RESUMO
Cancer stem cells (CSCs) have been blamed as the main culprit of tumor initiation, progression, metastasis, chemoresistance, and recurrence. However, few anti-CSCs agents have achieved clinical success so far. Here we report a novel derivative of lonidamine (LND), namely HYL001, which selectively and potently inhibits CSCs by targeting mitochondria, with 380-fold and 340-fold lower IC50 values against breast cancer stem cells (BCSCs) and hepatocellular carcinoma stem cells (HCSCs), respectively, compared to LND. Mechanistically, we reveal that HYL001 downregulates glutaminase (GLS) expression to block glutamine metabolism, blunt tricarboxylic acid cycle, and amplify mitochondrial oxidative stress, leading to apoptotic cell death. Therefore, HYL001 displays significant antitumor activity in vivo, both as a single agent and combined with paclitaxel. Furthermore, HYL001 represses CSCs of fresh tumor tissues derived from liver cancer patients. This study provides critical implications for CSCs biology and development of potent anti-CSCs drugs.
Assuntos
Antineoplásicos , Neoplasias Hepáticas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/metabolismo , Glutamina/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas , Linhagem Celular TumoralRESUMO
Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3-13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4+ and/or CD8+ T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4+ and CD8+ T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients.Trial registration ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016).
Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Células Dendríticas/imunologia , Glioblastoma/terapia , Neoplasias Pulmonares/terapia , Medicina de Precisão , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Imunização , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
Constructing a tumor microenvironment stimuli activatable theranostic nanoparticle with simple components and preparation procedures for multimodality imaging and therapy remains a major challenge for current theranostic systems. Here we report a novel and simple glutathione (GSH)-responsive turn-on theranostic nanoparticle for dual-modal imaging and combination therapy. The theranostic nanoparticle, DHP, consisting of a disulfide-bond-linked hydroxyethyl starch paclitaxel conjugate (HES-SS-PTX) and a near-infrared (NIR) cyanine fluorophore DiR, is prepared with a simple one-step dialysis method. As DiR is encapsulated within the hydrophobic core formed by HES-SS-PTX, the fluorescence of DiR is quenched by the aggregation-caused quenching (ACQ) effect. Nonetheless, once DHP is internalized by cancer cells, the disulfide bond of HES-SS-PTX can be cleaved by intracellular GSH, leading to the synchronized release of conjugated PTX and loaded DiR. The released PTX could exert its therapeutic effect, while DiR could adsorb onto nearby endosome/lysosome membranes and regain its fluorescence. Thus, DHP could monitor the release and therapeutic effect of PTX through the fluorescence recovery of DiR. Remarkably, DHP can also be used as an in vivo probe for both fluorescent and photoacoustic imaging and at the same time achieves potent antitumor efficacy through chemo-photothermal combination therapy. This study provides novel insights into designing clinically translatable turn-on theranostic systems.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Corantes Fluorescentes/uso terapêutico , Glutationa/metabolismo , Nanopartículas/uso terapêutico , Neoplasias/terapia , Paclitaxel/uso terapêutico , Animais , Linhagem Celular Tumoral , Terapia Combinada , Hipertermia Induzida , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Imagem Óptica , Técnicas Fotoacústicas , Fototerapia , Nanomedicina TeranósticaAssuntos
Antígenos de Neoplasias/metabolismo , Carcinoma Hepatocelular/terapia , Imunoterapia/métodos , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia/epidemiologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Humanos , Imunoterapia/tendências , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologiaRESUMO
Studies of human genetics have implicated the role of SIRT1 in regulating obesity, insulin resistance, and longevity. These researches motivated the identification of novel SIRT1 activators. The current study aimed to investigate the potential efficacy of agrimol B, a polyphenol derived from Agrimonia pilosa Ledeb., on mediating SIRT1 activity and fat metabolism. Results showed that agrimol B significantly induced cytoplasm-to-nucleus shuttle of SIRT1. Furthermore, we confirmed that agrimol B dramatically inhibited 3T3-L1 adipocyte differentiation by reducing PPARγ, C/EBPα, FAS, UCP-1, and apoE expression. Consequently, adipogenesis was blocked by treatment of agrimol B at the early stage of differentiation in a dose-dependent manner, the IC50 value was determined as 3.35 ± 0.32 µM. Taken together, our data suggest a therapeutic potential of agrimol B on alleviating obesity, through modulation of SIRT1-PPARγ signal pathway.
Assuntos
Adipogenia/efeitos dos fármacos , Butanonas/farmacologia , PPAR gama/metabolismo , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , CamundongosRESUMO
Due to drug-induced potential congestive heart failure and irreversible dilated cardiomyopathies, preclinical evaluation of cardiac dysfunction is important to assess the safety of traditional or novel treatments. The embryos of Nelumbo nucifera Gaertner seeds are a homology of traditional Chinese medicine and food. In this study, we applied the real time cellular analysis (RTCA) Cardio system, which can real-time monitor the contractility of cardiomyocytes (CMs), to evaluate drug safety in rat neonatal CMs and human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). This study showed detailed biomechanical CM contractility in vitro, and provided insights into the cardiac dysfunctions associated with liensinine and neferine treatment. These effects exhibited dose and time-dependent recovery. Neferine showed stronger blocking effect in rat neonatal CMs than liensinine. In addition, the effects of liensinine and neferine were further evaluated on hiPS-CMs. Our study also indicated that both liensinine and neferine can cause disruption of calcium homeostasis. For the first time, we demonstrated the potential cardiac side effects of liensinine or neferine. While the same inhibition was observed on hiPS-CMs, more importantly, this study introduced an efficient and effective approach to evaluate the cardiotoxicity of the existing and novel drug candidates.
Assuntos
Benzilisoquinolinas/efeitos adversos , Medicamentos de Ervas Chinesas/efeitos adversos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Isoquinolinas/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Fenóis/efeitos adversos , Animais , Benzilisoquinolinas/toxicidade , Cardiotoxicidade , Células Cultivadas , Medicamentos de Ervas Chinesas/toxicidade , Feminino , Humanos , Isoquinolinas/toxicidade , Masculino , Fenóis/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
Endothelin-1 (ET-1) autocrine and paracrine signaling modulate cell proliferation of tumor cells by activating its receptors, endothelin A receptor (ETAR) and endothelin B receptor (ETBR). Dysregulation of ETAR activation promotes tumor development and progression. The potential of ETAR antagonists and the dual-ETAR and ETBR antagonists as therapeutic approaches are under preclinical and clinical studies. Salvianolic acid A (Sal A) is a hydrophilic polyphenolic derivative isolated from Salvia miltiorrhiza Bunge (Danshen), which has been reported as an anti-cancer and cardio-protective herbal medicine. In this study, we demonstrate that Sal A inhibits ETAR activation induced by ET-1 in both recombinant and endogenous ETAR expression cell lines. The IC50 values were determined as 5.7 µM in the HEK293/ETAR cell line and 3.14 µM in HeLa cells, respectively. Furthermore, our results showed that Sal A suppressed cell proliferation and extended the doubling times of multiple cancer cells, including HeLa, DU145, H1975, and A549 cell lines. In addition, Sal A inhibited proliferation of DU145 cell lines stimulated by exogenous ET-1 treatment. Moreover, the cytotoxicity and cardio-toxicity of Sal A were assessed in human umbilical vein endothelial cells (HUVEC) and Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which proved that Sal A demonstrates no cytotoxicity or cardiotoxicity. Collectively, our findings indicate that Sal A is a novel anti-cancer candidate through targeting ETAR.
Assuntos
Ácidos Cafeicos/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Lactatos/farmacologia , Neoplasias/patologia , Receptor de Endotelina A/metabolismo , Cardiotoxinas/toxicidade , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Reprodutibilidade dos TestesRESUMO
The increasing demand for safe and effective treatments of chronic pain has promoted the investigation of novel analgesic drugs. Some herbals have been known to be able to relieve pain, while the chemical basis and target involved in this process remained to be clarified. The current study aimed to find anti-nociceptive candidates targeting transient receptor potential ankyrin 1 (TRPA1), a receptor that implicates in hyperalgesia and neurogenic inflammation. In the current study, 156 chemicals were tested for blocking HEK293/TRPA1 ion channel by calcium-influx assay. Docking study was conducted to predict the binding modes of hit compound with TRPA1 using Discovery Studio. Cytotoxicity in HEK293 was conducted by Cell Titer-Glo assay. Additionally, cardiotoxicity was assessed via xCELLigence RTCA system. We uncovered that cardamonin selectively blocked TRPA1 activation while did not interact with TRPV1 nor TRPV4 channel. A concentration-dependent inhibitory effect was observed with IC50 of 454 nM. Docking analysis of cardamonin demonstrated a compatible interaction with A-967079-binding site of TRPA1. Meanwhile, cardamonin did not significantly reduce HEK293 cell viability, nor did it impair cardiomyocyte constriction. Our data suggest that cardamonin is a selective TRPA1 antagonist, providing novel insight into the target of its anti-nociceptive activity.
Assuntos
Chalconas/química , Chalconas/farmacologia , Dor Crônica/tratamento farmacológico , Simulação de Acoplamento Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Canais de Cátion TRPC/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Dor Crônica/metabolismo , Dor Crônica/patologia , Células HEK293 , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Sprague-Dawley , Canal de Cátion TRPA1 , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/metabolismo , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
Considering that as many as 80% of the anticancer drugs have their roots in natural products derived from traditional medicine, we examined compounds other than curcumin from turmeric (Curcuma longa) that could exhibit anticancer potential. Present study describes the isolation and characterization of another turmeric-derived compound, ß-sesquiphellandrene (SQP) that exhibits anticancer potential comparable to that of curcumin. We isolated several compounds from turmeric, including SQP, α-curcumene, ar-turmerone, α-turmerone, ß-turmerone, and γ-turmerone, only SQP was found to have antiproliferative effects comparable to those of curcumin in human leukemia, multiple myeloma, and colorectal cancer cells. While lack of the NF-κB-p65 protein had no effect on the activity of SQP, lung cancer cells that expressed p53 were more susceptible to the cytotoxic effect of SQP than were cells that lacked p53 expression. SQP was also found to be highly effective in suppressing cancer cell colony formation and inducing apoptosis, as shown by assays of intracellular esterase activity, plasma membrane integrity, and cell-cycle phase. SQP was found to induce cytochrome c release and activate caspases that lead to poly ADP ribose polymerase cleavage. SQP exposure was associated with downregulation of cell survival proteins such cFLIP, Bcl-xL, Bcl-2, c-IAP1, and survivin. Furthermore, SQP was found to be synergistic with the chemotherapeutic agents velcade, thalidomide and capecitabine. Overall, our results indicate that SQP has anticancer potential comparable to that of curcumin.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Curcuma , Curcumina/química , Curcumina/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Curcumina/isolamento & purificação , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Sesquiterpenos/isolamento & purificaçãoRESUMO
Cycloastragenol (CAG), a bioactive triterpenoid sapogenin isolated from the Chinese herbal medicine Radix astragali, was reported to promote the phosphorylation of extracellular signal-regulated protein kinase (ERK). Here we investigated the effect of CAG on adipogenesis. The image-based Nile red staining analyses revealed that CAG dose dependently reduced cytoplasmic lipid droplet in 3T3-L1 adipocytes with the IC50 value of 13.0 µM. Meanwhile, cytotoxicity assay provided evidence that CAG was free of injury on HepG2 cells up to 60 µM. In addition, using calcium mobilization assay, we observed that CAG stimulated calcium influx in 3T3-L1 preadipocytes with a dose dependent trend, the EC50 value was determined as 21.9 µM. There were proofs that elevated intracellular calcium played a vital role in suppressing adipocyte differentiation. The current findings demonstrated that CAG was a potential therapeutic candidate for alleviating obesity and hyperlipidemia.
Assuntos
Adipócitos/metabolismo , Cálcio/metabolismo , Citoplasma/metabolismo , Medicamentos de Ervas Chinesas/química , Metabolismo dos Lipídeos/fisiologia , Sapogeninas/farmacologia , Células 3T3 , Adipócitos/efeitos dos fármacos , Animais , Astrágalo/química , Astragalus propinquus , Citoplasma/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , CamundongosRESUMO
The transient receptor potential ankyrin 1 (TRPA1) cation channel is one of the well-known targets for pain therapy. Herbal medicine is a rich source for new drugs and potentially useful therapeutic agents. To discover novel natural TRPA1 agonists, compounds isolated from Chinese herbs were screened using a cell-based calcium mobilization assay. Out of the 158 natural compounds derived from traditional Chinese herbal medicines, carnosol was identified as a novel agonist of TRPA1 with an EC50 value of 12.46 µM. And the agonistic effect of carnosol on TRPA1 could be blocked by A-967079, a selective TRPA1 antagonist. Furthermore, the specificity of carnosol was verified as it showed no significant effects on two other typical targets of TRP family member: TRPM8 and TRPV3. Carnosol exhibited anti-inflammatory and anti-nociceptive properties; the activation of TRPA1 might be responsible for the modulation of inflammatory nociceptive transmission. Collectively, our findings indicate that carnosol is a new anti-nociceptive agent targeting TRPA1 that can be used to explore further biological role in pain therapy.
Assuntos
Abietanos , Analgésicos , Anti-Inflamatórios , Proteínas do Tecido Nervoso/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Abietanos/química , Abietanos/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Canais de Cálcio/genética , Células HEK293 , Humanos , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/genética , Oximas/farmacologia , Manejo da Dor , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/agonistas , Canais de Potencial de Receptor Transitório/genéticaRESUMO
Layered ternary oxide LiNixMnyCo1-x-yO2 is a promising cathode candidate for high-energy lithium-ion batteries (LIBs). However, the capacity of LIBs is significantly restricted by several factors, including the repeated dissolution-regeneration of the interfacial film at high temperatures, the dissolution of transition metals, and the increase of impedance. Herein, a new precycling strategy in suitable voltage scope at room temperature is proposed to construct a uniform, thermally stable, and insoluble cathode-electrolyte interface (CEI), which helps to maintain stable cycling performances at high temperatures. Specifically, after 5 precycles in the range of 3.85-4.3 V at room temperature, a CEI layer containing numerous inorganic components and oligomers is formed on the surface of LiNi0.6Mn0.2Co0.2O2. Subsequently, the harmful side reactions are effectively suppressed, endowing the cell with an excellent capacity retention of 84.67% after 50 cycles at 0.5C and 55 °C, much higher than that of 65.61% under the conventional film-forming process conditions. This work emphasizes the crucial role of the precycling strategy in regulating the characteristics of CEI layer on the surface of cathode electrode, opening up a new avenue for the high-temperature application of positive electrodes of LIBs.
RESUMO
To investigate the strengthening effects and mechanisms of bioaugmentation on the microbial remediation of uranium-contaminated groundwater via bioreduction coupled to biomineralization, two exogenous microbial consortia with reducing and phosphate-solubilizing functions were screened and added to uranium-contaminated groundwater as the experimental groups (group B, reducing consortium added; group C, phosphate-solubilizing consortium added). ß-glycerophosphate (GP) was selected to stimulate the microbial community as the sole electron donor and phosphorus source. The results showed that bioaugmentation accelerated the consumption of GP and the proliferation of key functional microbes in groups B and C. In group B, Dysgonomonas, Clostridium_sensu_stricto_11 and Clostridium_sensu_stricto_13 were the main reducing bacteria, and Paenibacillus was the main phosphate-solubilizing bacteria. In group C, the microorganisms that solubilized phosphate were mainly unclassified_f_Enterobacteriaceae. Additionally, bioaugmentation promoted the formation of unattached precipitates and alleviated the inhibitory effect of cell surface precipitation on microbial metabolism. As a result, the formation rate of U-phosphate precipitates and the removal rates of aqueous U(VI) in both groups B and C were elevated significantly after bioaugmentation. The U(VI) removal rate was poor in the control group (group A, with only an indigenous consortium). Propionispora, Sporomusa and Clostridium_sensu_stricto_11 may have played an important role in the removal of uranium in group A. Furthermore, the addition of a reducing consortium promoted the reduction of U(VI) to U(IV), and immobilized uranium existed in the form of U(IV)-phosphate and U(VI)-phosphate precipitates in group B. In contrast, U was present mainly as U(VI)-phosphate precipitates in groups A and C. Overall, bioaugmentation with an exogenous consortium resulted in the rapid removal of uranium from groundwater and the formation of U-phosphate minerals and served as an effective strategy for improving the treatment of uranium-contaminated groundwater in situ.
Assuntos
Água Subterrânea , Urânio , Fosfatos/metabolismo , Urânio/metabolismo , Oxirredução , Bactérias/metabolismo , Biodegradação AmbientalRESUMO
High reactive oxygen species (ROS) levels provide a therapeutic opportunity to eradicate cancer stem cells (CSCs), a population of cells responsible for tumorigenesis, progression, metastasis, and recurrence. However, enhanced antioxidant systems in this population of cells attenuate ROS-inducing therapies. Here, we developed a nanoparticle-assisted combination therapy to eliminate CSCs by employing photodynamic therapy (PDT) to yield ROS while disrupting ROS defense with glutaminolysis inhibition. Specifically, we leveraged an oleic acid-hemicyanine conjugate (CyOA) as photosensitizer, a new entity molecule HYL001 as glutaminolysis inhibitor, and a biocompatible folic acid-hydroxyethyl starch conjugate (FA-HES) as amphiphilic surfactant to construct cellular and mitochondrial hierarchical targeting nanomedicine (COHF NPs). COHF NPs inhibited glutaminolysis to reduce intracellular ROS scavengers, including glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH), and to blunt oxidative phosphorylation (OXPHOS) for oxygen-conserved PDT. Compared to COLF NPs without glutaminolysis inhibitor, COHF NPs exhibited higher phototoxicity to breast cancer stem cells (BCSCs) both in vitro and in vivo. More importantly, we corroborated that marketed glutaminolysis inhibitors, such as CB839 and V9302, augment the clinically used photosensitizer (Hiporfin) for BCSCs elimination. This study develops a potent CSCs targeting strategy by combining glutaminolysis inhibition with PDT and provides significant implications for cancer therapy.
Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio , Terapia Combinada , Glutationa , Linhagem Celular Tumoral , Nanopartículas/química , Neoplasias/tratamento farmacológicoRESUMO
Cuproptosis-based cancer nanomedicine has received widespread attention recently. However, cuproptosis nanomedicine against pancreatic ductal adenocarcinoma (PDAC) is severely limited by cancer stem cells (CSCs), which reside in the hypoxic stroma and adopt glycolysis metabolism accordingly to resist cuproptosis-induced mitochondria damage. Here, we leverage hyperbaric oxygen (HBO) to regulate CSC metabolism by overcoming tumor hypoxia and to augment CSC elimination efficacy of polydopamine and hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@PH NPs). Mechanistically, while HBO and CuET@PH NPs inhibit glycolysis and oxidative phosphorylation, respectively, the combination of HBO and CuET@PH NPs potently suppresses energy metabolism of CSCs, thereby achieving robust tumor inhibition of PDAC and elongating mice survival importantly. This study reveals novel insights into the effects of cuproptosis nanomedicine on PDAC CSC metabolism and suggests that the combination of HBO with cuproptosis nanomedicine holds significant clinical translation potential for PDAC patients.
RESUMO
Coating and single crystal are two common strategies for cobalt-free nickel-rich layered oxides to solve its poor rate performance and cycle stability. However, the action mechanism of different modification protocols to suppress the attenuation are unclear yet. Herein, the Li2MoO4 layer-coated polycrystalline LiNi0.9Mn0.1O2 (1.0 %-Mo + NM91) and single crystal LiNi0.9Mn0.1O2 (SC-NM91) are prepared to investigate this difference, respectively. By focusing on the interior of particles, the relationship between structure evolution and electrochemical behavior is systematically studied, and the intrinsic mechanism of coating/single-crystallization modifications on suppressing the attenuation is clarified. The results show that microcracks in LiNi0.9Mn0.1O2 (NM91) are the main culprit leading to the rate capability decay, and the coating can effectively prevent the radial diffusion of microcracks from the center to surface, inhibiting the generation of surface side reactions. Therefore, the coating has a more advantage in improving the rate performance at 5.0C, the discharge capacity of 1.0 %-Mo + NM91 (130.6 mAh/g) is 7.9 % higher than that of SC-NM91 (121.0 mAh/g). In contrast, the single-crystallization can effectively prevent the formation of intergranular cracks arising from the anisotropic stress in NM91, which causes the severe cycle degradation. Correspondingly, the grain boundary-free SC-NM91 shows superior cyclability. The capacity retention rate of SC-NM91 (80.8 %) at 0.2C after 100cycles is 6.3 % higher than that of 1.0 %-Mo + NM91 (74.5 %). This work concludes the effect difference of different modification methods on enhancing the electrochemical performance, which provides theoretical and technical guidance for the optimized and targeted modification design in the cobalt-free high nickel cathode materials.
RESUMO
Aberrant tumor mechanical microenvironment (TMME), featured with overactivated cancer-associated fibroblasts (CAFs) and excessive extracellular matrix (ECM), severely restricts penetration and accumulation of cancer nanomedicines, while mild-hyperthermia photothermal therapy (mild-PTT) has been developed to modulate TMME. However, photothermal agents also encounter the barriers established by TMME, manifesting in limited penetration and heterogeneous distribution across tumor tissues and ending with attenuated efficiency in TMME regulation. Herein, it is leveraged indocyanine green (ICG)-loaded soft nanogels with outstanding deformability, for efficient tumor penetration and uniform distribution, in combination with mild-PTT to achieve potent TMME regulation by inhibiting CAFs and degrading ECM. As a result, doxorubicin (DOX)-loaded stiff nanogels gain greater benefits in tumor penetration and antitumor efficacy than soft counterparts from softness-mediated mild-PTT. This study reveals the crucial role of nanomedicine mechanical properties in tumor distribution and provides a novel strategy for overcoming the barriers of solid tumors with soft deformable nanogels.
Assuntos
Doxorrubicina , Hipertermia Induzida , Verde de Indocianina , Nanomedicina , Microambiente Tumoral , Nanomedicina/métodos , Animais , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Hipertermia Induzida/métodos , Doxorrubicina/administração & dosagem , Verde de Indocianina/administração & dosagem , Nanogéis , Humanos , Terapia Fototérmica/métodos , Modelos Animais de Doenças , Neoplasias/terapia , Linhagem Celular Tumoral , Fibroblastos Associados a Câncer/metabolismoRESUMO
Giant salvinia (Salvinia molesta) is one of the most noxious invasive species in the world. Our bioactivity-guided fractionation of ethanol extract of giant salvinia led to the isolation of 50 compounds. Of the six new compounds (1-6), salviniol (1) is a rare abietane diterpene with a new ferruginol-menthol coupled skeleton and both salviniside I (2) and salviniside II (3) are novel benzofuran glucose conjugates with unique 10-membered macrodiolide structures. Sixteen abietane diterpenes (1, 7-17, and 19-22) demonstrated in vitro activities against human tumor cells, and 7 and 8 showed selective cytotoxicity to tumor cells over normal cells.
Assuntos
Abietanos/química , Abietanos/toxicidade , Antineoplásicos Fitogênicos/toxicidade , Benzofuranos/química , Glucosídeos/química , Macrolídeos/química , Extratos Vegetais/toxicidade , Traqueófitas/química , Abietanos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Benzofuranos/isolamento & purificação , Benzofuranos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/toxicidade , Glucosídeos/isolamento & purificação , Glucosídeos/toxicidade , Humanos , Espécies Introduzidas , Macrolídeos/isolamento & purificação , Macrolídeos/toxicidade , Espectroscopia de Ressonância Magnética , Mentol/química , Conformação Molecular , Traqueófitas/metabolismoRESUMO
Phytochemical study on the constituents of the heartwood of Pterocarpus soyauxii led to the isolation of five new isoflavonoids and one new 3-arylcoumarin, pterosonins A-F (1-6), together with 17 known analogues, among which 8, 9, and 18 were reported as natural products for the first time. Structure elucidation was achieved by way of spectroscopic measurements as well as by comparison with literature data. Only Compound 6 showed potent cytotoxicity against human non-small cell lung cancer (A549), pancreatic cancer (Panc-28), and colon carcinoma (HCT-116) cells with GI50 values at 7.39, 25, and 19.17 µM, respectively; the other isolates showed no cytotoxicity against the above tested cell lines with GI50 values > 50 µM.