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1.
Front Chem ; 12: 1450339, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39286001

RESUMO

Our research is dedicated to combating HIV by targeting its Matrix (MA) domain, which is crucial for viral assembly and replication. This strategy specifically aims to interrupt early-stage infection and deter drug resistance by focusing on this essential domain. Due to the MA domain's conservation across different HIV strains, our approach promises broad-spectrum efficacy, which is particularly crucial in regions marked by significant genetic diversity and resistance issues. In our study, we introduce CNP0269688, a natural product that exhibits high affinity for the HIV-1 Matrix. Through detailed molecular dynamics simulations, we have assessed the compound's structural stability and interaction dynamics, particularly its potential to hinder Protein-tRNA interactions. This analysis lays the groundwork for future experimental investigations. Our efforts are steps toward enhancing HIV treatment, reducing viral transmission, and curbing drug resistance, with the ultimate aim of controlling and eradicating the pandemic, thereby contributing significantly to public health and scientific advancement.

2.
Phytother Res ; 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39091056

RESUMO

Pancreatic adenocarcinoma (PDAC) is one of the most lethal malignant tumors with an urgent need for precision medicine strategies. The present study seeks to assess the antitumor effects of fisetin, and characterize its impact on PDAC. Multi-omic approaches include proteomic, transcriptomic, and metabolomic analyses. Further validation includes the assessment of mitochondria-derived reactive oxygen species (mtROS), mitochondrial membrane potential, as well as ATP generation. Molecular docking, immunoprecipitation, and proximity ligation assay were used to detect the interactions among fiseitn, superoxide dismutase 2 (SOD2), and sirtuin 2 (SIRT2). We showed that fisetin disrupted mitochondrial homeostasis and induced SOD2 acetylation in PDAC. Further, we produced site mutants to determine that fisetin-induced mtROS were dependent on SOD2 acetylation. Fisetin inhibited SIRT2 expression, thus blocking SOD2 deacetylation. SIRT2 overexpression could impede fisetin-induced SOD2 acetylation. Additionally, untargeted metabolomic analysis revealed an acceleration of folate metabolism with fisetin. Collectively, our findings suggest that fisetin disrupts mitochondrial homeostasis, eliciting an important cancer-suppressive role; thus, fisetin may serve as a promising therapeutic for PDAC.

3.
Front Mol Biosci ; 11: 1441550, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39170746

RESUMO

Introduction: Drugs that target reactive oxygen species (ROS) metabolism have progressed the treatment of pancreatic cancer treatment, yet their efficacy remains poor because of the adaptation of cancer cells to high concentration of ROS. Cells cope with ROS by recognizing 8-oxoguanine residues and processing severely oxidized RNA, which make it feasible to improve the efficacy of ROS-modulating drugs in pancreatic cancer by targeting 8-oxoguanine regulators. Methods: Poly(rC)-binding protein 1 (PCBP1) was identified as a potential oncogene in pancreatic cancer through datasets of The Cancer Genome Atlas (TCGA) project and Gene Expression Omnibus (GEO). High-throughput virtual screening was used to screen out potential inhibitors for PCBP1. Computational molecular dynamics simulations was used to verify the stable interaction between the two compounds and PCBP1 and their structure-activity relationships. In vitro experiments were performed for functional validation of silychristin. Results: In this study, we identified PCBP1 as a potential oncogene in pancreatic cancer. By applying high-throughput virtual screening, we identified Compound 102 and Compound 934 (silychristin) as potential PCBP1 inhibitors. Computational molecular dynamics simulations and virtual alanine mutagenesis verified the structure-activity correlation between PCBP1 and the two identified compounds. These two compounds interfere with the PCBP1-RNA interaction and impair the ability of PCBP1 to process RNA, leading to intracellular R loop accumulation. Compound 934 synergized with ROS agent hydrogen peroxide to strongly improve induced cell death in pancreatic cancer cells. Discussion: Our results provide valuable insights into the development of drugs that target PCBP1 and identified promising synergistic agents for ROS-modulating drugs in pancreatic cancer.

4.
Crit Rev Eukaryot Gene Expr ; 34(5): 69-79, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38842205

RESUMO

Gastric cancer is a most malignancy in digestive tract worldwide. This study aimed to investigate the roles of protein arginine methyltransferase 6 (PRMT6) in gastric cancer. Immunohistochemistry was performed to detect PRMT6 expression in gastric tumors. Real-time transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to detected mRNA levels. Protein expression was determined using western blot. Gastric cancer cells were co-cultured with CD8+ T cells. Colony formation assay was performed to detect cell proliferation. Flow cytometry was performed to determine CD8+ T cell function and tumor cell apoptosis. PRMT6 was overexpressed in gastric tumors. High level of PRMT6 predicted poor outcomes of gastric cancer patients and inhibition of CD8+ T cell infiltration. PRMT6 promoted proliferation of CD8+ T cells and enhanced its tumor killing ability. Moreover, PRMT6 upregulated annexin A1 (ANXA1) and promoted ANXA1 protein stability. ANXA1 overexpression suppressed the proliferation of CD8+ T cells and promoted tumor cell survival. PRMT6 functions as an oncogene in gastric cancer. PRMT6-mediated protein stability inhibits the infiltration of CD8+ T cells, resulting in immune evasion of gastric cancer. The PRMT6-ANXA1 may be a promising strategy for gastric cancer.


Assuntos
Anexina A1 , Linfócitos T CD8-Positivos , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteína-Arginina N-Metiltransferases , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Humanos , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Anexina A1/genética , Anexina A1/metabolismo , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Regulação para Cima , Apoptose , Evasão Tumoral/genética , Masculino , Evasão da Resposta Imune , Feminino , Proteínas Nucleares
5.
Int J Biochem Cell Biol ; 169: 106548, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38360264

RESUMO

Lung cancer, the leading cause of cancer-related deaths, presents significant challenges to patients due to its poor prognosis. Recent research has increasingly implicated circular RNAs in the development and progression of lung cancer. These circular RNAs have been found to impact various aspects of tumor behavior, including proliferation, metastasis, cell cycle regulation, apoptosis, cancer stem cells, therapy response, and the tumor microenvironment. One of the key mechanisms by which circular RNAs exert their influence is through their ability to act as miRNA sponges, sequestering microRNAs and preventing them from targeting other RNA molecules. Accumulating evidence suggests that circular RNAs can function as competing endogenous RNAs, affecting the expression of target mRNAs by sequestering microRNAs. Dysregulation of competing endogenous RNAs networks involving circular RNAs, microRNAs, and mRNAs leads to the aberrant expression of oncogenes and tumor suppressors involved in lung cancer pathogenesis. Understanding the dynamic interplay and molecular mechanisms among circular RNAs, microRNAs, and mRNAs holds great promise for advancing early diagnosis, personalized therapeutic interventions, and improved patient outcomes in lung cancer. Therefore, this study aims to provide an in-depth exploration of the executive roles of circular RNAs/microRNAs/ mRNAs interactions in lung cancer pathogenesis and their potential utility for diagnosing lung cancer, predicting patient prognosis, and guiding targeted therapies. By offering a comprehensive overview of the dysregulation of the axes as driving factors in lung cancer, we aim to pave the way for their translation into clinical practice in the future.


Assuntos
Neoplasias Pulmonares , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Pulmonares/genética , Biologia , Redes Reguladoras de Genes , Microambiente Tumoral
7.
J Diabetes Complications ; 38(2): 108688, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38281457

RESUMO

Diabetes mellitus is a chronic metabolic disorder marked by hyperglycemia and systemic complications, including hepatic dysfunction, significantly contributing to disease progression and morbidity. This article reviews recent advances in gene-based therapeutic strategies targeting hepatic complications in diabetes, offering a promising approach for precision medicine by addressing underlying molecular mechanisms. Traditional treatments for hepatic complications in diabetes often manage symptoms rather than molecular causes, showing limited efficacy. Gene-based therapies are poised to correct dysfunctional pathways and restore hepatic function. Fundamental gene therapy approaches include gene silencing via small interfering RNAs (siRNAs) to target hepatic glucose production, lipid metabolism, and inflammation. Viral vectors can restore insulin sensitivity and reduce oxidative stress in diabetic livers. Genome editing, especially CRISPR-Cas9, allows the precise modification of disease-associated genes, offering immense potential for hepatic complication treatment. Strategies using CRISPR-Cas9 to enhance insulin receptor expression and modulate aberrant lipid regulatory genes are explored. Safety challenges in gene-based therapies, such as off-target effects and immune responses, are discussed. Advances in nanoparticle-based delivery systems and targeted gene editing techniques offer solutions to enhance specificity and minimize adverse effects. In conclusion, gene-based therapeutic approaches are a transformative direction in managing hepatic complications in diabetes. Further research is needed to optimize efficacy, safety, and long-term outcomes. Nevertheless, these innovative strategies promise to improve the lives of individuals with diabetes by addressing hepatic dysfunction's genetic root causes.


Assuntos
Sistemas CRISPR-Cas , Diabetes Mellitus , Humanos , Edição de Genes/métodos , Diabetes Mellitus/genética , Insulina/genética
8.
Transl Oncol ; 40: 101847, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38035445

RESUMO

BACKGROUND: Identifying biomarkers may lead to easier detection and a better understanding of pathogenesis of pancreatic ductal adenocarcinoma (PDAC). METHODS: Plasma small extracellular vesicles (sEV) from 106 participants, including 20 healthy controls (HC), 12 chronic pancreatitis (CP) patients, 12 benign pancreatic tumour (BPT) patients, and 58 PDAC patients, were profiled for microRNA (miRNA) sequencing. Three machine learning methods were applied to establish and evaluate the diagnostic model. RESULTS: The plasma sEV miRNA diagnostic signature (d-signature) selected using the three machine learning methods could distinguish PDAC patients from non-PDAC individuals, HC, and benign pancreatic disease (BPD, CP plus BPT) both in training and validation cohort. Combining the d-signature with carbohydrate antigen 19-9 (CA19-9) performed better than with each model alone. Plasma sEV miR-664a-3p was selected by all methods and used to predict PDAC diagnosis with high accuracy combined with CA19-9. Plasma sEV miR-664a-3p was significantly positively associated with the presence of vascular invasion, lower surgery ratio, and poor differentiation. MiR-664a-3p was mainly distributed in the PDAC cancer stroma, including fibers and vessels, and was accompanied by VEGFA expression. Overexpression of miR-664a-3p could promote the epithelial-mesenchymal transition (EMT) and angiogenesis. CONCLUSION: In conclusion, our study demonstrated the potential utility of the sEV-miRNA d-signature in the diagnosis of PDAC via machine learning methods. A novel sEV biomarker, miR-664a-3p, was identified for the diagnosis of PDAC. It can also potentially promote angiogenesis and metastasis, provide insight into PDAC pathogenesis, and reveal novel regulators of this disease.

9.
Biomed Pharmacother ; 169: 115821, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-37952355

RESUMO

Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, have emerged as critical mediators in the communication between the human microbiota and its host. As the first responder to the inflammatory site, neutrophils play an important role in protecting the host against bacterial infections. Recent investigations revealed that SCFAs generated from microbiota influence various neutrophil activities, including activation, migration, and generation of mediators of inflammatory processes. SCFAs have also been demonstrated to exhibit potential therapeutic benefits in a variety of disorders related to neutrophil dysfunction, including inflammatory bowel disease, viral infectious disorders, and cancer. This study aims to examine the molecular processes behind the complicated link between SCFAs and neutrophils, as well as their influence on neutrophil-driven inflammatory disorders. In addition, we will also provide an in-depth review of current research on the diagnostic and therapeutic value of SCFAs as possible biomarkers for neutrophil-related diseases.


Assuntos
Microbiota , Neutrófilos , Humanos , Ácidos Graxos Voláteis/farmacologia , Butiratos/farmacologia , Biomarcadores
10.
Cell Biosci ; 13(1): 176, 2023 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-37743465

RESUMO

BACKGROUND: Pancreatic cancer stem cells (CSCs) promote pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and chemoresistance. Cyclin-dependent kinase 1 (CDK1) plays an important role in tumor initiation in other tumors, but the function of CDK1 in PDAC remains unclear. Fisetin is a bioactive flavonoid with anti-tumor properties in multiple tumors, while its function in CSCs remains elusive. RESULTS: In this study, we demonstrated that CDK1 was correlated with prognosis and was highly expressed in pancreatic cancer tissue and gemcitabine-resistant cells. Silencing CDK1 impaired tumor stemness and reduced a subset of CSCs. We found that fisetin blocked the kinase pocket domain of CDK1 and inhibited pancreatic CSC characteristics. Using acetylation proteomics analysis and phosphorylation array assay, we confirmed that fisetin reduced CDK1 expression and increased CDK1 acetylation at lysine 33 (K33), which resulted in the suppression of CDK1 phosphorylation. Silencing CDK1 or STAT3 suppressed tumor stemness properties, while overexpressing CDK1 or STAT3 showed the opposite effect. Mutation or acetylation of CDK1 at K33 weakened STAT3 phosphorylation at Y705, impairing the expression of stem-related genes and pancreatic cancer stemness. In addition, lack of histone deacetylase 3 (HDAC3), which deacetylates CDK1, contributed to weakening STAT3 phosphorylation by regulating the post-translational modification of CDK1, thereby decreasing the stemness of PDAC. Moreover, our results revealed that fisetin enhanced the effect of gemcitabine through eliminating a subpopulation of pancreatic CSCs by inhibiting the CDK1-STAT3 axis in vitro and in vivo. CONCLUSION: Our findings highlight the role of post-translational modifications of CDK1-STAT3 signaling in maintaining cancer stemness of PDAC, and indicated that targeting the CDK1-STAT3 axis with inhibitors such as fisetin is a potential therapeutic strategy to diminish drug resistance and eliminate PDAC.

11.
Cell Biochem Biophys ; 81(3): 409-419, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37581721

RESUMO

Posttranslational modifications (PTMs) play important roles in the regulation of protein function. Acetylation and deacetylation are among the most important PTMs. SIRT7 is a relatively understudied member of the sirtuin family, but recent studies have revealed that it plays a regulatory role in a variety of cellular activities, such as genome stabilization and repair, gene translation, ribosome production and other important processes. Here, we provide a list of the functions and mechanisms of SIRT7 in various organelles and show the important role of SIRT7 in maintaining normal cell function.


Assuntos
Histonas , Sirtuínas , Histonas/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo
12.
Biomed Pharmacother ; 165: 115049, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37364480

RESUMO

The management and treatment of disease are achieved via the use of pharmacologically active substances or drugs. Drugs do not, however, have an intrinsic ability to be effective; rather, how well they work depends on how they are administered or supplied. Treatment of a variety of biological illnesses, such as autoimmune disorders, cancer, and bacterial infections, requires effective drug delivery. Drug absorption, distribution, metabolism, duration of therapeutic impact, pharmacokinetics, excretion, and toxicity can all be impacted by drug administration. Improved chemistry and materials are required for the delivery of therapeutic concentration of novel treatments to the specified targets within the body, as well as for the necessary duration of time. This requirement is accompanied by the development of new therapeutics. Formulating a medication as a DDS is a promising strategy for directly addressing numerous typical barriers to adherence, such as frequent dosage, such as frequent dosage, side effects, and a delayed beginning of the action. In the current review, we give a compendium of drug delivery and controlled release and subsequently highlight some of the newest developments in the realm, with a particular emphasis on cutting-edge methods for targeted therapy. In each instance, we outline the obstacles to efficient drug administration as well as the chemical and material developments that are allowing the sector to overcome these obstacles and have a positive clinical impact.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias , Humanos , Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas , Neoplasias/tratamento farmacológico
13.
J Proteome Res ; 22(7): 2516-2524, 2023 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-37126797

RESUMO

Exosomes are nanoscale, membrane-enclosed vesicles with contents similar to their parent cells, which are rich in potential biomarkers. Urine, as a noninvasive sampling body fluid, has the advantages of being simple to collect, stable in protein, diverse and not regulated by homeostatic mechanisms of the body, making it a favorable target for studying tumor biomarkers. In this report, the urinary exosomal proteome was analyzed and high-throughput downstream validation was performed using a supramolecular probe-based capture and in situ detection. The technology demonstrated the efficient enrichment of exosomes with a high concentration (5.5 × 1010 particles/mL) and a high purity (2.607 × 1010 particles/mg) of exosomes from urine samples. Proteomic analysis of urine samples from patients with hepatocellular carcinoma and healthy individuals combined with proteomic screening techniques revealed that 68 proteins were up-regulated in patients with hepatocellular carcinoma. As a proof-of-principle study, three of these differentially expressed proteins, including OLFM4, HDGF and GDF15, were validated using the supramolecular probe-based array (48 samples per batch). These findings demonstrate the great potential of this approach toward a liquid biopsy for the discovery and validation of biomarkers from urinary exosomes, and it can be extended to various biological samples with lower content of exosomes.


Assuntos
Carcinoma Hepatocelular , Exossomos , Neoplasias Hepáticas , Humanos , Exossomos/química , Proteômica , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Biomarcadores/metabolismo , Biomarcadores Tumorais/metabolismo , Proteoma/análise , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo
14.
Antibiotics (Basel) ; 12(5)2023 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-37237826

RESUMO

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

15.
Biochim Biophys Acta Gene Regul Mech ; 1866(2): 194941, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37146713

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a poor prognosis. As a tumor inhibitor, the specific tumor suppressor mechanism of Sirtuin4(SIRT4) in PDAC remains elusive. In this study, SIRT4 was found to inhibit PDAC by impacting mitochondrial homeostasis. SIRT4 deacetylated lysine 547 of SEL1L and increased the protein level of an E3 ubiquitin ligase HRD1. As a central member of ER-associated protein degradation (ERAD), HRD1-SEL1L complex is recently reported to regulate the mitochondria, though the mechanism is not fully delineated. Here, we found the increase in SEL1L-HRD1 complex decreased the stability of a mitochondrial protein, ALKBH1. Downregulation of ALKBH1 subsequently blocked the transcription of mitochondrial DNA-coded genes, and resulted in mitochondrial damage. Lastly, a putative SIRT4 stimulator, Entinostat, was identified, which upregulated the expression of SIRT4 and effectively inhibited pancreatic cancer in vivo and in vitro.


Assuntos
Degradação Associada com o Retículo Endoplasmático , Neoplasias Pancreáticas , Humanos , Mitocôndrias , Neoplasias Pancreáticas/genética , Homeostase , Enzimas AlkB , Homólogo AlkB 1 da Histona H2a Dioxigenase , Proteínas
16.
Front Oncol ; 13: 1064616, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36874133

RESUMO

Lung cancer is one of the most prevalent cancer types and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all cancer incidences. Lung cancer therapy and prognosis largely depend on the disease's degree at the diagnosis time. Cytokines are soluble polypeptides that contribute to cell-to-cell communication, acting paracrine or autocrine on neighboring or distant cells. Cytokines are essential for developing neoplastic growth, but they are also known to operate as biological inducers following cancer therapy. Early indications are that inflammatory cytokines such as IL-6 and IL-8 play a predictive role in lung cancer. Nevertheless, the biological significance of cytokine levels in lung cancer has not yet been investigated. This review aimed to assess the existing literature on serum cytokine levels and additional factors as potential immunotherapeutic targets and lung cancer prognostic indicators. Changes in serum cytokine levels have been identified as immunological biomarkers for lung cancer and predict the effectiveness of targeted immunotherapy.

17.
Molecules ; 28(3)2023 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-36770959

RESUMO

Hepatocellular carcinoma (HCC) accounts for the most common form of primary liver cancer cases and constitutes a major health problem worldwide. The diagnosis of HCC is still challenging due to the low sensitivity and specificity of the serum α-fetoprotein (AFP) diagnostic method. Extracellular vesicles (EVs) are heterogeneous populations of phospholipid bilayer-enclosed vesicles that can be found in many biological fluids, and have great potential as circulating biomarkers for biomarker discovery and disease diagnosis. Protein glycosylation plays crucial roles in many biological processes and aberrant glycosylation is a hallmark of cancer. Herein, we performed a comprehensive glycoproteomic profiling of urinary EVs at the intact N-glycopeptide level to screen potential biomarkers for the diagnosis of HCC. With the control of the spectrum-level false discovery rate ≤1%, 756 intact N-glycopeptides with 154 N-glycosites, 158 peptide backbones, and 107 N-glycoproteins were identified. Out of 756 intact N-glycopeptides, 344 differentially expressed intact N-glycopeptides (DEGPs) were identified, corresponding to 308 upregulated and 36 downregulated N-glycopeptides, respectively. Compared to normal control (NC), the glycoproteins LG3BP, PIGR and KNG1 are upregulated in HCC-derived EVs, while ASPP2 is downregulated. The findings demonstrated that specific site-specific glycoforms in these glycoproteins from urinary EVs could be potential and efficient non-invasive candidate biomarkers for HCC diagnosis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Glicoproteínas , Biomarcadores , Glicopeptídeos/análise , Biomarcadores Tumorais
18.
Anal Chem ; 95(5): 2812-2821, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36625718

RESUMO

Exosomes are an emerging source for disease biomarker discovery due to the high stability of proteins protected by phospholipid bilayers. However, liquid biopsy with exosomes remains challenging due to the extreme complexity of biological samples. Herein, we introduced an amphiphile-dendrimer supramolecular probe (ADSP) for the efficient capture and high-throughput analysis of exosomes, enabling the array-based assay for marker proteins. Amphiphilic amphotericin B was functionalized onto highly branched globular dendrimers, which can then insert into the exosome membrane efficiently, forming a supramolecular complex through multivalent interactions between the probe and the bilayer of exosomes. The ADSP can be easily coated onto magnetic beads or the nitrocellulose membrane, facilitating the capture of exosomes from a minimum amount of clinical samples. The captured exosomes can be detected with target protein antibodies via Western blotting or in a high-throughput array-based dot blotting format. This new strategy exhibited excellent extraction capability from trace body fluids with superior sensitivity (less than 1 µL plasma), good quantitation ability (R2 > 0.99), and high throughput (96 samples in one batch) using clinical plasma samples. The combination of proteomics and ADSP will provide a platform for the discovery and validation of protein biomarkers for cancer diagnosis and prognosis.


Assuntos
Exossomos , Exossomos/química , Biomarcadores/metabolismo , Proteínas/metabolismo , Western Blotting , Plasma/química , Biomarcadores Tumorais/análise
19.
Cytotechnology ; 74(6): 657-667, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36389286

RESUMO

Pancreatic cancer is one of the deadliest malignancies. Three-dimensional (3D) pancreatic cancer cell models for drug screening have been established to improve treatment for pancreatic cancer. However, few studies focus on different drug responses and drug-related molecular mechanisms in various types of 3D cell models. In this study, we constructed 3D scaffold-free cell models and 3D scaffold-based cell models of pancreatic cancer, evaluated chemotherapeutic drug responses in different 3D models, assessed clinical relevance of the models, and investigated molecular mechanisms of chemoresistance and drug pathways in different 3D models. Both types of 3D models showed resistance to chemotherapeutic drugs, and scaffold-based pancreatic cancer models could better reflect in vivo drug efficacy than 2D and scaffold-free pancreatic cancer models did. Increased cell adhesion, extracellular matrix (ECM) synthesis and drug transport were essential for drug resistance in 3D models, and anti-apoptosis might contribute to extreme chemoresistance in scaffold-free models. Moreover, scaffold-based pancreatic cancer models were more suitable than scaffold-free models for drug pathway research.

20.
Appl Opt ; 61(20): 5934-5943, 2022 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-36255832

RESUMO

A key challenge in tailoring compact and high-performance illumination lenses for extended non-Lambertian sources is to take both the étendue and the radiance distribution of an extended non-Lambertian source into account when redirecting the light rays from the source. We develop a direct method to tailor high-performance illumination lenses with prescribed irradiance properties for extended non-Lambertian sources. A relationship between the irradiance distribution on a given observation plane and the radiance distribution of the non-Lambertian source is established. Both edge rays and internal rays emanating from the extended light source are considered in the numerical calculation of lens profiles. Three examples are given to illustrate the effectiveness and characteristics of the proposed method. The results show that the proposed method can yield compact and high-performance illumination systems in both the near field and far field.

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