RESUMEN
Cuproptosis is an emerging programmed cell death, displaying great potential in cancer treatment. However, intracellular copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble copper ions into polydopamine nanostructure (PDA-DTC/Cu) for reprogramming copper metabolism of tumor is developed. The deposited Cu2+ can effectively trigger the aggregation of lipoylated proteins to induce cuproptosis of tumor cells. Beyond elevating intracellular copper accumulation, PDA-DTC/Cu enables to break the balance of copper metabolism by disrupting mitochondrial function and restricting the adenosine triphosphate (ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of tumor cells to enhance cuproptosis. Meanwhile, the killed tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising "one stone two birds" strategy to realize copper accumulation and inhibit copper export simultaneously to enhance cuproptosis for 4T1 murine breast cancer immunotherapy.
Asunto(s)
Cobre , Inmunoterapia , Indoles , Nanoestructuras , Polímeros , Cobre/química , Polímeros/química , Animales , Inmunoterapia/métodos , Indoles/química , Indoles/farmacología , Ratones , Nanoestructuras/química , Línea Celular Tumoral , Humanos , Catálisis , Femenino , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismoRESUMEN
Sexual reproduction in angiosperms is siphonogamous, and the interaction between pollen tube and pistil is critical for successful fertilization. Our previous study demonstrated that mutation of the Arabidopsis turgor regulation defect 1 (TOD1) gene leads to reduced male fertility, a result of retarded pollen tube growth in the pistil. TOD1 encodes a Golgi-localized alkaline ceramidase, a key enzyme for the production of sphingosine-1-phosphate (S1P), which is involved in the regulation of turgor pressure in plant cells. However, whether TOD1s play a conserved role in the innovation of siphonogamy is largely unknown. In this study, we provide evidence that OsTOD1, which is similar to AtTOD1, is also preferentially expressed in rice pollen grains and pollen tubes. OsTOD1 knockout results in reduced pollen tube growth potential in rice pistil. Both the OsTOD1 genomic sequence with its own promoter and the coding sequence under the AtTOD1 promoter can partially rescue the attod1 mutant phenotype. Furthermore, TOD1s from other angiosperm species can partially rescue the attod1 mutant phenotype, while TOD1s from gymnosperm species are not able to complement the attod1 mutant phenotype. Our data suggest that TOD1 acts conservatively in angiosperms, and this opens up an opportunity to dissect the role of sphingolipids in pollen tube growth in angiosperms.
Asunto(s)
Magnoliopsida/genética , Proteínas de Plantas/metabolismo , Arabidopsis/genética , Arabidopsis/fisiología , Flores/genética , Flores/fisiología , Ginkgo biloba/genética , Ginkgo biloba/fisiología , Solanum lycopersicum/genética , Solanum lycopersicum/fisiología , Magnoliopsida/fisiología , Nelumbo/genética , Nelumbo/fisiología , Nymphaea/genética , Nymphaea/fisiología , Oryza/genética , Oryza/fisiología , Pinus taeda/genética , Pinus taeda/fisiología , Proteínas de Plantas/genética , Polen/genética , Polen/fisiología , Tubo Polínico/genética , Tubo Polínico/fisiología , ReproducciónRESUMEN
Black spotted frogs have rich nutrition and delicious meat, and its market consumption has increased year by year. However, outbreaks of the diseases have caused huge losses to the breeding industry. The crooked head disease caused by Elizabethkingia miricola (E. miricola) is highly contagious and lethal, and there is no effective treatment method. Vaccination is the most promising strategy to prevent infectious diseases. Immersion vaccination has attracted many researchers because of its simplicity of operation in preventing infectious diseases. In addition, immersion vaccines can be more effective when used with adjuvants. In this study, we prepared inactivated E. miricola with 0.3% formaldehyde, and the black spotted frogs were vaccinated by soaking in inactivated E. miricola vaccine, anisodamine + vaccine mixture, ß-glucan + vaccine mixture, chitosan + vaccine mixture for 60 min. PBS was used as a control. After being challenged by E. miricola, the survival rate of anisodamine + vaccine (57%) and chitosan + vaccine group (63%) was significantly higher than that of the control group (17%). By analyzing pathological sections, we found that the chitosan + vaccine and anisodamine + vaccine groups protected the brain, eye, liver and kidney tissues of the black spotted frogs compared to the control group, which was consistent with the trend of survival rate. In addition, chitosan + vaccine and anisodamine + vaccine groups had better effects on LZM, TSOD and C3 in serum than control group. Meanwhile, the numbers of the percentage of leukocytes/haemocytes in the peripheral blood of immunized black spotted frogs increased. The anisodamine + vaccine group (5.3%) and chitosan + vaccine (5.38%) group were significantly higher than the blank control group (2.24%), which indicate that the two groups induced a more significant immune response and were more resistant to bacterial invasion. The tissue bacterial loads in liver, brain, kidney and eye were significantly lower in the anisodamine + vaccine and chitosan + vaccine groups than that of the control group. This study explored and demonstrated the good efficiency of chitosan and anisodamine as adjuvants for immunization by immersion and provided a reference for improving the efficiency of immunization by immersion.
Asunto(s)
Anuros , Quitosano , Alcaloides Solanáceos , Adyuvantes Inmunológicos , Animales , Anuros/inmunología , Quitosano/inmunología , Alcaloides Solanáceos/inmunología , Eficacia de las Vacunas , Vacunas de Productos InactivadosRESUMEN
Hypoxia and high accumulation of lactic acid in the tumor microenvironment provide fertile soil for tumor development, maintenance and metastasis. Herein, we developed a calcium peroxide (CaO2)-loaded nanostructure that can play a role of "one stone kill two birds", i.e., acidic and hypoxic tumor microenvironment can be simultaneously regulated by CaO2 loaded nanostructure. Specifically, CaO2-loaded mesoporous polydopamine nanoparticles modified with sodium hyaluronate (denoted as CaO2@mPDA-SH) can gradually accumulate in a tumor site. CaO2 exposed in acidic microenvironment can succeed in consuming the lactic acid with oxygen generation simultaneously, which could remodel the acid and hypoxia tumor microenvironment. More importantly, the relief of hypoxia could further reduce lactate production from the source by down-regulating the hypoxia inducible factor-1α (HIF-1α), which further down-regulated the glycolysis associated enzymes including glycolysis-related glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). As a result, CaO2@mPDA-SH alone without the employment of other therapeutics can dually regulate the tumor hypoxia and lactic acid metabolism, which efficiently represses tumor progression in promoting immune activation, antitumor metastasis, and anti-angiogenesis.
Asunto(s)
Nanopartículas , Microambiente Tumoral , Humanos , Línea Celular Tumoral , Hipoxia , Nanopartículas/química , Ácido Láctico/metabolismoRESUMEN
Selenocysteine (Sec), a rare naturally proteinogenic amino acid, is the major form of essential trace element selenium in living organisms. Selenoproteins, with one or several Sec residues, are found in all three domains of life. Many selenoproteins play a role in critical cellular functions such as maintaining cell redox homeostasis. Sec is usually encoded by an in-frame stop codon UGA in the selenoprotein mRNA, and its incorporation in vivo is highly species-dependent and requires the reprogramming of translation. This mechanistic complexity of selenoprotein synthesis poses a big challenge to produce synthetic selenoproteins. To understand the functions of natural as well as engineered selenoproteins, many strategies have recently been developed to overcome the inherent barrier for recombinant selenoprotein production. In this review, we will describe the progress in selenoprotein production methodology.
Asunto(s)
Ingeniería Genética , Selenocisteína/genética , Selenoproteínas/genética , Homeostasis , Humanos , Oxidación-Reducción , Selenocisteína/metabolismo , Selenoproteínas/biosíntesis , Selenoproteínas/metabolismoRESUMEN
USP28, a member of the deubiquitinating enzymes family, plays a vital role in the physiological process of cell proliferation, differentiation and apoptosis, DNA repair, immune response, and stress response. USP28 has been reported to be overexpressed in bladder cancer, colon cancer, breast carcinomas, and so on. Nevertheless, the role of USP28 in gastric cancer has not yet been investigated. In our study, we examined the USP28 expression in 87 paired samples of gastric cancer and normal gastric tissues. We found that USP28 was overexpressed in gastric cancer compared with normal gastric tissues (P < 0.01), and its overexpression was related to the degree of differentiation and metastases. Inhibiting USP28 expression in vitro suppressed the proliferation and invasion of gastric cancer cells by downregulating lysine specific demethylase 1. On the basis of our data, it can be concluded that USP28 may be a novel therapeutic target for gastric cancer.
RESUMEN
BACKGROUND: Hypoxia is present in many solid tumors and is a prognostic factor for poor tumorigenesis. Here, we investigated whether carcinoembryonic antigen (CEA) plays a role in the hypoxic microenvironment of breast cancer. METHODS: We researched the expression of CEA in breast tumor tissues and the corresponding paracancerous tissues. Furthermore, western blotting was used to detect the expression levels of CEA in breast cancer cells cultured under hypoxia or normoxia. The expression levels of CEA, hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase IX (CA-IX) in tumor tissues were detected by immunohistochemical staining. In addition, the correlations between CEA and clinical parameters and prognosis of breast cancer patients were analyzed by statistical analysis. RESULTS: We found that CEA mRNA expression of tissues in breast cancer patients was significantly increased compared to the corresponding paracancerous tissues. Furthermore, the expression levels of CEA in breast cancer cells cultured under hypoxic conditions were elevated compared with those cultured under normoxic conditions. Immunohistochemical staining demonstrated that the expression of CEA in tumor tissues was increased with HIF-1α, and the area of CA-IX expression could be seen with CEA distribution. In addition, the clinical parameter analysis found that serum CEA was significantly associated with malignant clinical features. We also found that elevated CEA expression was related to poor prognosis in breast cancer patients. CONCLUSIONS: CEA expression was elevated in the breast cancer hypoxic microenvironment, and the data suggested a rationale for the use of CEA in breast cancer diagnosis, assessment, and prognosis.
Asunto(s)
Neoplasias de la Mama/genética , Antígeno Carcinoembrionario/genética , Regulación Neoplásica de la Expresión Génica , Regulación hacia Arriba , Adulto , Anciano , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Anhidrasa Carbónica IX/genética , Anhidrasa Carbónica IX/metabolismo , Antígeno Carcinoembrionario/sangre , Antígeno Carcinoembrionario/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Estimación de Kaplan-Meier , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
B vitamins play an essential role in the biosynthesis of nucleotides, replication of DNA, supply of methyl-groups, growth and repair of cells, aberrancies of which have all been implicated in carcinogenesis. Although the potential role of vitamin B in relation to the risk of cancer, including breast, and colorectal cancer, has been investigated in several observational studies, the mechanism of action is still unclear. In this study, vitamin B2 exhibited efficient activation of LSD1 by occupying the active sites where FAD stands. Interestingly, vitamin B2 significantly downregulated expression of CD86, a sensitive surrogate biomarker of LSD1 inhibition, and showed marked activation of gastric cancer cell migration and invasion. Meanwhile, vitamin B2 induced activation of LSD1 may attenuate the proliferation inhibition, and anti-migration effects of apatinib in gastric cancer cells. These findings suggested that vitamin B supplementation may interfere with the efficacy of apatinib in patients with gastric cancer.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Histona Demetilasas/metabolismo , Proteínas de Neoplasias/metabolismo , Piridinas/farmacología , Riboflavina/farmacología , Neoplasias Gástricas/enzimología , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Histona Demetilasas/genética , Humanos , Proteínas de Neoplasias/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND/AIMS: Cytokines are key players in tumorigenesis and are potential targets in cancer treatment. Although IL-6 has attracted considerable attention, interleukin 11 (IL-11), another member of the IL-6 family, has long been overlooked, and little is known regarding its specific function in non-small cell lung cancer (NSCLC). In this study, we explored IL-11's role in NSCLC and the detailed mechanism behind it. METHODS: Cell proliferation in response to IL-11 was determined by colony formation, BrdU incorporation and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Cell motility was measured by Transwell and wound healing assays. NSCLC xenograft models were used to confirm oncogenic function of IL-11 in vivo. Immunohistochemical staining and western blot assay were performed to detect epithelial-mesenchymal transition (EMT) markers and cell signaling pathway alterations. Eighteen NSCLC patients and 5 normal lung samples were collected together with data from an online database to determine the link between IL-11 expression and malignant progression. RESULTS: We observed that IL-11 was upregulated in NSCLC samples compared with normal tissue samples and correlated with poor prognosis. Data from in vitro and in vivo models indicated that IL-11 promotes cell proliferation and tumorigenesis. Cell migration and invasion were also enhanced by IL-11. Epithelial-mesenchymal transition (EMT) was also observed after IL-11 incubation. Furthermore, IL-11 activated AKT and STAT3 in our experimental models. In addition, we observed that hypoxia induced IL-11 expression in NSCLC cells. Deferoxamine (DFX) or dimethyloxalylglycine (DMOG) induced hypoxia-inducible factor 1-alpha (HIF1α) upregulation, which enhanced IL-11 expression in NSCLC cells. CONCLUSIONS: Taken together, our results indicate that IL-11 is an oncogene in NSCLC, and elucidating the mechanism behind it may provide insights for NSCLC treatment.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Interleucina-11/genética , Interleucina-6/genética , Neoplasias Pulmonares/genética , Pulmón/patología , Regulación hacia Arriba , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Ratones Desnudos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , PronósticoRESUMEN
Surface molecular imprinting in layer-by-layer (SMI-LbL) film is known as a facile and effective strategy to build imprinting sites that are more accessible to template molecules compared with molecular imprinting in polymers. Herein, we accomplished the formation of SMI-LbL film on electrospun nanofibers for the first time. The SMI-LbL nanofibers were prepared by a template-induced LbL process on the polyacrylonitrile (PAN) nanofiber substrates, followed by postinfiltrating and photo-cross-linking of photosensitive agent 4,4'-diazostilbene-2,2'-disulfonic acid disodium salt (DAS). The obtained nanofiber mat maintained the nanofibrous structure and showed rapid absorption and extraction of template molecules of meso-tetra(4-carboxyphenyl)-porphine (Por). The binding capacity of Por reached 2.1 mg/g when 3.5 bilayers were deposited on the nanofibers. After six cycles of extraction and reabsorption, the binding capacity of Por remained at 83%. Moreover, the absorption results of the targeted templated molecule of Por and the control molecule of Fast Green, which had a very similar chemical structure and charge status to Por, indicated the specific absorption for template molecule of Por. Thus, a surface molecular imprinted nanofiber mat with high selectivity of the templated molecule has been demonstrated.
RESUMEN
The Hippo signalling pathway can suppress the Wnt/ß-catenin signalling pathway through the last downstream effectors YAP (Yes-associated protein)/TAZ (tafazzin). MST (mammalian sterile 20-like kinase) 1 functions as the upstream kinase of the Hippo pathway, and CK1ε (casein kinase 1ε) plays roles in the up-stream signal transduction of the Wnt/ß-catenin pathway. In the present study, using tandem affinity purification and MS analysis, CK1ε was identified as a novel partner of MST1. Further analysis showed that the interaction between MST1 and CK1ε was mediated by their kinase domains and enhanced by the activation of MST1. To exclude the interference of the phosphorylated YAP/TAZ, the transduction from MST1 to YAP/TAZ was blocked using anti-WW45 shRNA. In the sh-WW45 cells, MST1 still inhibited the Wnt3A-induced phosphorylation of DVL2 (dishevelled 2) and Wnt/ß-catenin signalling by disturbing the interaction of DVL2 and CK1ε. The growth-suppressive effect of MST1 in the presence of Wnt3A was effectively relieved by the downstream activation of the Wnt/ß-catenin pathway. Moreover, MST2, the close homologue of MST1, also displayed the similar function in suppressing the Wnt/ß-catenin pathway. Therefore the results of the present study revealed that, in addition to the phosphorylated YAP/TAZ, the Hippo pathway can suppress the Wnt/ß-catenin pathway directly through MST1/2.
Asunto(s)
Caseína Cinasa 1 épsilon/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Línea Celular , Cromatografía Liquida , Humanos , Unión Proteica , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serina-Treonina Quinasa 3 , Espectrometría de Masas en TándemRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Pyrrosia petiolosa (Christ) Ching (YBSW) is a Traditional Chinese medicine rich in chlorogenic acids. It is an important component in many Traditional Chinese medicinal hypoglycemic formulas and is commonly used by the Miao people to treat diabetes with good efficacy. Our previous research has suggested that chlorogenic acids may be the active ingredients in YBSW. AIM OF THE STUDY: To explore the mechanisms underlying the anti-type 2 diabetes mellitus (T2DM) hypoglycemic effects of chlorogenic acids contained in YBSW. MATERIALS AND METHODS: In vivo experiments, hematoxylin-eosin staining (HE) staining, and immunohistochemistry (IHC) were used to determine the effects of chlorogenic acids contained in YBSW in rats. mRNA expression profiling, microarray analysis, and network pharmacology were used to analyze the underlying mechanisms of the effects. Finally, apoptosis and changes in the related pathways were evaluated in vitro using a 3-(4,5-dimethyl-2-thia-zolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, quantitative real-time polymerase chain reaction, immunofluorescence (IF) assessment, and flow cytometry. RESULTS: After the administration of isochlorogenic acid B, the levels of triglycerides, serum total cholesterol, and fasting blood glucose significantly decreased. HE and IHC staining revealed that isochlorogenic acid B significantly increased insulin expression in islet cells. Using network pharmacology and RNA-seq Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, we screened the advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) signaling pathway. We also verified that YBSW and its chlorogenic acid can inhibit apoptosis and downregulate the expression of related mRNA in the AGE-RAGE pathway in RIN-m5f cells. CONCLUSIONS: YBSW exhibits a significant hypoglycemic effect, with chlorogenic acid being an effective component. The therapeutic effect of chlorogenic acids contained in YBSW is mainly realized by promoting insulin secretion and pancreatic tissue repair. Moreover, YBSW substantially mitigates apoptosis via the AGE-RAGE pathway in T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Medicamentos Herbarios Chinos , Animales , Ratas , Ácido Clorogénico/farmacología , Ácido Clorogénico/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Perfilación de la Expresión Génica , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Simulación del Acoplamiento Molecular , Farmacología en Red , ARN MensajeroRESUMEN
Transforming macrophages into the anti-inflammatory M2 phenotype could markedly strengthen inflammatory bowel disease (IBD) treatment, which is considered as a promising strategy. However, the high ferroptosis sensitivity of M2 macrophages, which decreases their activity, is a major stumbling block to this strategy. Therefore, promoting M2 polarization while simultaneously inhibiting ferroptosis to tackle this challenge is indispensable. Herein, a calciumcarbonate (CaCO3) mineralized liposome encapsulating a ferroptosis inhibitor (Fer-1) was developed (CaCO3@Lipo@Fer-1, CLF). The CaCO3 mineralized coating shields the liposomes to prevent the release of Fer-1 in circulation, while releasing Ca2+ in the acidic-inflammatory environment. This released Ca2+ promotes M2 polarization through the CaSR/AKT/ß-catenin pathway. The subsequently released Fer-1 effectively upregulates GSH and GPX4, scavenges reactive oxygen species, and inhibits ferroptosis in M2 macrophages. In vivo, CLF improved the targeting efficiency of IBD lesions (about 4.17-fold) through the epithelial enhanced permeability and retention (eEPR) effect and enhanced IBD therapy by increasing the M2/M1 macrophage ratio and inhibiting ferroptosis. We demonstrate that the synergistic regulation of macrophage polarization and ferroptosis sensitivity by this mineralized nanoinhibitor is a viable strategy for IBD therapy.
Asunto(s)
Ferroptosis , Enfermedades Inflamatorias del Intestino , Humanos , Macrófagos/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Antiinflamatorios/farmacología , FenotipoRESUMEN
BACKGROUND: Sterol O-acyltransferase 1 (SOAT1) is an important target in the diagnosis and treatment of liver cancer. However, the prognostic value of SOAT1 in patients with hepatocellular carcinoma (HCC) is still not clear. AIM: To investigate the correlation of SOAT1 expression with HCC, using RNA-seq and gene expression data of The Cancer Genome Atlas (TCGA)-liver hepatocellular carcinoma (LIHC) and pan-cancer. METHODS: The correlation between SOAT1 expression and HCC was analyzed. Cox hazard regression models were conducted to investigate the prognostic value of SOAT1 in HCC. Overall survival and disease-specific survival were explored based on TCGA-LIHC data. Biological processes and functional pathways mediated by SOAT1 were characterized by gene ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes. In addition, the protein-protein interaction network and co-expression analyses of SOAT1 in HCC were performed to better understand the regulatory mechanisms of SOAT1 in this malignancy. RESULTS: SOAT1 and SOAT2 were highly expressed in unpaired samples, while only SOAT1 was highly expressed in paired samples. The area under the receiver operating characteristic curve of SOAT1 expression in tumor samples from LIHC patients compared with para-carcinoma tissues was 0.748, while the area under the curve of SOAT1 expression in tumor samples from LIHC patients compared with GTEx was 0.676. Patients with higher SOAT1 expression had lower survival rates. Results from GO/KEGG and gene set enrichment analyses suggested that the PI3K/AKT signaling pathway, the IL-18 signaling pathway, the calcium signaling pathway, secreted factors, the Wnt signaling pathway, the Jak/STAT signaling pathway, the MAPK family signaling pathway, and cell-cell communication were involved in such association. SOAT1 expression was positively associated with the abundance of macrophages, Th2 cells, T helper cells, CD56bright natural killer cells, and Th1 cells, and negatively linked to the abundance of Th17 cells, dendritic cells, and cytotoxic cells. CONCLUSION: Our findings demonstrate that SOAT1 may serve as a novel target for HCC treatment, which is helpful for the development of new strategies for immunotherapy and metabolic therapy.
RESUMEN
PURPOSE: With the improvements in first- and second-line treatments in non-small cell lung cancer (NSCLC), there is an increasing number of patients who receive third-line therapy. No other standard choice for third-line therapy aside from erlotinib is possible. This study investigated the efficacy and safety of single-agent chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), doublet chemotherapy and chemo-targeted therapy as third-line treatment in advanced NSCLC. METHODS: This study included 233 stage IIIb or IV NSCLC patients who were retrospectively reviewed to explore the differences in survival between different treatments. RESULTS: The median progression free survival (PFS) in the EGFR-TKIs, single-agent, doublet and chemo-targeted groups was 3.83, 2.72, 2.86 and 3.29 months, respectively (p = 0.073). The median OS from the initiation of the third-line treatment was 11.16, 8.24, 8.49 and 9.33 months in the 4 groups (p=0.02). The rates of grade IIIIV toxicities were 16.4, 27.6, 57.3 and 44.0% ( p <0.001), respectively with the third-line treatment, and overall survival (OS) was prolonged in patients who never smoked (p=0.040), had adenocarcinoma (p=0.034), had good ECOG performance status (PS) (p=0.012) and achieved disease control after both first-and second-line treatments (p =0.031). CONCLUSION: Patients with advanced NSCLC who never smoked, had adenocarcinoma, have good PS, and good disease control from the first- and second-line therapies could benefit more with third-line treatment. EGFR-TKIs and chemo-targeted therapy showed increased OS compared with single-agent and doublet chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Análisis Multivariante , Estadificación de Neoplasias , Selección de Paciente , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Periploca forrestii Schltr., a traditional Chinese medicine (TCM), is commonly used to treat autoimmune diseases such as rheumatoid arthritis (RA). However, its mechanism, involving a variety of cardiac glycosides, remains largely unknown. The immune knockout strategy can highly selectively deplete target components by immunoaffinity chromatography (IAC). We aimed to identify the common structural features of cardiac glycosides in P. forrestii and design IAC to specifically recognize these features to achieve the multi-component knockout of potential active substances from the extracts of P. forrestii. A content detection experiment confirmed that the content of a compound with periplogenin structure (CPS) in the extract of P. forrestii was reduced by 45% by IAC of periplogenin. The immunosuppressive ability of the extract on H9 human T lymphocytic cells was weakened after CPS knockout from P. forrestii extract. Molecular biology experiments showed that mRNA expression of interferon-γ (IFN-γ), interleukin-2 (IL-2), and interleukin-6 (IL-6) in H9 cells was up-regulated after CPS knockout, while no significant changes in the expression of interleukin-4 (IL-4) were found. CPS knockout from P. forrestii extract did not cause significant changes in the proliferation of lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells incubated with this extract. These results indicate that CPS exhibited immunosuppressive effects via inhibiting the T helper 1 (Th1) cell immune response and not via the anti-inflammatory components in P. forrestii. This is the first use of IAC to achieve multi-component knockout in TCM extracts for identifying effective compounds. This method is effective and reliable and warrants further exploration.
Asunto(s)
Artritis Reumatoide , Glicósidos Cardíacos , Humanos , Medicina Tradicional China , Extractos Vegetales/química , Antiinflamatorios/farmacología , Interleucina-6 , Glicósidos Cardíacos/uso terapéuticoRESUMEN
Apoptosis-based treatment plays an important role in regulating the death of tumor cells (e.g., chemotherapy, radiotherapy, and immunotherapy). Nevertheless, cancer cells can escape surveillance from apoptosis-associated signaling by bypassing other biological pathways and thus result in considerable resistance to therapies. Significantly, ferroptosis, a newly identified type of regulated cell death that is characterized by iron-dependent and lipid peroxidation accumulation, has aroused great research interest in cancer therapy. Increasing approaches have been developed to induce ferroptosis of tumor cells, including using clinically approved drugs, experimentally used compounds, and nanomedicine formulations. More importantly, the emerging nanomedicine-based strategy has made great advances in tumor treatment because of the promising targeting efficacy and enhanced therapeutic effects. In this review, we mainly overview state-of-the-art research on nanomedicine-mediated ferroptosis targeting strategies for synergistic cancer therapies, such as immunotherapy, chemotherapy, radiotherapy, and photothermal therapy. The potential targeting mechanism of nanomedicine for ferroptosis induction was also included. Finally, the future development of nanomedicine in the field of ferroptosis-based cell death in tumor treatment will be envisioned, aiming to provide new insight for tumor treatment in the clinic.
Asunto(s)
Ferroptosis , Neoplasias , Nanomedicina , Inmunoterapia , Apoptosis , Muerte Celular , Neoplasias/tratamiento farmacológicoRESUMEN
Soybean meal, excessively used in place of fish meal (FM) in aquaculture, has a detrimental impact on fish. In this study, the nanopeptide CI20, which was created by conjugating antimicrobial peptide gcIFN-20H and CMCS, were evaluated the feeding effect in mandarin fish (Siniperca chuatsi). Compared with the control group, 150 mg/kg C-I20-fed fish showed the second highest growth performance with no significant changes in body composition. C-I20-fed fish showed more goblet cells and thicker mucin after feeding. The 150 mg/kg CI20 diet boosted the antioxidant capacity, immunity, and digestive enzymes. After Aeromonas hydrophila and infection spleen and kidney necrosis virus infection, the survival rates in the 150 mg/kg CI20 group were highest. Meanwhile, many tissues in the 150 mg/kg CI20 group had significantly lower pathogen loads than the other groups. Treatment with 150 mg/kg CI20 was effective in increasing antioxidant capacity and immunity. The minimum tissue lesions were observed in the 150 mg/kg CI20 group. The goblet cell number and mucin thickness were significantly increased by CI20 treatment after infection. The study results herein showed that a reasonable dietary concentration of CI20 feed promoted growth performance and disease resistances in fish, suggesting a prospective nano antimicrobial peptide for the aquaculture.
Asunto(s)
Resistencia a la Enfermedad , Enfermedades de los Peces , Animales , Antioxidantes/farmacología , Estudios Prospectivos , Peces , Dieta , Mucinas , Enfermedades de los Peces/tratamiento farmacológico , Alimentación Animal/análisisRESUMEN
Tumour cells mainly generate energy from glycolysis, which is commonly coupled with lactate production even under normoxic conditions. As a critical lactate transporter, monocarboxylate transporter 4 (MCT4) is highly expressed in glycolytic tissues, such as muscles and tumours. Overexpression of MCT4 is associated with poor prognosis for patients with various tumours. However, how MCT4 function is post-translationally regulated remains largely unknown. Taking advantage of human lung adenocarcinoma (LUAD) cells, this study revealed that MCT4 can be polyubiquitylated in a nonproteolytic manner by SYVN1 E3 ubiquitin ligase. The polyubiquitylation facilitates the localization of MCT4 into the plasma membrane, which improves lactate export by MCT4; in accordance, metabolism characterized by reduced glycolysis and lactate production is effectively reprogrammed by SYVN1 knockdown, which can be reversed by MCT4 overexpression. Biologically, SYVN1 knockdown successfully compromises cell proliferation and tumour xenograft growth in mouse models that can be partially rescued by overexpression of MCT4. Clinicopathologically, overexpression of SYVN1 is associated with poor prognosis in patients with LUAD, highlighting the importance of the SYVN1-MCT4 axis, which performs metabolic reprogramming during the progression of LUAD.