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BACKGROUND: Bi-allelic variants in DNAH11 have been identified as causative factors in Primary Ciliary Dyskinesia, leading to abnormal respiratory cilia. Nonetheless, the specific impact of these variants on human sperm flagellar and their involvement in male infertility remain largely unknown. METHODS: A collaborative effort involving two Chinese reproductive centers conducted a study with 975 unrelated infertile men. Whole-exome sequencing was employed for variant screening, and Sanger sequencing confirmed the identified variants. Morphological and ultrastructural analyses of sperm were conducted using Scanning Electron Microscopy and Transmission Electron Microscopy. Western Blot Analysis and Immunofluorescence Analysis were utilized to assess protein levels and localization. ICSI was performed to evaluate its efficacy in achieving favorable pregnancy outcomes for individuals with DNAH11 variants. RESULTS: In this study, we identified seven novel variants in the DNAH11 gene in four asthenoteratozoospermia subjects. These variants led the absence of DNAH11 proteins and ultrastructure defects in sperm flagella, particularly affecting the outer dynein arms (ODAs) and adjacent structures. The levels of ODA protein DNAI2 and axoneme related proteins were down regulated, instead of inner dynein arms (IDA) proteins DNAH1 and DNAH6. Two out of four individuals with DNAH11 variants achieved clinical pregnancies through ICSI. The findings confirm the association between male infertility and bi-allelic deleterious variants in DNAH11, resulting in the aberrant assembly of sperm flagella and contributing to asthenoteratozoospermia. Importantly, ICSI emerges as an effective intervention for overcoming reproductive challenges caused by DNAH11 gene variants.
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Astenozoospermia , Dineínas Axonemales , Secuenciación del Exoma , Infertilidad Masculina , Humanos , Masculino , Astenozoospermia/genética , Astenozoospermia/patología , Dineínas Axonemales/genética , Femenino , Infertilidad Masculina/genética , Infertilidad Masculina/patología , Adulto , Cola del Espermatozoide/patología , Cola del Espermatozoide/ultraestructura , Cola del Espermatozoide/metabolismo , Inyecciones de Esperma Intracitoplasmáticas , Embarazo , Espermatozoides/ultraestructura , Espermatozoides/patología , Dineínas/genéticaRESUMEN
BACKGROUND: Hepatitis B virus (HBV) infection poses a substantial threat to human health, impacting not only infected individuals but also potentially exerting adverse effects on the health of their offspring. The underlying mechanisms driving this phenomenon remain elusive. This study aims to shed light on this issue by examining alterations in paternally imprinted genes within sperm. METHODS: A cohort of 35 individuals with normal semen analysis, comprising 17 hepatitis B surface antigen (HBsAg)-positive and 18 negative individuals, was recruited. Based on the previous research and the Online Mendelian Inheritance in Man database (OMIM, https://www.omim.org/ ), targeted promoter methylation sequencing was employed to investigate 28 paternally imprinted genes associated with various diseases. RESULTS: Bioinformatic analyses revealed 42 differentially methylated sites across 29 CpG islands within 19 genes and four differentially methylated CpG islands within four genes. At the gene level, an increase in methylation of DNMT1 and a decrease in methylation of CUL7, PRKAG2, and TP53 were observed. DNA methylation haplotype analysis identified 51 differentially methylated haplotypes within 36 CpG islands across 22 genes. CONCLUSIONS: This is the first study to explore the effects of HBV infection on sperm DNA methylation and the potential underlying mechanisms of intergenerational influence of paternal HBV infection.
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Islas de CpG , Metilación de ADN , Impresión Genómica , Virus de la Hepatitis B , Hepatitis B , Regiones Promotoras Genéticas , Espermatozoides , Humanos , Masculino , Metilación de ADN/genética , Regiones Promotoras Genéticas/genética , Espermatozoides/metabolismo , Islas de CpG/genética , Impresión Genómica/genética , Hepatitis B/genética , Hepatitis B/virología , Adulto , Virus de la Hepatitis B/genética , Haplotipos/genética , Persona de Mediana EdadRESUMEN
Photodynamic therapy (PDT) is a promising cancer therapy modality due to its intrinsically negligible side effects and treatment resistance. However, the development of the high-efficiency PDT still remains a challenge. Herein, a nanodrug platform PEG-Ce6-PEI@PB combined tumor acidity-induced polyethyleneimine (PEI) cytotoxicity with an oxygen self-supply property is developed for dual-enhanced PDT. The obtained PEG-Ce6-PEI@PB presents suppressed PEI cytotoxicity and chlorin e6 (Ce6) phototoxicity during the bloodstream before becoming active in tumor tissues/cells. The acidic tumor microenvironment can shed PEG coating to rebound PEI positive charges, facilitating tumor cell uptake and reverting the PEI cytotoxicity to enhance following PDT. Moreover, Prussian blue (PB) nanozymes with catalase-like activity can convert endogenous hydrogen peroxide into oxygen to relieve tumor hypoxia, which is attributed to the photosensitizer Ce6 producing more cytotoxic reactive oxygen species upon laser irradiation to further strengthen PDT. Moreover, PEG-Ce6-PEI@PB exhibits good biocompatibility and long blood circulation. More importantly, PEG-Ce6-PEI@PB-treated breast cancer cells and tumor-bearing mice present effective therapeutic efficacy upon laser irradiation, verifying the synergistic antitumor effects of PEI cytotoxicity and oxygen self-supplying PDT.
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Nanopartículas , Fotoquimioterapia , Animales , Ferrocianuros , Ratones , Oxígeno , Polietilenglicoles , Polietileneimina , Hipoxia TumoralRESUMEN
Metaplasticity is referred to adjustment in the requirements for induction of synaptic plasticity based on the prior history of activity. Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), has been considered to be the neural processes underlying learning and memory. Previous observations that cordycepin (an adenosine derivative) improved learning and memory seemed to be contradictory to the findings that cordycepin inhibited LTP. Therefore, we speculated that the conflicting reports of cordycepin might be related to metaplasticity. In the current study, population spike (PS) in hippocampal CA1 area of rats was recorded by using electrophysiological method in vivo. The results showed that cordycepin reduced PS amplitude in hippocampal CA1 with a concentration-dependent relationship, and high frequency stimulation (HFS) failed to induce LTP when cordycepin was intrahippocampally administrated but improved LTP magnitude when cordycepin was pre-treated. Cordycepin increased LTD induced by activating N-Methyl-D-aspartate (NMDA) receptors and subsequently facilitated LTP induced by HFS. Furthermore, we found that 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an adenosine A1 receptors antagonist, could block the roles of cordycepin on LTD and LTP. Collectively, cordycepin was able to modulate metaplasticity in hippocampal CA1 area of rats through adenosine A1 receptors. These findings would be helpful to reconcile the conflicting reports in the literatures and provided new insights into the mechanisms underlying cognitive function promotions with cordycepin treatment.
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Agonistas del Receptor de Adenosina A1/farmacología , Región CA1 Hipocampal/efectos de los fármacos , Desoxiadenosinas/farmacología , Plasticidad Neuronal/efectos de los fármacos , Receptor de Adenosina A1/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Región CA1 Hipocampal/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Receptor de Adenosina A1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de TiempoRESUMEN
Cordycepin exerted significant neuroprotective effects and protected against cerebral ischemic damage. Learning and memory impairments after cerebral ischemia are common. Cordycepin has been proved to improve memory impairments induced by cerebral ischemia, but its underlying mechanism has not been revealed yet. The plasticity of synaptic structure and function is considered to be one of the neural mechanisms of learning and memory. Therefore, we investigated how cordycepin benefits dendritic morphology and synaptic transmission after cerebral ischemia and traced the related molecular mechanisms. The effects of cordycepin on the protection against ischemia were studied by using global cerebral ischemia (GCI) and oxygen-glucose deprivation (OGD) models. Behavioral long-term potentiation (LTP) and synaptic transmission were observed with electrophysiological recordings. The dendritic morphology and histological assessment were assessed by Golgi staining and hematoxylin-eosin (HE) staining, respectively. Adenosine A1 receptors (A1R) and adenosine A2A receptors (A2AR) were evaluated with western blotting. The results showed that cordycepin reduced the GCI-induced dendritic morphology scathing and behavioral LTP impairment in the hippocampal CA1 area, improved the learning and memory abilities, and up-regulated the level of A1R but not A2AR. In the in vitro experiments, cordycepin pre-perfusion could alleviate the hippocampal slices injury and synaptic transmission cripple induced by OGD, accompanied by increased adenosine content. In addition, the protective effect of cordycepin on OGD-induced synaptic transmission damage was eliminated by using an A1R antagonist instead of A2AR. These findings revealed that cordycepin alleviated synaptic dysfunction and dendritic injury in ischemic models by modulating A1R, which provides new insights into the pharmacological mechanisms of cordycepin for ameliorating cognitive impairment induced by cerebral ischemia.
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BET inhibitors (BETi) exhibit a strong anti-tumor activity in triple-negative breast cancer (TNBC). However, BETi resistance has been reported in TNBC. The mechanisms of resistance have not been demonstrated. Tumor-associated macrophages (TAMs) are frequently involved in cancer cells resistance to chemotherapy, also associated with poor prognosis in TNBC. However, the role of TAMs in BETi resistance remains unknown. Here, we found that BETi JQ1 and I-BET151 exerted anti-tumor effects in TNBC by decreasing IKBKE expression to attenuate NF-κB signaling. TAMs have been reported to associate with chemoresistance in breast cancer. Here, we firstly found that TNBC-stimulated TAMs activated NF-κB signaling by upregulating IKBKE expression to enhance breast cancer cells resistance to BETi. The IKBKE levels were also proved to be higher in clinical TNBC tissues than Non-TNBC tissues, suggesting feedback induction of IKBKE expression by TNBC-stimulated TAMs in TNBC. Moreover, the induction of IKBKE by TAMs in TNBC cells was identified to be associated with STAT3 signaling, which was activated by TAM-secreted IL-6 and IL-10. Lastly, the combination of inhibitors of BET and STAT3 exerted a synergistic inhibition effects in TAM-cocultured or TAM CM-treated TNBC cells in vitro and in vivo. Altogether, our findings illustrated TNBC-activated macrophages conferred TNBC cells resistance to BETi via IL-6 or IL-10/STAT3/IKBKE/NF-κB axis. Blockade of IKBKE or double inhibition of BET and STAT3 might be a novel strategy for treatment of TNBC.
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Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Quinasa I-kappa B/genética , Proteínas/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/metabolismo , Macrófagos Asociados a Tumores/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Técnicas de Cocultivo , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Células MCF-7 , Ratones Desnudos , Células THP-1 , Neoplasias de la Mama Triple Negativas/patología , Macrófagos Asociados a Tumores/patología , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cordycepin, an adenosine analog, has been reported to improve cognitive function, but which seems to be inconsistent with the reports showing that cordycepin inhibited long-term potentiation (LTP). Behavioral-LTP is usually used to study long-term synaptic plasticity induced by learning tasks in freely moving animals. In order to investigate simultaneously the effects of cordycepin on LTP and behavior in rats, we applied the model of behavioral-LTP induced by Y-maze learning task through recording population spikes in hippocampal CA1 region. Golgi staining and Sholl analysis were employed to assess the morphological structure of dendrites in pyramidal cells of hippocampal CA1 area, and western blotting was used to examine the level of adenosine A1 receptors and A2A receptors (A2AR). We found that cordycepin significantly improved behavioral-LTP magnitude, accompanied by increases in the total length of dendrites, the number of intersections and spine density but did not affect Y-maze learning task. Furthermore, cordycepin obviously reduced A2AR level without altering adenosine A1 receptors level; and the agonist of A2AR (CGS 21680) rather than antagonist (SCH 58261) could reverse the potentiation of behavioral-LTP induced by cordycepin. These results suggested that cordycepin improved behavioral-LTP and morphological structure of dendrite in hippocampal CA1 but did not contribute to the improvement of learning and memory. And cordycepin improved behavioral-LTP may be through reducing the level of A2AR in hippocampus. Collectively, the effects of cordycepin on cognitive function and LTP were complex and involved multiple mechanisms.
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Región CA1 Hipocampal/efectos de los fármacos , Dendritas/efectos de los fármacos , Desoxiadenosinas/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Animales , Masculino , Células Piramidales/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Cerebral ischemia impairs physiological form of synaptic plasticity such as long-term potentiation (LTP). Clinical symptoms of cognitive dysfunction resulting from cerebral ischemia are associated with neuron loss and synaptic function impairment in hippocampus. It has been widely reported that cordycepin displays neuroprotective effect on ameliorating cognitive dysfunction induced by cerebral ischemia. Therefore, it is necessary to study whether cordycepin recovers cognitive function after brain ischemia through improving LTP induction. However, there has been very little discussion about the effects of cordycepin on LTP of cerebral ischemia so far. In the present study, we investigated the effects of cordycepin on LTP impairment and neuron loss induced by cerebral ischemia and excitotoxicity, using electrophysiological recording and Nissl staining techniques. The models were obtained by bilateral common carotid artery occlusion (BCCAO) and intrahippocampal NMDA microinjection. We also explored whether adenosine A1 receptors involve in the neuroprotection of cordycepin by using western blot. We found that cordycepin remarkably alleviated LTP impairment and protected pyramidal cell of hippocampal CA1 region against cerebral ischemia and excitotoxicity. Meanwhile, cordycepin prevented the reduction on adenosine A1 receptor level caused by ischemia but did not alter the adenosine A2A receptor level in hippocampal CA1 area. The improvement of LTP in the excitotoxic rats after cordycepin treatment could be blocked by DPCPX, a selective antagonist of adenosine A1 receptor. In summary, our findings provided new insights into the mechanisms of cordycepin neuroprotection in excitotoxic diseases, which is through regulating adenosine A1 receptor to improve LTP formation and neuronal survival.
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Desoxiadenosinas/farmacología , N-Metilaspartato/toxicidad , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Receptor de Adenosina A1/metabolismo , Animales , Recuento de Células , Regulación de la Expresión Génica/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Neuronas/citología , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacos , Sinapsis/fisiologíaRESUMEN
The study reports a facile and eco-friendly approach for nanomaterial synthesis and enzyme immobilization. A corresponding glucose biosensor was fabricated by immobilizing the gold nanoparticles (AuNPs) and glucose oxidase (GOD) multilayer films onto the polypyrrole (PPy)/reduced graphene oxide (RGO) modified glassy carbon electrode (GCE) via the electrodeposition and self-assembly. PPy and graphene oxide were first coated on the surface of a bare GCE by the electrodeposition. Then, AuNPs and GOD were alternately immobilized onto PPy-RGO/GCE electrode using the electrodeposition of AuNPs and self-assembly of GOD to obtain AuNPs-GOD multilayer films. The resulting PPy-RGO-(AuNPs-GOD)n/GCE biosensors were used to characterize and assess their electrocatalytic activity toward glucose using cyclic voltammetry and amperometry. The response current increased with the increased number of AuNPs-GOD layers, and the biosensor based on four layers of AuNPs-GOD showed the best performance. The PPy-RGO-(AuNPs-GOD)4/GCE electrode can detect glucose in a linear range from 0.2 mM to 8 mM with a good sensitivity of 0.89 µA/mM, and a detection limit of 5.6 µM (S/N = 3). This study presents a promising eco-friendly biosensor platform with advantages of electrodeposition and self-assembly, and would be helpful for the future design of more complex electrochemical detection systems.
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Oral drug delivery has attracted substantial attention due to its advantages over other administration routes. Bacillus spores, as oral probiotic agents, are applied widely. In this paper, a novel Bacillus spore-based oral colon targeted carrier loading curcumin was developed for colon cancer treatment. Curcumin was linked covalently with the outer coat of Bacillus spore and folate, respectively (SPORE-CUR-FA). Bacillus spores are capable of delivering drugs to the colon area through gastric barrier, taking the advantage of its tolerance to the harsh conditions and disintegration of the outer coat of spores after germination in the colon. The drug release in vitro and in vivo of SPORE-CUR-FA was investigated. Results showed that SPORE-CUR-FA had the characteristics of colon-targeted drug release. Pharmacokinetic studies confirmed that Bacillus spore-based carriers could efficiently improve the oral bioavailability of curcumin. In vitro and in vivo anti-tumor studies showed that SPORE-CUR-FA had substantial ability for inhibiting colon cancer cells. These findings suggest that this Bacillus spore-based oral drug delivery system has a great potential for the treatment of colon cancer.
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Antineoplásicos/administración & dosificación , Bacillus coagulans , Neoplasias del Colon/tratamiento farmacológico , Curcumina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Ácido Fólico/administración & dosificación , Esporas Bacterianas , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Curcumina/química , Curcumina/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Ácido Fólico/química , Ácido Fólico/farmacocinética , Células HT29 , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Ratas Sprague-DawleyRESUMEN
A realistic control of cell cycle arrest is an attractive goal for the development of new effective anti-cancer drugs. Any clinical application of an effective anti-cancer drug necessarily relies on the understanding of cellular interaction mechanisms. In the present study, we prepared a co-immobilized TNF-α plus IFN-γ biomaterial, which showed a significant inhibition effect on cervical cancer cell growth, as demonstrated by a series of structural and cellular characterizations. We found that co-immobilized TNF-α plus IFN-α induced a long-term G1 phase cell cycle arrest in HeLa, SiHa, and CaSki cells, respectively. More surprisingly, the expression level of the p27 protein decreased, even when p27 mRNA was highly expressed. In addition, gene-chip results and microarray analysis showed that p57 may be downstream from p27, which acts as a direct regulator of the long-term G1 cell cycle arrest in these cells, leaving no escape for cervical cancer cells. Finally, we also investigated the anti-tumor mechanism of co-immobilized TNF-α plus IFN-γin vivo, using a nude mice animal model. To sum up, our findings suggested that the co-immobilized TNF-α plus IFN-γ can induce a long-term cell cycle arrest in cancer, thus serving as a very efficient tool for treating cervical cancer.
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Photodynamic therapy (PDT), combining the laser and photosensitizers to kill tumor cells, has the potential to address many current medical requirements. In this study, magnetic Fe3O4 nanoparticles were first employed as cores and modified with oleic acid (OA) and 3-triethoxysilyl-1-propanamine. Then, the photosensitizers phycocyanin (PC) and hematoporphyrin monomethyl ether (HMME), which might be able to stimulate the cell release of reactive oxygen species after the irradiation of a near-infrared (NIR) laser, were grafted on the surface of such nanoparticles. Our results revealed the high-efficiency inhibition of breast cancer MCF-7 cells growing upon near-infrared irradiation both in vitro and in vivo. Furthermore, it was the synergy between the natural photosensitizers PC and the synthetic photosensitizers HMME that deeply influenced such inhibition compared to the groups that used either of these medicines alone. To utilize the combination of different photosensitive agents, our study thus provides a new strategy for breast cancer treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hematoporfirinas/uso terapéutico , Nanopartículas de Magnetita/química , Fármacos Fotosensibilizantes/química , Ficocianina/uso terapéutico , Animales , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Femenino , Hematoporfirinas/administración & dosificación , Hematoporfirinas/farmacología , Hematoporfirinas/toxicidad , Humanos , Rayos Infrarrojos , Células MCF-7 , Nanopartículas de Magnetita/toxicidad , Ratones Endogámicos BALB C , Fotoquimioterapia , Ficocianina/administración & dosificación , Ficocianina/farmacología , Ficocianina/toxicidadRESUMEN
Stimuli-responsive nanoparticles with multiple therapeutic/diagnostic functions are highly desirable for effective tumor treatment. Herein novel caspase-3 responsive functionalized upconversion nanoparticles (CFUNs) were fabricated with three-in-one functional integration: near-infrared (NIR) triggered photodynamic damage along with caspase-3 activation, subsequent caspase-3 responsive drug release, and cascade chemotherapeutic activation. CFUNs were formulated from the self-assembly of caspase-3 responsive doxorubicin (DOX) prodrug tethered with DEVD peptide (DEVD-DOX), upconversion nanoparticles (UCNP), a photosensitizer (pyropheophorbide-a methyl ester, MPPa), and tumor-targeting cRGD-PEG-DSPE to afford multifunctional CFUNs, MPPa/UCNP-DEVD-DOX/cRGD. Upon cellular uptake and NIR irradiation, the visible light emission of UCNP could excite MPPa to produce reactive oxygen species for photodynamic therapy (PDT) along with the activation of caspase-3, which further cleaved DEVD peptide to release DOX within tumor cells, thus accomplishing NIR-triggered PDT and cascade chemotherapy. CFUNs presented silent therapeutic potency and negligible cytotoxicity in the dark, whereas in vitro and in vivo experiments demonstrated the NIR-triggered cascade therapeutic activation and tumor inhibition due to consecutive PDT and chemotherapy. Current NIR-activated cascade tumor therapy with two distinct mechanisms is significantly favorable to overcome multidrug resistance and tumor heterogeneity for persistent tumor treatment.
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Antineoplásicos/administración & dosificación , Caspasa 3/metabolismo , Preparaciones de Acción Retardada/metabolismo , Doxorrubicina/administración & dosificación , Nanopartículas/metabolismo , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Doxorrubicina/uso terapéutico , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Rayos Infrarrojos , Ratones Endogámicos BALB C , Neoplasias/metabolismo , Neoplasias/patología , Péptidos Cíclicos/metabolismo , Fosfatidiletanolaminas/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Polietilenglicoles/metabolismo , Porfirinas/uso terapéutico , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Autophagy plays a key role in supporting cell survival against chemotherapy-induced apoptosis. In this study, we found the chemotherapy agent SN-38 induced autophagy in colorectal cancer (CRC) cells. However, inhibition of autophagy using a small molecular inhibitor 3-methyladenine (3-MA) and ATG5 siRNA did not increase SN-38-induced cytotoxicity in CRC cells. Notably, another autophagy inhibitor chloroquine (CQ) synergistically enhanced the anti-tumor activity of SN-38 in CRC cells with wild type (WT) p53. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that CQ and SN-38 acted together to trigger reactive oxygen species (ROS) burst, upregulate p53 expression, elicit the loss of lysosomal membrane potential (LMP) and mitochondrial membrane potential (∆ψm). In addition, ROS induced by CQ plus SN-38 upregulated p53 levels by activating p38, conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce CRC cell death. Moreover, we showed induction of ROS and p53 by the two agents provoked the loss of LMP and ∆ψm. Altogether, all results suggested that CQ synergistically sensitized human CRC cells with WT p53 to SN-38 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk. Lastly, we showed that CQ could enhance CRC cells response to CPT-11 (a prodrug of SN-38) in xenograft models. Thus the combined treatment might represent an attractive therapeutic strategy for the treatment of CRC.
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Cloroquina/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Irinotecán , Lisosomas/metabolismo , Lisosomas/patología , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Undesired physiological instability of nanocarriers and premature drug leakage during blood circulation result in compromised therapeutic efficacy and severe side effects, which have significantly impeded the development of nanomedicine. Facile crosslinking of drug-loaded nanocarriers while keeping the potency of site-specific degradation and drug release has emerged as a viable strategy to overcome these drawbacks. Additionally, combination therapy has already shown advantages in inhibiting advanced tumors and life extension than single drug therapy. Herein, three kinds of diselenide-rich polymers were fabricated with distinct hydrophobic side chains. The component effect was interrogated to screen out PEG-b-PBSe diblock copolymer due to its favorable self-assembly controllability and high drug loading of camptothecin (CPT) and doxorubicin (DOX) that had synergistic antitumor property. Facile visible light-induced diselenide metathesis and regeneration was employed to crosslink nanocarriers for the first time. The dual drug-loaded crosslinked micelles (CPT/DOX-CCM) were stable in physiological conditions with minimal drug leakage, possessing extended blood circulation, whereas hand-in-hand dual drug release was significantly accelerated in tumor's redox microenvironments. In vitro cytotoxicity evaluation and in vivo tumor suppression with low dosage drugs further demonstrated the favorable potency of the redox-responsive nanoplatform in tumor combination chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/administración & dosificación , Nanocápsulas/administración & dosificación , Neoplasias Experimentales/tratamiento farmacológico , Compuestos de Selenio/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/química , Reactivos de Enlaces Cruzados/química , Reactivos de Enlaces Cruzados/efectos de la radiación , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/efectos de la radiación , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Estabilidad de Medicamentos , Humanos , Luz , Células MCF-7 , Nanocápsulas/química , Nanocápsulas/efectos de la radiación , Neoplasias Experimentales/patología , Oxidación-Reducción/efectos de la radiación , Compuestos de Selenio/química , Resultado del TratamientoRESUMEN
Cordycepin has been successfully used as a natural anti-cancer drug, but it is rapidly metabolized in vivo. Nanoencapsulation is thus a promising method to improve its bioavailability. In this study, we adopted a green synthesis process to develop novel self-assembling phycocyanin-dextran-cordycepin (Phy-Dex-Cord) micelles for efficient cordycepin encapsulation and delivery. We first used the Maillard reaction method to graft dextran onto phycocyanin, forming a phycocyanin-dextran complex. Through the self-assembly of the cordycepin parcel to the phycocyanin-dextran complex, the micelles were formed. Their physical and chemical properties and characterization results showed that Phy-Dex-Cord micelles have a spherical shape and consistent size distribution of about 60 nm. In addition, anti-cancer activities in vitro and in vivo revealed that the Phy-Dex-Cord micelles have a comparable or even stronger inhibitory effect against C6 cells than do free cordycepin and free phycocyanin and no side effects.
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Estrogen-dependent breast cancer is often treated with the aromatase inhibitors or estrogen receptor (ER) antagonists. Tamoxifen as a major ER antagonist is usually used to treat those patients with ERα-positive breast cancer. However, a majority of patients with ERα positive fail to respond to tamoxifen due to the presence of intrinsic or acquired resistance to the drug. Altered expression and functions of microRNAs (miRNAs) have been reportedly associated with tamoxifen resistance. In this study, we investigated the role of miR-27b-3p in resistance of breast cancer to tamoxifen. MiR-27b-3p levels were remarkably reduced in the tamoxifen-resistant breast cancer cells compared with their parental cells. In addition, miR-27b-3p was also significantly downregulated in breast tumor tissues relative to adjacent non-tumor tissues. Moreover, the expression levels of miR-27b-3p were lower in the breast cancer tissues from tamoxifen-resistant patients compared with that from untreated-tamoxifen patients. Notably, tamoxifen repressed miR-27b-3p expression, whereas estrogen induced miR-27b-3p expression in breast cancer cells. Besides, we provided experimental evidences that miR-27b-3p enhances the sensitivity of breast cancer cells to tamoxifen in vitro and in vivo models. More importantly, we validated that miR-27b-3p directly targeted and inhibited the expression of nuclear receptor subfamily 5 group A member 2 (NR5A2) and cAMP-response element binding protein 1 (CREB1) and therefore augmented tamoxifen-induced cytotoxicity in breast cancer. Lastly, miR-27b-3p levels were found to be significantly negatively correlated with both NR5A2 and CREB1 levels in breast cancer tissues. Our findings provided further evidence that miR-27b-3p might be considered as a novel and potential target for the diagnosis and treatment of tamoxifen-resistant breast cancer.
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Neoplasias de la Mama/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , MicroARNs/genética , Receptores Citoplasmáticos y Nucleares/genética , Tamoxifeno/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias de la Mama/patología , Supervivencia Celular/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación hacia Abajo/genética , Resistencia a Antineoplásicos/genética , Estrógenos/farmacología , Femenino , Humanos , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/metabolismo , Modelos Biológicos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chemoresistance is a major obstacle to effective breast cancer chemotherapy. However, the underlying molecular mechanisms remain unclear. In this study, nuclear receptor coactivator 3 (NCOA3) was found to be significantly increased in taxol-resistant breast cancer tissues and cells. Moreover, overexpression of NCOA3 enhanced breast cancer cell resistance to taxol, whereas depletion of NCOA3 decreased taxol resistance. Subsequently, we investigated whether NCOA3 expression was regulated by miRNAs in breast cancer. By bioinformatics prediction in combination with the data of previous report, miR-17 and miR-20b were selected as the potential miRNAs targeting NCOA3. By real-time PCR analysis, we found that miR-17 and miR-20b were significantly reduced in taxol-resistant breast cancer tissues and cells. In addition, we provided some experimental evidences that miR-17 and miR-20b attenuated breast cancer resistance to taxol in vitro and in vivo models. Furthermore, by luciferase reporter assays, we further validated that both miR-17 and miR-20b directly binded the 3'-untranslated region of NCOA3 mRNA and inhibited its expression in breast cancer cells. Finally, both miR-17 and miR-20b levels were found to be significantly negatively correlated with NCOA3 mRNA levels in breast cancer tissues. Together, our results indicated that loss of miR-17 and miR-20b enhanced breast cancer resistance to taxol by upregulating NCOA3 levels. Our study suggested miR-17, miR-20b and NCOA3 may serve as some predictive biomarkers and potential therapeutic targets in taxol-resistant breast cancer treatment.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/efectos de los fármacos , MicroARNs/genética , Coactivador 3 de Receptor Nuclear/genética , Paclitaxel/uso terapéutico , Regulación hacia Arriba/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Secuencia de Bases , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones Desnudos , MicroARNs/metabolismo , Coactivador 3 de Receptor Nuclear/metabolismo , Paclitaxel/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Tamoxifeno/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
SRC-3 is widely expressed in multiple tumor types and involved in cancer cell proliferation and apoptosis. Histone deacetylase (HDAC) inhibitors are promising antitumor drugs. However, the poor efficacy of HDAC inhibitors in solid tumors has restricted its further clinical application. Here, we reported the novel finding that depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors (SAHA and romidepsin). In contrast, overexpression of SRC-3 decreased SAHA-induced cancer cell apoptosis. Furthermore, we found that SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. The combination of bufalin and SAHA was particular efficient in attenuating AKT activation and reducing Bcl-2 levels. Taken together, these accumulating data might guide development of new breast and lung cancer therapies.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Inhibidores de Histona Desacetilasas/administración & dosificación , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Coactivador 3 de Receptor Nuclear/genética , Coactivador 3 de Receptor Nuclear/metabolismo , Células A549 , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Depsipéptidos/administración & dosificación , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Silenciador del Gen , Humanos , Neoplasias Experimentales/patología , Coactivador 3 de Receptor Nuclear/antagonistas & inhibidoresRESUMEN
The combination of diagnostics and therapeutics is growing rapidly in cancer treatment. Here, using upconversion nanoparticles coated with chitosan conjugated with a targeting molecule and loaded with indocyanine green (ICG), we develop an excitation-selectable nanoprobe with highly integrated functionalities, including the emission of visible and near-infrared (NIR) light, strong optical absorption in the NIR region and high photostability. After intravenous injection in tumor bearing mice, the nanoprobes target to the tumor vascular system. NIR lasers (980 and 808 nm) are then selectively applied to the mice. The results show that the emitted upconversion fluorescence and NIR fluorescence can be used in a complementary manner for high signal/noise ratio and sensitive tumor imaging for more precise tumor localization. Highly effective photothermal therapy is realized using 808 nm laser irradiation, and the upconversion fluorescence at 654 nm can be used for monitoring treatment effect during the thermal therapy. In summary, using the nanoprobes, outstanding therapeutic efficacy could be realized through flexible excitation control, precise tumor localization, highly effective photothermal conversion and real-time treatment monitoring. The nanofabrication strategy highlights the promise of nanoparticles in cancer theranostics.