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The preliminary study revealed that the ethyl acetate eluate of Youngia japonica (YJ-E) could inhibit the expression of key proteins of p-p65, p-IκBα, p-IKKα/ß, and p-AKT in LPS stimulated BV2 cell. Further phytochemical study led to the isolation of eight compounds from YJ-E, including one new sesquiterpene lactone. Their structures were elucidated by several spectroscopic data, and comparing the NMR data of known compound. In addition, all of the isolates were evaluated for the anti-inflammatory effect. As a result, compounds 3 and 4 distinctly attenuated the expressions of p-IκBα, p-p65, and p-AKT in LPS stimulated BV2 cell, respectively.
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In the process of searching for anti-breast cancer agents, five sesquiterpene lactones (1-5), including two previously undescribed ones, yjaponica B-C (1-2), were isolated from the herb of Youngia japonica. Their structures were elucidated by spectroscopic data analyses and Marfey's method. Cytotoxic activities of all compounds against A549, U87, and 4T1 cell lines were tested using the CCK8 assay. The result showed that compound 3 possessed the highest cytotoxic activity against 4T1 cells with an IC50 value of 10.60 µM. Furthermore, compound 3 distinctly induced apoptosis, inhibited immigration, and blocked the cell cycle of 4T1 cells. In addition, compound 3 induced the production of reactive oxygen species. Further anticancer mechanism studies showed that compound 3 significantly upregulated expression of the cleaved caspase 3 and PARP, whereas it downregulated the expression of Bcl-2, cyclin D1, cyclin A2, CDK4, and CDK2. Taken together, our results demonstrate that compound 3 has a high potential of being used as a leading compound for the discovery of new anti-breast cancer agent.
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BACKGROUND: Increased level of serum cholic acid (CA) is often accompanied with decreased CYP2E1 expression in hepatocellular carcinoma (HCC) patients. However, the roles of CA and CYP2E1 in hepatocarcinogenesis have not been elucidated. This study aimed to investigate the roles and the underlying mechanisms of CYP2E1 and CA in HCC cell growth. METHODS: The proteomic analysis of liver tumors from DEN-induced male SD rats with CA administration was used to reveal the changes of protein expression in the CA treated group. The growth of CA-treated HCC cells was examined by colony formation assays. Autophagic flux was assessed with immunofluorescence and confocal microscopy. Western blot analysis was used to examine the expression of CYP2E1, mTOR, AKT, p62, and LC3II/I. A xenograft tumor model in nude mice was used to examine the role of CYP2E1 in CA-induced hepatocellular carcinogenesis. The samples from HCC patients were used to evaluate the clinical value of CYP2E1 expression. RESULTS: CA treatment significantly increased the growth of HCC cells and promoted xenograft tumors accompanied by a decrease of CYP2E1 expression. Further studies revealed that both in vitro and in vivo, upregulated CYP2E1 expression inhibited the growth of HCC cells, blocked autophagic flux, decreased AKT phosphorylation, and increased mTOR phosphorylation. CYP2E1 was involved in CA-activated autophagy through the AKT/mTOR signaling. Finally, decreased CYP2E1 expression was observed in the tumor tissues of HCC patients and its expression level in tumors was negatively correlated with the serum level of total bile acids (TBA) and gamma-glutamyltransferase (GGT). CONCLUSIONS: CYP2E1 downregulation contributes to CA-induced HCC development presumably through autophagy regulation. Thus, CYP2E1 may serve as a potential target for HCC drug development.
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Autofagia , Carcinoma Hepatocelular , Proliferación Celular , Ácido Cólico , Citocromo P-450 CYP2E1 , Neoplasias Hepáticas , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inducido químicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inducido químicamente , Humanos , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP2E1/genética , Masculino , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Ratas , Proliferación Celular/efectos de los fármacos , Ratones , Ratas Sprague-Dawley , Transducción de Señal , Proteómica/métodos , Modelos Animales de Enfermedad , Ratones DesnudosRESUMEN
Prevalent neurological disorders such as Alzheimer's disease, Parkinson's disease, and stroke are increasingly becoming a global burden as society ages. It is well-known that degeneration and loss of neurons are the fundamental underlying processes, but there are still no effective therapies for these neurological diseases. In recent years, plenty of studies have focused on the pharmacology and feasibility of natural products as new strategies for the development of drugs that target neurological disorders. Antrodia camphorata has become one of the most promising candidates, and the crude extracts and some active metabolites of it have been reported to play various pharmacological activities to alleviate neurological symptoms at cellular and molecular levels. This review highlights the current evidence of Antrodia camphorata against neurological disorders, including safety evaluation, metabolism, blood-brain barrier penetration, neuroprotective activities, and the potential on regulating the gut-microbiome-brain axis. Furthermore, potential strategies to resolve problematic issues identified in previous studies are also discussed. We aim to provide an overview for the ongoing development and utilization of Antrodia camphorata in cerebral neuropathology.
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Infections of hepatotropic viruses cause a wide array of liver diseases including acute hepatitis, chronic hepatitis and the consequently developed cirrhosis and hepatocellular carcinoma (HCC). Among the five classical hepatotropic viruses, hepatitis B virus (HBV) and hepatitis C virus (HCV) usually infect human persistently and cause chronic hepatitis, leading to major troubles to humanity. Previous studies have revealed that several types of inflammasomes are involved in the infections of HBV and HCV. Here, we summarize the current knowledge about their roles in hepatitis B and C. NLRP3 inflammasome can be activated and regulated by HBV and HCV. It is found to exert antiviral function or mediates inflammatory response in viral infections depending on different experimental models. Besides NLRP3 inflammasome, IFI16 and AIM2 inflammasomes participate in the pathological process of hepatitis B, and NALP3 inflammasome may sense HCV infection in hepatocytes. The inflammasomes affect the pathological process of viral hepatitis through its downstream secretion of inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 or induction of pyroptosis resulting from cleaved gasdermin D (GSDMD). However, the roles of inflammasomes in different stages of viral infection remains mainly unclear. More proper experimental models of viral hepatitis should be developed for specific studies in future, so that we can understand more about the complexity of inflammasome regulation and multifunction of inflammasomes and their downstream effectors during HBV and HCV infections.
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Hepacivirus , Virus de la Hepatitis B , Hepatitis B Crónica , Hepatitis C Crónica , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Inflamasomas/metabolismo , Inflamasomas/inmunología , Hepatitis C Crónica/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Hepacivirus/inmunología , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/metabolismo , Virus de la Hepatitis B/inmunología , Proteínas de Unión al ADN/metabolismo , Interleucina-1beta/metabolismo , Piroptosis , Animales , Fosfoproteínas/metabolismo , Proteínas Nucleares/metabolismo , Hepatocitos/virología , Hepatocitos/inmunología , Interleucina-18/metabolismo , Proteínas de Unión a Fosfato/metabolismo , GasderminasRESUMEN
AIMS: This study was designed to investigate the role of growth arrest and DNA damage-inducible ß (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. MAIN METHODS: Adeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. KEY FINDINGS: Knockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SIGNIFICANCE: These results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.
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Región CA1 Hipocampal , Miedo , Proteinas GADD45 , Ratones Endogámicos C57BL , Animales , Masculino , Miedo/fisiología , Ratones , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Cognición/fisiología , Memoria/fisiología , Potenciación a Largo Plazo/fisiología , Aprendizaje por Laberinto/fisiología , Plasticidad Neuronal/fisiología , Antígenos de Diferenciación/metabolismo , Antígenos de Diferenciación/genética , Técnicas de Silenciamiento del GenRESUMEN
BACKGROUND: Ischemic stroke remains the predominant contributor to mortality and disability globally. Microglia undergo rapid activation and initiate inflammatory cascade reactions by phenotypic polarization, participating in the regulation of inflammatory injury and tissue repair post-ischemic stroke. Regulating microglia-mediated neuroinflammation is a promising therapeutic strategy for ischemic stroke. Previously, we designed and synthesized a novel p55PIK inhibitor, TAT-N15 polypeptide, which presents inhibitive activity on NF-κB signaling-mediated inflammation in acute conjunctivitis and allergic rhinitis. The present study aimed to explore the therapeutic effect and mechanism of TAT-N15 on ischemia stroke. METHODS: The mouse model of transient cerebral ischemia was made using the intraluminal filament method. After being treated with daily intraperitoneal injections of TAT-N15 (10 mg/kg) for 7 d, the neurological outcomes and the cerebral infarction volume were evaluated. Histopathology of the ischemia cerebral hemisphere was observed by H&E and Nissl staining. Neuronal survival, astrogliosis, and co-labeling of CD86/Iba1 and CD206/Iba1 were detected by immunofluorescence. The cell apoptosis was estimated by TUNEL staining. The expression levels of apoptosis-associated proteins, proinflammatory cytokines, protein markers of M1 and M2 microglia, and the phosphorylation of NF-κB and STAT3 proteins in the ischemic penumbra were detected by Western blot. RESULTS: TAT-N15 treatment significantly decreased the infarct volume and alleviated neurological functional impairment, neuronal injury, and neuron apoptosis. Meanwhile, TAT-N15 treatment restrained the activation of microglia and astrocytes as well as the protein expression of proinflammatory cytokine in ischemic penumbra. Additionally, the administration of TAT-N15 treatment resulted in a significant reduction in the density of M1 phenotype microglia while concurrently increasing the density of M2 phenotype microglia within the ischemic penumbra. Finally, mechanical analysis unveiled that TAT-N15 exerted a substantial inhibitory effect on the protein expression of phosphorylated STAT3 and NF-κB. CONCLUSION: TAT-N15 may inhibit neuroinflammation via regulating microglia activation and polarization through the STAT3/NF-κB pathway, which exhibits the neuroprotection effect in ischemic stroke.
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Antiinflamatorios , Apoptosis , Modelos Animales de Enfermedad , Mediadores de Inflamación , Ratones Endogámicos C57BL , Microglía , FN-kappa B , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , FN-kappa B/metabolismo , FN-kappa B/antagonistas & inhibidores , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Fármacos Neuroprotectores/farmacología , Masculino , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Ataque Isquémico Transitorio/tratamiento farmacológico , Ataque Isquémico Transitorio/metabolismo , Ataque Isquémico Transitorio/patología , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patologíaRESUMEN
The NACHT, leucine-rich repeat, and pyrin domains-containing protein 3 (collectively known as NLRP3) inflammasome activation plays a critical role in innate immune and pathogenic microorganism infections. However, excessive activation of NLRP3 inflammasome will lead to cellular inflammation and tissue damage, and naturally it must be precisely controlled in the host. Here, we discovered that solute carrier family 25 member 3 (SLC25A3), a mitochondrial phosphate carrier protein, plays an important role in negatively regulating NLRP3 inflammasome activation. We found that SLC25A3 could interact with NLRP3, overexpression of SLC25A3 and knockdown of SLC25A3 could regulate NLRP3 inflammasome activation, and the interaction of NLRP3 and SLC25A3 is significantly boosted in the mitochondria when the NLRP3 inflammasome is activated. Our detailed investigation demonstrated that the interaction between NLRP3 and SLC25A3 disrupted the interaction of NLRP3-NEK7, promoted ubiquitination of NLRP3, and negatively regulated NLRP3 inflammasome activation. Thus, these findings uncovered a new regulatory mechanism of NLRP3 inflammasome activation, which provides a new perspective for the therapy of NLRP3 inflammasome-associated inflammatory diseases.
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Inflamasomas , Proteínas Mitocondriales , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas de Transporte de Fosfato , Animales , Humanos , Ratones , Células HEK293 , Inflamasomas/metabolismo , Mitocondrias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas de Transporte de Fosfato/metabolismo , Proteínas de Transporte de Fosfato/genética , Ubiquitinación , Línea Celular , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Técnicas de Silenciamiento del GenRESUMEN
Although parasitic copepods of the genus Ergasilus von Nordmann, 1832 are globally distributed parasites of fish, their phylogenetic relationships with other Copepoda are not clear, and the characteristics of their mitochondrial genomes (mitogenomes) are not thoroughly understood. The objective of this study was to address these knowledge gaps by sequencing the complete mitogenome of Ergasilus tumidus Markevich, 1940. The complete mitogenome (GenBank Acc. No. OQ596537) was 14,431 bp long and it comprised 13 protein-coding genes (PCGs), 22 tRNAs, two tRNAs, and two control regions (CRs). Phylogenetic analyses, conducted using concatenated nucleotide and amino acid sequences of 13 protein-coding genes, produced two partially incongruent topologies. While the order Calanoida was consistently resolved as the sister lineage to the other three orders, topological instability was observed in the relationships of the orders Cyclopoida, Siphonostomatoida and Harpacticoida. Siphonostomatoida clustered with Cyclopoida in the nucleotide-based phylogeny, but with Harpacticoida in the amino acid-based phylogeny. The latter topology conforms to the widely accepted relationships, but we speculate that the former topology is more likely to be the correct one. Our study provides a complete mitogenome sequence of E. tumidus, which helps us better understand the molecular evolution of the genus Ergasilus. Additionally, we suggest a different perspective on the controversial phylogenetic relationships among Siphonostomatoida, Cyclopoida and Harpacticoida, diverging from previously accepted views.
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Copépodos , Genoma Mitocondrial , Animales , Copépodos/genética , Filogenia , Secuencia de Aminoácidos , NucleótidosRESUMEN
Fourteen sesquiterpenes, including one undescribed sesquiterpene lactone, were isolated from Youngia japonica, and their structures were identified by NMR, HRESIMS, ECD and calculated ECD. Cytotoxic activities of all isolates against A549, HeLa, and 4 T1 cell lines were detected by CCK8 assay. Among them, 2 showed obvious cytotoxic activity against A549 cells. Subsequently, the production of ROS, and apoptosis of A549 cells treated with 2 were evaluated. The result showed that 2 distinctly increased the ROS level, and induced the apoptosis of A549 cells. Further anticancer mechanism studies showed that 2 increased the expression of cleaved caspase 3. Taken together, our results demonstrated that 2 might become potential leading compounds for the treatment of lung cancer.
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Antineoplásicos , Asteraceae , Sesquiterpenos , Humanos , Línea Celular Tumoral , Estructura Molecular , Especies Reactivas de Oxígeno , Antineoplásicos/farmacología , Apoptosis , Sesquiterpenos/farmacología , Sesquiterpenos/químicaRESUMEN
Four undescribed coumarin derivatives, ficusalt A (1) and ficusalt B (2), a pair of racemic coumarins, (±) ficudimer A (3a/3b), along with ten known amides, were isolated from the roots of Ficus hirta. Their structures were elucidated by several spectroscopic data analyses, including HRESIMS, NMR, and X-ray single-crystal diffraction. The cytotoxic activities of all compounds against HeLa, HepG2, MCF-7, and H460 cell lines were detected using the MTT assay. Among these, 5 showed the highest activity against HeLa cells. Subsequently, the apoptotic, anti-invasive, and anti-migration effects of 5 on HeLa cells were determined by flow cytometer, transwell invasion assay, and wound-healing assay, respectively. The result suggested that 5 distinctly induced the apoptosis in HeLa cells and inhibited their invasion and migration. Further studies on anticancer mechanisms were conducted using Western blotting. As a result, 5 increased the cleavage of PARP and the expression of pro-apoptotic protein Bax. Moreover, 5 notably upregulated the phosphorylation of p38 and JNK, whereas inhibited the expression of p-ERK and p-AKT. Our results demonstrated that 5 could be a potential leading compound for further application in the treatment of cervical cancer.
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Antineoplásicos , Ficus , Femenino , Humanos , Células HeLa , Ficus/química , Amidas/farmacología , Cumarinas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , ApoptosisRESUMEN
Ambient fine particulate matter (PM2.5) is a threat to public health. The P2 X 7purinergic receptor (P2X7R) is a modulator that responds to inflammation. Yet the role of P2X7R in the mediation of PM2.5-induced pulmonary cytotoxicity is rarely investigated. In this study, the expression of P2X7R and its effect on cell viability, oxidative damage, apoptosis, mitochondrial dysfunction and underlying mechanism following PM2.5 treatment in rat alveolar macrophages (NR8383) were analyzed. The outcome indicated that PM2.5 exposure significantly increased the expression of P2X7R, while P2X7R antagonist oATP markedly alleviate the production of reactive oxygen species (ROS), Nitrite Oxidation (NO), mitochondrial membrane potential, apoptosis rate, and release of inflammatory cytokines. In contrast, P2X7 agonist BzATP showed opposite effect in PM2.5-treated NR8383 cells. Therefore, these results demonstrated that P2X7R participated in PM2.5-induced pulmonary toxicity, while the blockade of P2X7R is a promising therapeutic approach of treating PM2.5-induced lung diseases.
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Material Particulado , Receptores Purinérgicos P2X7 , Ratas , Animales , Receptores Purinérgicos P2X7/metabolismo , Material Particulado/toxicidad , Pulmón , Especies Reactivas de Oxígeno/metabolismo , Estrés OxidativoRESUMEN
Background: HIV-1 Vpu acts by counteracting the tethering function of tetherin and resulting in the release of HIV-1 virion. Disrupting Vpu-tetherin interactions may provide a promising new target for antiretroviral therapy. Methods: Polypeptides that covered the amino acid sequence on the interface of Vpu-tetherin complex were designed. Phenotypic susceptibilities and cellular toxicities to the polypeptides were measured. The mechanisms of the anti-HIV-1 polypeptides were determined by the Western blot analysis and laser confocal scanning. Seven 20-mer polypeptides from wild-type Vpu amino acid sequence were designed. Results: We report the design and identification of 3 novel anti-HIV-1 polypeptides that derived from Vpu sequence which can efficiently inhibit HIV-1 infection. A pilot mechanism study showed that the active polypeptide could counteract Vpu-mediated tetherin downregulation. Laser confocal image scanning study showed that the polypeptides bound on the cell surface with a receptor specific binding manner, which may target tetherin that expressed on cell surface. Conclusion: Our work provided first evidence that counteracting Vpu-mediated tetherin downregulation could be a target for novel anti-HIV-1 drug design. Future works to provide direct evidence of inhibitors interact with tetherin at atomic resolution and the development of small molecules inhibitors targeting Vpu-tetherin interactions may open a new avenue for novel antiretroviral therapy.
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The original version of this article unfortunately contains an error in Figures 4B,C,H-J and 5C,D [...].
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N6-methyladenosine (m6A) methylation of human immunodeficiency virus type 1 (HIV-1) RNA regulates viral replication, and the m6A of host RNA is affected by HIV-1 infection, but its global pattern and function are still unclear. In this study, we report that the number and position of m6A peaks in huge genes of human microglial HMC3 cells were modulated by a single cycle HIV-1 pseudotyped with VSV-G envelope glycoprotein infection using methylated RNA immunoprecipitation sequencing (MeRIP-seq). A conjoint analysis of MeRIP-seq and high-throughput sequencing for mRNA (RNA-seq) explored four groups of clearly classified genes, including 45 hyper-up (m6A-mRNA), 45 hyper-down, 120 hypo-up, and 54 hypo-down genes, in HIV-1 infected cells compared to uninfected ones. KEGG pathway analysis showed that these genes were mainly enriched in the Wnt and TNF signaling pathway, and cytokine-cytokine receptor interaction, which might be related to the immune response in HMC3 cells. And some of these genes might be associated with the pathway of axon guidance and neuroactive ligan-receptor interaction, which affect the neuronal state. However, the cognitive disorders caused by HIV-1 is associated with inflammatory changes that have not yet been well clarified. Furthermore, we confirmed the expression and m6A levels of four genes using RT-PCR and MeRIP-qPCR. Similar to the sequencing results, the expressions of these genes were significantly upregulated by HIV-1 infection. And the m6A level of IL-6 was downregulated, and those of HLA-B, CFB, and OLR1 were upregulated. These results suggest that HIV-1-induced changes in gene expression may be achieved through the regulation of methylation. Our study revealed the global m6A methylation and gene expression patterns under HIV-1 infection in human microglia, which might provide clues for understanding the interaction between HIV-1 and host cells and the cognitive disorders caused by HIV-1.
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Enterovirus D68 (EV-D68), a member of Enterovirus genus of the Picornaviridae family, mainly causes respiratory system-related diseases as well as neurological complications in some patients. At present, there is no effective vaccine or treatment for the virus. The aim of this research was to systematically analyse the molecular epidemiology, recombination and changes in the epitope of EV-D68 in China from 2008 to 2022. Through phylogenetic analysis based on VP1 sequences, it was found that there was limited information about EV-D68 infection before 2011 and that EV-D68 infection was dominated by the A2 gene subtype from 2011 to 2013 and the B3 genotype from 2014 to 2018, during which A2 and B3 were coprevalent and alternately prevalent. We also constructed a phylogenetic tree using the EV-D68 full-length genome sequences, and the genotype of each sequence was consistent with that of the VP1 sequence evolutionary tree. Recombination analysis showed that MH341715 underwent intertypic recombination with the A2 genotype MH341729 at the 5' untranslated region (5'UTR) and that P1-P3 underwent recombination with the B3 genotype MH341712. The capsid protein VP1 is one of the most important structural proteins. In VP1, the BC-loop (89-105 amino acids) and DE-loop (140-152 amino acids) are the most variable domains on the surface of the virus and are associated with epitopes. In this study, it was found that the dominant amino acid composition of the BC-loop and DE-loop continued to change with the epidemic of the virus; the amino acid composition also differed in different regions of the same genotypes. The ongoing genomic and molecular epidemiology of EV-D68 remains important for predicting emergence of new viruses and preventing major outbreaks of respiratory diseases.
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Enterovirus Humano D , Infecciones por Enterovirus , Enterovirus , Infecciones del Sistema Respiratorio , Humanos , Enterovirus Humano D/genética , Epidemiología Molecular , Filogenia , China/epidemiología , Enterovirus/genética , Infecciones por Enterovirus/epidemiología , Recombinación Genética , Aminoácidos/genéticaRESUMEN
Bisphenol P (BPP) and bisphenol M (BPM) are increasing in our living environment as analogues of bisphenol A (BPA), but little is known about their biological effect. In this study, we investigated the effects of low to medium dose exposure of BPP and BPM on triple negative breast cancer (TNBC). We found that BPP and BPM exposure didn't affect proliferation of TNBC cell lines MDA-MB-231 and 4 T1, but significantly promoted cells migration and invasion. The effect of BPP and BPM on promoting TNBC metastasis was further confirmed in mouse models. Low concentrations of BPP and BPM significantly increased the expression of epithelial-mesenchymal transition (EMT) marker and related proteins such as N-cadherin, MMP-9, MMP-2 and Snail, and also enhanced phosphorylation of AKT both in vitro and in vivo. When PI3K inhibitor wortmannin was applied to specifically inhibit phosphorylation of AKT, the expression of target genes markedly decreased, and the TNBC metastasis induced by low-concentration BPP and BPM were reversed. In conclusion, these results showed that PI3K/AKT signaling regulate BPP/BPM-induced metastasis of TNBC by triggering EMT. This study provides insights into the effects and the potential mechanisms of BPP and BPM on TNBC, raising concerns about the risk of using these two bisphenols as the alternative of BPA.
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Proteínas Proto-Oncogénicas c-akt , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasas/metabolismo , Proliferación CelularRESUMEN
Sono-photodynamic therapy (SPDT) is an oxidative stress-dependant antitumour treatment modality. Due to the hypoxic tumour microenvironment, the antitumour effect of SPDT is limited. In this study, we developed lipid vesicles to transport a photosensitizer (chlorin e6, Ce6) and oxygen into tumours to promote SPDT efficiency on triple-negative breast cancer in vitro and in vivo. The results showed that compared with the same concentration of free Ce6, Lipo-Ce6 produced a higher singlet oxygen level under light irradiation. Cellular Lipo-Ce6 accumulation was 4-fold higher than that of free Ce6. The cytotoxicity on 4T1 cells caused by Lipo-Ce6-SPDT was significantly stronger than that caused by free Ce6-SPDT, and oxygen microbubbles (O2MB) further enhanced the cytotoxicity of Lipo-Ce6-SPDT under hypoxic conditions. Cellular ROS production in the Lipo-Ce6-SPDT+O2MB group was approximately 2.5-fold higher than that in the Lipo-Ce6-SPDT+C3F8MB group. Furthermore, O2MB rapidly relieved 4T1 subcutaneous xenograft hypoxia conditions under ultrasound exposure and significantly improved the antitumour activity of SPDT in vivo. These results indicate that the combination of O2MB and a high-activity liposome photosensitizer can significantly enhance the antitumour efficiency of SPDT for hypoxic tumours.
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Clorofilidas , Fotoquimioterapia , Porfirinas , Neoplasias de la Mama Triple Negativas , Humanos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Hipoxia Tumoral , Línea Celular Tumoral , Microburbujas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Oxígeno , Porfirinas/farmacología , Microambiente TumoralRESUMEN
Epidemiological investigations and clinical studies have confirmed that human chewing of betel nut is an addictive behavior, and the proportion of teenagers chewing betel nut is increasing. Previous studies have shown that adolescence shows higher sensitivity to many addictive substances compared with adulthood, and that adult susceptibility to addictive substances is usually changed after exposure to addictive substances during adolescence. However, there are no reports of age-related animal experiments on betel nut or dependence to its active ingredients. Therefore, the two-bottle choice (TBC) (experiment 1 and 2) and conditioned place preference (CPP) (experiment 3 and 4) models with mice were used in this study to explore age-related differences in intake and preference of arecoline, the alkaloid in betel nut with highest content, and to explore the effect of arecoline exposure during adolescence on the re-exposure of arecoline in adulthood in mice. The results of experiment 1 showed that the intake of 80 µg/ml arecoline in adolescent mice was significantly higher than that in adult mice. However, there was no significant difference between adult and adolescent mice in preference for arecoline at any tested concentration (5-80 µg/ml), which may be due to the significantly higher intake of total fluid in adolescent mice compared to adult mice. The preference of arecoline in adolescent mice peaked at 20 µg/ml, and in adult mice peaked at 40 µg/ml. The results of experiment 2 showed that oral arecoline (5-80 µg/ml) in mice during adolescence caused a significant increase in the intake (days 3-16) and preference (days 5-8) for 40 µg/ml arecoline in adulthood. The results of experiment 3 showed that the doses of 0.03 or 0.1 mg/kg of arecoline produced the highest CPP response in adolescent or adult mice, respectively. The results of experiment 4 showed that mice exposed to arecoline in adolescence had significantly increased the CPP scores induced by arecoline in adulthood compared to mice that were not exposed. These data suggested that adolescent mice were more sensitive to arecoline, and exposure of mice to arecoline during adolescence increased the susceptibility to arecoline in adulthood.