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1.
Anal Chim Acta ; 1189: 338701, 2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-34815048

RESUMO

Highly sensitive and specific imaging of low-level microRNAs (miRNAs) in cytoplasm is vital for early diagnosis of cancers. In this work, we have developed the amplification strategies for miRNA-155 detection based on the combination the nicked rolling circle amplification (N-RCA) and catalyzed hairpin assembly (CHA). In this system, the target miRNA-155 acts as a polymerase primer to activate N-RCA to produce nicked fragment1 (NF1) and NF2. NF1 acted as new primer could further initiate a new N-RCA reaction over and over. Then, the NF2s could serve as triggers to induce the CHA reaction, and the Y-shaped DNA nanostructure (Y-SDN) was formed. Thus, an amplified fluorescence signal was obtained based on the multiple amplification. Under the optimized experimental conditions, a high sensitivity with a detection limit as low as 1.8 pM at 3σ miRNA-155 and excellent specificity in buffer condition have been achieved by applying this method. Meanwhile, the proposed method enables the application in miRNA-155 detection in human serum. Moreover, we have shown that the method performs well for the intracellular miRNA-155 imaging in cellular environments. Therefore, the present strategy was expected to apply into the clinical disease diagnosis effectively.


Assuntos
Técnicas Biossensoriais , MicroRNAs , Nanoestruturas , DNA , Testes Diagnósticos de Rotina , Fluorescência , Humanos , Limite de Detecção , Técnicas de Amplificação de Ácido Nucleico
4.
J Exp Clin Cancer Res ; 40(1): 300, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556175

RESUMO

BACKGROUND: The global epidemiological studies reported lower cancer risk after long-term use of contraceptives. Our systematic studies demonstrated that abortifacients are effective in preventing cancer metastases induced by circulating tumor cells (CTCs). However, the molecular and cellular mechanisms by which abortifacients prevent CTC-based cancer metastases are almost unknown. The present studies were designed to interdisciplinarily explore similarities and differences between embryo implantation and cancer cell adhesion/invasion. METHODS: Biomarker expressions on the seeding embryo JEG-3 and cancer MCF-7 cells, as well as embedding uterine endometrial RL95-2 and vascular endothelial HUVECs cells were examined and compared before and after treatments with 17ß-estradiol plus progesterone and abortifacients. Effects of oral metapristone and mifepristone on embryo implantation in normal female mice and adhesion/invasion of circulating tumor cells (CTCs) in BALB/C female mice were examined. RESULTS: Both embryo JEG-3 and cancer MCF-7 cells expressed high sLex, CD47, CAMs, while both endometrial RL95-2 and endothelial HUVECs exhibited high integrins and ICAM-1. Near physiological concentrations of 17ß-estradiol plus progesterone promoted migration and invasion of JEG-3 and MCF-7 cells via upregulating integrins and MMPs. Whereas, mifepristone and metapristone significantly inhibited migration and invasion of JEG-3 and MCF-7 cells, and inhibited JEG-3 and MCF-7 adhesion to matrigel, RL95-2 cells and HUVECs, respectively. The inhibitions were realized by downregulating sLex, MMPs in JEG-3 and MCF-7 cells, and downregulating integrins in RL95-2 cells and HUVECs, respectively. Mifepristone and metapristone significantly inhibited both embryo implantation and cancer cell metastasis in mice. CONCLUSIONS: The similarities between the two systems provide fundamentals for abortifacients to intervene CTC adhesion/invasion to the distant metastatic organs. The present studies offer the rationale to repurpose abortifacients for safe and effective cancer metastasis chemoprevention.

5.
J Cancer ; 12(14): 4240-4246, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093824

RESUMO

Although tumor-derived exosomes play an important role in the process of metastasis, differences in exosomes secreted by the same cells at different stages or conditions have not been noticed by most of the relevant researchers. Here we developed a lung cancer model in nude mice, and the phenotype and inclusions of exosomes secreted by early and advanced tumors were analysed. The size distribution and surface topography of these two exosomes were not significantly different, but the expression of CD63 in early tumor exosome (E-exosome) was significantly lower than that in advanced tumor exosome (A-exosome). α-SMA expression on HELF cells treated with A-exosome was significantly higher than that treated with E-exosome. The ability of A-exosome to promote the migration of A549 cells was better than E-exosome. Furthermore, small RNA sequence showed that only 3 of the 171 detected-small RNAs were expressed simultaneously in both exosomes. These findings proved that there are significant differences in inclusions and functions between the early and late exosomes of the same tumor. The study highlights the importance of exosomes in cancer metastasis, and might suggest exosomes can be used as biomarkers and therapeutic targets for cancer metastasis.

6.
ACS Chem Neurosci ; 12(11): 1854-1859, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33999600

RESUMO

Abnormal aggregation and deposition of Aß is one of the causative agents for Alzheimer's disease. The development of inhibitors for Aß aggregation has been considered a possible method to prevent and treat Alzheimer's disease. Edible sea cucumbers contain many bioactive molecules, including saponins, phospholipids, peptides, and polysaccharides. Herein, we report that polysaccharides extracted from sea cucumber Cucumaria frondosa could reduce the aggregation and cytotoxicity of Aß40. By utilizing multiple biochemical and biophysical instruments, we found that the polysaccharides could inhibit the aggregation of Aß40. A chemical kinetics analysis further suggested that the major inhibitory effects of the polysaccharides were achieved by disassembling mature fibrils, which in turn reduced the cytotoxicity of Aß. These results suggested that the polysaccharides extracted from sea cucumber could be used as an effective inhibitor for Aß.


Assuntos
Cucumaria , Pepinos-do-Mar , Peptídeos beta-Amiloides , Animais , Polissacarídeos/farmacologia , Sulfatos
7.
Drug Discov Today ; 26(3): 631-636, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33385574

RESUMO

The Coronavirus 2019 (COVID-19) pandemic represents the greatest worldwide public health crisis of recent times. The lack of proven effective therapies means that COVID-19 rages relatively unchecked. Current anti-COVID-19 pharmacotherapies are drugs originally designed for other diseases, and administered orally or intravascularly. Thus, they can have various adverse effects. A specific anti-Coronavirus drug should not only target the virus per se, but also treat the related respiratory and cardiovascular symptoms. Here, we examine the advantages and disadvantages of current anti-COVID-19 pharmacotherapies, and analyze the reasons why in the era of big data we have not yet established specific coronavirus therapies and related technical bottlenecks. Finally, we present our design of a novel nebulized S-nitrosocaptopril that is under development for targeting both coronaviruses and their related symptoms.


Assuntos
Antivirais , COVID-19 , Captopril/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antivirais/classificação , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , COVID-19/fisiopatologia , COVID-19/virologia , Captopril/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/metabolismo , Desenvolvimento de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Humanos , Nebulizadores e Vaporizadores , Preparações Farmacêuticas , Sistema Respiratório/diagnóstico por imagem , Sistema Respiratório/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Resultado do Tratamento
8.
J Control Release ; 331: 404-415, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33485883

RESUMO

Each type of cancer has its own specific metastatic route developed by disseminating circulating tumor cells (CTCs) and related extracellular vesicles to the target organ, i.e., metastasis organotropism. Tumor-derived small extracellular vesicles (herein exosomes, EXO) play an important role in determining cancer organotropic metastases to pre-metastasis niches. We therefore hypothesized that drug-loaded EXO may mix well with their companion small extracellular vesicles to specifically target the aimed metastatic organ via organotropism. Here, we demonstrate that the circulating breast-cancer-derived EXO loaded with doxorubicin (EXO-DOX) can mingled with their original companion EXO and inhibit breast cancer metastasis to lungs. The CD47 on the EXO-DOX prevented EXO-DOX from immune attack and prolonged their circulation in blood. The tissue distribution ratio of EXO-DOX is identical to the ratio of their companion EXO due to the specific affinity of EXO to integrins in targeted tissues. Quantitative accumulation of EXO-DOX in the mouse lungs is proportional to the organotropism of the circulating breast cancer cells that disseminate from subcutaneously-implanted human breast cancer cells in mice. EXO-DOX inhibited angiogenesis and cancer cell proliferation, resulting in prevention of breast cancer metastasis to the lungs. This study opens a novel path to use Trojan small extracellular vesicles for specifically controlled release of active components by small extracellular vesicles organotropism mechanism to the targeted organ for disease chemoprevention.


Assuntos
Exossomos , Células Neoplásicas Circulantes , Preparações Farmacêuticas , Animais , Linhagem Celular Tumoral , Proliferação de Células , Doxorrubicina , Humanos , Camundongos
9.
Biologicals ; 69: 22-29, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33431232

RESUMO

The quality of antivenom is governed by its safety and efficacy profiles. These quality characteristics are much influenced by the purity of antivenom content. Rigorous assessment and meticulous monitoring of antivenom purity at the preclinical setting is hence crucial. This study aimed to explore an integrative proteomic method to assess the physicochemical purity of four commercially available antivenoms in the region. The antivenoms were subjected to Superdex 200 HR 10/30 size-exclusion fast-protein liquid chromatography (SE-FPLC). The proteins in each fraction were trypsin-digested and analyzed by nano-ESI-liquid chromatography-tandem mass spectrometry (LC-MS/MS). SE-FPLC resolved the antivenom proteins into three major protein components of very high (>200 kDa), high (100-120 kDa) and medium (<60 kDa) molecular weights. The major components (80-95% of total proteins) in the antivenoms were proteins of 100-120 kDa consisting of mainly the light and partially digested heavy immunoglobulin chains, consistent with F(ab')2 as the active principle of the antivenoms. However, LC-MS/MS also detected substantial quantity of large proteins (e.g. alpha-2-macroglobulins), immunoglobulin aggregates and impurities e.g. albumins in some products. The method is practical and able to unveil the quantitative and qualitative aspects of antivenom protein compositions. It is therefore a potentially useful preclinical assessment tool of antivenom purity.


Assuntos
Antivenenos , Proteômica , Antivenenos/química , Cromatografia Líquida , Espectrometria de Massas em Tandem
10.
Asian J Pharm Sci ; 15(6): 685-700, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33363625

RESUMO

Ursolic acid (UA), a natural pentacyclic triterpenoid, possesses widespread biological and pharmacological activities. However, drawbacks such as low bioavailability, poor targeting and rapid metabolism greatly hinder its further clinical application. Recently, with the development of nanotechnology, various UA nanosystems have emerged as promising strategies for effective cancer therapy. This article reviews various types of UA-based nano-delivery systems, primarily with emphasis placed on novel UA-based carrier-free nano-drugs, which are considered to be innovative methods for cancer therapy. Moreover, this review presents carrier-free nano-drugs that co-assembled of UA and photosensitizers that displayed synergistic antitumor performance. Finally, the article also describes the development and challenges of UA nanosystems for future research in this field. Overall, the information presented in this review will provide new insight into the rational utilization of nano-drugs in cancer therapy.

11.
Signal Transduct Target Ther ; 5(1): 238, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051439

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

13.
Talanta ; 219: 121302, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32887044

RESUMO

Extremely sensitive and visual measurements of microRNA (miRNA) in situ for early detection and monitoring of diseases remains a major challenge. To address this issue, this work reports a rapid, highly sensitive and selective microRNA (miRNA) biosensing strategy based on isothermal circular strand-displacement polymerization (ICSDP), and miRNA imaging was performed inside cells. In this work, a double hairpin DNA probe (HP1/HP2 complex) embedded with a sensing region and polymerase primer region was designed. Briefly, after the specific binding of target miRNA with the HP1/HP2 probe, HP1/HP2 itself can function as a primer to initiate the ICSDP with the help of Klenow Fragment (KF), yielding target miRNA for new rounds of ICSDP. In this process, one target can produce multiple signal outputs (1: n), achieving low abundance of miRNA detection. Under optimized conditions, the proposed strategy showed high sensitivity with a detection limit of 5 pM within 15 min and can also easily distinguish the control miRNA from the target miRNA. This method can be further applied to image the intracellular miRNA of interest in situ inside the cancer cells.


Assuntos
Técnicas Biossensoriais , MicroRNAs , DNA , Sondas de DNA/genética , Limite de Detecção , MicroRNAs/genética , Técnicas de Amplificação de Ácido Nucleico
14.
Artigo em Inglês | MEDLINE | ID: mdl-32742279

RESUMO

Background: The Asiatic pit vipers from the Trimeresurus complex are medically important venomous snakes. These pit vipers are often associated with snakebite that leads to fatal coagulopathy and tissue necrosis. The cytotoxic venoms of Trimeresurus spp.; however, hold great potential for the development of peptide-based anticancer drugs. Methods: This study investigated the cytotoxic effect of the venom from Trimeresurus purpureomaculatus, the mangrove pit viper (also known as shore pit viper) which is native in Malaysia, across a panel of human cancer cell lines from breast, lung, colon and prostate as well as the corresponding normal cell lines of each tissue. Results: The venom exhibited dose-dependent cytotoxic activities on all cell lines tested, with median inhibition concentrations (IC50) ranging from 0.42 to 6.98 µg/mL. The venom has a high selectivity index (SI = 14.54) on breast cancer cell line (MCF7), indicating that it is significantly more cytotoxic toward the cancer than to normal cell lines. Furthermore, the venom was fractionated using C18 reversed-phase high-performance liquid chromatography and the anticancer effect of each protein fraction was examined. Fraction 1 that contains a hydrophilic low molecular weight (approximately 7.5 kDa) protein was found to be the most cytotoxic and selective toward the breast cancer cell line (MCF7). The protein was identified using liquid chromatography-tandem mass spectrometry as a venom disintegrin, termed purpureomaculin in this study. Conclusion: Taken together, the findings revealed the potent and selective cytotoxicity of a disintegrin protein isolated from the Malaysian T. purpureomaculatus venom and suggested its anticancer potential in drug discovery.

16.
Cells ; 9(3)2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32131438

RESUMO

The Wnt signaling is one of the major pathways known to regulate embryonic development, tissue renewal and regeneration in multicellular organisms. Dysregulations of the pathway are a common cause of several types of cancer and other diseases, such as osteoporosis and rheumatoid arthritis. This makes Wnt signaling an important therapeutic target. Small molecule activators and inhibitors of signaling pathways are important biomedical tools which allow one to harness signaling processes in the organism for therapeutic purposes in affordable and specific ways. Natural products are a well known source of biologically active small molecules with therapeutic potential. In this article, we provide an up-to-date overview of existing small molecule modulators of the Wnt pathway derived from natural products. In the first part of the review, we focus on Wnt pathway activators, which can be used for regenerative therapy in various tissues such as skin, bone, cartilage and the nervous system. The second part describes inhibitors of the pathway, which are desired agents for targeted therapies against different cancers. In each part, we pay specific attention to the mechanisms of action of the natural products, to the models on which they were investigated, and to the potential of different taxa to yield bioactive molecules capable of regulating the Wnt signaling.


Assuntos
Produtos Biológicos/uso terapêutico , Descoberta de Drogas/métodos , Via de Sinalização Wnt/fisiologia , Humanos
17.
Oncogene ; 39(13): 2741-2755, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32005977

RESUMO

The key molecules and underlying mechanisms of melanoma metastasis remain poorly understood. Using isobaric tag for relative and absolute quantitation (iTRAQ) proteomic screening, probing of patients' samples, functional verification, and mechanistic validation, we identified the important role of the WD repeat-containing protein 74 (WDR74) in melanoma progression and metastasis. Through gain- and loss-of-function approaches, WDR74 was found to promote cell proliferation, apoptosis resistance, and aggressive behavior in vitro. Moreover, WDR74 contributed to melanoma growth and metastasis in vivo. Mechanistically, WDR74 modulates RPL5 protein levels and consequently regulates MDM2 and insulates the ubiquitination degradation of p53 by MDM2. Our study is the first to reveal the oncogenic role of WDR74 in melanoma progression and the regulatory effect of WDR74 on the RPL5-MDM2-p53 pathway. Collectively, WDR74 can serve as a candidate target for the prevention and treatment of melanoma in the clinic.


Assuntos
Carcinogênese/patologia , Melanoma/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Neoplasias Cutâneas/patologia , Animais , Apoptose/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Técnicas de Inativação de Genes , Humanos , Melanoma/genética , Camundongos , Fosforilação , Proteólise , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas Ribossômicas/metabolismo , Transdução de Sinais/genética , Pele/patologia , Neoplasias Cutâneas/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitinação/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Chem Commun (Camb) ; 56(11): 1681-1684, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31939961

RESUMO

A functionalized dumbbell probe (FDP) based amplification method, termed as a cascading exponential amplification DNA machine (CEA-DNA machine), has been developed to autonomously accumulate single G-quadruplexes (SGQs) and twin-G-quadruplexes (TGQs) for robust fluorescence signal-on probing of miRNA-21.


Assuntos
DNA/química , MicroRNAs/sangue , Técnicas de Amplificação de Ácido Nucleico/métodos , Espectrometria de Fluorescência/métodos , Benzotiazóis/química , Técnicas Biossensoriais/métodos , Linhagem Celular Tumoral , DNA/genética , Sondas de DNA/química , Sondas de DNA/genética , Corantes Fluorescentes/química , Quadruplex G , Humanos , Sequências Repetidas Invertidas , Limite de Detecção , MicroRNAs/genética , Hibridização de Ácido Nucleico
19.
Nat Commun ; 11(1): 243, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913267

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

20.
Cancer Lett ; 471: 103-115, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31838084

RESUMO

Lung cancer has been notorious for its lack of advance in clinical therapy, urging for effective therapeutic targets. WD repeat-containing protein 74 (WDR74) has previously been implicated in tumorigenesis, but its mechanistic functions remain not well understood. Herein, WDR74 expression was observed to be increased upon lung cancer progression from healthy normal tissues to the primary cancer and further to the metastatic cancer. Through gain- and loss-of-function approaches, we found that WDR74 regulated lung cancer cell proliferation, cell cycle progression, chemoresistance and cell aggressiveness in vitro. Moreover, a xenograft mouse model disclosed that WDR74 knockout inhibited lung cancer growth and metastasis, whereas WDR74 overexpression reciprocally enhanced these characteristics. Mechanistically, WDR74 promoted nuclear ß-catenin accumulation and drove downstream Wnt-responsive genes, thus revealing that WDR74 activated the Wnt/ß-catenin signaling pathway. Collectively, WDR74 inducing nuclear ß-catenin accumulation and driving the downstream Wnt-responsive genes expression facilitates lung cancer growth and metastasis. WDR74 can serve as a candidate target for the prevention and treatment of lung cancer in clinic.


Assuntos
Neoplasias Pulmonares/genética , Proteínas de Ligação a RNA/genética , Via de Sinalização Wnt/genética , beta Catenina/metabolismo , Células A549 , Animais , Ciclo Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Progressão da Doença , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Fosforilação , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/metabolismo , beta Catenina/genética
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