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Background and Objectives. The prognostic role of adjacent nontumor tissue in patients with breast cancer (BC) is still unclear. The activity changes in immunologic and hallmark gene sets in normal tissues adjacent to BC may play a crucial role in predicting the prognosis of BC patients. The aim of this study was to identify BC subtypes and ribosome-associated prognostic genes based on activity changes of immunologic and hallmark gene sets in tumor and adjacent nontumor tissues to improve patient prognosis. Materials and Methods. Gene set variation analysis (GSVA) was applied to assess immunoreactivity changes in the overall sample and three immune-related BC subtypes were identified by non-negative matrix factorization (NMF). KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) analyses were after determining the prognostic gene set using the least absolute shrinkage and selection operator (LASSO) method. Ribosome-related genes were identified by PPI (protein-protein interaction) analysis, and finally a prognostic risk model was constructed based on the expression of five ribosomal genes (RPS18, RPL11, PRLP1, RPL27A, and RPL38). Results. A comprehensive analysis of immune and marker genomic activity changes in normal breast tissue and BC tissue identified three immune-related BC subtypes. BC subtype 1 has the best prognosis, and subtype 3 has the worst overall survival rate. We identified a prognostic gene set in nontumor tissue by the least absolute shrinkage and selection operator (LASSO) method. We found that the results of both KEGG and GO analyses were indistinguishable from those of ribosome-associated genes. Finally, we determined that genes associated with ribosomes exhibit potential as a reliable predictor of overall survival in breast cancer patients. Conclusions. Our research provides an important guidance for the treatment of BC. After a mastectomy, the changes in gene set activity of both BC tissues and the nontumor tissues adjacent to it should be thoroughly evaluated, with special attention to changes in ribosome-related genes in the nontumor tissues.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Prognóstico , Mastectomia , Ribossomos/genética , MamaRESUMO
Atractylodes is the dry root of atractylodes macrocephala koidz and has been commonly used as a traditional Chinese medicine (TCM). Atractylenolide III, a main component of atractylodes, has displayed significant effects on anti-inflammation and anticancer. However, the effects of atractylenolide III on growth inhibition and apoptosis induction in colon cancer remain unclear. The results showed that atractylenolide III significantly inhibited the cell growth and induce cellular apoptosis in HCT-116 cells in a concentration dependence manner in vitro. Mechanistic studies further showed that atractylenolide III could regulate the Bax/Bcl-2 apoptotic signaling pathway through promoting the expression of proapoptotic related gene/proteins Bax, caspase-9 and caspase-3 but inhibiting the expression of antiapoptotic related gene/protein Bcl-2 in HCT-116 cells. Furthermore, atractylenolide III also significantly inhibited the tumor growth of HCT-116 tumor xenografts bearing in nude mice through inducing apoptosis by upregulation of the expressions of Bax, cleaved caspase-3 and p53 but downregulation of the expressions of Bcl-2 in HCT-116 tumor tissues in vivo. The studies may provide the scientific rationale for the understanding of the anticancer effect of atractylenolide III. Therefore, atractylenolide III may have the potential to be developed as a promising novel anticancer agent for the treatment of colorectal cancer clinically.
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Neoplasias do Colo/patologia , Lactonas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Sesquiterpenos/farmacologia , Proteína X Associada a bcl-2/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Caspase 3/efeitos dos fármacos , Caspase 9/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ratos , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: Glioma, an aggressive brain tumor, poses a challenge in understanding the mechanisms of treatment resistance, despite promising results from immunotherapy. Methods: We identified genes associated with immunotherapy resistance through an analysis of The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases. Subsequently, qRT-PCR and western blot analyses were conducted to measure the mRNA and protein levels of TBC1 Domain Family Member 1 (TBC1D1), respectively. Additionally, Gene Set Enrichment Analysis (GSEA) was employed to reveal relevant signaling pathways, and the expression of TBC1D1 in immune cells was analyzed using single-cell RNA sequencing (scRNA-seq) data from GEO database. Tumor Immune Dysfunction and Exclusion (TIDE) database was utilized to assess T-cell function, while Tumor Immunotherapy Gene Expression Resource (TIGER) database was employed to evaluate immunotherapy resistance in relation to TBC1D1. Furthermore, the predictive performance of molecules on prognosis was assessed using Kaplan-Meier plots, nomograms, and ROC curves. Results: The levels of TBC1D1 were significantly elevated in tumor tissue from glioma patients. Furthermore, high TBC1D1 expression was observed in macrophages compared to other cells, which negatively impacted T cell function, impaired immunotherapy response, promoted treatment tolerance, and led to poor prognosis. Inhibition of TBC1D1 was found to potentially synergistically enhance the efficacy of immunotherapy and prolong the survival of cancer patients with gliomas. Conclusion: Heightened expression of TBC1D1 may facilitate an immunosuppressive microenvironment and predict a poor prognosis. Blocking TBC1D1 could minimize immunotherapy resistance in cancer patients with gliomas.
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Neoplasias Encefálicas , Glioma , Imunoterapia , Humanos , Biomarcadores , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/imunologia , Glioma/terapia , Proteínas Ativadoras de GTPase/genética , Prognóstico , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Human umbilical vein endothelial cells (HUVECs) serve a critical role in maintaining normal vascular function. Lipopolysaccharide (LPS), which is released from pathogenic bacteria in the blood, induces HUVEC apoptosis and injury to cause vascular dysfunction and infectious vascular diseases. Procyanidin B2 (PB2) possesses numerous functions, including antioxidant, antitumor, antiinflammatory and antiapoptosis effects, but the molecular mechanism is not completely understood. The present study investigated the effects of PB2 on LPSinduced cytotoxicity and apoptosis in HUVECs, as well as the underlying mechanisms. The effects of PB2 on LPSmediated alterations to cytotoxicity, mitochondrial membrane potential, apoptosis were assessed by performing Cell Counting Kit8, JC1 fluorescence, Hoechst 33258 staining assays, respectively. IL1ß, IL6 and TNFα mRNA expression and protein levels were measured by performing reverse transcriptionquantitative PCR and ELISAs, respectively. Bcl2, Bax, cleaved caspase3, cleaved caspase7, cleaved caspase9, phosphorylated (p)IκBα, pIκBß, pNFκBp65 and total NFκB p65 protein expression levels were determined via western blotting. NFκB p65 nuclear translocation was assessed via immunofluorescence. PB2 pretreatment markedly attenuated LPSinduced cytotoxicity and apoptosis in HUVECs. PB2 also significantly downregulated the expression levels of IL1ß, IL6, TNFα, Bax, cleaved caspase3, cleaved caspase7, cleaved caspase9 and pNFκBp65, but upregulated the expression levels of Bcl2, pIκBα and pIκBß in LPSinduced HUVECs. Moreover, PB2 markedly inhibited LPSinduced NFκB p65 nuclear translocation in HUVECs. The results suggested that the potential molecular mechanism underlying PB2 was associated with the Bax/Bcl2 and NFκB signalling pathways. Therefore, PB2 may serve as a useful therapeutic for infectious vascular diseases.
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Apoptose/efeitos dos fármacos , Biflavonoides/farmacologia , Catequina/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Proantocianidinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Alzheimer's disease (AD) is a very common progressive neurodegenerative disorder with the highest incidence in the world. Dysfunction of the blood-brain barrier (BBB) may be responsible for the pathogenesis and pathology of AD for abnormally transporting amyloid-ß (Aß, the main component of the senile plaques) from the sera into the central nervous system. Aß peptides induce apoptosis in human brain microvascular endothelial cells (hBMECs), the main component of BBB. Apoptosis in neuronal cells plays a critical role in the pathogenesis of AD. Asiaticoside, a natural glycoside extracted from Centella asiatica (L.) Urban, has an anti-apoptotic effect on hBMECs but the molecule mechanism remains unclear. Therefore, we investigate the protective effect of asiaticoside on Aß1-42-induced cytotoxicity and apoptosis as well as associated mechanism in hBMECs with commonly used in vitro methods for clinical development of asiaticoside as a novel anti-AD agent. In the present study, we investigated the effects of asiaticoside on cytotoxicity by Cell Counting Kit-8 assay, mitochondrial membrane potential by JC-1 fluorescence analysis, anti-apoptosis by Hoechst 33258 staining and Annexin V-FITC (fluorescein isothiocyanate) and propidium iodide (PI) analyses, the expressions of TNF-α and IL-6 by enzyme-linked immunosorbent assay (ELISA) and TLR4, MyD88, TRAF6, p-NF-κB p65, and total NF-κB p65 by Western blotting, and nuclear translocation of NF-κB p65 by immunofluorescence analysis in hBMECs. The results showed that pretreatment of asiaticoside (25, 50, and 100 µM) for 12 h significantly attenuated cell growth inhibition and apoptosis, and restored declined mitochondrial membrane potential induced by Aß1-42 (50 µM) in hBMECs. Asiaticoside also significantly downregulated the elevated expressions of TNF-α, IL-6, TLR4, MyD88, TRAF6, and p-NF-κB p65, as well as inhibited NF-κB p65 translocation from cytoplasm to nucleus induced by Aß1-42 in hBMECs in a concentration-dependent manner. The possible underlying molecular mechanism of asiaticoside may be through inhibiting the TLR4/NF-κB signaling pathway. Therefore, asiaticoside may be developed as a novel agent for the prevention and/or treatment of AD clinically.
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Background: Increased consumption of fruit and vegetables has been shown to be associated with a reduced risk of cognitive impairment and dementia in many epidemiological studies. The purpose of this study was to assess the strength of this association in a meta-analysis. Methods: We identified relevant studies by searching Medline, Embase, and Cochrane Library electronic databases (from 1970 to January 2016). Study were included if they reported relative risks and corresponding 95% confidence intervals (CIs) of cognitive impairment and dementia with respect to frequency of fruit and vegetable intake. Results: Nine studies (five cohort studies and four cross-sectional studies) met the inclusion criteria and were included in the meta-analysis. There were a total of 31,104 participants and 4,583 incident cases of cognitive impairment and dementia. The meta-analysis showed that an increased consumption of fruit and vegetables was associated with a significant reduction in the risk of cognitive impairment and dementia (OR = 0.80, 95% CI 0.71-0.89). Subgroup analysis indicated this inverse association was only found among participants with mean age over 65 years and combined sexes. Dose-response meta-analysis showed that an increment of 100 g per day of fruit and vegetable consumption was related to an approximately 13% (OR = 0.87, 95% CI 0.77-0.99) reduction in cognitive impairment and dementia risk. There was no potential publication bias in the meta-analysis and the dose-response meta-analysis. Conclusion: The increased consumption of fruit and vegetables is associated with a reduced risk of cognitive impairment and dementia.
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Gastrodin (GAS), a phenolic glucoside derived from Gastrodiaelata Blume, has been reported to have anti-inflammatory effect. The aim of this study was to investigate the effects of GAS on LPS-induced acute lung injury in mice. ALI was induced by the intranasal administration of LPS and GAS was given 1 h or 12 h after LPS treatment. The results indicated that GAS treatment markedly attenuated the damage of lung injury induced by LPS. GAS attenuated the activity of myeloperoxidase (MPO) and down-regulated the levels of pro-inflammatory cytokines TNF-α, IL-6 and IL-1ß in BALF. LPS-induced lung edema and lung function were also reversed by GAS. Furthermore, GAS was found to inhibit LPS-induced inflammatory cells infiltration. In addition, treatment of GAS inhibited LPS-induced NF-κB activation and up-regulated the expression of Nrf2 and HO-1. In conclusion, our results indicated that GAS had anti-inflammatory effects on LPS-induced acute lung injury. The anti-inflammatory mechanism of GAS was through the inhibition of NF-κB and activation of Nrf2 signaling pathways.
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Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Álcoois Benzílicos/farmacologia , Glucosídeos/farmacologia , Lipopolissacarídeos/efeitos adversos , Fator 2 Relacionado a NF-E2/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Animais , Biomarcadores , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Mediadores da Inflamação/metabolismo , Camundongos , NF-kappa B/metabolismo , Peroxidase/metabolismo , Testes de Função RespiratóriaRESUMO
Lidocaine (Lido) is reported to suppress inflammatory responses and exhibit a therapeutic effect in models of cecal ligation and puncture (CLP)-induced acute lung injury (ALI). The receptor for advanced glycation end product (RAGE) exerts pro-inflammatory effects by enhancing pro-inflammatory cytokine production. However, the precise mechanism by which Lido confers protection against ALI is not clear. ALI was induced in RAGE WT and RAGE knockout (KO) rats using cecal ligation and puncture (CLP) operations for 24 h. The results showed that Lido significantly inhibited CLP-induced lung inflammation and histopathological lung injury. Furthermore, Lido significantly reduced CLP-induced upregulation of HMGB1 and RAGE expression and activation of the NF-κB and MAPK signaling pathways. With the use of RAGE KO rats, we demonstrate here that RAGE deficiency attenuates the protective effect of Lido against CLP-induced lung inflammatory cell infiltration and histopathological lung injury. These results suggest that RAGE deficiency attenuates the protective effect of Lido against CLP-induced ALI by attenuating the pro-inflammatory cytokines production.