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The proliferation and differentiation of skeletal muscle satellite cells is a complex physiological process involving various transcription factors and small RNA molecules. This study aimed to understand the regulatory mechanisms underlying these processes, focusing on interferon-related development factor 2 (IFRD2) as a target gene of miRNA-2400 in bovine skeletal MuSCs (MuSCs). IFRD2 was identified as a target gene of miRNA-2400 involved in regulating the proliferation and differentiation of bovine skeletal MuSCs. Our results indicate that miR-2400 can target binding the 3'UTR of IFRD2 and inhibit its translation. mRNA and protein expression levels of IFRD2 increased significantly with increasing days of differentiation. Moreover, overexpression of the IFRD2 gene inhibited proliferation and promoted differentiation of bovine MuSCs. Conversely, the knockdown of the gene had the opposite effect. Overexpression of IFRD2 resulted in the inhibition of ERK1/2 phosphorylation levels in bovine MuSCs, which in turn promoted differentiation. In summary, IFRD2, as a target gene of miR-2400, crucially affects bovine skeletal muscle proliferation and differentiation by precisely regulating ERK1/2 phosphorylation.
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BACKGROUND: In 2021, China had a population of 264·01 million individuals over the age of 60, indicating a high prevalence of chronic diseases. Among older adults, physical inactivity (PI) is a significant risk factor for chronic diseases. However, few studies have been conducted on the correlation of physical activity (PA) with the economic status, geography and chronic disease risks in Chinese elderly. The objectives of this study were to better understand the distribution of PA among older adults in China and its relationship with economic status, geography, and chronic disease risks. METHODS: This study utilized data from the China Longitudinal Aging Social Survey (CLASS) in 2020, post-COVID-19. The study employed a stratified, multistage, probabilistic sampling approach and included 11,396 adults over the age of 59 from 28 provinces in China. Data on demographics, the duration and intensity of PA, history of diseases and personalized factors influencing PA were collected via structured interviews by researchers. In this study, we conducted a comprehensive analysis, employing a range of statistical methods including descriptive analysis, Wilcoxon rank-sum tests, Bayesian networks, and chi-square tests. RESULTS: The prevalence of PI among older adults over 59 in China is 28·82%. Significant regional differences were observed in the duration of PA at different intensities. Older adults residing in more economically developed areas were more likely to engage in moderate-to-vigorous physical activity (MVPA) and exhibited longer sedentary behavior. Economic status and urban-rural disparities consistently emerged as direct influential factors across all intensity types. Chronic disease risks were significantly lower in active older adults compared to inactive ones. Lack of social guidance, family support, and personal inclination towards sedentary behavior were the main personalized factors affecting PA among older adults, and these factors could be relatively easily modified. CONCLUSIONS: Economic status, geography, and living areas (urban and rural) significantly influenced the distribution of physical activities in China. Particularly, economic status and living areas acted as direct factors. Older adults reaching the recommended standards for PA had significantly lower chronic disease risks, highlighting the importance of improving personalized factors which are crucial for promoting PA.
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COVID-19 , Status Econômico , Humanos , Idoso , Estudos Transversais , Teorema de Bayes , COVID-19/epidemiologia , Exercício Físico , Envelhecimento , Surtos de Doenças , Doença Crônica , China/epidemiologiaRESUMO
E2F transcription factor 5 (E2F5) gene is a transcription factor, plays an important role in the development of a variety of cells. E2F5 is expressed in human and mouse adipocytes, but its specific function in adipogenesis is unclear. Krüppel-like factor 7 (KLF7) facilitates proliferation and inhibits differentiation in chicken preadipocytes. Our previous KLF7 chromatin immunoprecipitation-sequencing analysis revealed a KLF7-binding peak in the 3' flanking region of the E2F5, indicating a regulatory role of KLF7 in this region. In the present study, we investigated E2F5 potential role, the overexpression and knockdown analyses revealed that E2F5 inhibited the differentiation and promoted the proliferation of chicken preadipocytes. Moreover, we identified enhancer activity in the 3' flanking region (nucleotides +22661/+22900) of E2F5 and found that KLF7 overexpression increased E2F5 expression and luciferase activity in this region. Deleting the putative KLF7-binding site eliminated the promoting effect of KLF7 overexpression on E2F5 expression. Further, E2F5 reversed the KLF7-induced decrease in preadipocyte differentiation and increase in preadipocyte proliferation. Taken together, our findings demonstrate that KLF7 inhibits differentiation and promotes proliferation in preadipocytes by enhancing E2F5 transcription.
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Adipócitos , Adipogenia , Diferenciação Celular , Proliferação de Células , Galinhas , Fatores de Transcrição Kruppel-Like , Animais , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Adipogenia/fisiologia , Galinhas/genética , Adipócitos/metabolismo , Adipócitos/fisiologia , Fator de Transcrição E2F5/metabolismo , Fator de Transcrição E2F5/genética , Fator de Transcrição E2F5/fisiologia , Proteínas Aviárias/metabolismo , Proteínas Aviárias/genéticaRESUMO
Ferroptosis has recently attracted much attention as an anti-tumor therapy. Evidence suggests that ferroptosis can induce oxidative stress and accumulation of lethal lipid peroxides in cancer cells, leading to cell damage. However, unsuitable pH, H2 O2 levels, and high glutathione (GSH) expression in the tumor microenvironment hinder the development of ferroptosis-mediated therapy. In this study, an l-arginine (l-arg)-modified CoWO4 /FeWO4 (CFW) S-scheme heterojunction is strategically designed and constructed for ultrasound (US)-triggered sonodynamic- and gas therapy-induced ferroptosis. CFW not only has excellent Fenton-catalytic activity, outstanding GSH consumption capacity, and excellent ability to overcome tumor hypoxia, but its S-scheme heterostructure can also avoid the rapid combination of electron (e) and hole (h+ ) pairs, thereby enhancing the sonodynamic effects. As a precursor of nitric oxide (NO), l-arg is modified on the surface of CFW (CFW@l-arg) to achieve controlled NO release under US irradiation, thereby enhancing ferroptosis. In addition, poly(allylamine hydrochloride) is further modified on the surface of CFW@l-arg to stabilize l-arg and achieve controllable NO release. Both in vitro and in vivo results demonstrate that such a multifunctional therapeutic nanoplatform can achieve high therapeutic efficacy through sonodynamic and gas therapy-enhanced ferroptosis. This designed oncotherapy nanoplatform provides new inspiration for ferroptosis-mediated therapy.
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Ferroptose , Neoplasias , Humanos , Arginina/farmacologia , Glutationa , Peróxidos Lipídicos , Óxido Nítrico , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio , Microambiente TumoralRESUMO
Eukaryotic nuclear genome is extensively folded in the nuclei, and the chromatin structure experiences dramatic changes, i.e., condensation and decondensation, during the cell cycle. However, a model to persuasively explain the preserved chromatin interactions during cell cycle remains lacking. In this paper, we developed two simple, lattice-based models that mimic polymer fiber decondensation from initial fractal or anisotropic condensed status, using Markov Chain Monte Carlo (MCMC) methods. By simulating the dynamic decondensation process, we observed about 8.17% and 2.03% of the interactions preserved in the condensation to decondensation transition, in the fractal diffusion and anisotropic diffusion models, respectively. Intriguingly, although interaction hubs, as a physical locus where a certain number of monomers inter-connected, were observed in diffused polymer models in both simulations, they were not associated with the preserved interactions. Our simulation demonstrated that there might exist a small portion of chromatin interactions that preserved during the diffusion process of polymers, while the interacted hubs were more dynamically formed and additional regulatory factors were needed for their preservation.
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OBJECTIVE: To investigate the effects of down-regulating MDR1 gene expression by CRISPRi on enhancing the sensitivity of lung adenocarcinoma A549/DDP cells to cisplatin. METHODS: The potential CRISPRi interference sites on the MDR1 gene promoter were predicted by bioinformatics software, and the interference fragments were designed and constructed. The mRNA and protein expression levels of MDR1 gene in each group of cells were detected by qRT-PCR and Western blot methods, and the recombinant vectors with high interference efficiency were screened. Human lung cancer A549/DDP cells were divided into three groups: A549/DDP, Scrambed and sgRNA-MDR1-1, with three multiple holes in each group. After each vector was transfected into the cells for 48 h, the efflux of cells in each group was detected by flow cytometry, the IC50 value of cells in each group was detected by MTT method, and the cell morphology of cells treated with cisplatin was observed under laser confocal microscope. RESULTS: After sequencing and comparison, two kinds of CRISPRi recombinant vectors interfering with MDR1 gene transcription were constructed successfully. After transfection of A549/DDP cells, the mRNA and protein levels of MDR1 gene in all transfection groups were decreased significantly (Pï¼ 0.01). Among them, the interference efficiency of sgRNA-MDR1-1 was the highest, and the interference efficiency of mRNA and protein was 60% and 51%, respectively. After transfection of sgRNA-MDR1-1 vector, compared with the control group, the efflux ability of cells was decreased (Pï¼0.01), the IC50 value of cells to cisplatin was decreased significantly (Pï¼0.01), and the intracellular chromatin gathered and marginalized, and apoptotic bodies appeared. CONCLUSION: CRISPRi interference with MDR1 gene in drug-resistant A549/DDP cells can significantly enhance the sensitivity to cisplatin.
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Adenocarcinoma de Pulmão , Antineoplásicos , Neoplasias Pulmonares , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Antineoplásicos/farmacologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Apoptose , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , RNA Mensageiro , Expressão GênicaRESUMO
BACKGROUND: Mammalian intestinal microbiomes are necessary for antagonizing systemic viral infections. However, very few studies have identified whether poultry commensal bacteria play a crucial role in protecting against systemic viral infections. Nephropathogenic infectious bronchitis virus (IBV) is a pathogenic coronavirus that causes high morbidity and multiorgan infection tropism in chickens. RESULTS: In this study, we used broad-spectrum oral antibiotics (ABX) to treat specific pathogen free (SPF) chickens to deplete the microbiota before infection with nephropathogenic IBV to analyze the impact of microbiota on IBV infections in vivo. Depletion of the SPF chicken microbiota increases pathogenicity and viral burden following IBV infection. The gnotobiotic chicken infection model further demonstrated that intestinal microbes are resistant to nephropathogenic IBV infection. In addition, ABX-treated chickens showed a severe reduction in macrophage activation, impaired type I IFN production, and IFN-stimulated gene expression in peripheral blood mononuclear cells and the spleen. Lactobacillus isolated from SPF chickens could restore microbiota-depleted chicken macrophage activation and the IFNAR-dependent type I IFN response to limit IBV infection. Furthermore, exopolysaccharide metabolites of Lactobacillus spp. could induce IFN-ß. CONCLUSIONS: This study revealed the resistance mechanism of SPF chicken intestinal microbiota to nephropathogenic IBV infection, providing new ideas for preventing and controlling nephropathogenic IBV. Video abstract.
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Microbioma Gastrointestinal , Vírus da Bronquite Infecciosa , Doenças das Aves Domésticas , Animais , Antibacterianos , Galinhas , Vírus da Bronquite Infecciosa/genética , Leucócitos Mononucleares , MamíferosRESUMO
Various cancer therapies have advanced remarkably over the past decade. Unlike the direct therapeutic targeting of tumor cells, cancer immunotherapy is a new strategy that boosts the host's immune system to detect specific cancer cells for efficient elimination. Unfortunately, the efficacy of these treatments has been limited to a fraction of patients within a subset of tumor types, and further studies are still needed to clarify these mechanisms and develop novel approaches to improve the efficacy of cancer immunotherapy. Emerging data suggest that the innate immune system also plays a key role in tumor immunosurveillance and generation of antitumor immune responses. Nanoparticles incorporating immunomodulatory agents can activate immune cells and modulate the tumor microenvironment to enhance antitumor immunity. Such nanoparticle-based cancer immunotherapies have received considerable attention and have been extensively studied in recent years. In this review, we will discuss the anticancer activities of nanoparticles designed to target innate immune pathways, including Toll-like receptor, nucleotide-binding oligomerization domain-like receptor, and retinoic acid-inducible gene-I-like receptor pathways, as well as DNA sensing pathways. In addition, nanoparticles that target key innate immune cell types, such as macrophages, myeloid-derived suppressor cells, dendritic cells, natural killer cells, and neutrophils, also will be investigated. In summary, although further research and clinical studies are still needed to solve the safety concerns and improve the efficacy of nanoplatform-based cancer immunotherapy, the recent studies presented in this review prove that nanoparticle-incorporated cancer immunotherapy is a highly promising treatment for cancer patients.
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Nanopartículas , Neoplasias , Humanos , Sistema Imunitário/patologia , Imunoterapia , Neoplasias/patologia , Microambiente Tumoral/fisiologiaRESUMO
Photodynamic therapy (PDT) mainly relies on reactive oxygen species generated by light- activated photosensitizers and oxygen to kill tumor cells. However, a critical limitation of the current PDT is that it is less effective in solid tumors where the microenvironment is hypoxic, and, therefore, repeated treatment is required. Here, non-stoichiometric Co2.19S4 nanodots (NDs), which can be rapidly degraded to cobalt (Co2+) and sulfur (S2-) ions, were developed to enhance tumor photothermal therapy (PTT) and chemodynamic therapy (CDT) via the capture of copper (Cu2+) ions (starvation therapy) in the hypoxic tumor microenvironment under near-infrared irradiation. Co2.19S4 NDs with excellent photothermal conversion efficiency (ɳ = 52%) can be used for PTT, and the Co2+ ions produced by their degradation can catalyze the endogenous hydrogen peroxide of tumor cells to produce highly toxic hydroxyl radicals to achieve tumor CDT. The mechanism of starvation therapy was explored using western blotting, and the results indicated that blocking the uptake of Cu2+ ions could restrain the growth and proliferation of tumors by inhibiting the BRAF/mitogen-activated extracellular signal regulated kinase (MEK)/extracellular regulated protein kinases (ERK) signaling pathway. Our work highlights the great potential of Co2.19S4 NDs as a theranostic agent for implementing photoacoustic/photothermal imaging and starvation therapy-enhanced PTT/CDT.
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Nanopartículas , Neoplasias , Fotoquimioterapia , Linhagem Celular Tumoral , Cobalto , Humanos , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Microambiente TumoralRESUMO
Resistance to chemotherapy is a long-standing problem in the management of cancer, and cancer stem cells are regarded as the main source of this resistance. This study aimed to investigate metallothionein (MT)-1G involvement in the regulation of cancer stemness and provide a strategy to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). Methods: MT1G was identified as a critical factor related with gemcitabine resistance in PDAC cells by mRNA microarray. Its effects on PDAC stemness were evaluated through sphere formation and tumorigenicity. LC-MS/MS analysis of conditional medium revealed that activin A, a NF-κB target, was a major protein secreted from gemcitabine resistant PDAC cells. Both loss-of-function and gain-of-function approaches were used to validate that MT1G inhibited NF-κB-activin A pathway. Orthotopic pancreatic tumor model was employed to explore the effects on gemcitabine resistance with recombinant follistatin to block activin A. Results: Downregulation of MT1G due to hypermethylation of its promoter is related with pancreatic cancer stemness. Secretome analysis revealed that activin A, a NF-κB target, was highly secreted by drug resistant cells. It promotes pancreatic cancer stemness in Smad4-dependent or independent manners. Mechanistically, MT1G negatively regulates NF-κB signaling and promotes the degradation of NF-κB p65 subunit by enhancing the expression of E3 ligase TRAF7. Blockade of activin A signaling with follistatin could overcome gemcitabine resistance. Conclusions: MT1G suppresses PDAC stemness by limiting activin A secretion via NF-κB inhibition. The blockade of the activin A signaling with follistatin may provide a promising therapeutic strategy for overcoming gemcitabine resistance in PDAC.
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Ativinas/metabolismo , Metalotioneína/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , China , Cromatografia Líquida , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Metalotioneína/genética , Camundongos Endogâmicos C57BL , Camundongos Nus , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/fisiologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas em Tandem , Fator de Transcrição RelA/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias PancreáticasRESUMO
Avian infectious bronchitis virus (IBV), which causes respiratory disease in infected birds, belongs to coronavirus group 3. IBV encodes 15 nonstructural proteins (nsp2-nsp16) which play crucial roles in RNA transcription and genome replication. Nonstructural protein 9 (nsp9) has been identified as a protein that is essential to viral replication because of its single-stranded RNA-binding ability. The gene segment encoding IBV nsp9 has been cloned and expressed in Escherichia coli. The protein has been crystallized and the crystals diffracted X-rays to 2.44 A resolution. They belonged to the cubic space group I432, with unit-cell parameters a = b = c = 123.4 A, alpha = beta = gamma = 90 degrees . The asymmetric unit appeared to contain one molecule, with a solvent content of 62% (V(M) = 3.26 A(3) Da(-1)).
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Vírus da Bronquite Infecciosa/química , Proteínas não Estruturais Virais/química , Cristalização , Cristalografia por Raios XRESUMO
Gene flow between species may cause variations in branch length and topology of gene tree, which are beyond the expected variations from ancestral processes. These additional variations make it difficult to estimate parameters during speciation with gene flow, as the pattern of these additional variations differs with the relationship between isolation and migration. As far as we know, most methods rely on the assumption about the relationship between isolation and migration by a given model, such as the isolation-with-migration model, when estimating parameters during speciation with gene flow. In this article, we develop a multispecies coalescent approach which does not rely on any assumption about the relationship between isolation and migration when estimating parameters and is called mstree. mstree is available at https://github.com/liujunfengtop/MStree/ and uses some mathematical inequalities among several factors, which include the species divergence time, the ancestral population size, and the number of gene trees, to estimate parameters during speciation with gene flow. Using simulations, we show that the estimated values of ancestral population sizes and species divergence times are close to the true values when analyzing the simulation data sets, which are generated based on the isolation-with-initial-migration model, secondary contact model, and isolation-with-migration model. Therefore, our method is able to estimate ancestral population sizes and speciation times in the presence of different modes of gene flow and may be helpful to test different theories of speciation.
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Classificação/métodos , Fluxo Gênico , Especiação Genética , Variação Genética , Modelos Biológicos , Modelos Genéticos , Software , Animais , Simulação por Computador , Genética Populacional , Humanos , Densidade Demográfica , Especificidade da Espécie , Fatores de TempoRESUMO
Drug resistance is the major obstacle of gemcitabine-based chemotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC). Many long non-coding RNAs (lncRNAs) are reported to play vital roles in cancer initiation and progression. Here, we report that lncRNA SLC7A11-AS1 is involved in gemcitabine resistance of PDAC. SLC7A11-AS1 is overexpressed in PDAC tissues and gemcitabine-resistant cell lines. Knockdown of SLC7A11-AS1 weakens the PDAC stemness and potentiates the sensitivity of resistant PDAC cells toward gemcitabine in vitro and in vivo. SLC7A11-AS1 promotes chemoresistance through reducing intracellular reactive oxygen species (ROS) by stabilizing nuclear factor erythroid-2-related factor 2 (NRF2), the key regulator in antioxidant defense. Mechanically, SLC7A11-AS1 is co-localized with ß-TRCP1 in the nucleus. The exon 3 of SLC7A11-AS1 interacts with the F-box motif of ß-TRCP1, the critical domain that recruits ß-TRCP1 to the SCFß-TRCP E3 complex. This interaction prevents the consequent ubiquitination and proteasomal degradation of NRF2 in the nucleus. Our results demonstrate that the overexpression of SLC7A11-AS1 in gemcitabine-resistant PDAC cells can scavenge ROS by blocking SCFß-TRCP-mediated ubiquitination and degradation of NRF2, leading to a low level of intracellular ROS, which is required for the maintenance of cancer stemness. These findings suggest SLC7A11-AS1 as a therapeutic target to overcome gemcitabine resistance for PDAC treatment.
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The lack of freshwater resources, or the freshwater crisis, is an important issue in the resource field. One potential green and sustainable method to solve this problem is to implement solar energy-driven water evaporation to collect freshwater. Capitalizing on the low cost, high production yield, and simplified fabrication process properties of nonstoichiometric Co2.67S4 nanoparticles, we strategically designed and synthesized a Co2.67S4-deposited Teflon (PTFE) membrane for realizing efficient solar water evaporation and photothermal antibacterial properties under light irradiation. Compared with previously reported cellulose acetate and poly(vinylidene fluoride) membranes, the PTFE membrane displayed significantly enhanced mechanical properties. Additionally, a Co2.67S4-deposited PTFE membrane with a hydrophobic treatment (termed as the Final-PTFE membrane) exhibited excellent durability. The light-to-heat conversion efficiency (η) of water evaporation reached a value of 82% for our as-prepared Final-PTFE membrane under two sun irradiation conditions. Moreover, the antibacterial mechanism observed by scanning electron microscopy was attributed to the thermal effect, which damaged the cell wall of bacteria. Our work highlights the great potentials of the Final-PTFE membrane as a versatile system for implementing solar energy-driven photothermal water evaporation and water purification.
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Antibacterianos/química , Membranas , Nanopartículas/química , Luz Solar , Microscopia Eletrônica de Transmissão , Politetrafluoretileno/química , Água/química , Purificação da Água/métodosRESUMO
After publication of this article, the below errors were noticed:1. The SOX2 primer is incorrect in Table S2.2. The Poly(T) adaptor sequence of reverse transcription for miR-145 detection is missing in Table S2.This error did not impact the conclusions of the article. We apologize for any confusion or inconvenience to the readers.An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Repurposing already approved drugs as new anticancer agents is a promising strategy considering the advantages such as low costs, low risks and less time-consumption. Disulfiram (DSF), as the first drug for antialcoholism, was approved by the U.S. Food and Drug Administration (FDA) over 60 years ago. Increasing evidence indicates that DSF has great potential for the treatment of various human cancers. Several mechanisms and targets of DSF related to cancer therapy have been proposed, including the inhibition of ubiquitin-proteasome system (UPS), cancer cell stemness and cancer metastasis, and alteration of the intracellular reactive oxygen species (ROS). This article provides a brief review about the history of the use of DSF in humans and its molecular mechanisms and targets of anticancer therapy, describes DSF delivery strategies for cancer treatment, summarizes completed and ongoing cancer clinical trials involving DSF, and offers strategies to better use DSF in cancer therapies.
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Dissulfiram/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Complexos Ubiquitina-Proteína Ligase/antagonistas & inibidores , Humanos , Metástase Neoplásica/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma , Espécies Reativas de Oxigênio/metabolismoRESUMO
Photothermal therapy (PTT) has emerged as one of the promising methodologies for the treatment of cancer, and ideal photothermal agents need to be biodegradable and have strong optical absorbance in the near-infrared (NIR) optical window. Here, we report a new phthalocyanine molecule, 4OCSPC, which expands the absorbance edge to 850 nm. Under 808 nm NIR laser irradiation, 4OCSPC polymeric micelles showed robust photostability and a high photothermal conversion of 47.0%. Also, the 4OCSPC polymeric micelles exhibit a high in vivo PTT efficacy against 4T1 tumors in mice.
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Hipertermia Induzida/métodos , Indóis/uso terapêutico , Neoplasias/terapia , Fototerapia/métodos , Polímeros/uso terapêutico , Radiossensibilizantes/uso terapêutico , Animais , Células HeLa , Humanos , Raios Infravermelhos/uso terapêutico , Isoindóis , Camundongos , Micelas , Técnicas Fotoacústicas/métodosRESUMO
Natural products serve as a main resource for drug discovery. The ubiquitin-proteasome system (UPS) is one of the primary intracellular protein degradation systems, which is responsible for the degradation of most short-lived, mis-folded and aged proteins. The proteasome is a validated target for cancer treatment, since cancer cells are more reliant on high levels of proteasome activity to maintain the dynamic protein homeostasis required for enhanced metabolism and unrestricted proliferation. Encouraged by success of bortezomib in the treatment of multiple myeloma, several second-generation proteasome inhibitors have been developed based on natural resources, and are being tested in various clinical settings. In this paper, we reviewed the most widely investigated proteasome inhibitors, including their natural product origins, compound-discovery and optimization, as well as their current status in both preclinical and clinical studies.
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Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Animais , Antineoplásicos/química , Bortezomib/uso terapêutico , Descoberta de Drogas/métodos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Relação Estrutura-AtividadeRESUMO
Specificity protein (Sp1) plays an important role in invasion-metastasis cascade. Sp1 regulation on protein coding genes has been extensively investigated; however, little is known about its regulation on protein non-coding genes. In this study, miR-3178 is reported as a novel target of Sp1 in multiple cancer cell models. Sp1 functions as its transcriptional suppressor as evidenced by luciferase reporter and chromatin immunoprecipitation (ChIP) assays. In line with the pro-metastatic role of Sp1, miR-3178 exerts anti-metastasis function. Overexpression of miR-3178 inhibits both migration and invasion of highly metastatic prostate, lung, and breast cancer cells whereas antagonizing miR-3178 promotes those events in their lowly metastatic counterparts. The in vivo study demonstrates that miR-3178 suppresses the tail vein inoculated prostate cancer cells to form colonies in lung, lymph node, and liver of BALB/c nude mice. miR-3178 directly targets the 3' UTR of TRIOBP-1 and TRIOBP-5, two isoforms of TRIOBP expressed in prostate, lung, and breast cancer cells. Overexpression of TRIOBP-1 could rescue miR-3178 inhibition on cell migration and invasion. Collectively, our findings reveal the regulatory axis of Sp1/miR-3178/TRIOBP in metastasis cascade. Our results suggest miR-3178 as a promising application to suppress metastasis in Sp1-overexpressed cancers.
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Humic acids, a major constituent of natural organic carbon resources, are naturally formed through the microbial biodegradation of animal and plant residues. Due to numerous physiologically active groups (phenol, carboxyl, and quinone), the biomedical applications of humic acid have been already investigated across different cultures for several centuries or even longer. In this work, sodium humate, the sodium salt of humic acid, is explored as phototheranostic agent for light-induced photoacoustic imaging and photothermal therapy based on intrinsic absorption in the near-infrared region. The purified colloidal sodium humate exhibits a high photothermal conversion efficiency up to 76.3%, much higher than that of the majority of state-of-the-art photothermal agents including gold nanorods, Cu9 S5 nanoparticles, antimonene quantum dots, and black phosphorus quantum dots, leading to obvious photoacoustic enhancement in vitro and in vivo. Besides, highly effective photothermal ablation of HeLa tumor is achieved through intratumoral injection. Impressively, sodium humate reveals ultralow toxicity at the cellular and animal levels. This work promises the great potential of humic acids as light-mediated theranostic agents, thus expanding the application scope of traditional humic acids in biomedical field.