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For metastatic prostate cancer, androgen deprivation therapy (ADT) is the key strategy to control the disease. However, after 18-24 months of treatment, most patients will progress from metastatic hormone-sensitive prostate cancer (mHSPC) to metastatic castration-resistant prostate cancer (mCRPC) even with ADT. Once patients enter into mCRPC, they face with significant declines in quality of life and a dramatically reduced survival period. Thus, doublet therapy, which combines ADT with new hormone therapy (NHT) or ADT with docetaxel chemotherapy, substitutes ADT alone and has become the "gold standard" for the treatment of mHSPC. In recent years, triplet therapy, which combines ADT with NHT and docetaxel chemotherapy, has also achieved impressive effects in mHSPC. This article provides a comprehensive review of the recent applications of the triplet therapy in the field of mHSPC.
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ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba leaf and seed have been traditionally used in ancient China for the treatment of cough and asthma. However, there is limited literature available on the anti-COPD effects and mechanisms of Ginkgo biloba. AIMS OF THE STUDY: The aim of this study was to comprehensively investigate the therapeutic potential of ginkgo extracts in COPD through a combination of in vivo and in vitro functional experiments. Transcriptomic analyses were also employed to uncover novel molecular mechanisms underlying the therapeutic effects of ginkgetin in COPD. MATERIALS AND METHODS: The therapeutic efficacy of ginkgo extracts was assessed in a COPD model. The anti-inflammatory effects of ginkgetin and its underlying molecular mechanisms were examined in A549 cells treated with cigarette smoke extract (CSE). Additionally, transcriptomic analyses were conducted to identify novel molecular pathways influenced by ginkgetin. These findings were further validated using quantitative real-time polymerase chain reaction (qPCR) and Western blot techniques. RESULTS: The ethyl acetate extract of Ginkgo biloba L. seeds and ginkgetin treatment significantly reduced cytokine production in COPD mice. Following drug administration, lung function improved in different groups. The transcriptome data strongly supports the inhibitory effect of ginkgetin on CSE-induced inflammation through the downregulation of the c/EBPß signaling pathway and subsequent inhibition of CCL2 expression. CONCLUSION: Our results demonstrate that ginkgetin, one of the biflavones found in Ginkgo biloba, exhibits inhibitory effects on smoke-induced airway inflammation. This effect is achieved through the downregulation of the c/EBPß signaling pathway and the reduction of CCL2 expression.
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Biflavonoides , Quimiocina CCL2 , Regulação para Baixo , Ginkgo biloba , Doença Pulmonar Obstrutiva Crônica , Transdução de Sinais , Animais , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Biflavonoides/farmacologia , Biflavonoides/uso terapêutico , Humanos , Transdução de Sinais/efeitos dos fármacos , Ginkgo biloba/química , Regulação para Baixo/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Camundongos , Masculino , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fumaça/efeitos adversos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Células A549 , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Extrato de GinkgoRESUMO
Tyrosine kinase inhibitors (TKIs) are commonly used in tumor targeting therapy. However, the rapid analysis of TKIs remains a significant challenge, especially in complex biological fluid environments. In this work, we have constructed a supramolecular fluorescence sensor array based on a cucurbituril-dye host-guest complex. The binding affinity between the three complexes and each TKI is different, resulting in different cross-response signals of the complexes to the fluorescence of each TKI. Combined with linear discriminant analysis(LDA), five kinds of TKIs can be well identified. The supramolecular fluorescence sensor array could accurately identify and distinguish the five TKIs in water and could classify mixtures containing different concentrations of TKIs in serum. The concentration and Factor 1 exhibited a good linear relationship and the detection limit (LOD) was as low as 10-7 mol L-1. The method has good reproducibility and stability. In addition, the differentiation of four clinical concentrations of first-generation TKIs further validated the potential application of arrays in drug monitoring. Finally, our proposed array enabled drug imaging in living cells. Our array platform provided the foundation for the rapid and easy monitoring of 4-anilinoquinazoline TKIs.
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Monitoramento de Medicamentos , Reprodutibilidade dos Testes , Diferenciação Celular , Análise DiscriminanteRESUMO
Objective: Our previous studies have demonstrated that Plasmodium immunotherapy (infection) has antitumor effects in mice. However, as a new form of immunotherapy, this therapy has a weakness: its specific killing effect on tumor cells is relatively weak. Therefore, we tested whether Plasmodium immunotherapy combined with gemcitabine (Gem), a representative chemotherapy drug, has synergistic antitumor effects. Methods: We designed subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) models to test the antitumor effect of Plasmodium chabaudi ASS (Pc) infection in combination with Gem treatment and explored its underlying mechanisms. Results: We found that both Pc infection alone and Gem treatment alone significantly inhibited tumor growth in the subcutaneous model, and combination therapy was more effective than either monotherapy. Monotherapy only tended to prolong the survival of tumor-bearing mice, while the combination therapy significantly extended the survival of mice, indicating a significant synergistic effect of the combination. In the mechanistic experiments, we found that the combination therapy significantly upregulated E-cadherin and downregulated Snail protein expression levels, thus inhibiting epithelial-mesenchymal transition (EMT) of tumor cells, which may be due to the blockade of CXCR2/TGF-ß-mediated PI3K/Akt/GSK-3ß signaling pathway. Conclusion: The combination of Pc and Gem plays a synergistic role in inhibiting tumor growth and metastasis, and prolonging mice survival in murine lung cancer models. These effects are partially attributed to the inhibition of EMT of tumor cells, which is potentially due to the blockade of CXCR2/TGF-ß-mediated PI3K/Akt/GSK-3ß/Snail signaling pathway. The clinical transformation of Plasmodium immunotherapy combined with Gem for lung cancer is worthy of expectation.
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The noble metal-based electrochemical sensor design for efficient and stable formaldehyde(FA) detection is important ongoing research. In this paper, PtPd/Nafion/GCE is prepared by electrochemical cyclic voltammetry deposition method based on electrodepositing nanostructured platinum (Pt)-palladium (Pd) nanoparticles in Nafion film-coated glassy carbon electrode (GCE). The influence of deposition parameters and chemical composition (atomic ratio of Pt and Pd) on the electrochemical behaviour of PtPd/Nafion/GCE has been investigated. PtPd/Nafion/GCE displays a remarked electrocatalytic activity for the oxidation of FA and exhibits a linear relationship in the range of 10-5000µM, with a detection limit of 3.3µM in 0.1 M H2SO4solution. It is proved that the detection performance of PtPd/Nafion/GCE electrode is valuable for further application with low detection limit, wide linear range, favourable selectivity and high response.
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The simultaneous detection of multiple quaternary ammonium pesticides (QAPs) in water is a challenge due to their high solubility in water and similar structures. In this paper, we have developed a quadruple-channel supramolecular fluorescence sensor array for the simultaneous analysis of five QAPs, including paraquat (PQ), diquat (DQ), difenzoquat (DFQ), mepiquat (MQ), and chlormequat (CQ). Not only were QAP samples of different concentrations (10, 50, and 300 µM) in water distinguished with 100% accuracy but also single QAP and binary QAP mixed samples (DFQ-DQ) were sensitively quantified. Our experimental interference study confirmed that the developed array has good anti-interference ability. The array can quickly identify five QAPs in river and tap water samples. In addition, it also qualitatively detected QAP residues in Chinese cabbage and wheat seedlings extract. This array has rich output signals, low cost, easy preparation, and simple technology, demonstrating great potential in environmental analysis.
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Compostos de Amônio , Praguicidas , Praguicidas/análise , Fluorescência , Diquat , ÁguaRESUMO
The present single-center retrospective clinical real-world study aimed to assess the feasibility and outcomes of patients who underwent simultaneous prostate biopsy and general urological surgeries. The medical records of 49 patients who underwent prostate biopsy and general urological surgeries simultaneously from October 2016 to June 2019 were retrospectively reviewed. Patients' outcomes were evaluated 3 days, 1 month and 6 months after biopsy. Of the 49 biopsy cases, 41 were treated by transurethral prostatectomy, two by ureteroscopic lithotripsy, two by laparoscopic renal cyst decortication, two by cystostomy and two by ureteral stent extraction. The overall detection rate of clinically significant prostate cancer was 22.4%. The rate in patients with a prostate imaging reporting and data system (PI-RADS) score of 4-5 was 100%, while in cases with a PI-RADS score of <3 it was 7.1%. Postoperative complications within 3 days included hematuria in 39 (79.6%) cases, fever in three (6.1%) cases and hematochezia in two (4.1%) cases. There was no significant difference in the incidence of hematuria between the transrectal and transperineal approaches; however, the overall incidence of complications was significantly reduced after switching from a transrectal approach to a transperineal approach. No complications were observed after 1 or 6 months. In summary, combining simultaneous prostate biopsy to general urological surgeries is a safe and feasible approach. The transperineal approach has a lower incidence of complications. This method may benefit certain patients who are concurrently undergoing general urological surgeries and are under suspicion of prostate cancer in real-world clinical practice.
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This article described a patient with metastatic bladder cancer (mBC) who was successfully treated with nab-paclitaxel plus sintilimab. Localized muscle-invasive bladder cancer (MIBC) was discovered in a 56-year-old man who received radical cystectomy and platinum-based adjuvant chemotherapy. Eleven months after cystectomy, this patient developed numerous hepatic and pelvic metastases and progressed to mBC. The patient was given an anti-PD-1 antibody (sintilimab 200mg, q3w) in combination with Nab-paclitaxel (100mg, qw) for mBC. Complete remission (CR) was achieved after nine cycles of therapy, and the patient had no severe side effects during the treatment. The disease remained in CR after 41 months of follow-up. This case suggests that nab-paclitaxel combined with sintilimab is a safe and effective option in treatment of mBC.
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Immune checkpoint blockade therapy (ICB) is ineffective against cold tumors and, although it is effective against some hot tumors, drug resistance can occur. We have developed a Plasmodium immunotherapy (PI) that can overcome these shortcomings. However, the specific killing effect of PI on tumor cells is relatively weak. Radiotherapy (RT) is known to have strong specific lethality to tumor cells. Therefore, we hypothesized that PI combined with RT could produce synergistic antitumor effects. We tested our hypothesis using orthotopic and subcutaneous models of mouse glioma (GL261, a cold tumor) and a subcutaneous model of mouse non-small cell lung cancer (NSCLC, LLC, a hot tumor). Our results showed that, compared with each monotherapy, the combination therapy more significantly inhibited tumor growth and extended the life span of tumor-bearing mice. More importantly, the combination therapy could cure approximately 70 percent of glioma. By analyzing the immune profile of the tumor tissues, we found that the combination therapy was more effective in upregulating the perforin-expressing effector CD8+ T cells and downregulating the myeloid-derived suppressor cells (MDSCs), and was thus more effective in the treatment of cancer. The clinical transformation of PI combined with RT in the treatment of solid tumors, especially glioma, is worthy of expectation.
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Carcinoma Pulmonar de Células não Pequenas , Glioma , Neoplasias Pulmonares , Plasmodium , Camundongos , Animais , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Glioma/terapia , Glioma/patologia , Imunoterapia/métodosRESUMO
Benzene, toluene and pyridine are widely used as essential raw materials in industry and laboratory research, with stringent purity requirements. Herein, we show that solid double-cavity host nor-seco-cucurbit[10]uril (ns-Q[10]) functions as an efficient adsorption separator for pyridine; benzene and toluene can be obtained in >99.9 % purity by this method. Thermal removal of pyridine from ns-Q[10]â Py2 allows 10 separation cycles without erosion of performance. The geometry of the ns-Q[10]â Py2 ternary complex was established by single-crystal X-ray diffraction methods. The ns-Q[10] cage facilitates the removal of pyridine from toluene and benzene, with >99.9 % purity for the separated compounds.
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A supramolecular polymer was developed through the encapsulation of polypyrrole by cucurbit[6]uril (PPy@Q[6]), which was employed as the electrode material to improve the capacitor ability of conductive polypyrrole. In the optimized ratio of 2 : 1 (CPPy : CQ[6]), the capacitor properties of the supramolecular material were evaluated, and a high specific capacitance of 414 F g-1 at 10 mV s-1 was obtained, which was 3.1 times higher than that of pure polypyrrole (132 F g-1). A comprehensive analysis suggested that the capacitance performances should be relevant to the component, surface area, and pore volume of the materials. The addition of 0.4 M Fe2(SO4)3 into the electrolyte provided a surprising specific capacitance of 3530 F g-1 on the cucurbituril-encapsulated polypyrrole electrode material, with a high energy density of 707 W h kg-1 at a power density of 32 000 W kg-1 and a current density of 8 A g-1. The 81.6% capacitance retention maintained after 1000 cycles revealed the acceptable cycling capacity of the proposed supramolecular supercapacitor system, which demonstrated good performance even at a low temperature of -20 °C.
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In order to prevent and control the effects of pesticide residues on human health and the ecological environment, the rapid, highly sensitive, and selective detection of multiple pesticide residues has become an urgent problem to be solved. Herein, a lab-on-a-molecule probe based on a host-guest complex (ThT@Q[8] probe) has been developed to simultaneously analyze multiple aromatic pesticides under single wavelength excitation, such as fuberidazole, thiabendazole, carbendazim, thidiazuron, and tricyclazole. The fluorescence titration spectra of the ThT@Q[8] probe with the five pesticides mentioned above showed that the fluorescence intensity exhibited a good linear correlation with the pesticide concentration and the limit of detection was as low as 10-7 M. Because the ThT@Q[8] probe exhibits diverse fluorescence color changes to the five pesticides studied under a 365 nm ultraviolet lamp, we fabricated a single probe used to detect multiple analytes in the RGB triple channel by extracting the RGB variations. Principal component analysis and linear discriminant analysis proved that the ThT@Q[8] probe can recognize and distinguish five pesticides and can be applied at different concentrations. In real samples, the ThT@Q[8] probe recognized and distinguished five pesticides in tap water and Huaxi River water. The 1H NMR spectra results proved that a charge-transfer complex of ThT and pesticides in the Q[8] cavity may be formed. Moreover, we selected a test strip as a carrier to detect pesticides. The results indicate it can be used to quickly and conveniently detect different pesticides due to the rapid color change. Besides, the ThT@Q[8] probe has good cell permeability and can be used to detect pesticide residues in living cells. This work has laid the foundation for the qualitative and quantitative multitarget detection of pesticide residues.
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Resíduos de Praguicidas , Praguicidas , Humanos , Sondas Moleculares/análise , Resíduos de Praguicidas/análise , Praguicidas/análise , Espectrometria de Fluorescência/métodos , Água/análiseRESUMO
PURPOSE: The purpose of this study is to explore the value of combining bpMRI and clinical indicators in the diagnosis of clinically significant prostate cancer (csPCa), and developing a prediction model and Nomogram to guide clinical decision-making. METHODS: We retrospectively analyzed 530 patients who underwent prostate biopsy due to elevated serum prostate specific antigen (PSA) levels and/or suspicious digital rectal examination (DRE). Enrolled patients were randomly assigned to the training group (n = 371, 70%) and validation group (n = 159, 30%). All patients underwent prostate bpMRI examination, and T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) sequences were collected before biopsy and were scored, which were respectively named T2WI score and DWI score according to Prostate Imaging Reporting and Data System version 2 (PI-RADS v.2) scoring protocol, and then PI-RADS scoring was performed. We defined a new bpMRI-based parameter named Total score (Total score = T2WI score + DWI score). PI-RADS score and Total score were separately included in the multivariate analysis of the training group to determine independent predictors for csPCa and establish prediction models. Then, prediction models and clinical indicators were compared by analyzing the area under the curve (AUC) and decision curves. A Nomogram for predicting csPCa was established using data from the training group. RESULTS: In the training group, 160 (43.1%) patients had prostate cancer (PCa), including 128 (34.5%) with csPCa. Multivariate regression analysis showed that the PI-RADS score, Total score, f/tPSA, and PSA density (PSAD) were independent predictors of csPCa. The prediction model that was defined by Total score, f/tPSA, and PSAD had the highest discriminatory power of csPCa (AUC = 0.931), and the diagnostic sensitivity and specificity were 85.1% and 87.5%, respectively. Decision curve analysis (DCA) showed that the prediction model achieved an optimal overall net benefit in both the training group and the validation group. In addition, the Nomogram predicted csPCa revealed good estimation when compared with clinical indicators. CONCLUSION: The prediction model and Nomogram based on bpMRI and clinical indicators exhibit a satisfactory predictive value and improved risk stratification for csPCa, which could be used for clinical biopsy decision-making.
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Postoperative recurrence causes a high mortality rate among patients with hepatocellular carcinoma (HCC). The current study aimed to determine the effects of Plasmodium infection on HCC metastasis and recurrence. The antitumor effects of Plasmodium infection were determined using two murine orthotopic HCC models: The nonresection model and the resection model. Tumour tissues derived from tumourbearing mice treated with or without Plasmodium infection were harvested 15 days posttumour inoculation. The expression levels of biomarkers related to epithelialmesenchymal transition (EMT) and molecules associated with CCchemokine receptor 10 (CCR10)mediated PI3K/Akt/GSK3ß/Snail signalling were identified using reverse transcriptionquantitative PCR and western blotting. The results demonstrated that Plasmodium infection significantly suppressed the progression, recurrence and metastasis of HCC in the two mouse models. The expression levels of Ecadherin were significantly higher in the Plasmodiumtreated group compared with that in the control group, whereas the expression levels of Vimentin and Snail were significantly lower in the Plasmodiumtreated group. Furthermore, Plasmodium infection inhibited the activation of Akt and GSK3ß in the tumour tissues by downregulating the expression levels of CCR10 and subsequently suppressing the accumulation of Snail, which may contribute to the suppression of EMT and the prevention of tumour recurrence and metastasis. In conclusion, the results of the present study demonstrated that Plasmodium infection inhibited the recurrence and metastasis and improved the prognosis of HCC by suppressing CCR10mediated PI3K/Akt/GSK3ß/Snail signalling and preventing the EMT. These results may be important for the development of novel therapies for HCC recurrence and metastasis, especially for patients in the perioperative period.
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Carcinoma Hepatocelular/prevenção & controle , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/prevenção & controle , Malária , Animais , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neoplasias Hepáticas/genética , Malária/imunologia , Malária/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Fosfatidilinositol 3-Quinases/metabolismo , Receptores CCR10 , Transdução de Sinais , Vimentina/metabolismoRESUMO
We previously reported that Plasmodium infection promotes antitumor immunity in a murine Lewis lung cancer. In this study, we investigated the effects of Plasmodium infection on the tumor inhibition and antitumor CD8+ T cell responses in a murine triple negative breast cancer (TNBCA) model. The results showed that Plasmodium infection significantly inhibited tumor growth, and increased the survival rate of the tumor-bearing mice. Both effector and memory CD8+ T cells were increased in peripheral blood and tumor-draining lymph node (DLN) in the infected mice. The co-stimulatory (CD40L, GITR and OX-40) and co-inhibitory (PD-1, CTLA-4, TIM-3, LAG3) immune checkpoints were up-regulated on CD8+ T cells in infected mice. Importantly, Py induced remarkable effects on the infiltration of CD8+ T cells in the tumor and granzym B+ CD8+ T cells in tumor-bearing mice while not in tumor-free mice. In summary, the results suggested that the effects of Plasmodium infection on murine 4T1 breast cancer might be related to the induction of CD8+ T cell-mediated antitumor immune responses. This finding may provide a novel strategy for the treatment of triple negative breast cancer.
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Linfócitos T CD8-Positivos/imunologia , Imunidade Celular/imunologia , Malária/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Carga Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias de Mama Triplo Negativas/prevenção & controleRESUMO
In order to model various aspects of Huntington's disease (HD) pathology, in particular protein spread, we administered adeno-associated virus (AAV) expressing green fluorescent protein (GFP) or GFP coupled to HTT-Exon1 (19Q or 103Q) to the central nervous system of adult wild-type (WT) mice and non-human primates. All animals underwent behavioral testing and post-mortem analyses to determine the long-term consequences of AAV injection. Both mice and non-human primates demonstrated behavioral changes at 2-3 weeks post-surgery. In mice, these changes were absent after 3 months while in non-human primates, they persisted in the majority of tested animals. Post-mortem analysis revealed that spreading of the aggregates was limited, although the virus did spread between synaptically-connected brain regions. Despite circumscribed spreading, the presence of mHTT generated changes in endogenous huntingtin (HTT) levels in both models. Together, these results suggest that viral expression of mHTTExon1 can induce spreading and seeding of HTT in both mice and non-human primates.
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Dependovirus/genética , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Agregação Patológica de Proteínas , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Proteínas de Fluorescência Verde/genética , Humanos , Macaca mulatta , Masculino , Camundongos Endogâmicos C57BLRESUMO
Cucurbit[10]uril {Q[10]} has the largest portal size and cavity in the series of Q[n] (n = 5-10) molecules. In contrast to its rich host-guest chemistry, its coordination chemistry is underdeveloped with only limited metal ions being investigated so far. In this work, we initiated the study of Q[10] complexes with Th(iv) and U(vi) ions in HCl solutions via a self-assembly approach. The coordination of Th(iv) ions with Q[10] led to the formation of a compound, {Th4(Cl)16(H2O)20(Q[10])}·nH2O (Q[10]-Th), with a unique nano-tubular structure, while U(vi) ions facilitated the formation of a compound, [(UO2)2(Cl)4(H2O)6]·(Q[10])2·HCl·nH2O (Q[10]-U), with a Q[10]-based supramolecular framework structure via intermolecular outer-surface and second-shell interactions. The structural and spectroscopic aspects of the two compounds together with their optical and thermal properties have been investigated. The successful preparation and characterization of the first two Q[10] compounds with Th(iv)/U(vi) ions highlighted the potential for further exploration of Q[10] coordination chemistry with actinide ions.
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Targeted delivery of antitumor drugs is especially important for tumor therapy. Cell-penetrating peptides (CPPs) have been shown to be very effective drug carriers for tumor therapy. However, most CPPs lack tumor cell specificity. Here, we identified a highly efficient CPP, CAT, from the newly identified buffalo-derived cathelicidin family, which exhibits a preferential binding capacity for multiple tumor cell lines and delivers carried drug molecules into cells. CAT showed an approximately threefold to sixfold higher translocation efficiency than some reported cell-penetrating antimicrobial peptides, including the well-known classical CPP TAT. Moreover, the delivery efficiency of CAT was greater in a variety of tested tumor cells than in normal cells, especially for the human hepatoma cell line SMMC-7721, for which delivery was 7 times more efficient than the normal human embryonic lung cell line MRC-5, according to fluorescent labeling experiment results. CAT was conjugated to the Momordica charantia-derived type-I ribosome-inactivating protein MAP 30, and the cytotoxicity of the MAP 30-CAT fusion protein in the tumor cell line SMMC-7721 was significantly enhanced compared with that of the unconjugated MAP 30. The IC50 value of MAP 30-CAT was approximately 83 times lower than the IC50 value of the original MAP 30. Interestingly, the IC50 value of MAP 30 alone for MRC-5 was approximately twofold higher than the value for SMMC-7721, showing a small difference. However, when MAP 30 was conjugated to CAT, the difference in IC50 values between the two cell lines was significantly increased by 38-fold. The results of the flow cytometric detection of apoptosis revealed that the increase in cytotoxicity after CAT conjugation was mainly caused by the increased induction of apoptosis by the fusion protein. These results suggest that CAT, as a novel tumor-homing CPP, has great potential in drug delivery applications in vivo and will be beneficial to the development of tumor therapeutics.
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Peptídeos Catiônicos Antimicrobianos/metabolismo , Antineoplásicos/farmacologia , Animais , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Búfalos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Portadores de Fármacos/isolamento & purificação , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , CatelicidinasRESUMO
BACKGROUND: A major challenge in the development of effective cancer immunotherapy is the ability of tumors and their microenvironment to suppress immune cells through immunosuppressive cells such as myeloid -derived suppressor cells and regulatory T cells. We previously demonstrated that Plasmodium infection promotes innate and adaptive immunity against cancer in a murine Lewis lung cancer model but its effects on immunosuppressive cells in the tumor microenvironment are unknown. METHODS: Whole Tumors and tumor-derived sorted cells from tumor-bearing mice treated with or without plasmodium infected red blood cells were harvested 17 days post tumor implantation and analyzed using QPCR, western blotting, flow cytometry, and functional assays. Differences between groups were analyzed for statistical significance using Student's t-test. RESULTS: Here we found that Plasmodium infection significantly reduced the proportions of MDSCs and Tregs in the lung tumor tissues of the treated mice by downregulating their recruiting molecules and blocking cellular activation pathways. Importantly, CD8+ T cells isolated from the tumors of Plasmodium-treated mice exhibited significantly higher levels of granzyme B and perforin and remarkably lower levels of PD-1. CONCLUSION: We reveal for the first time, the effects of Plasmodium infection on the expansion and activation of MDSCs and Tregs with a consequent elevation of CD8+T cell-mediated cytotoxicity within the tumor microenvironment and hold great promise for the development of effective immunotherapeutic strategies.
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Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/terapia , Terapia de Imunossupressão/métodos , Malária/imunologia , Células Supressoras Mieloides/imunologia , Plasmodium yoelii/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Feminino , Granzimas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Citotóxicas Formadoras de Poros/imunologia , Receptor de Morte Celular Programada 1/imunologiaRESUMO
The authors wish to make the following correction to their paper [...].