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Aqueous zinc batteries are practically promising for large-scale energy storage because of cost-effectiveness and safety. However, application is limited because of an absence of economical electrolytes to stabilize both the cathode and anode. Here, we report a facile method for advanced zinc-iodine batteries via addition of a trace imidazolium-based additive to a cost-effective zinc sulfate electrolyte, which bonds with polyiodides to boost anti-self-discharge performance and cycling stability. Additive aggregation at the cathode improves the rate capacity by boosting the I2 conversion kinetics. Also, the introduced additive enhances the reversibility of the zinc anode by adjusting Zn2+ deposition. The zinc-iodine pouch cell, therefore, exhibits industrial-level performance evidenced by a â¼99.98% Coulombic efficiency under ca. 0.4C, a significantly low self-discharge rate with 11.7% capacity loss per month, a long lifespan with 88.3% of initial capacity after 5000 cycles at a 68.3% zinc depth-of-discharge, and fast-charging of ca. 6.7C at a high active-mass loading >15 mg cm-2. Highly significant is that this self-discharge surpasses commercial nickel-metal hydride batteries and is comparable with commercial lead-acid batteries, together with the fact that the lifespan is over 10 times greater than reported works, and the fast-charging performance is better than commercial lithium-ion batteries.
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BACKGROUND: Hepatocellular carcinoma (HCC) cells usually show strong resistance to chemotherapy, which not only reduces the efficacy of chemotherapy but also increases the side effects. Regulation of autophagy plays an important role in tumor treatment. Cell senescence is also an important anti-cancer mechanism, which has become an important target for tumor treatment. Therefore, it is of great clinical significance to find anti-HCC drugs that act through this new mechanism. Platycodin D2 (PD2) is a new saponin compound extracted from the traditional Chinese medicine Platycodon grandiflorum. PURPOSE: Our study aimed to explore the effects of PD2 on HCC and identify the underlying mechanisms. METHODS: First, the CCK8 assay was used to detect the inhibitory effect of PD2 on HCC cells. Then, different pathways of programmed cell death and cell cycle regulators were measured. In addition, we assessed the effects of PD2 on the autophagy and senescence of HCC cells by flow cytometry, immunofluorescence staining, and Western blotting. Finally, we studied the in vivo effect of PD2 on HCC cells by using a mouse tumor-bearing model. RESULTS: Studies have shown that PD2 has a good anti-tumor effect, but the specific molecular mechanism has not been clarified. In this study, we found that PD2 has no obvious toxic effect on normal hepatocytes, but it can significantly inhibit the proliferation of HCC cells, induce mitochondrial dysfunction, enhance autophagy and cell senescence, upregulate NIX and P21, and downregulate CyclinA2. Gene silencing and overexpression indicated that PD2 induced mitophagy in HCC cells through NIX, thereby activating the P21/CyclinA2 pathway and promoting cell senescence. CONCLUSIONS: These results indicate that PD2 induces HCC cell death through autophagy and aging. Our findings provide a new strategy for treating HCC.
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Zinc-iodine (Zn-I2) batteries are gaining popularity due to cost-effectiveness and ease of manufacturing. However, challenges like polyiodide shuttle effect and Zn dendrite growth hinder their practical application. Here, we report a cation exchange membrane to simultaneously prevent the polyiodide shuttle effect and regulate Zn2+ deposition. Comprised of rigid polymers, this membrane shows superior swelling resistance and ion selectivity compared to commercial Nafion. The resulting Zn-I2 battery exhibits a high Coulombic efficiency of 99.4% and low self-discharge rate of 4.47% after 48 h rest. By directing a uniform Zn2+ flux, the membrane promotes a homogeneous electric field, resulting in a dendrite-free Zn surface. Moreover, its microporous structure enables pre-adsorption of additional active materials prior to battery assembly, boosting battery capacity to 287 mA h g-1 at 0.1 A g-1. At 2 A g-1, the battery exhibits a steady running for 10,000 cycles with capacity retention up to 96.1%, demonstrating high durability of the membrane. The practicality of the membrane is validated via a high loading (35 mg cm-2) pouch cell with impressive cycling stability, paving a way for membrane design towards advanced Zn-I2 batteries.
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The extensively studied Prussian blue analogs (PBAs) in various batteries are limited by their low discharge capacity, or subpar rate etc., which are solely reliant on the cation (de)intercalation mechanism. In contrast to the currently predominant focus on cations, we report the overlooked anion-cation competition chemistry (Cl-, K+, Zn2+) stimulated by high-voltage scanning. With our designed anion-cation combinations, the KFeMnHCF cathode battery delivers comprehensively superior discharge performance, including voltage plateau >2.0â V (vs. Zn/Zn2+), capacity >150â mAh g-1, rate capability with capacity maintenance above 96 % from 0.6 to 5â A g-1, and cyclic stability exceeding 3000â cycles. We further verify that such comprehensive improvement of electrochemical performance utilizing anion-cation competition chemistry is universal for different types of PBAs. Our work would pave a new and efficient road towards the next-generation high-performance PBAs cathode batteries.
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Coronavirus disease 2019 is a global pandemic caused by SARS-CoV-2. The emergence of its variant strains has posed a considerable challenge to clinical treatment. Therefore, drugs capable of inhibiting SARS-CoV-2 infection, regardless of virus variations, are in urgently need. Our results showed that the endosomal acidification inhibitor, Bafilomycin A1 (Baf-A1), had an inhibitory effect on the viral RNA synthesis of SARS-CoV-2, and its Beta and Delta variants at the concentration of 500 nM. Moreover, the human lung xenograft mouse model was used to investigate the anti-SARS-CoV-2 effect of Baf-A1. It was found that Baf-A1 significantly inhibited SARS-CoV-2 replication in the human lung xenografts by in situ hybridization and RT-PCR assays. Histopathological examination showed that Baf-A1 alleviated SARS-CoV-2-induced diffuse inflammatory infiltration of granulocytes and macrophages and alveolar endothelial cell death in human lung xenografts. In addition, immunohistochemistry analysis indicated that Baf-A1 decreased inflammatory exudation and infiltration in SARS-CoV-2-infected human lung xenografts. Therefore, Baf-A1 may be a candidate drug for SARS-CoV-2 treatment.
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COVID-19 , Humanos , Animales , Ratones , Xenoinjertos , SARS-CoV-2 , Células Epiteliales Alveolares , Modelos Animales de EnfermedadRESUMEN
OBJECTIVE: Oncolytic adenoviruses are capable of exerting anticancer effects via a variety of mechanisms, including apoptosis and autophagy. In the present study, the dual-specific antitumor oncolytic adenovirus, Ad-Apoptin-hTERT-E1a (ATV), was used to infect cervical cancer cell lines to test its antitumor effects. METHODS: To explore the use of apoptin in tumor gene therapy, a recombinant adenovirus ATV expressing the apoptin protein was assessed to determine its lethal and growth-inhibitory effects on human cervical cancer cell line (HeLa) cells in vitro . Nonapoptotic autophagy of HeLa cells infected with ATV was assessed by examining the cell morphology, development of acidic vesicular organelles and the conversion of microtubule-associated protein 1 light chain 3 (LC3) from its cytoplasmic to autophagosomal membrane form. Using gene silencing (knockdown of LC3 and Belin-1), autophagy-associated molecules (e.g. ATG5, ATG12 and ULK1) were monitored by real-time PCR and western blot. RESULTS: A series of experiments demonstrated that ATV could significantly induce apoptosis and autophagy in cervical cancer cells, and provided evidence that ATV not only induced apoptosis but also autophagy and ATG5, ATG12 and ULK1 related pathways were not entirely dependent on LC3 and Beclin-1. CONCLUSION: These results indicate that ATV may have a potential application in tumor gene therapy.
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Muerte Celular Autofágica , Viroterapia Oncolítica , Neoplasias del Cuello Uterino , Femenino , Humanos , Adenoviridae/genética , Células HeLa , Línea Celular Tumoral , Apoptosis , Autofagia , Viroterapia Oncolítica/métodosRESUMEN
This study presents a convenient approach to the synthesis of indole- and benzofuran-based benzylic sulfones using unactivated alkynes containing aryl iodides and sodium sulfinates under visible light irradiation. The procedure involves a sequential series of dehalogenation, carbo-cyclization, and radical sulfonylation. Plausible insights into the reaction mechanism are derived from control experiments, leading to the proposal of a radical cascade reaction pathway.
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Zn electrodes in aqueous media exhibit an unstable Zn/electrolyte interface due to severe parasitic reactions and dendrite formation. Here, a dynamic Zn interface modulation based on the molecular switch strategy is reported by hiring γ-butyrolactone (GBL) in ZnCl2 /H2 O electrolyte. During Zn plating, the increased interfacial alkalinity triggers molecular switch from GBL to γ-hydroxybutyrate (GHB). GHB strongly anchors on Zn surface via triple Zn-O bonding, leading to suppressive hydrogen evolution and texture-regulated Zn morphology. Upon Zn stripping, the fluctuant pH turns the molecular switch reaction off through the cyclization of GHB to GBL. This dynamic molecular switch strategy enables high Zn reversibility with Coulombic efficiency of 99.8 % and Zn||iodine batteries with high-cyclability under high Zn depth of discharge (50 %). This study demonstrates the importance of dynamic modulation for Zn electrode and realizes the reversible molecular switch strategy to enhance its reversibility.
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As a burgeoning electrolyte system, eutectic electrolytes based on ZnCl2 /Zn(CF3 SO3 )2 /Zn(TFSI)2 have been widely proposed in advanced Zn-I2 batteries; however, safety and cost concerns significantly limit their applications. Here, we report new-type ZnSO4 -based eutectic electrolytes that are both safe and cost-effective. Their universality is evident in various solvents of polyhydric alcohols, in which multiple -OH groups not only involve in Zn2+ solvation but also interact with water, resulting in the high stability of electrolytes. Taking propylene glycol-based hydrated eutectic electrolyte as an example, it features significant advantages in non-flammability and low price that is <1/200 cost of Zn(CF3 SO3 )2 /Zn(TFSI)2 -based eutectic electrolytes. Moreover, its effectiveness in confining the shuttle effects of I2 cathode and side reactions of Zn anodes is evidenced, resulting in Zn-I2 cells with high reversibility at 1â C and 91.4 % capacity remaining under 20â C. After scaling up to the pouch cell with a record mass loading of 33.3â mg cm-2 , super-high-capacity retention of 96.7 % is achieved after 500â cycles, which exceeds other aqueous counterparts. This work significantly broadens the eutectic electrolyte family for advanced Zn battery design.
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In this study, we compared the inhibitory effects of recombinant oncolytic adenovirus (Ad-apoptin-hTERTp-E1a, Ad-VT) with that of doxorubicin (DOX), a first-line chemotherapy drug, and tamoxifen (TAM), an endocrine therapy drug, on the proliferation of breast cancer cells. We found that Ad-VT could effectively inhibit the proliferation of breast cancer cells (p < 0.01); the inhibition rate of Ad-VT on normal mammary epithelial MCF-10A cells was less than 20%. DOX can effectively inhibit the proliferation of breast cancer cells and also has a strong inhibitory effect on MCF-10A cells (p < 0.01). TAM also has a strong inhibitory effect on breast cancer cells, among which the oestrogen-dependent MCF-7 cell inhibition was stronger (p < 0.01), At higher concentrations, TAM also had a high rate of inhibition (>70%) on the proliferation of MCF-10A cells. We also found that both recombinant adenovirus and both drugs could successfully induce tumour cell apoptosis. Further Western blot results showed that the recombinant adenovirus killed breast cancer cells through the endogenous apoptotic pathway. Analysis of the nude mouse subcutaneous breast cancer model showed that Ad-VT significantly inhibited tumour growth (the luminescence rate of cancer cells was reduced by more than 90%) and improved the survival rate of tumour-bearing mice (p < 0.01). Compared with DOX and TAM, Ad-VT has a significant inhibitory effect on breast cancer cells, but almost no inhibitory effect on normal breast epithelial cells, and this inhibitory effect is mainly through the endogenous apoptotic pathway. These results indicate that Ad-VT has significant potential as a drug for the treatment of breast cancer.
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Adenoviridae , Neoplasias , Adenoviridae/genética , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Doxorrubicina/farmacología , Estrógenos/farmacología , Ratones , Tamoxifeno/farmacologíaRESUMEN
Autophagy is thought to be involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, how SARS-CoV-2 interferes with the autophagic pathway and whether autophagy contributes to virus infection in vivo is unclear. In this study, we identified SARS-CoV-2-triggered autophagy in animal models, including the long-tailed or crab-eating macaque (Macaca fascicularis), human angiotensin-converting enzyme 2 (hACE2) transgenic mice, and xenografted human lung tissues. In Vero E6 and Huh-7 cells, SARS-CoV-2 induces autophagosome formation, accompanied by consistent autophagic events, including inhibition of the Akt-mTOR pathway and activation of the ULK-1-Atg13 and VPS34-VPS15-Beclin1 complexes, but it blocks autophagosome-lysosome fusion. Modulation of autophagic elements, including the VPS34 complex and Atg14, but not Atg5, inhibits SARS-CoV-2 replication. Moreover, this study represents the first to demonstrate that the mouse bearing xenografted human lung tissue is a suitable model for SARS-CoV-2 infection and that autophagy inhibition suppresses SARS-CoV-2 replication and ameliorates virus-associated pneumonia in human lung tissues. We also observed a critical role of autophagy in SARS-CoV-2 infection in an hACE2 transgenic mouse model. This study, therefore, gives insights into the mechanisms by which SARS-CoV-2 manipulates autophagosome formation, and we suggest that autophagy-inhibiting agents might be useful as therapeutic agents against SARS-CoV-2 infection. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with limited therapeutics. Insights into the virus-host interactions contribute substantially to the development of anti-SARS-CoV-2 therapeutics. The novelty of this study is the use of a new animal model: mice xenografted with human lung tissues. Using a combination of in vitro and in vivo studies, we have obtained experimental evidence that induction of autophagy contributes to SARS-CoV-2 infection and improves our understanding of potential therapeutic targets for SARS-CoV-2.
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Enzima Convertidora de Angiotensina 2/genética , Autofagia , Tratamiento Farmacológico de COVID-19 , COVID-19/virología , Pulmón/virología , SARS-CoV-2 , Replicación Viral , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Autofagosomas , Línea Celular Tumoral , Chlorocebus aethiops , Humanos , Pulmón/patología , Macaca , Masculino , Ratones , Ratones Transgénicos , Neumonía Viral/tratamiento farmacológico , ARN Interferente Pequeño/metabolismo , Células VeroRESUMEN
Background One of the main challenges in the clinical treatment of lung cancer is resistance to chemotherapeutic drugs. P-glycoprotein (P-gp)-mediated drug resistance is the main obstacle to successfully implementing microtubule-targeted tumor chemotherapy. Purpose In this study, we explored the effect of Ad-hTERTp-E1a-Apoptin (Ad-VT) on drug-resistant cell lines and the molecular mechanism by which Ad-VT combined with chemotherapy affects drug-resistant cells and parental cells. Methods In vitro, cell proliferation, colony formation, resistance index (RI), apoptosis and autophagy assays were performed. Protein expression was analyzed by Western blotting. Finally, a xenograft tumor model in nude mice was used to detect tumor growth and evaluate histological characteristics. Results Our results showed that Ad-VT had an obvious killing effect on A549, A549/GEM and A549/Paclitaxel cancer cells, and the sensitivity of drug-resistant cell lines to Ad-VT was significantly higher than that of parental A549 cells. Compared with A549 cells, A549/GEM and A549/Paclitaxel cells had higher autophagy levels and higher viral replication ability. Ad-VT decreased the levels of p-PI3k, p-Akt and p-mTOR and the expression of P-gp. In vivo, Ad-VT combined with chemotherapy can effectively inhibit the growth of chemotherapy-resistant tumors and prolong the survival of mice. Conclusions Thus, the combination of Ad-VT and chemotherapeutic drugs will be a promising strategy to overcome chemoresistance.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/tratamiento farmacológico , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
BACKGROUND: Apoptin, as a tumor-specific pro-apoptotic protein, plays an important anti-tumoral role, but its mechanism of autophagy activation and the interaction between autophagy and apoptosis have not been accurately elucidated. Here, we studied the mechanism of apoptin-induced apoptosis and autophagy and the interaction between two processes. METHODS: Using crystal violet staining and the CCK-8 assay, we analyzed the effect of apoptin in the inhibition of liver cancer cells in vitro and analyzed the effect of inhibiting liver cancer in vivo by establishing a nude mouse tumor model. Flow cytometry and fluorescence staining were used to analyze the main types of apoptin-induced apoptosis and autophagy. Subsequently, the relationship between the two events was also analyzed. Flow cytometry was used to analyze the effect of ROS on apoptin-mediated apoptosis and autophagy mediated by apoptin. The effect of ROS on two phenomena was analyzed. Finally, the role of key genes involved in autophagy was analyzed using gene silencing. RESULTS: The results showed that apoptin can significantly increase the apoptosis and autophagy of liver cancer cells, and that apoptin can cause mitophagy through the increase in the expression of NIX protein. Apoptin can also significantly increase the level of cellular ROS, involved in apoptin-mediated autophagy and apoptosis of liver cancer cells. The change of ROS may be a key factor causing apoptosis and autophagy. CONCLUSION: The above results indicate that the increase in ROS levels after apoptin treatment of liver cancer cells leads to the loss of mitochondrial transmembrane potential, resulting in endogenous apoptosis and mitophagy through the recruitment of NIX. Therefore, ROS may be a key factor connecting endogenous apoptosis and autophagy induced by apoptin in liver cancer cells. Video abstract.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Apoptosis , Proteínas de la Cápside , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Ratones , Ratones Desnudos , Mitofagia , Especies Reactivas de OxígenoRESUMEN
Ad-apoptin is a recombinant oncolytic adenovirus constructed by our laboratory that can express apoptin. It can selectively kill tumor cells without damaging normal cells. This study investigated the effects of Ad-apoptin on glycolysis, migration and invasion of non-small cell lung cancer. Cell viability and apoptosis were detected by CCK-8 and flow cytometry, respectively. Glycolysis was investigated by glucose consumption, lactic acid production and glycolytic key enzyme protein levels. Migration and invasion were evaluated via wound healing, transwell assays and epithelial-mesenchymal transition (EMT) protein levels. The interaction between apoptin and AMPK was detected by Co-IP. A nude mice tumor model was established to investigate the anti-cancer role of Ad-apoptin in vivo. The results showed that Ad-apoptin inhibits cell viability and induces apoptosis of A549 and NCI-H23 cells. Ad-apoptin can reduce the glucose uptake and lactic production in lung cancer cells, and reduce the expression of related glycolysis-limiting enzymes. At the same time, Ad-apoptin inhibited the migration and invasion of lung cancer. Immunoprecipitation showed that apoptin and AMPK could interact directly. Moreover, knockdown of AMPK significantly attenuated the inhibitory effect of Ad-apoptin on glycolysis, migration and invasion of A549 and NCI-H23 cells. Ad-apoptin can inhibit the growth of tumors in nude mice. Compared with the control group, Ad-apoptin had a significant inhibitory effect on AMPK knockdown tumors. The immunohistochemical results of tumor tissues were consistent with those in vitro. Collectively, Ad-apoptin targets AMPK and inhibits glycolysis, migration and invasion of lung cancer cells through the AMPK/mTOR signaling pathway. This suggests that Ad-apoptin may have therapeutic potential for lung cancer by targeting AMPK activation.
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Proteínas Quinasas Activadas por AMP/metabolismo , Adenoviridae/genética , Proteínas de la Cápside/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Glucólisis , Viroterapia Oncolítica/métodos , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Ciclo Celular , Movimiento Celular , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Serina-Treonina Quinasas TOR/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Apoptin can specifically kill cancer cells but has no toxicity to normal cells. Human telomerase reverse transcriptase (hTERT) can act as a tumour-specific promoter by triggering the expression of certain genes in tumour cells. This study aims to investigate the inhibitory effects and to explore the inhibitory pathway of a dual cancer-specific recombinant adenovirus (Ad-apoptin-hTERTp-E1a, Ad-VT) on breast cancer stem cells. Breast cancer cell spheres were obtained from MCF-7 cells through serum-free suspension culture. The cell spheres were detected by flow cytometry for CD44+ CD24- cell subsets. The stemness of MCF-7-CSC cells was confirmed by in vivo tumorigenesis experiments. The inhibitory effect of the recombinant adenoviruses on MCF-7-CSC cells was evaluated by CCK-8 assay. In addition, the stemness of adenovirus-infected MCF-7-CSC cells was analysed by testing the presence of CD44+ CD24- cell subsets. The ability of the recombinant adenovirus to induce MCF-7-CSC cell apoptosis was detected by staining JC-1, TMRM and Annexin V. Our results showed that a significantly higher proportion of the CD44+ CD24- cell subsets was present in MCF-7-CSC cells with a significantly increased expression of stem cell marker proteins. The MCF-7-CSC cells, whlist exhibited a strong tumorigenic ability with a certain degree of stemness in mice, were shown to be strongly inhibited by recombinant adenovirus Ad-VT through cell apoptosis. In addition, Ad-VT was shown to exert a killing effect on BCSCs. These results provide a new theoretical basis for the future treatment of breast cancer.
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Antígeno CD24/metabolismo , Receptores de Hialuranos/metabolismo , Células Madre Neoplásicas/metabolismo , Apoptosis/genética , Apoptosis/fisiología , Western Blotting , Antígeno CD24/genética , Citometría de Flujo , Humanos , Receptores de Hialuranos/genética , Células MCF-7 , Potencial de la Membrana Mitocondrial/genética , Potencial de la Membrana Mitocondrial/fisiologíaRESUMEN
As a potential cancer therapy, we developed a recombinant adenovirus named Ad-VT, which was designed to express the apoptosis-inducing gene (apoptin) and selectively replicate in cancer cells via E1a manipulation. However, how it performs in bladder cancer remains unclear. We examined the antitumor efficacy of Ad-VT in bladder cancers using CCK-8 assays and xenograft models. Autophagy levels were evaluated by western blotting, MDC staining, and RFP-GFP-LC3 aggregates' analyses. Here, we report the selective replication and antitumor efficacy (viability inhibition and apoptosis induction) of Ad-VT in bladder cancer cells. Using xenograft tumor models, we demonstrate that its effects are tumor specific resulting in the inhibition of tumor growth and improvement of the survival of mice models. Most Importantly, Ad-VT induced a complete autophagy flux leading to autophagic cancer cell death through a signaling pathway involving AMPK, raptor and mTOR. Finally, we suggest that treatment combination of Ad-VT and rapamycin results in a synergistic improvement of tumor control and survival compared to monotherapy. This study suggests that Ad-VT can induce selective autophagic antitumor activities in bladder cancer through the AMPK-Raptor-mTOR pathway, which can be further improved by rapamycin.
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Adenoviridae/genética , Autofagia/genética , Viroterapia Oncolítica/métodos , Neoplasias de la Vejiga Urinaria/terapia , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Proteínas de la Cápside/genética , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteína Reguladora Asociada a mTOR/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 and broke out as a global pandemic in late 2019. The acidic pH environment of endosomes is believed to be essential for SARS-CoV-2 to be able to enter cells and begin replication. However, the clinical use of endosomal acidification inhibitors, typically chloroquine, has been controversial with this respect. METHODS: In this study, RT-qPCR method was used to detect the SARS-CoV-2N gene to evaluate viral replication. The CCK-8 assay was also used to evaluate the cytotoxic effect of SARS-CoV-2. In situ hybridization was used to examine the distribution of the SARS-CoV-2 gene in lung tissues. Hematoxylin and eosin staining was also used to evaluate virus-associated pathological changes in lung tissues. RESULTS: In this study, analysis showed that endosomal acidification inhibitors, including chloroquine, bafilomycin A1 and NH4CL, significantly reduced the viral yields of SARS-CoV-2 in Vero E6, Huh-7 and 293T-ACE2 cells. Chloroquine and bafilomycin A1 also improved the viability and proliferation of Vero E6 cells after SARS-CoV-2 infection. Moreover, in the hACE2 transgenic mice model of SARS-CoV-2 infection, chloroquine and bafilomycin A1 reduced viral replication in lung tissues and alleviated viral pneumonia with reduced inflammatory exudation and infiltration in peribronchiolar and perivascular tissues, as well as improved structures of alveolar septum and pulmonary alveoli. CONCLUSIONS: Our research investigated the antiviral effects of endosomal acidification inhibitors against SARS-CoV-2 in several infection models and provides an experimental basis for further mechanistic studies and drug development.
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Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , COVID-19/virología , Endosomas/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Replicación Viral/efectos de los fármacos , Cloruro de Amonio/farmacología , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19/metabolismo , COVID-19/patología , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Cloroquina/farmacología , Endosomas/metabolismo , Femenino , Células HEK293 , Humanos , Concentración de Iones de Hidrógeno , Pulmón/patología , Macrólidos/farmacología , Ratones , Ratones Transgénicos , Distribución Aleatoria , SARS-CoV-2/genética , Células VeroRESUMEN
BACKGROUND: Apoptin can specifically kill cancer cells but has no toxicity to normal cells. Human telomerase reverse transcriptase (hTERT) acts as a tumor-specific promoter, triggering certain genes to replicate or express only in tumor cells, conferring specific replication and killing abilities. This study aimed at investigating the anticancer potential of the recombinant adenovirus Ad-apoptin-hTERTp-E1a (Ad-VT) in ovarian cancer treatment. METHODS: Crystal Violet staining and WST-1 assays were used to analyze the inhibitory effect of Ad-VT on ovarian cancer SKOV3 and OVCAR-3 cells. Ad-VT-induced apoptosis of ovarian cancer cells, was detected using Hoechst, Annexin V-FITC/PI, JC-1 staining. Cell migration and invasion of ovarian cancer cells were detected using cell-scratch and Transwell assays. The pGL4.51 plasmid was used to transfect and to generate SKOV3-LUC cells, that stably express luciferase. The in vivo tumor inhibition effect of Ad-VT was subsequently confirmed using a tumor-bearing nude mouse model. RESULTS: Ad-VT had a strong apoptosis-inducing effect on SKOV3 and OVCAR-3 cells, that was mainly mediated through the mitochondrial apoptotic pathway. The Ad-VT could significantly increase the inhibition of ovarian cancer cell migration and invasion. The Ad-VT also can inhibit tumor growth and reduce toxicity in vivo. CONCLUSIONS: The recombinant adenovirus, comprising the apoptin protein and the hTERTp promoter, was able to inhibit the growth of ovarian cancer cells and promote their apoptosis.
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Adenoviridae/genética , Carcinoma Epitelial de Ovario/genética , Virus de la Anemia del Pollo/genética , Viroterapia Oncolítica/métodos , Neoplasias Ováricas/genética , Proteínas Virales/genética , Adenoviridae/metabolismo , Animales , Apoptosis/genética , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/virología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Virus de la Anemia del Pollo/metabolismo , Femenino , Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/genética , Mitocondrias/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/virología , Análisis de Supervivencia , Transgenes , Carga Tumoral , Proteínas Virales/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Aqueous Zn-ion batteries (ZIBs) are regarded as alternatives to Li-ion batteries benefiting from both improved safety and environmental impact. The widespread application of ZIBs, however, is compromised by the lack of high-performance cathodes. Currently, only the intercalation mechanism is widely reported in aqueous ZIBs, which significantly limits cathode options. Beyond Zn-ion intercalation, we comprehensively study the conversion mechanism for Zn2+ storage and its diffusion pathway in a CuI cathode, indicating that CuI occurs a direct conversion reaction without Zn2+ intercalation due to the high energy barrier for Zn2+ intercalation and migration. Importantly, this direct conversion reaction mechanism can be readily generalized to other high-capacity cathodes, such as Cu2 S (336.7â mA h g-1 ) and Cu2 O (374.5â mA h g-1 ), indicating its practical universality. Our work enriches the Zn-ion storage mechanism and significantly broadens the cathode horizons towards next-generation ZIBs.
RESUMEN
Oncolytic virus therapy is emerging as important means in cancer treatment. In a previous study, we constructed a dual cancer-specific antitumor recombinant adenovirus, designating it Ad-apoptin-hTERTp-E1a (Ad-VT). This study aimed to investigate the anticancer potential of recombinant adenovirus Ad-apoptin-hTERTp-E1a (Ad-VT) in liver cancer. Crystal Violet staining and CCK-8 assays were used to analyse the inhibitory effect of recombinant adenovirus on human hepatoma cell line QGY-7703 and SMMC-7721. Ad-VT had a significant tumour killing inhibitory effect on QGY-7703 and SMMC-7721 cells that was both dose and a time dependent. Ad-VT-induced apoptosis of QGY-7703 cells was detected using Hoechst, Annexin V, and JC-1 staining, as well as western blotting. Recombinant adenovirus had a strong apoptosis-inducing effect on QGY-7703 cells, and killed QGY-7703 cells mainly through the mitochondrial apoptotic pathway. QGY-7703 cells invasion were detected using cell-scratch and Transwell assays. Recombinant adenovirus could significantly inhibit the invasion of QGY-7703 cells over a short period of time. The pGL4.51 plasmid was used to transfect QGY-7703 cells to construct tumour cells stably expressing luciferase (QGY-7703-LUC). The tumour inhibition effect of Ad-VT in vivo was subsequently confirmed by establishing a tumour-bearing nude mouse model. Ad-VT could effectively inhibit tumour growth and prolong survival of the mice. Recombinant adenovirus Ad-VT has the characteristics of tumour-specific replication and specific tumour killing, and could inhibit the growth of liver cancer QGY-7703 cells and promote their apoptosis.