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Chemoresistance mechanisms of colorectal cancer remain largely elusive. We aim to compare the difference of chemotherapy responses between FOLFOX-resistant and wild-type colorectal cancer cells by proteomic profiling to suggest novel treatment targets. FOLFOX-resistant colorectal cancer cells DLD1-R and HCT116-R were developed by chronic exposure to progressive FOLFOX doses. Proteomic profiling of FOLFOX-resistant and wild-type cells under FOLFOX exposure were conducted by mass-spectrometry-based protein-analysis technology. Verification of selected KEGG pathways was conducted by Western blot. DLD1-R had significantly higher FOLFOX-chemoresistance (10.81 times) than its wild-type counterpart. A total of 309 and 90 differentially expressed proteins were identified in DLD1-R and HCT116-R, respectively. In terms of gene ontology molecular function, RNA binding and cadherin binding ranked first for DLD1 and HCT116 groups, respectively. For gene set enrichment analysis, ribosome pathway and DNA replication were significantly up-regulated and down-regulated in DLD1-R, respectively. The most significantly up-regulated pathway in HCT116-R was regulation of the actin cytoskeleton. Up-regulations in the ribosome pathway (DLD1-R) and actin cytoskeleton (HCT116-R) were verified by Western blot. There were several significantly altered signaling pathways in FOLFOX-resistant colorectal cancer cells under FOLFOX with notable up-regulations in the ribosomal process and actin cytoskeleton.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Proteômica , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Transdução de Sinais/genética , Fluoruracila/farmacologia , Fluoruracila/uso terapêuticoRESUMO
The recreational drug γ-hydroxybutyric acid (GHB) is a central nervous system depressant, and can produce euphoria at low doses. GHB is a controlled substance in Taiwan. However, the organic solvents γ-butyrolactone (GBL) and 1,4-butanediol (BD), which are unregulated, may be used as an alternative source of GHB. There is no clinical report of analytically confirmed GHB use in Taiwan. We retrospective reviewed the clinical characteristics from the medical charts between May 2017 and April 2020. The urine samples of patients presented to the emergency departments with drug-related complaints were sent for toxicological analysis. Patients with urine samples detected GHB >10 µg/mL by liquid chromatography/tandem mass spectrometry were included. Overall, 11 men and one woman with an average age of 35.3 ± 8.7 years were included. Most patients co-ingested amphetamine (n = 6) and initially presented with depressed consciousness levels (n = 7). One patient presented with out-of-hospital cardiac arrest and one with respiratory depression. All patients regained consciousness within 6 h of admission. All patients used GBL to evade conviction. Although patients recovered with supportive care, respiratory failure and cardiac arrest occurred after GHB/GBL use. It is important to legislate GBL and BD as controlled chemical substances in Taiwan.
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Oxibato de Sódio , 4-Butirolactona/efeitos adversos , Adulto , Serviço Hospitalar de Emergência , Feminino , Humanos , Hidroxibutiratos , Masculino , Estudos Retrospectivos , Oxibato de Sódio/efeitos adversos , TaiwanRESUMO
RATIONALE: The presence of α-pyrrolidinovalerophenone (α-PVP) and its metabolites in urine is evidence of the administration of α-PVP. A toxicological challenge is that the metabolites of α-PVP exhibit amphoteric properties, which make them unsuitable for detection using gas chromatography-mass spectrometry (GC/MS). In the study reported, proper derivatization and sample extraction were essential for improving the sensitivity for GC/MS analysis. METHODS: An automated solid-phase extraction (SPE) method has been developed and optimized. The derivatization efficiency was tested using longer reaction time and the addition of polar pyridine into a mixture of N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane. Method validation, including linearity, limit of detection, precision, accuracy, and recovery, was evaluated using automatic SPE and GC/MS. RESULTS: The results suggested that adding pyridine to BSTFA (1:1, v/v) significantly improved derivatization efficiency and precision. After optimization, the linear range was from 25 to 1000 ng mL-1 with R2 > 0.9950. The limit of detection was 5 ng mL-1 for α-PVP and 25 ng mL-1 for OH-α-PVP. The recovery for SPE was over 88%. The inter-day and intra-day precisions were less than 15%. A forensic sample has been found containing α-PVP (67.3 ng mL-1 ) and OH-α-PVP (560.2 ng mL-1 ). CONCLUSIONS: This study is the first to validate an auto-SPE-GC/MS method for the quantification and qualification of α-PVP and OH-α-PVP in urine. We have successfully improved the derivatization efficiency and developed a sensitive and semi-automatic approach. This approach is desirable for the detection of synthetic cathinone at trace levels in biological samples.
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Alcaloides/urina , Cromatografia Gasosa-Espectrometria de Massas/métodos , Pirrolidinas/urina , Alcaloides/metabolismo , Drogas Desenhadas/metabolismo , Drogas Desenhadas/farmacocinética , Humanos , Limite de Detecção , Pirrolidinas/metabolismo , Extração em Fase Sólida/métodos , Detecção do Abuso de Substâncias/métodosRESUMO
BACKGROUND/PURPOSE: Although illicit substance use-induced toxicity or complication is a frequent cause of visit to the emergency department (ED), there are limited data on cases confirmed by liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis. This study aimed to describe clinical presentations of patients who visited the ED because of acute illicit substance-related complications. METHODS: We performed a retrospective study between May 2017 and August 2018 on patients presenting to the ED with positive urine illicit substance analysis by LC-MS/MS. RESULTS: Of 203 patients with at least one illicit substance detected in their urine, 162 (79.8%) showed traditional illicit substances, and 56 (32.0%) showed new psychoactive substances (NPS). Methamphetamine was the most common illicit substance (67.9%). The most common NPS was ketamine (21.7%), followed by synthetic cathinones (14.8%). We divided patients into traditional, NPS and combined (both traditional illicit substance and NPS) groups. Polysubstance use was more common in the NPS group than in the traditional group (P < 0.001). Most patients were men (78.3%), and the average age was lower in the NPS group compared to the traditional group (P < 0.001). Although the chemical structures of cathinones are similar to that of amphetamine, 92.0% of the cathinone use cases without combination with methamphetamine use showed negative immunoassay results. CONCLUSION: Our study provided the acute illicit substance complications at ED by LC-MS/MS analysis in Taiwan. Our study showed that more than one-third cases studied were NPS users. Young adults and polysubstance users were more common among NPS users.
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Drogas Ilícitas , Transtornos Relacionados ao Uso de Substâncias , Cromatografia Líquida , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Estudos Retrospectivos , Detecção do Abuso de Substâncias , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Taiwan/epidemiologia , Espectrometria de Massas em TandemRESUMO
As a super-antigen, staphylococcal enterotoxin C2 (SEC2) stimulates the release of massive inflammatory cytokines such as interferon-gamma (IFN-γ), interleukin-1 (IL-1) and interleukin-2 (IL-2) which are documented to implicate osteoblast differentiation. In the present study, SEC2 was found to significantly improve the osteoblast differentiation by up-regulating BMP2 and Runx2/Cbfa1 expression. Interferon (IFN)-inducible gene IFI16, a co-activator of Runx2/Cbfa1, was also activated by SEC2 in the osteoblast differentiation. In addition, exogenous introduction of SEC2 stimulated OPG expression and suppressed RANKL, suggesting suppression of osteoclastogenesis in hMSCs. Therefore, our results displayed that SEC2 plays an important role in the commitment of MSC to the osteoblast and it might be a potential new therapeutic candidate for bone regeneration.
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Enterotoxinas/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/fisiologia , Proteínas Nucleares/fisiologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Osteoclastos/fisiologia , Fosfoproteínas/fisiologiaRESUMO
Methcathinone, a psychoactive substance with stimulant properties, has raised concerns in recent years due to its presence in urine screenings, even among individuals with no history of drug abuse. To prevent misjudgment, this work aims to explore the source of methcathinone in urine. A total of 58 urine samples tested positive for methcathinone in the National Taiwan University Hospital cohort, with 27 linked to illicit drug use and 31 from individuals with no drug use history. Co-occurrence analysis revealed a strong association between methcathinone and over-the-counter cold medications containing pseudoephedrine or ephedrine. In an in vivo experiment, participants who consumed pseudoephedrine-containing drugs showed the presence of methcathinone in their urine, suggesting a connection between these substances. Additionally, tests on pharmaceutical products containing pseudoephedrine detected small amounts of methcathinone as impurities. The findings suggest that the presence of methcathinone in nonillicit drug users may be attributed to impurities in over-the-counter pseudoephedrine-containing medications. This raises concerns about potential misinterpretations of drug screening results and underscores the need for more comprehensive criteria for assessing drug use. This study contributes to our understanding of the origin of methcathinone in urine, which has implications for legal justice and drug screening practices.
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Líquidos Corporais , Propiofenonas , Transtornos Relacionados ao Uso de Substâncias , Humanos , Pseudoefedrina , Efedrina , Transtornos Relacionados ao Uso de Substâncias/diagnósticoRESUMO
BACKGROUND: Staphylococcal enterotoxin C2 (SEC2) is used as an immunotherapeutic drug in China. However, SEC2 are limited due to its immunosuppressive and toxic effects. A SEC2 2M-118 (H118A/T20L/G22E) mutant generated by site-directed mutagenesis was studied to elucidate the underlying antitumor mechanism. METHODS: The effects of 2M-118 on mouse fibrosarcoma (Meth-A) cells and cytokine responses were tested in vitro using a transwell assay and ELISA, respectively. 2M-118 effect on immune function in tumor-bearing mice was tested. Cytokine levels and antitumor responses were measured using ELISA and flow cytometry, respectively. TUNEL staining and immunohistochemistry were employed to detect the tumor apoptosis and CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) in tumor tissue. RESULTS: 2M-118 demonstrated the growth inhibition on tumor cells, increase of cytokines production (IL-2, IFN-γ, and TNF-α) and splenocyte proliferation in vitro. 2M-118 effectively inhibited tumor development and increased lymphocytes and cytokines in a tumor-bearing mouse model. Additionally, 2M-118 regulated the tumormicroenvironment by reducing the number of myeloid-derived suppressor cells (MDSCs), increasing the number of TILs, and inducing tumorcell apoptosis. CONCLUSION: 2M-118 promotes immune function and enhances antitumor response. This indicates that 2M-118 could potentially be developed as a novel anti-tumor drug with-highefficiencyandlowtoxicity.
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Citocinas , Enterotoxinas , Animais , Enterotoxinas/imunologia , Linhagem Celular Tumoral , Camundongos , Citocinas/metabolismo , Camundongos Endogâmicos BALB C , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/imunologia , Fibrossarcoma/patologia , Apoptose/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Feminino , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Mutação , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacosRESUMO
Drug abuse is a severe social problem worldwide. Particularly, the issue of new psychoactive substances (NPSs) have increasingly emerged. NPSs are structural or functional analogs of traditional illicit drugs, such as cocaine, cannabis, and amphetamine; these molecules provide the same or more severe neurological effects. Usually, immunoassays are utilized in the preliminary screening method. However, NPSs have poor detectability in commercially available immunoassay kits. Meanwhile, various chromatography combined with the mass spectrometry platform have been developed to quantify NPSs. Still, a significant amount of time and resources are required during these procedures. Therefore, we established a rapid analytical platform for NPSs employing paper-loaded direct analysis in real time triple quadrupole mass spectrometry (pDART-QqQ-MS). We implemented this platform for the semiquantitative analysis of forensic drug tests in urine. This platform significantly shrinks the analytical time of a single sample within 30 s and requires a low volume of the specimen. The platform can detect 21 NPSs in urine mixtures at a lower limit of qualification of concentration ranging from 20 to 75 nanograms per milliliter (ng mL-1) and is lower than the cutoff value of currently available immune-based devices for detecting multiple drugs (1000 ng mL-1). Urine samples from drug addicts have been collected to verify the platform's effectiveness. By combining efficiency and accuracy, our platform offers a promising solution for addressing the challenges posed by NPSs in drug abuse detection.
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Drogas Ilícitas , Psicotrópicos , Detecção do Abuso de Substâncias , Humanos , Psicotrópicos/análise , Psicotrópicos/urina , Detecção do Abuso de Substâncias/métodos , Drogas Ilícitas/análise , Drogas Ilícitas/urina , Limite de Detecção , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massas/métodosRESUMO
Antemortem specimens are sometimes the sole sources available for forensic investigation, and samples collected in nonideal ways are inevitably employed to achieve toxicological analysis. It is essential to assess the effects of blood collection tubes on the recoveries of emerging synthetic cathinones (SC) to estimate actual drug concentrations, and no such systematic investigations have been previously carried out. Seventy-one SC with various LogP values were employed to examine commonly used blood collection tubes, including plasma tubes, serum tubes and gel-containing tubes in recoveries which determined by a reliable LC-MS/MS method. Significantly poor recoveries for hydrophobic SC were obtained using serum separating tubes (SST). Notably, the suppressed recoveries in SST can be reversed by adding anticoagulants. Adding a procoagulant to a plasma separating tube (PST) considerably reduced recoveries, which indicated that clotting processes in the presence of polymeric gels contributed to poor recoveries of these hydrophobic drugs. In this study, we find that clotting formation in the presence of polymeric gels could significantly affect the determination of hydrophobic drugs. However, in real-world scenarios, nonideal collection methods are inevitably employed for antemortem specimens. Thus, it is important to rigorously interpret forensic toxicological results, especially for susceptible species.
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Catinona Sintética , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida , Anticoagulantes , Coleta de Amostras Sanguíneas/métodos , GéisRESUMO
The application of dried blood spots (DBS) has gradually increased in different fields because of its several advantages. The hematocrit (Hct) effect is one major analytical challenge that may affect the quantification accuracy of DBS samples and should be investigated when developing a novel DBS method. However, previous studies usually overlooked the Hct-related distribution bias when evaluating the Hct effect. This study aimed to propose an effective DBS preparation protocol for the comprehensive evaluation of the Hct effect. We selected voriconazole and posaconazole as the demonstration drugs. Fifteen microliters of the blood samples were spotted on DBS cards followed by whole spot extraction. An LC-MS/MS method was first developed to quantify voriconazole and posaconazole in DBS samples. The quantitation accuracy for both azole drugs was within 93.5%-111.7%, except for the accuracies of posaconazole at the LLOQ, which were less than 119%. The intra- and interday precision were below 11%. The validated LC-MS/MS method was used to develop the DBS preparation protocol for evaluating the Hct effect. Three critical parameters that may affect the observed Hct effect were investigated. The results showed that using the solid-state of the target analytes, spiking the target analytes before preparing different Hct levels, and allowing enough equilibrium time after spiking target analytes can provide a more holistic Hct effect evaluation. The validity of the proposed new protocol was verified by conversion factors obtained from 71 paired DBS and plasma samples. Conversion factors calculated by clinical samples were consistent with the Hct effect evaluated by manually prepared DBS samples. This new DBS preparation protocol eliminated the common pitfalls in studying the Hct effect and offered a comprehensive strategy to assess the Hct effect for further DBS studies.
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Teste em Amostras de Sangue Seco , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Voriconazol , Hematócrito , Espectrometria de Massas em Tandem/métodos , Teste em Amostras de Sangue Seco/métodos , Reprodutibilidade dos TestesRESUMO
Determination of urine organic acids (UOAs) is essential to understand the disease progress of inborn errors of metabolism (IEM) and often relies on GC-MS analysis. However, the efficiency of analytical reports is sometimes restricted by data processing due to labor-intensive work if no proper tool is employed. Herein, we present a simple and rapid workflow with an R-based script for automated data processing (AutoDP) of GC-MS raw files to quantitatively analyze essential UOAs. AutoDP features automatic quality checks, compound identification and confirmation with specific fragment ions, retention time correction from analytical batches, and visualization of abnormal UOAs with age-matched references on chromatograms. Compared with manual processing, AutoDP greatly reduces analytical time and increases the number of identifications. Speeding up data processing is expected to shorten the waiting time for clinical diagnosis, which could greatly benefit clinicians and patients with IEM. In addition, with quantitative results obtained from AutoDP, it would be more feasible to perform retrospective analysis of specific UOAs in IEM and could provide new perspectives for studying IEM.
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Erros Inatos do Metabolismo , Humanos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Estudos Retrospectivos , Fluxo de Trabalho , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/metabolismoRESUMO
Studies in recent years have highlighted an elaborate crosstalk between T cells and bone cells, suggesting that T cells may be alternative therapeutic targets for the maintenance of bone homeostasis. Here, it is reported that systemic administration of low-dose staphylococcal enterotoxin C2 (SEC2) 2M-118, a form of mutant superantigen, dramatically alleviates ovariectomy (OVX)-induced bone loss via modulating T cells. Specially, SEC2 2M-118 treatment increases trabecular bone mass significantly via promoting bone formation in OVX mice. These beneficial effects are largely diminished in T-cell-deficient nude mice and can be rescued by T-cell reconstruction. Neutralizing assays determine interferon gamma (IFN-γ) as the key factor that mediates the beneficial effects of SEC2 2M-118 on bone. Mechanistic studies demonstrate that IFN-γ stimulates Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling, leading to enhanced production of nitric oxide, which further activates p38 mitogen-activated protein kinase (MAPK) and Runt-related transcription factor 2 (Runx2) signaling and promotes osteogenic differentiation. IFN-γ also directly inhibits osteoclast differentiation, but this effect is counteracted by proabsorptive factors tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1ß) secreted from IFN-γ-stimulated macrophages. Taken together, this work provides clues for developing innovative approaches which target T cells for the prevention and treatment of osteoporosis.
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Emerging new psychoactive substances (NPS) poses a great risk to public health. Analyzing these large numbers of NPS and other associated substances often relies on liquid chromatography coupled to triple quadrupole mass spectrometry (LC-QqQ-MS) with multiple-reaction monitoring (MRM) mode. However, the differentiation of critical pairs, coeluted isobaric and/or isomeric species, is one of the challenges for this analytical platform. MRM transitions with poor selectivity can jeopardize accurate quantification and lead to biased interpretation. Herein, we refined a novel workflow for developing an MRM-based method with in-house CriticalPairFinder and TransitionFinder tools for the effective identification of unique and selective MRM transitions. Transitions selected by TransitionFinder showed much better accuracies than those selected only by fragment abundance in some mixtures of critical pairs. Using the proposed analytical strategy, a method that can simultaneously determine 219 NPS and 65 other substances across a variety of NPS classes in urine samples was developed, validated and applied to analyze clinical urine samples. This automated workflow is anticipated to facilitate method development for analyzing complex analytes while considering selectivity.
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Espectrometria de Massas em Tandem , Cromatografia Líquida , Limite de DetecçãoRESUMO
Most bio-inspired antireflective nanostructures are extremely vulnerable and suffer from complicated lithography-based fabrication procedures. To address the issues, we report a scalable and simple non-lithography-based approach to engineer robust antireflective structures, inspired by the longtail glasswing butterfly, in a single step. The resulting two-dimensional randomly arranged 80/130/180 nm silica colloids, partially embedded in a polymeric matrix, generate a gradual refractive index transition at the air/substrate interface to suppress light reflection. Importantly, the randomly arranged subwavelength silica colloids display even better antireflection performance for large incident angles than that of two-dimensional non-close-packed silica colloidal crystals. The biomimetic coating is of considerable technological importance in numerous practical applications.
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BACKGROUND: Synthetic cathinones (SC) are popular new psychoactive substances that produce sympathomimetic toxicity. Meth/amphetamine and SC have similar chemical structures and pharmacological effects. We aimed to compare the clinical characteristics between meth/amphetamine and SC users presenting to the emergency department (ED). METHODS: This retrospective observational cohort study included patients who presented to six EDs from May 2017 to April 2021 with symptoms that related to recreational drug use and whose urine toxicology tests were positive only for meth/amphetamine or SC through liquid chromatography-tandem mass spectrometry. RESULTS: There were 379 patients who tested positive only for meth/amphetamine (MA group), and 87 patients tested positive only for SC (SC groups). Patients in the MA group were older than those in the SC group (median (IQR); MA: 37.0 (30-43.7), SC: 25.0 (21.0-32.7), p < 0.001). There were no significant between-group differences in the sex distribution and initial chief complaints. Compared with the MA group, the SC group had more cases of tachycardia (≥ 135/min; MA: 29 (8.2%), SC:16 (19.0%), p = 0.0031) and hyperthermia (≥ 38 °C; MA: 31 (8.2%), SC:18 (20.7%), p = 0.001). Besides, the SC group had significantly higher levels of creatinine kinase (CK, IU/L; MA: 263 (115-601), SC: 497 (206-9216), p = 0.008) as well as a higher risk of rhabdomyolysis (CK > 1000; MA:32 (8.4%), SC: 16 (18.4%), p = 0.006) and severe rhabdomyolysis (CK > 10,000; MA:10 (2.6%), SC:10 (11.5%), p = 001). Multivariable logistic regression analyses indicated SC group in comparison with the MA group (adjusted odds ratio: 2.732, 95% confidence interval: 1. 250-5.972, p = 0.012) was an association with the risk of rhabdomyolysis. CONCLUSION: Our findings demonstrate that tachycardia, hyperthermia, and rhabdomyolysis were more common among cathinone users than among meth/amphetamine users presented to EDs.
Assuntos
Metanfetamina , Rabdomiólise , Alcaloides , Anfetamina , Creatinina , Serviço Hospitalar de Emergência , Humanos , Estudos Retrospectivos , Rabdomiólise/induzido quimicamente , Rabdomiólise/epidemiologia , SimpatomiméticosRESUMO
The development of nanotheranostics for precision imaging-guided regulated cell death-mediated synergistic tumor therapy is still challenging. Herein, a novel multifunctional nanotheranostic agent, iRGD-coated maleimide-poly(ethylene glycol)-poly(lactic acid/glycolic acid)-encapsulated hydrophobic gold nanocages (AuNCs) and hydrophilic epigallocatechin gallate (EGCG) (PAuE) is developed for multispectral optoacoustic tomography (MSOT)-guided photothermal therapy (PTT) and chemotherapy. The portions of necroptotic and apoptotic tumor cells were 52.9 and 5.4%, respectively, at 6 h post-incubation after the AuNC-induced mild PTT treatment, whereas they became 14.0 and 46.1% after 24 h, suggesting that the switch of the cell death pathway is a time-dependent process. Mild PTT facilitated the release of EGCG which induces the downregulation of hypoxia-inducible factor-1 (HIF-1α) expression to enhance apoptosis at a later stage, realizing a remarkable tumor growth inhibition in vivo. Moreover, RNA sequence analyses provided insights into the significant changes in genes related to the cross-talk between necroptosis and apoptosis pathways via PAuE upon laser irradiation. In addition, the biodistribution and metabolic pathways of PAuE have been successfully revealed by 3D MSOT. Taken together, this strategy of first combination of EGCG and AuNC-based photothermal agent via triggering necroptosis/apoptosis to downregulate HIF-1α expression in a tumor environment provides a new insight into anti-cancer therapy.
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Glioblastoma (GBM) is one of the most devastating cancers, with an approximate median survival of only 16 months. Although some new insights into the fantastic heterogeneity of this kind of brain tumor have been revealed in recent studies, all subclasses of GBM still demonstrate highly aggressive invasion properties to the surrounding parenchyma. This behavior has become the main obstruction to current curative therapies as invasive GBM cells migrate away from these foci after surgical therapies. Therefore, this review aimed to provide a relatively comprehensive study of GBM invasion mechanisms, which contains an intricate network of interactions and signaling pathways with the extracellular matrix (ECM). Among these related molecules, TGF-ß, the ECM, Akt, and microRNAs are most significant in terms of cellular procedures related to GBM motility and invasion. Moreover, we also review data indicating that Musashi-1 (MSI1), a neural RNA-binding protein (RBP), regulates GBM motility and invasion, maintains stem cell populations in GBM, and promotes drug-resistant GBM phenotypes by stimulating necessary oncogenic signaling pathways through binding and regulating mRNA stability. Importantly, these necessary oncogenic signaling pathways have a close connection with TGF-ß, ECM, and Akt. Thus, it appears promising to find MSI-specific inhibitors or RNA interference-based treatments to prevent the actions of these molecules despite using RBPs, which are known as hard therapeutic targets. In summary, this review aims to provide a better understanding of these signaling pathways to help in developing novel therapeutic approaches with better outcomes in preclinical studies.
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Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Invasividade Neoplásica/patologia , Movimento Celular , Humanos , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador betaRESUMO
The rapid surge and wide spread of the coronavirus disease-2019 (COVID-19) overshadows the entire medical industries worldwide. The stringent medical resources hinder the diagnostic capacity globally, while 84 000 of new cases confirmed within a single day of April 14, 2020. Real-time reverse-transcription polymerase chain reaction (RT-PCR) with is the current first-line diagnosis, but the false-negative rate remains concerned. Radiographic technologies and tools, including computed tomography (CT) and chest X-ray, were applied for initial screening and follow-up, from which the tools provide detail diagnosis with specific pathologic features for staging and treatment arrangement. Although the radiographic imaging is found less sensitive, numerous CT-positive patients were not screened out by RT-PCR initially and later confirmed as COVID-19 positive. Besides, the shortage of sampling kits and the longer turn-over time of PCR examinations in some areas were noticed due to logistic issues and healthcare burden. In this review, we will discuss the challenges and the future perspectives of using radiographic modalities for COVID-19 diagnosis in view of securing human lives amid the crisis.
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Betacoronavirus , Infecções por Coronavirus/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , COVID-19 , Humanos , Pandemias , SARS-CoV-2 , Tomografia Computadorizada por Raios XRESUMO
In clinical tumor therapy, chemotherapeutic routes have caused severe side effects; current delivery methods are unsatisfactory. Successful design of a remotely folate (FA)-grafted chitosan (CS)-coated magnetic nanoparticle (MNP) with low toxicity, has been achieved. A chemotherapeutic drug such as doxorubicin (DOX), is loaded in the MNP-based matrix (FA-grafted CS-DOX-TPP-MNP), which is coated by an activated target tumor molecule of FA-grafted CS biopolymer with the inclusion of tripolyphosphate (TPP) as a linker. The resultant nano-complexes exhibited random aggregates (~240 nm) and zeta potential (-24.9 mV). In vivo experiments using athymic BALB/c nude mice with human glioblastoma U87 cells in a subcutaneous tumor model revealed that magnetic guidance of FA-grafted CS-DOX-TPP-MNP, injected via the tail vein, significantly decreased tumor growth. This manuscript demonstrates the feasibility of magnetizing control of FA-grafted CS-DOX-TPP-MNP to enhance the localization of drug release.
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To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA)-based nanoparticles (NPs) with dual magnetic resonance (MR) and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU] NPs) to deliver BCNU for inhibition of brain tumor cells (MBR 261-2). These BSA-based NPs are water dispersible, stable, and biocompatible as confirmed by XTT cell viability assay. In vitro phantoms and in vivo MR and fluorescence imaging experiments show that the developed FITC-BSA-Gd/BCNU NPs enable dual MR and fluorescence imaging for monitoring cellular uptake and distribution in tumors. The T1 relaxivity (R1) of FITC-BSA-Gd/BCNU NPs was 3.25 mM(-1) s(-1), which was similar to that of the commercial T1 contrast agent (R1 =3.36 mM(-1) s(-1)). The results indicate that this multifunctional drug delivery system has potential bioimaging tracking of chemotherapeutic agents ability in vitro and in vivo for cancer therapy.