RESUMO
BACKGROUND: Gastric cancer (GC) is one of the most common cancers, and the noninvasive diagnostic methods for monitoring GC are still lacking. Growing evidence shows that human microbiota has potential value for identifying digestive diseases. AIMS: The present study aimed to explore the association of the tongue coating microbiota with the serum metabolic features and inflammatory cytokines in GC patients and seek a potential, noninvasive biomarker for diagnosing GC. METHODS: The tongue coating microbiota was profiled by 16S rRNA and 18S rRNA genes sequencing technology in the original population with 181 GC patients and 112 healthy controls (HCs). Propensity score matching method was used to eliminate potential confounders including age, gender, and six lifestyle factors and a matching population with 66 GC patients and 66 HCs generated. Serum metabolomics profiling was performed by ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) in the matching population. Random forest model was constructed for the diagnosis of GC. RESULTS: Linear discriminant analysis effect size (LEfSe) revealed that the differential bacterial taxa between GC patients and HCs in the matching population were similar to that in the original population, while the differential fungal taxa between GC patients and HCs dramatically changed before and after PSM. By random forest analysis, the combination of six bacterial genera (Peptostreptococcus, Peptococcus, Porphyromonas, Megamonas, Rothia, and Fusobacterium) was the optimal predictive model to distinguish GC patients from HCs effectively, with an area under the curve (AUC) value of 0.85. The model was verified with a high predictive potential (AUC = 0.76 to 0.96). In the matching population, eighteen specific HCs-enriched bacterial genera (Porphyromonas, Parvimonas, etc.) had negative correlations with lysophospholipids metabolites, and three of them had also negative correlations with serum IL-17α. CONCLUSIONS: The alteration of tongue coating microbiota had a possible linkage with the inflammations and metabolome, and the tongue coating bacteria could be a potential noninvasive biomarker for diagnosing GC, which might be independent of lifestyle.
Assuntos
Bactérias , Inflamação , Microbiota/genética , Micobioma/fisiologia , Neoplasias Gástricas , Língua , Área Sob a Curva , Bactérias/classificação , Bactérias/isolamento & purificação , China/epidemiologia , Correlação de Dados , Feminino , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Interleucina-17/sangue , Estilo de Vida , Masculino , Espectrometria de Massas/métodos , Microbiota/imunologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , RNA Ribossômico 16S/análise , RNA Ribossômico 18S/análise , Análise de Sequência de RNA/métodos , Neoplasias Gástricas/sangue , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia , Língua/metabolismo , Língua/microbiologiaRESUMO
Non-small-cell lung cancer (NSCLC) is the most common cancer in the world. Previous studies have shown that Raddeanin A (RA) exhibited distinct antitumor properties in gastric and colon cancer. This study aimed to investigate the pharmacological actions and intrinsic mechanisms of RA in NSCLC. Through the application of network pharmacology, the potential targets of RA for NSCLC therapy such as SRC, MAPK1, and STAT3 were excavated. Enrichment analyses showed that these targets were concerned with the regulation of cell death, regulation of MAPK cascade, Ras signaling pathway, and PI3K/AKT signaling pathway. Meanwhile, 13 targets of RA were identified as autophagy-related genes. Our experiment data showed that RA effectively inhibited proliferation and induced apoptosis in lung cancer cells A549. We also found that RA could induce autophagy simultaneously. Furthermore, the autophagy induced by RA had a synergistic effect with apoptosis and contributed to cell death. Additionally, RA could downregulate the activity of the PI3K/AKT/mTOR pathway. Generally, our results indicated the antitumor effect and underlying mechanisms of RA on apoptosis and autophagy in A549 cells, suggesting that RA could be used as an effective antineoplastic agent.
Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Pulmonares/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Apoptose , Autofagia , Proliferação de CélulasRESUMO
Purpose: Solanine is the main component of the plant Solanum, which has been shown to provide growth-limiting activities in a variety of human cancers. However, little is known about its function in gastric cancer (GC). Methods: We investigated the effect of solanine on GC in vivo and in vitro. The inhibition rate of solanine on the tumor was observed by constructing a subcutaneous tumor in nude mice. Morphological changes were analyzed with H&E staining. The expression of ATF4 was detected by IF analysis. MTT assays, EdU staining, and colony formation assays were used to detect the inhibition rate of solanine on GC cells. Matrigel transwells were used to detect the invasion of GC cells. Cell migration was measured using the wound healing assay. The flow cytometric analysis was used to monitor changes in the cell cycle and cell apoptosis. Western blotting was used to detect major proteins in cells and tumors. Results: Solanine suppressed gastric tumorigenesis. Solanine also inhibited the proliferation, invasion and mitigation of GC cells, and induced cell cycle arrest and apoptosis in vitro. Moreover, the growth-limiting activities of solanine in gastric cancer were related to the suppression of the AAMDC/MYC/ATF4/Sesn2 pathway-mediated autophagy. Overexpression of AAMDC reversed the inhibitory effect of solanine on autophagy and gastric cancer. Conclusion: In summary, our findings indicate that solanine confers growth-limiting activities by deactivating the AAMDC-regulated autophagy in gastric cancer.
Assuntos
Solanina , Neoplasias Gástricas , Animais , Camundongos , Humanos , Neoplasias Gástricas/metabolismo , Solanina/farmacologia , Camundongos Nus , Linhagem Celular Tumoral , Transdução de Sinais , Proliferação de Células , Autofagia , Apoptose , Regulação Neoplásica da Expressão Gênica , Sestrinas/metabolismo , Fator 4 Ativador da Transcrição/metabolismoRESUMO
Sparganii rhizoma (SL) has potential therapeutic effects on gastric cancer (GC), but its main active ingredients and possible anticancer mechanism are still unclear. In this study, we used HPLC-Q-TOF-MS/MS to comprehensively analyse the chemical components of the aqueous extract of SL. On this basis, a network pharmacology method incorporating target prediction, gene function annotation, and molecular docking was performed to analyse the identified compounds, thereby determining the main active ingredients and hub genes of SL in the treatment of GC. Finally, the mRNA and protein expression levels of the hub genes of GC patients were further analysed by the Oncomine, GEPIA, and HPA databases. A total of 41 compounds were identified from the aqueous extract of SL. Through network analysis, we identified seven main active ingredients and ten hub genes: acacetin, sanleng acid, ferulic acid, methyl 3,6-dihydroxy-2-[(2-hydroxyphenyl) ethynyl]benzoate, caffeic acid, adenine nucleoside, azelaic acid and PIK3R1, PIK3CA, SRC, MAPK1, AKT1, HSP90AA1, HRAS, STAT3, FYN, and RHOA. The results indicated that SL might play a role in GC treatment by controlling the PI3K-Akt and other signalling pathways to regulate biological processes such as proliferation, apoptosis, migration, and angiogenesis in tumour cells. In conclusion, this study used HPLC-Q-TOF-MS/MS combined with a network pharmacology approach to provide an essential reference for identifying the chemical components of SL and its mechanism of action in the treatment of GC.
Assuntos
Curcuma/química , Medicamentos de Ervas Chinesas/química , Rizoma/química , Neoplasias Gástricas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinases/genética , Mapas de Interação de Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Espectrometria de Massas em TandemRESUMO
Although intestinal microbial dysbiosis was confirmed to be associated with many chronic diseases and health status through complicated interaction with the host, the effect on gastric cancer was less studied. In this study, we sequenced the 16S rRNA and 18S rRNA genes of fecal bacteria and fungi, respectively, in 134 gastric cancer patients and 58 healthy controls matched by age and gender. Propensity score matching (PSM) was adopted for adjusting diet habits and lifestyle, and 44 patients and 44 healthy controls (matching population) were enrolled. Serum antibody to H. pylori and metabolites of the matching population were detected. The positive rates of antibody to H. pylori between the patients and the control group did not reach the statistical difference. LEfSe analysis indicated that bacteria were more stable than fungi when adjusting diet and lifestyle. Veillonella, Megasphaera, and Prevotella 7 genus and Streptococcus salivarius subsp. Salivarius, Bifidobacterium dentium, and Lactobacillus salivarius species in bacteria were related to the risk of gastric cancer and showed a good diagnostic value in distinguishing the patients from healthy controls. Streptococcus mitis showed a risk effect for gastric cancer; however, the effect turned into be protective after PSM. Serum L-alanine, L-threonine, and methionol were positively associated with Veillonella and Streptococcus and several fungi genus. Overall, our findings indicated that fecal microbiome constitution alteration may be associated with gastric cancer through influencing the amino acid metabolism.
Assuntos
Biomarcadores Tumorais/análise , Fezes/microbiologia , Infecções por Helicobacter/complicações , Helicobacter pylori/isolamento & purificação , Microbiota , Neoplasias Gástricas/diagnóstico , Idoso , Estudos de Casos e Controles , China/epidemiologia , Feminino , Infecções por Helicobacter/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/microbiologiaRESUMO
This study aimed to investigate the in vitro and in vivo effects of Raddeanin A on apoptosis and the cell cycle in the human colorectal cell line, HCT116, and to explore the possible underlying mechanisms of action. We found the growth inhibition rate gradually increased as the drug concentration increased via the 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, which indicated that Raddeanin A significantly inhibited the growth of HCT116 cells. Flow cytometry (FCM) showed that Raddeanin A concentration-dependently induced apoptosis in HCT116 cells. In addition, the percentage of cells in the G0/G1 phase was noticeably increased, which indicated that Raddeanin A blocked cell cycle progression in HCT116 cells and caused arrest in the G0/G1 phase. Moreover, the expression of proteins involved in the PI3K/AKT signaling pathway (e.g., p-PI3K and p-AKT) was decreased. The results showed that in vivo revealed that Raddeanin A significantly inhibited tumor growth in an HCT116-xenografted mouse model; apoptotic cells were also detected in the tumor tissue. The expression of the tissue proteins cyclinD1, cyclinE, p-PI3K, and p-AKT was decreased. The above results show that the Raddeanin A exerted a strong antitumor effect in the human colorectal cell line HCT116 both in vitro and in vivo. This effect may be caused by the induction of apoptosis and cycle arrest achieved through PI3K/AKT signaling pathway regulation.
RESUMO
Cinnamaldehyde, the main chemical component of the essential oil separated from the traditional herb Cinnamomum cassia, has been demonstrated to be an efficient cytotoxic agent against several human cancers. The present experiment showed that cinnamaldehyde dose-dependently depresses the proliferation of three types of NSCLC cells and induces cell apoptosis in vitro and in vivo. Moreover, cinnamaldehyde attenuated CoCl2-induced EMT and decreased matrix metalloprotease (MMP) family while the in vivo study showed the same trend. Mechanistically, cinnamaldehyde imitated the suppressive effect of XAV939 on cell motility and EMT which could be impaired by LiCl. Collectively, our research demonstrated for the first time that cinnamaldehyde is able to inhibit NSCLC cell growth by inducing apoptosis and reverse EMT through terminating Wnt/ß-catenin pathway, which might supply further insight into cinnamaldehyde-mediated anti-tumor effect against NSCLC for better prognosis.
Assuntos
Acroleína/análogos & derivados , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Acroleína/administração & dosagem , Acroleína/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cobalto/toxicidade , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismoRESUMO
Gastric cancer (GC) is the third primary cause of cancer-related mortality and one of the most common type of malignant diseases worldwide. Despite remarkable progress in multimodality therapy, advanced GC with high aggressiveness always ends in treatment failure. Epithelial-mesenchymal transition (EMT) has been widely recognized to be a key process associating with GC evolution, during which cancer cells go through phenotypic variations and acquire the capability of migration and invasion. Wnt/ß-catenin pathway has established itself as an EMT regulative signaling due to its maintenance of epithelial integrity as well as tight adherens junctions while mutations of its components will lead to GC initiation and diffusion. The E-cadherin/ß-catenin complex plays an important role in stabilizing ß-catenin at cell membrane while disruption of this compound gives rise to nuclear translocation of ß-catenin, which accounts for upregulation of EMT biomarkers and unfavorable prognosis. Additionally, several microRNAs positively or negatively modify EMT by reciprocally acting with certain target genes of Wnt/ß-catenin pathway in GC. Thus, this review centers on the strong associations between Wnt/ß-catenin pathway and microRNAs during alteration of EMT in GC, which may induce advantageous therapeutic strategies for human gastric cancer.
Assuntos
Transição Epitelial-Mesenquimal/fisiologia , MicroRNAs/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Via de Sinalização Wnt/fisiologia , Animais , Humanos , MicroRNAs/genética , Neoplasias Gástricas/genéticaRESUMO
Cinnamaldehyde (CA) is a bioactive compound isolated from the stem bark of Cinnamomum cassia, that has been identified as an antiproliferative substance with pro-apoptotic effects on various cancer cell lines in vitro. In the present study, the effects of CA on human colon cancer cells were investigated at both the molecular and cellular levels. Three types of colorectal cancer cells at various stages of differentiation and invasive ability (SW480, HCT116 and LoVo) were treated with CA at final concentrations of 20, 40 and 80 µg/ml for 24 h. Compared with the control group, the proliferation inhibition rate of the human colorectal cancer cells following treatment with CA increased in a dose- and time-dependent manner. The invasion and adhesion abilities of the cells were significantly inhibited as indicated by Transwell and cell-matrix adhesion assays. Meanwhile, CA also upregulated the expression of E-cadherin and downregulated the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9. CA also elevated the apoptotic rate. The levels of pro-apoptotic genes were upregulated while the levels of apoptosis inhibitory genes were decreased which further confirmed the pro-apoptotic effect of CA. In order to explore the mechanism of CA-induced apoptosis, insulin-like growth factor-1 (IGF-1) and PI3K inhibitor (LY294002) were used to regulate the phosphoinositide 3-kinase (PI3K)/AKT pathway. The transcription activity of PI3K/AKT was markedly inhibited by CA, as well as IGF-1 which functions as an anti-apoptotic factor. In conclusion, CA has the potential to be developed as a new antitumor drug. The mechanisms of action involve the regulation of expression of genes involved in apoptosis, invasion and adhesion via inhibition of the PI3K/Akt signaling pathway.
Assuntos
Acroleína/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Fator de Crescimento Insulin-Like I/biossíntese , Proteína Oncogênica v-akt/biossíntese , Fosfatidilinositol 3-Quinases/biossíntese , Acroleína/administração & dosagem , Apoptose/efeitos dos fármacos , Caderinas/biossíntese , Caderinas/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Células HCT116 , Humanos , Fator de Crescimento Insulin-Like I/genética , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/genética , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Raddeanin A (RA) is an extractive from Anemone raddeana Regel, a traditional Chinese medicine. The aim of this study is to assess the efficacy of RA against human gastric cancer (GC) cells (SGC-7901) and explore its mechanism. MTT assay showed that RA inhibition of proliferation of SGC-7901 cells increased in a dose-dependent manner. Flow cytometry analysis and Hoechst 33258 staining showed that RA induced apoptosis on SGC-7901 cells. Meanwhile, it induced autophagy. Western blotting analysis showed that the RA induces apoptosis and autophagy by activating p38 MAPK pathway and inhibiting mTOR pathway. Further studies showed that autophagy inhibition could protect from RA-induced apoptosis in SGC-7901 cells. In conclusion, RA can induce SGC-7901 cell apoptosis and autophagy by activating p38 MAPK pathway. And autophagy can protect SGC-7901 cells from apoptosis induced by RA.
RESUMO
Tou Nong San (TNS) is a traditional Chinese medicinal decoction used to treat sores and carbuncles. It contains four herbal drugs and one animal medicine: Radix Astragaliseu Seu Hedysari, Angelica sinensis, Ligustici Chuanxiong, Spina Gleditsiae, and stir-baked Squama Manis. Previous studies have shown that it has anticancer effects. This report validates in vivo antitumor properties of TNS. The compounds contained in TNSE were confirmed by liquid chromatographmass spectrometer (LC-MS) analysis. The in vivo antitumor activity of TNS extract (TNSE) was tested by feeding it to athymic mice harboring a human colonic tumor subcutaneous xenograft. Toxicity was monitored by recording behavior and weight parameters. Seven compounds were detected in TNSE by LC-MS. TNSE was fed to athymic mice for 2 weeks. No adverse reactions were reported. Compared to the control group, administration of TNSE to tumor bearing mice significantly reduced both tumor weight and volume. The expressions of p-PI3K, p-AKT, p-mTOR, p-p70s6k1, VEGF, and CD31 were significantly reduced, the expression levels of cleaved Caspase-9 and cleaved Caspase-3 were significantly increased in the TNSE groups compared to the control group as determined by western blot and immunohistochemistry. TNSE produced anticolonic cancer effects and the underlying mechanisms involved inhibition of the PI3K/AKT signal transduction pathway, inhibition of angiogenesis, and promotion of apoptotic proteins.
RESUMO
Jianpi Huayu Decoction (JHD), a Chinese medicine formula, is a typical prescription against multiple tumors in the clinical treatment, which can raise quality of life and decrease complications. The aim of this study is to assess the efficacy of JHD against human colorectal carcinoma cells (SW480) and explore its mechanism. MTT assay showed that JHD decreased the cellular viability of SW480 cells in dose-dependent and time-dependent manner. Flow cytometry analysis revealed that JHD induced G0/G1-phase cell cycle arrest in SW480 cells and had a strong apoptosis-inducing effect on SW480 cells. Meanwhile it enhanced the expression of p27, cleaved PARP, cleaved caspase-3, and Bax and decreased the levels of PARP, caspase-3, Bcl-2, CDK2, CDK4, CDK6, cyclin D1, cyclin D2, cyclin D3, and cyclin E1, which was evidenced by RT-qPCR and Western blot analysis. In conclusion, these results indicated that JHD inhibited proliferation in SW480 cells by inducing G0/G1-phase cell cycle arrest and apoptosis, providing a practicaltherapeutic strategy against colorectal cancer.