RESUMEN
BACKGROUND: Oral microbiota imbalance is associated with the progression of various lung diseases, including lung cancer. Pulmonary nodules (PNs) are often considered a critical stage for the early detection of lung cancer; however, the relationship between oral microbiota and PNs remains unknown. METHODS: We conducted a 'Microbiome with pulmonary nodule series study 1' (MCEPN-1) where we compared PN patients and healthy controls (HCs), aiming to identify differences in oral microbiota characteristics and discover potential microbiota biomarkers for non-invasive, radiation-free PNs diagnosis and warning in the future. We performed 16 S rRNA amplicon sequencing on saliva samples from 173 PN patients and 40 HCs to compare the characteristics and functional changes in oral microbiota between the two groups. The random forest algorithm was used to identify PN salivary microbial markers. Biological functions and potential mechanisms of differential genes in saliva samples were preliminarily explored using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cluster of Orthologous Groups (COG) analyses. RESULTS: The diversity of salivary microorganisms was higher in the PN group than in the HC group. Significant differences were noted in community composition and abundance of oral microorganisms between the two groups. Neisseria, Prevotella, Haemophilus and Actinomyces, Porphyromonas, Fusobacterium, 7M7x, Granulicatella and Selenomonas were the main differential genera between the PN and HC groups. Fusobacterium, Porphyromonas, Parvimonas, Peptostreptococcus and Haemophilus constituted the optimal marker sets (area under curve, AUC = 0.80), which can distinguish between patients with PNs and HCs. Further, the salivary microbiota composition was significantly correlated with age, sex, and smoking history (P < 0.001), but not with personal history of cancer (P > 0.05). Bioinformatics analysis of differential genes showed that patients with PN showed significant enrichment in protein/molecular functions related to immune deficiency and energy metabolisms, such as the cytoskeleton protein RodZ, nicotinamide adenine dinucleotide phosphate dehydrogenase (NADPH) dehydrogenase, major facilitator superfamily transporters and AraC family transcription regulators. CONCLUSIONS: Our study provides the first evidence that the salivary microbiota can serve as potential biomarkers for identifying PN. We observed a significant association between changes in the oral microbiota and PNs, indicating the potential of salivary microbiota as a new non-invasive biomarker for PNs. TRIAL REGISTRATION: Clinical trial registration number: ChiCTR2200062140; Date of registration: 07/25/2022.
Asunto(s)
Neoplasias Pulmonares , Microbiota , Humanos , Saliva/microbiología , ARN Ribosómico 16S/genética , Microbiota/genética , Biomarcadores , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , OxidorreductasasRESUMEN
Colorectal cancer (CRC) is a common gastrointestinal malignancy with higher incidence and mortality rates in men compared to women, potentially due to the effects of estrogen signaling. There is substantial evidence supporting the significant role of 17ß-Estradiol (E2) in reducing CRC risk in females, although this perspective remains debated. E2 has been demonstrated to inhibit CRC cell proliferation and migration at the cellular level by enhancing DNA mismatch repair, modulating key gene expression, triggering cell cycle arrest, and reducing activity of migration factors. Furthermore, E2 contributes to promote a tumor microenvironment unfavorable for CRC growth by stimulating ERß expression, reducing inflammatory responses, reversing immunosuppression, and altering the gut microbiome composition. Conversely, under conditions of high oxidative stress, hypoxia, and nutritional deficiencies, E2 may facilitate CRC development through GPER-mediated non-genomic signaling. E2's influence on CRC involves the genomic and non-genomic signals mediated by ERß and GPER, respectively, leading to its dual roles in anticancer activity and carcinogenesis. This review aims to summarize the potential mechanisms by which E2 directly or indirectly impacts CRC development, providing insights into the phenomenon of sexual dimorphism in CRC and suggesting potential strategies for prevention and treatment.
Asunto(s)
Neoplasias Colorrectales , Estradiol , Humanos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Estradiol/metabolismo , Animales , Receptor beta de Estrógeno/metabolismo , Receptor beta de Estrógeno/genética , Microambiente Tumoral , Transducción de SeñalRESUMEN
Colorectal cancer (CRC) is a significant public health concern, and its development is associated with mitochondrial dysfunction. Mitochondria can adapt to the high metabolic demands of cancer cells owing to their plasticity and dynamic nature. The fusion-fission dynamics of mitochondria play a crucial role in signal transduction and metabolic functions of CRC cells. Enhanced mitochondrial fission promotes the metabolic reprogramming of CRC cells, leading to cell proliferation, metastasis, and chemoresistance. Excessive fission can also trigger mitochondria-mediated apoptosis. In contrast, excessive mitochondrial fusion leads to adenosine triphosphate (ATP) overproduction and abnormal tumor proliferation, whereas moderate fusion protects intestinal epithelial cells from oxidative stress-induced mitochondrial damage, thus preventing colitis-associated cancer (CAC). Therefore, an imbalance in mitochondrial dynamics can either promote or inhibit CRC progression. This review provides an overview of the mechanism underlying mitochondrial fusion-fission dynamics and their impact on CRC biology. This revealed the dual role of mitochondrial fusion-fission dynamics in CRC development and identified potential drug targets. Additionally, this study partially explored mitochondrial dynamics in immune and vascular endothelial cells in the tumor microenvironment, suggesting promising prospects for targeting key fusion/fission effector proteins against CRC.
Asunto(s)
Neoplasias Colorrectales , Dinámicas Mitocondriales , Humanos , Células Endoteliales/metabolismo , Mitocondrias/metabolismo , Transducción de Señal , Neoplasias Colorrectales/patología , Proteínas Mitocondriales/metabolismo , Microambiente TumoralRESUMEN
Sexual dimorphism has been observed in the incidence and prognosis of colorectal cancer (CRC), with men generally exhibiting a slightly higher incidence than women. Research suggests that this difference may be attributed to variations in sex steroid hormone levels and the gut microbiome. The gut microbiome in CRC shows variations in composition and function between the sexes, leading to the concept of 'microgenderome' and 'sex hormone-gut microbiome axis.' Conventional research indicates that estrogens, by promoting a more favorable gut microbiota, may reduce the risk of CRC. Conversely, androgens may have a direct pro-tumorigenic effect by increasing the proportion of opportunistic pathogens. The gut microbiota may also influence sex hormone levels by expressing specific enzymes or directly affecting gonadal function. However, this area remains controversial. This review aims to explore the differences in sex hormone in CRC incidence, the phenomenon of sexual dimorphism within the gut microbiome, and the intricate interplay of the sex hormone-gut microbiome axis in CRC. The objective is to gain a better understanding of these interactions and their potential clinical implications, as well as to introduce innovative approaches to CRC treatment.
Asunto(s)
Neoplasias Colorrectales , Microbioma Gastrointestinal , Femenino , Humanos , Masculino , Caracteres Sexuales , Hormonas Esteroides Gonadales , AndrógenosRESUMEN
This paper investigates the intervention effect and mechanism of Banxia Xiexin Decoction(BXD) on colitis-associated colorectal cancer(CAC) infected with Fusobacterium nucleatum(Fn). C57BL/6 mice were randomly divided into a control group, Fn group, CAC group [azoxymethane(AOM)/dextran sulfate sodium salt(DSS)](AOM/DSS), model group, and BXD group. Except for the control and AOM/DSS groups, the mice in the other groups were orally administered with Fn suspension twice a week. The AOM/DSS group, model group, and BXD group were also injected with a single dose of 10 mg·kg~(-1) AOM combined with three cycles of 2.5% DSS taken intragastrically. The BXD group received oral administration of BXD starting from the second cycle until the end of the experiment. The general condition and weight changes of the mice were monitored during the experiment, and the disease activity index(DAI) was calculated. At the end of the experiment, the colon length and weight of the mice in each group were compared. Hematoxylin-eosin(HE) staining was used to observe the pathological changes in the colon tissue. Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of interleukin(IL)-2, IL-4, and IL-6 inflammatory factors in the serum. Immunohistochemistry(IHC) was used to detect the expression of Ki67, E-cadherin, and ß-catenin in the colon tissue. Western blot was used to detect the protein content of Wnt3a, ß-catenin, E-cadherin, annexin A1, cyclin D1, and glycogen synthase kinase-3ß(GSK-3ß) in the colon tissue. The results showed that compared with the control group, the Fn group had no significant lesions. The mice in the AOM/DSS group and model group had decreased body weight, increased DAI scores, significantly increased colon weight, and significantly shortened colon length, with more significant lesions in the model group. At the same time, the colon histology of the model group showed more severe adenomas, inflammatory infiltration, and cellular dysplasia. The levels of IL-4 and IL-6 in the serum were significantly increased, while the IL-2 content was significantly decreased. The IHC results showed low expression of E-cadherin and high expression of Ki67 and ß-catenin in the model group, with a decreased protein content of E-cadherin and GSK-3ß and an increased protein content of Wnt3a, ß-catenin, annexin A1, and cyclin D1. After intervention with BXD, the body weight of the mice increased; the DAI score decreased; the colon length increased, and the tumor decreased. The histopathology showed reduced tumor proliferation and reduced inflammatory infiltration. The levels of IL-6 and IL-4 in the serum were significantly decreased, while the IL-2 content was increased. Meanwhile, the expression of E-cadherin was upregulated, and that of Ki67 and ß-catenin was downregulated. The protein content of E-cadherin and GSK-3ß increased, while that of Wnt3a, ß-catenin, annexin A1, and cyclin D1 decreased. In conclusion, BXD can inhibit CAC infected with Fn, and its potential mechanism may be related to the inhibition of Fn binding to E-cadherin, the decrease in annexin A1 protein level, and the regulation of the Wnt/ß-catenin pathway.
Asunto(s)
Anexina A1 , Neoplasias Asociadas a Colitis , Colitis , Medicamentos Herbarios Chinos , Ratones , Animales , Colitis/complicaciones , Colitis/tratamiento farmacológico , Colitis/genética , beta Catenina/genética , beta Catenina/metabolismo , Ciclina D1/metabolismo , Fusobacterium nucleatum/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Antígeno Ki-67/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Ratones Endogámicos C57BL , Cadherinas/metabolismo , Peso Corporal , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , AzoximetanoRESUMEN
The oral cavity contains a site-specific microbiota that interacts with host cells to regulate many physiological processes in the human body. Emerging evidence has suggested that changes in the oral microbiota can increase the risk of lung cancer (LC), and the oral microbiota is also altered in patients with LC. Human and animal studies have shown that oral microecological disorders and/or specific oral bacteria may play an active role in the occurrence and development of LC through direct and/or indirect mechanisms. These studies support the potential of oral microbiota in the clinical treatment of LC. Oral microbiota may therefore be used in the prevention and treatment of LC and to improve the side effects of anticancer therapy by regulating the balance of the oral microbiome. Specific oral microbiota in LC may also be used as screening or predictive biomarkers. This review summarizes the main findings in research on oral microbiome-related LC and discusses current challenges and future research directions.
RESUMEN
Targeted chemo-phototherapy has received widespread attention in cancer treatment for its advantages in reducing the side effects of chemotherapeutics and improving therapeutic effects. However, safe and efficient targeted-delivery of therapeutic agents remains a major obstacle. Herein, we successfully constructed an AS1411-functionalized triangle DNA origami (TOA) to codeliver chemotherapeutic drug (doxorubicin, DOX) and a photosensitizer (indocyanine green, ICG), denoted as TOADI (DOX/ICG-loaded TOA), for targeted synergistic chemo-phototherapy. In vitro studies show that AS1411 as an aptamer of nucleolin efficiently enhances the nanocarrier's endocytosis more than 3 times by tumor cells highly expressing nucleolin. Subsequently, TOADI controllably releases the DOX into the nucleus through the photothermal effect of ICG triggered by near-infrared (NIR) laser irradiation, and the acidic environment of lysosomes/endosomes facilitates the release. The downregulated Bcl-2 and upregulated Bax, Cyt c, and cleaved caspase-3 indicate that the synergistic chemo-phototherapeutic effect of TOADI induces the apoptosis of 4T1 cells, causing ~ 80% cell death. In 4T1 tumor-bearing mice, TOADI exhibits 2.5-fold targeted accumulation in tumor region than TODI without AS1411, and 4-fold higher than free ICG, demonstrating its excellent tumor targeting ability in vivo. With the synergetic treatment of DOX and ICG, TOADI shows a significant therapeutic effect of ~ 90% inhibition of tumor growth with negligible systemic toxicity. In addition, TOADI presents outstanding superiority in fluorescence and photothermal imaging. Taken together, this multifunctional DNA origami-based nanosystem with the advantages of specific tumor targeting and controllable drug release provides a new strategy for enhanced cancer therapy.
Asunto(s)
Hipertermia Inducida , Nanopartículas , Neoplasias , Animales , Ratones , Sistemas de Liberación de Medicamentos/métodos , Hipertermia Inducida/métodos , Fototerapia/métodos , Doxorrubicina , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , ADN/uso terapéutico , Concentración de Iones de Hidrógeno , Nanopartículas/uso terapéutico , Liberación de Fármacos , Línea Celular TumoralRESUMEN
Objective: To uncover and identify the differences in salivary microbiota profiles and their potential roles between patients with pulmonary nodules (PN) and healthy controls, and to propose new candidate biomarkers for the early warning of PN. Methods: 16S rRNA amplicon sequencing was performed with the saliva samples of 173 PN patients, or the PN group, and 40 health controls, or the HC group, to compare the characteristics, including diversity, community composition, differential species, and functional changes of salivary microbiota in the two groups. Random forest algorithm was used to identify salivary microbial markers of PN and their predictive value for PN was assessed by area under the curve (AUC). Finally, the biological functions and potential mechanisms of differentially-expressed genes in saliva samples were preliminarily investigated on the basis of predictive functional profiling of Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt2). Results: The α diversity and ß diversity of salivary microbiota in the PN group were higher than those in the HC group (P<0.05). Furthermore, there were significant differences in the community composition and the abundance of oral microorganisms between the PN and the HC groups (P<0.05). Random forest algorithm was applied to identify differential microbial species. Porphyromonas, Haemophilus, and Fusobacterium constituted the optimal marker sets (AUC=0.79, 95% confidence interval: 0.71-0.86), which can be used to effectively identify patients with PN. Bioinformatics analysis of the differentially-expressed genes revealed that patients with PN showed significant enrichment in protein/molecular functions involved in immune deficiency and redox homeostasis. Conclusion: Changes in salivary microbiota are closely associated with PN and may induce the development of PN or malignant transformation of PN, which indicates the potential of salivary microbiota to be used as a new non-invasive humoral marker for the early diagnosis of PN.
Asunto(s)
Microbiota , Saliva , Humanos , Estudios Prospectivos , ARN Ribosómico 16S/genética , FilogeniaRESUMEN
We investigated the effects of decursin on the proliferation, apoptosis, and migration of colorectal cancer HT29 and HCT116 cells through the phosphatidylinositol 3-kinase(PI3K)/serine-threonine kinase(Akt) pathway. Decursin(10, 30, 60, and 90 µmol·L~(-1)) was used to treat HT29 and HCT116 cells. The survival, colony formation ability, proliferation, apoptosis, wound hea-ling area, and migration of the HT29 and HCT116 cells exposed to decursin were examined by cell counting kit-8(CCK8), cloning formation experiments, Ki67 immunofluorescence staining, flow cytometry, wound healing assay, and Transwell assay, respectively. Western blot was employed to determine the expression levels of epithelial cadherin(E-cadherin), neural cadherin(N-cadherin), vimentin, B-cell lymphoma/leukemia-2(Bcl-2), Bcl-2-associated X protein(Bax), tumor suppressor protein p53, PI3K, and Akt. Compared with the control group, decursin significantly inhibited the proliferation and colony number and promoted the apoptosis of HT29 and HCT116 cells, and it significantly down-regulated the expression of Bcl-2 and up-regulated the expression of Bax. Decursin inhibited the wound healing and migration of the cells, significantly down-regulated the expression of N-cadherin and vimentin, and up-regulated the expression of E-cadherin. In addition, it significantly down-regulated the expression of PI3K and Akt and up-regulated that of p53. In summary, decursin may regulate epithelial-mesenchymal transition(EMT) via the PI3K/Akt signaling pathway, thereby affecting the proliferation, apoptosis, and migration of colorectal cancer cells.
Asunto(s)
Neoplasias Colorrectales , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína X Asociada a bcl-2 , Vimentina/metabolismo , Proliferación Celular , Transducción de Señal , Apoptosis , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Cadherinas/genética , Movimiento CelularRESUMEN
This study aims to investigate the intervention effect and mechanism of Tongxie Yaofang in regulating tumor-associated macrophage polarization on colorectal cancer under chronic stress. BALB/C mice were randomized into blank, control, model, mifepristone, and low-, medium-, and high-dose Tongxie Yaofang groups. The other groups except the blank and model groups were subjected to chronic restraint stress and subcutaneous implantation of colon cancer cells for the modeling of colon cancer under stress. Du-ring this period, the body mass and tumor size of each group of mice were recorded. The degree of depression in mice was assessed by behavioral changes. Enzyme-linked immunosorbent assay was employed to determine the levels of cortisol(CORT), 5-hydroxytryptamine(5-HT), norepinephrine(NE), M1-associated inflammatory cytokines [interleukin(IL)-1ß, IL-12, and tumor necrosis factor(TNF)-α], and M2-associated inflammatory cytokines(IL-4 and IL-10) in the serum. The tumor growth of mice in each group was regularly monitored by in vivo imaging. The histopathological changes of tumors in each group of mice were observed by hematoxylin-eosin staining. The proportions of CD86 and CD206 in the tumor tissue were detected by flow cytometry and immunofluorescence staining. Western blot was employed to determine the protein levels of Janus kinase(JAK)1, JAK2, JAK3, signal transducer and activator of transcription(STAT)3, and STAT6 in the tumor tissue. The results showed that chronic stress increased the immobility time of mice, elevated the serum levels of CORT, IL-4, and IL-10, lowered the levels of 5-HT, NE, IL-1ß, IL-12, and TNF-α, and promoted the growth of subcutaneous tumors. The tumor cells in the tumor tissue grew actively, with obvious atypia and up-regulated protein levels of CD206, JAK1, JAK2, JAK3, STAT3, and STAT6, and down-regulated protein level of CD86. The treatment with Tongxie Yaofang shortened the immobility time of mice, lowered the serum levels of CORT, IL-4, and IL-10, elevated the serum levels of 5-HT, NE, IL-1ß, IL-12, and TNF-α, and inhibited the growth of subcutaneous tumors in mice. Moreover, the treatment caused different degrees of necrosis in the tumor tissues, down-regulated the protein levels of CD206, JAK1, JAK2, JAK3, STAT3, and STAT6, and up-regulated the protein level of CD86. In summary, Tongxie Yaofang can promote the transformation of M2 macrophages to M1 macrophages and change the tumor microenvironment under chronic stress to inhibit the development of colorectal cancer, which may be related to the JAK/STAT signaling pathway.
Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Ratones , Animales , Interleucina-10 , Macrófagos Asociados a Tumores/metabolismo , Factor de Necrosis Tumoral alfa , Interleucina-4 , Serotonina , Ratones Endogámicos BALB C , Citocinas/metabolismo , Interleucina-12 , Microambiente TumoralRESUMEN
This study aims to analyze the current status and development trend of the prevention and treatment of pulmonary nodules(PN) with traditional Chinese medicine(TCM) based on knowledge map and to provide both references and suggestions for future research directions. CNKI, Wanfang, VIP, and SinoMed were searched for relevant papers from the inception to December 31, 2021. Eligible articles were included according to the inclusion and exclusion criteria. The line chart was drawn based on the annual publication volume of articles, and the research interests of this field were learned. The knowledge maps of prevention and treatment of PN with TCM were drawn in CiteSpace 5.8.R1, and the authors, institutions, contents, and hotspots were analyzed. A total of 122 articles were included and the line chart demonstrated that the annual publication volume has been rising since 2018. According to the knowledge maps, the most prolific author was ZHANG Xiao-mei and there were four main research teams. Beijing University of Chinese Medicine and its affiliated hospitals were in a leading position in this field. The main research contents were disease, pathogenesis, and treatment, and the hotspots were data mining and TCM syndrome. The research on prevention and treatment of PN with TCM has become an increasing field of interest in recent years. In the future, the cross-regional cooperation and communication between research teams and institutions should be strengthened for more real-world studies and basic studies about the prevention and treatment of PN with TCM, so that the high-level evidence can be obtained and the underlying mechanisms of TCM formulae in the treatment of PN be clarified.
Asunto(s)
Conocimiento , Medicina Tradicional China , Humanos , Beijing , Hospitales , SíndromeRESUMEN
Anlotinib is a multi-target tyrosine kinase inhibitor. Previous studies confirmed that anlotinib exerts anti-cancer efficiency. However, the functional roles of anlotinib on cancer stem cells (CSCs) are yet to be elucidated. In this study, lung CSCs were isolated and identified in vitro, and mouse xenografts were established in vivo. MTT assays, tumour sphere formation assays, TdT-mediated dUTP nick-end labelling (TUNEL) staining, Annexin V-FITC/PI staining, immunofluorescence analysis and Western blot were performed to investigate the anti-cancer effects of anlotinib on lung CSCs. The results showed that anlotinib inhibits the growth of lung CSCs in vitro and in vivo. In addition, anlotinib induced apoptosis of these cells along with down-regulated expression level of Bcl-2 whereas up-regulated Bax and cleaved caspase-3 expression. It also sensitized lung CSCs to the cytotoxicity of cisplatin and paclitaxel; the tumour sphere formation and expression levels of multiple stemness-associated markers, such as ALDH1 and CD133, were also decreased. Furthermore, the underlying mechanism indicated that anlotinib reduces the phosphorylated levels of NF-κB p65 and IκB-α in lung CSCs. Taken together, these findings suggested that anlotinib exerts potent anti-cancer effects against lung CSCs through apoptotic induction and stemness phenotypic attenuation. The mechanism could be associated with the suppression of NF-κB activity.
Asunto(s)
Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Indoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , FN-kappa B/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Quinolinas/farmacología , Animales , Apoptosis , Proliferación Celular , Femenino , Humanos , Técnicas In Vitro , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , FN-kappa B/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Circulating tumor cells (CTCs) are associated with a higher risk of metastasis in tumor patients. The adhesion and arrest of CTCs at a secondary site is an essential prerequisite for the occurrence of tumor metastasis. CTC reattachment has shown to be dependent on microtentacle (McTN) formation in vivo. However, the specific molecular mechanism of McTN formation in suspended cancer cells remains largely unclear. Here, we demonstrated that the activation of Notch-1 signaling triggers McTN formation to facilitate cell reattachment in suspended cell culture conditions. Moreover, molecular mechanistic studies revealed that McTN formation is governed by the balance between microtubule-driven outgrowth and actomyosin-driven cell contractility. The activation of Notch-1 downregulates the acetylation level of microtubules via the Cdc42/HDAC6 pathway, which contributes to microtubule polymerization. Simultaneously, Notch-1 signaling-induced Cdc42 activation also reduced phosphorylation of myosin regulatory light chain, leading to cell contractility attenuation. Altogether, these results defined a novel mechanism by which Notch-1 signaling disturbs the balance between the expansion of microtubules and contraction of the cortical actin, which promotes McTN formation and cell reattachment. Our findings provide a new perspective on the effective therapeutic target to prevent CTC reattachment.
Asunto(s)
Neoplasias de la Mama/patología , Células Neoplásicas Circulantes/patología , Receptor Notch1/metabolismo , Proteína de Unión al GTP cdc42/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Adhesión Celular , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Ratones , Cadenas Ligeras de Miosina/metabolismo , Metástasis de la Neoplasia , Trasplante de Neoplasias , Células Neoplásicas Circulantes/metabolismo , Fosforilación , Transducción de SeñalRESUMEN
Circular dorsal ruffles (CDRs) are a kind of special ring-shaped membrane structure rich in F-actin, it is highly involved in the invasion-metastasis of tumor. Shear stress is one of the biophysical elements that affects the fate of tumor cells. However, how shear stress contributes to the CDRs formation is still unclear. In this study, we found that shear stress stimulated the formation of CDRs and promoted the migration of human breast MDA-MB-231 carcinoma cells. Integrin-linked kinase (ILK) mediated the recruiting of ADP-ribosylation factors (ARAP1/Arf1) to CDRs. Meanwhile, the transfection of ARAP1 or Arf1 mutant decreased the number of cells with CDRs, the CDRs areas and perimeters, thus blocked the cancer cell migration. This indicated that the ARAP1/Arf1 were necessary for the CDRs formation and cancer cell migration. Further study revealed that shear stress could stimulate the formation of intracellular macropinocytosis (MPS) thus promoted the ARAP1/Arf1 transportation to early endosome to regulate cancer cell migration after the depolymerization of CDRs. Our study elucidates that the CDRs formation is essential in shear stress-induced breast cancer cell migration, which provides a new research target for exploring the cytoskeletal mechanisms of breast cancer malignance.
Asunto(s)
Citoesqueleto de Actina/metabolismo , Membrana Celular/metabolismo , Movimiento Celular/fisiología , Extensiones de la Superficie Celular/metabolismo , Neoplasias/metabolismo , Factor 1 de Ribosilacion-ADP/metabolismo , Citoesqueleto de Actina/química , Actinas/metabolismo , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Membrana Celular/química , Membrana Celular/ultraestructura , Extensiones de la Superficie Celular/química , Proteínas Activadoras de GTPasa/metabolismo , Humanos , Neoplasias/patología , Pinocitosis/fisiología , Polimerizacion , Proteínas Serina-Treonina Quinasas/metabolismo , Estrés MecánicoRESUMEN
Inhibition of Aurora-B kinase is a synthetic lethal therapy for tumors that overexpress the MYC oncoprotein. It is currently unclear whether co-occurring oncogenic alterations might influence this synthetic lethality by conferring more or less potency in the killing of tumor cells. To identify such modifiers, isogenic cell lines were utilized to test a variety of cancer genes that have been previously demonstrated to promote survival under conditions of cellular stress, contribute to chemoresistance and/or suppress MYC-primed apoptosis. It was found that Bcl-2 and Bcl-xL, two antiapoptotic members of the Bcl-2 family, can partially suppress the synthetic lethality, but not multinucleation, elicited by a pan-aurora kinase inhibitor, VX-680. Suppression was show to stem from the inhibition of autophagy, specifically in multinucleated cells, rather than a general inhibition of apoptosis. The anti-autophagic activity of Bcl-2 also impacted polyploid cell recovery in colony-forming assays, suggesting a route of escape from MYC-VX-680 synthetic lethality that may have clinical consequences. These findings expand on previous conclusions that autophagic death of VX-680-induced polyploid cells is mediated by Atg6. Bcl-2 and Bcl-xL negatively modulate MYC-VX-680 synthetic lethality and it is the anti-autophagic activity of these two Bcl-2 family proteins, specifically in multinucleate cells, that contributes to resistance to Aurora kinase-targeting drugs.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagia/fisiología , Beclina-1/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína bcl-X/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Beclina-1/genética , Línea Celular Tumoral , Humanos , Proteínas de la Membrana/metabolismoRESUMEN
To further identify the real efficacy and safety of dexmedetomidine as an adjuvant to local wound infiltration anaesthesia, we conducted this meta-analysis. The systematic search strategy was performed using PubMed, Embase, Cochrane Library, and Chinese databases. As a result, a total of 23 RCTs (1445 patients) were included. Patients receiving dexmedetomidine combined with local anaesthetics had a lower rescue analgesia rate [risk ratio (RR): 0.48; 95% confidence interval (CI): 0.36-0.65] and lower rescue analgesic consumption [weighted mean difference (WMD): -10.80 mg; 95%CI: -13.28 to -8.31 mg] than patients receiving local anaesthetics alone. The dexmedetomidine-related adverse reactions included bradycardia (RR: 1.33; 95%CI: 0.32-5.56) and hypotension (RR: 3.00; 95%CI: 0.49-18.42). In addition, the time to first analgesic request (WMD: 296.16 minutes; 95%CI: 165.69 minutes ~ 426.63 minutes), incidence of postoperative nausea and vomiting (PONV) and pain scores at 4 hours postoperatively were also significantly lower in patients receiving dexmedetomidine combined with local anaesthetics. This meta-analysis demonstrated that the use of dexmedetomidine as an adjuvant to wound infiltration is effective for reducing the rescue analgesia rate, rescue analgesic consumption and PONV. In addition, limited evidence shows that dexmedetomidine can prolong postoperative analgesia for approximately 5 hours. Further investigations on dexmedetomidine-related adverse reactions and the dose-response effect of dexmedetomidine in wound infiltration are warranted.
Asunto(s)
Anestesia Local , Dexmedetomidina , Heridas y Lesiones/terapia , Anestésicos Locales/uso terapéutico , Dexmedetomidina/uso terapéutico , Femenino , Humanos , Embarazo , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Artemisinin and its derivatives are a family of anti-malarial drugs with known clinical safety and efficacy. Apart from its anti-malarial effect, artemisinin has also been reported to show anti-cancer, anti-viral, anti-parasitosis, anti-inflammatory properties in vitro and in vivo. An increasing number of studies report that artemisinin can impact the fibrotic process through various ways, such as TGF-ß, MAPK, Wnt/ß-catenin, PI3K/AKT/mTRO, FRX and Notch signaling pathways, as well as regulation of BMP-7 and cell autophagy. Moreover, the anti-inflammatory properties of artemisinin also contribute to the anti-fibrotic process. The present review summarizes the related studies on artemisinin treatment in fibrosis and elucidates the underlying mechanisms. We believe that this review can explain the potential anti-fibrotic value of artemisinin, outlining its potential use in the development of a safe and effective therapeutic method to alleviate fibrosis in the future.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Reposicionamiento de Medicamentos , Transducción de Señal/efectos de los fármacos , Animales , Antiinflamatorios/efectos adversos , Antimaláricos/efectos adversos , Artemisininas/efectos adversos , Fibrosis , HumanosRESUMEN
A promising approach toward cancer therapy is expected to integrate imaging and therapeutic agents into a versatile nanocarrier for achieving improved antitumor efficacy and reducing the side effects of conventional chemotherapy. Herein, we designed a poly(d,l-lactic- co-glycolic acid) (PLGA)-based theranostic nanoplatform using the double emulsion solvent evaporation method (W/O/W), which is associated with bovine serum albumin (BSA) modifications, to codeliver indocyanine green (ICG), a widely used near-infrared (NIR) dye, and doxorubicin (Dox), a chemotherapeutic drug, for dual-modality imaging-guided chemo-photothermal combination cancer therapy. The resultant ICG/Dox co-loaded hybrid PLGA nanoparticles (denoted as IDPNs) had a diameter of around 200 nm and exhibited excellent monodispersity, fluorescence/size stability, and biocompatibility. It was confirmed that IDPNs displayed a photothermal effect and that the heat induced faster release of Dox, which led to enhanced drug accumulation in cells and was followed by their efficient escape from the lysosomes into the cytoplasm and drug diffusion into the nucleus, resulting in a chemo-photothermal combinatorial therapeutic effect in vitro. Moreover, the IDPNs exhibited a high ability to accumulate in tumor tissue, owing to the enhanced permeability and retention (EPR) effect, and could realize real-time fluorescence/photoacoustic imaging of solid tumors with a high spatial resolution. In addition, the exposure of tumor regions to NIR irradiation could enhance the tumor penetration ability of IDPNs, almost eradicating subcutaneous tumors. In addition, the inhibition rate of IDPNs used in combination with laser irradiation against EMT-6 tumors in tumor-bearing nude mice (chemo-photothermal therapy) was approximately 95.6%, which was much higher than that for chemo- or photothermal treatment alone. Our study validated the fact that the use of well-defined IDPNs with NIR laser treatment could be a promising strategy for the early diagnosis and passive tumor-targeted chemo-photothermal therapy for cancer.
Asunto(s)
Terapia Combinada/métodos , Doxorrubicina/química , Verde de Indocianina/química , Rayos Infrarrojos/uso terapéutico , Nanopartículas/química , Neoplasias/terapia , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Albúmina Sérica Bovina/química , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Doxorrubicina/efectos adversos , Doxorrubicina/metabolismo , Portadores de Fármacos/química , Liberación de Fármacos , Estabilidad de Medicamentos , Femenino , Calor , Verde de Indocianina/efectos adversos , Verde de Indocianina/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células 3T3 NIH , Nanopartículas/efectos adversos , Nanopartículas/metabolismo , Imagen Óptica , Fototerapia/métodos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/efectos adversos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/metabolismo , Albúmina Sérica Bovina/efectos adversos , Albúmina Sérica Bovina/metabolismo , Distribución Tisular , Resultado del TratamientoRESUMEN
BACKGROUND: Angiogenesis is a pathobiological hallmark of gastric cancer. However, rare studies focus on angiogenesis in gastric precancerous lesions (GPL). Weipixiao (WPX), a Chinese herbal preparation, is proved clinically effective in treating GPL. Here, we evaluated WPX's anti-angiogenic potential for GPL, and also investigated the possibility of its anti-angiogenic mechanisms. METHODS: HPLC analysis was applied to screen the major chemical components of WPX. After modeling N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced GPL in male Sprague-Dawley rats, different doses of WPX were administrated orally for 10 weeks. Next, we performed histopathological examination using routine H&E staining and HID-AB-PAS staining. In parallel, we assessed angiogenesis revealed by microvessel density (MVD) using CD34 immunostaining, and subsequently observe microvessel ultrastructure in gastric mucosa under Transmission Electron Microscope. Finally, we detect expression of angiogenesis-associated markers VEGF and HIF-1α using immunohistochemistry. Moreover, mRNA expressions of ERK1, ERK2, Cylin D1 as well as HIF-1α in gastric mucosa were determined by quantitative real-time reverse transcription- polymerase chain reaction. RESULTS: We observed the appearance of active angiogenesis in GPL rats, and demonstrated that WPX could reduce microvascular abnormalities and attenuate early angiogenesis in most of GPL specimens with a concomitant regression of most intestinal metaplasia (IM) and a portion of gastric epithelial dysplasia (GED). In parallel, WPX could suppress HIF-1α mRNA expression (P < 0.01) as well as protein expression (although without statistical significance), and could markedly inhibit VEGF protein expression in GPL rats. Mechanistically, WPX intervention, especially at low dose, caused a significant decrease in the ERK1 and Cylin D1 mRNA levels. However, WPX might probably have no regulatory effect on ERK2 amplification. CONCLUSIONS: WPX could attenuate early angiogenesis and temper microvascular abnormalities in GPL rats. This might be partly achieved by inhibiting on the angiogenesis-associated markers HIF-1α and VEGF, and on the ERK1/Cylin D1 aberrant activation.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Medicamentos Herbarios Chinos/farmacología , Mucosa Gástrica/efectos de los fármacos , Neovascularización Patológica , Neoplasias Gástricas/irrigación sanguínea , Estómago/efectos de los fármacos , Animales , Mucosa Gástrica/irrigación sanguínea , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Ratas , Ratas Sprague-Dawley , Estómago/irrigación sanguínea , Estómago/patología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The incidence and mortality rates of colorectal cancer have elevated its status as a significant public health concern. Recent research has elucidated the crucial role of mitochondrial fusion-fission dynamics in the initiation and progression of colorectal cancer. Elevated mitochondrial fission or fusion activity can contribute to the metabolic reprogramming of tumor cells, thereby activating oncogenic pathways that drive cell proliferation, invasion, migration, and drug resistance. Nevertheless, excessive mitochondrial fission can induce apoptosis, whereas moderate mitochondrial fusion can protect cells from oxidative stress. This imbalance in mitochondrial dynamics can exert dual roles as both promoters and inhibitors of colorectal cancer progression. This review provides an in-depth analysis of the fusion-fission dynamics and the underlying pathological mechanisms in colorectal cancer cells. Additionally, it offers partial insights into the mitochondrial kinetics in colorectal cancer-associated cells, such as immune and endothelial cells. This review is aimed at identifying key molecular events involved in colorectal cancer progression and highlighting the potential of mitochondrial dynamic proteins as emerging targets for pharmacological intervention.