prognostic value with the AJCC staging system in adults diagnosed with ccRCC.Patients and Methods: We used the SEER database to identify 24477 cases of ccRCC between 2010 and 2015. The patients were randomly divided into two groups. In the development cohort, we used multivariate Cox proportional-hazards analyses to select significant variables, and used R software to establish a nomogram for predicting the 3-year and 5-year survival rates of ccRCC patients. In the development and validation cohorts, we compared our survival model with the AJCC prognosis model to evaluate the performance of the nomogram by calculating the concordance index (C-index), area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI), and performing calibration plotting and decision curve analyses (DCAs). Results: Eleven identified independent prognostic factors were used to establish the nomogram. Age at diagnosis, being unmarried, higher grades, larger tumor size, higher AJCC stage, lymph node metastases, bone metastases, liver metastases, lung metastases, radiotherapy, and no surgery were risk factors for the survival of ccRCC. The C-index, AUC, NRI, IDI, and calibration plots demonstrated the good performance of the nomogram compared to the AJCC staging system. Moreover, the 3-year and 5-year DCA curves showed that the nomogram yielded net benefits that were greater than the traditional AJCC staging system.Conclusion: This study is the first to indicate that married status is an important prognostic parameter in ccRCC. Our results also demonstrate that the developed nomogram can predict survival more accurately than the AJCC staging system alone. The prognostic factors were easily obtained.
Background: It has limitations in predicting patient cancer-specific survival to use of the traditional American Joint Committee on Cancer (AJCC) staging system alone. Objectives: We aimed to establish and evaluate a comprehensive prognostic nomogram and compare its prognostic value with the AJCC-7th staging system in adults diagnosed with ccRCC.Methods: We used the SEER database to identify 24477 cases of ccRCC between 2010 and 2015. In the development cohort, we used multivariate Cox proportional-hazards analyses to select significant variables, and used R software to establish a nomogram for predicting the 3-year and 5-year cancer-specific survival rates of ccRCC patients. In the development and validation cohorts, we compared our cancer-specific survival model with the AJCC-7th prognosis model to evaluate the performance of the nomogram by calculating the concordance index (C-index), Youden Index, area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI), and performing calibration plotting and decision curve analyses (DCAs). Results: Eleven identified independent prognostic factors were used to establish the nomogram. Age at diagnosis, being unmarried, higher grades, larger tumor size, higher AJCC-7th stage, lymph node metastases, bone metastases, liver metastases, lung metastases, radiotherapy, and no surgery were risk factors for the cancer-specific survival of ccRCC. The C-index, Youden Index, AUC, NRI, IDI, and calibration plots demonstrated the good performance of the nomogram compared to the AJCC-7th staging system. Moreover, the 3-year and 5-year DCA curves showed that the nomogram yielded net benefits that were greater than the traditional AJCC-7th staging system. Conclusion: This study is the first to indicate that married status is an important prognostic parameter in ccRCC. Our results also demonstrate that the developed nomogram can predict cancer-specific survival more accurately than the AJCC-7th staging system alone. The prognostic factors were easily obtained.
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