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Antibody-drug conjugates (ADCs), which combine the precise targeting capabilities of antibodies with the powerful cytotoxicity of small-molecule drugs, have evolved into a promising approach for tumor treatment. However, the traditional covalent coupling method requires the design of a specific linker tailored to the properties of the small-molecule drugs, which greatly limits the development of ADCs and the range of drugs that can be used. Herein, a novel type of antibody-calixarene drug conjugates (ACDCs) that function similarly to ADCs by delivering drugs to their targets using antibodies but without the requirement of covalent conjugation of the drugs with antibodies is presented. By replacement of conventional linkers with supramolecular linkers, the ACDCs can load various chemotherapeutic drugs through host-guest interactions. Furthermore, ACDCs are readily reduced upon reaching the hypoxic microenvironment, resulting in rapid release of the drugs. With this precise drug encapsulation and controlled release mechanism, ACDCs deliver drugs to tumor tissues effectively and achieve a significantly enhanced antitumor effect. Considering that the ACDCs can be easily prepared by combining antibody-calixarene conjugates derived from tumor-targeting antibodies with various small-molecule drugs, ACDCs may provide a promising platform technology to accelerate ADC development and thus improve the therapeutic efficacy of chemotherapy.
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Antineoplásicos , Calixarenos , Imunoconjugados , Calixarenos/química , Imunoconjugados/química , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Humanos , Animais , Camundongos , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Camundongos Endogâmicos BALB C , Portadores de Fármacos/química , Feminino , Liberação Controlada de FármacosRESUMO
BACKGROUND: Traumatic brain injury (TBI) could induce multiple forms of cell death, ferroptosis, a novel form of cell death distinct from apoptosis and autophagy, plays an important role in disease progression in TBI. Therapies targeting ferroptosis are beneficial for recovery from TBI. Paeoniflorin (Pae) is a water-soluble monoterpene glycoside and the active ingredient of Paeonia lactiflora pall. It has been shown to exert anti-inflammatory and antioxidant effects. However The effects and mechanisms of paeoniflorin on secondary injury after TBI are unknown. PURPOSE: To investigate the mechanism by which Pae regulates ferroptosis after TBI. METHODS: The TBI mouse model and cortical primary neurons were utilized to study the protective effect of paeoniflorin on the brain tissue after TBI. The neuronal cell ferroptosis model was established by treating cortical primary neurons with erastin. Liproxstatin-1(Lip-1) was used as a positive control drug. Immunofluorescence staining, Nissl staining, biochemical analyses, pharmacological analyses, and western blot were used to evaluate the effects of paeoniflorin on TBI. RESULTS: Pae significantly ameliorated neuronal damage after TBI, inhibited mitochondrial damage, increased glutathione peroxidase 4 (GPX4) activity, decreased malondialdehyde (MDA) production, restored neurological function and inhibited cerebral edema. Pae promotes the degradation of P53 in the form of proteasome, promotes its ubiquitination, and reduces the stability of P53 by inhibiting its acetylation, thus alleviating the P53-mediated inhibition of cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) by P53. CONCLUSION: Pae inhibits ferroptosis by promoting P53 ubiquitination out of the nucleus, inhibiting P53 acetylation, and modulating the SLC7A11-GPX4 pathway.
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BACKGROUND: Clinical trials support the efficacy of immune checkpoint blockades (ICBs) plus chemotherapy in a subset of patients with metastatic gastric cancer (mGC). To identify the determinants of response, we developed a TMEscore model to assess tumor microenvironment (TME), which was previously proven to be a biomarker for ICBs. METHODS: A reference database of TMEscore assays was established using PCR assay kits containing 30 TME genes. This multi-center prospective clinical trial (NCT#04850716) included patients with mGC who were administered ICB combined with chemotherapy as a first-line regimen. Eighty-six tumor samples extracted from five medical centers before treatment were used to estimate the TMEscore, PD-L1 (CPS), and mismatch repair deficiency. FINDINGS: The objective response rate (ORR) and median PFS of the cohort were 31.4% and six months. Enhanced ORR was observed in TMEscore-high mGC patients (ORR = 59%). The survival analysis demonstrated that high TMEscore was significantly associated with a more favorable PFS and OS. Moreover, TMEscore was found to be a predictive biomarker that surpassed MSI and CPS (AUC = 0.873, 0.511, and 0.524, respectively). By integrating the TMEscore and clinical variables, the fused model further enhances the predictive efficiency and translational application in a clinical setting. CONCLUSIONS: This prospective clinical study indicates that the TMEscore assay is a robust biomarker for screening patients with mGC who may derive survival benefits from ICB plus chemotherapy. FUNDING: Guangdong Basic and Applied Basic Research Foundation (2023A1515011214), Science and Technology Program of Guangzhou (202206080011), and Guangzhou Science and Technology Project (2023A03J0722 and 2023A04J2357).
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BACKGROUND: Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process. METHODS: Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation. RESULTS: We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis. CONCLUSIONS: Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.
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Leptina , Lipase Lipoproteica , Metástase Linfática , Neoplasias Gástricas , Lipase Lipoproteica/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Humanos , Animais , Camundongos , Leptina/metabolismo , Metabolismo dos Lipídeos , Masculino , Linhagem Celular Tumoral , Proteína 4 Semelhante a Angiopoietina/metabolismo , Feminino , FosforilaçãoAssuntos
Hidroxiureia , Esplenectomia , Trombocitose , Talassemia beta , Humanos , Hidroxiureia/uso terapêutico , Trombocitose/etiologia , Trombocitose/tratamento farmacológico , Talassemia beta/tratamento farmacológico , Talassemia beta/complicações , Talassemia beta/cirurgia , Masculino , Feminino , Antidrepanocíticos/uso terapêutico , CriançaRESUMO
Exogenous insulin-like growth factor-1 (IGF-1) has been reported to promote wound healing through regulation of vascular endothelial cells (VECs). Despite the existing studies of IGF-1 on VEC and its role in angiogenesis, the mechanisms regarding anti-inflammatory and angiogenetic effects of IGF-1 remain unclear. In this study, we investigated the wound-healing process and the related signaling pathway of IGF-1 using an inflammation model induced by IFN-γ. The results demonstrated that IGF-1 can increase cell proliferation, suppress inflammation in VECs, and promote angiogenesis. In vivo studies further confirmed that IGF-1 can reduce inflammation, enhance vascular regeneration, and improve re-epithelialization and collagen deposition in acute wounds. Importantly, the Ras/PI3K/IKK/NF-κB signaling pathways was identified as the mechanisms through which IGF-1 exerts its anti-inflammatory and pro-angiogenic effects. These findings contribute to the understanding of IGF-1's role in wound healing and may have implications for the development of new wound treatment approaches.
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Inflamação , Fator de Crescimento Insulin-Like I , NF-kappa B , Transdução de Sinais , Cicatrização , Fator de Crescimento Insulin-Like I/metabolismo , Animais , Cicatrização/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Inflamação/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas ras/metabolismo , Masculino , Quinase I-kappa B/metabolismo , Proliferação de Células/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Interferon gama/metabolismo , Interferon gama/farmacologia , AngiogêneseRESUMO
BACKGROUND: Effective management of cancer pain critically depends on timely medication administration and adherence to precise medication guidelines. In the context of limited time and a busy healthcare environment, tailoring the optimal medication schedule for each patient with cancer pain presents a significant challenge for physicians and clinical pharmacists. METHODS: To address this challenge, we conducted a comprehensive analysis of healthcare professionals' needs in guiding cancer pain medication. By developing core features based on key user needs and continuously updating them, we have created the Universal Medication Schedule System (UMSS). We invited 20 physicians and pharmacists specializing in oncology or cancer pain to trial the system and assessed UMSS usage through distributed questionnaires. RESULTS: We identified five key needs of healthcare professionals in cancer pain medication guidance. Based on these needs, we (1) constructed a comprehensive drug information database, including basic information for 1135 drugs, 130,590 drug interaction data entries, and 1409 individual medication timing constraints, and (2) developed a web-based system that provides essential reference information such as drug interactions and dietary restrictions. It can create medication schedules and provide medication education tailored to the patient's daily routine. Participating evaluators unanimously agreed (100%) that the system aids in accurately assessing the risks of polypharmacy and quickly scheduling medication regimens. CONCLUSION: UMSS, by offering personalized medication schedule support, assists healthcare professionals in better managing patients' medication treatment plans. However, further improvements are needed in the automation of database updates and maintenance, as well as in integrating it with electronic health records.
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Dor do Câncer , Humanos , Dor do Câncer/tratamento farmacológico , Farmacêuticos/organização & administração , Inquéritos e Questionários , Esquema de Medicação , Pessoal de Saúde , Assistência Farmacêutica/organização & administração , Manejo da Dor/métodos , Analgésicos/administração & dosagem , Analgésicos/uso terapêuticoRESUMO
BACKGROUD: Li-Fraumeni syndrome is a hereditary tumor syndrome characterized by an elevated risk of malignancy, particularly acute lymphoblastic leukemia (ALL), which can be caused by the heterozygous germline mutation. TP53 gene germline mutation is considered a potential risk factor and crucial prognostic parameter for acute leukemia development and diagnosis, but rarely occurs in adults, and its specific pathogenic significance in acute leukemia is unclear. CASE PRESENTATION: We describes a case of a 45-year-old woman diagnosed with ALL. Whole-exome sequencing approach identified one of the TP53 germline mutations from her bone marrow sample with possible pathogenic significance, c.848G>A (p.Arg283His) heterozygous missense mutation located on exon 8, which was further verified in her hair, oral mucous and nail samples. Family pedigree screening revealed that the same TP53 genetic variant was present in the patient's father and non-donor son, whereas not in the donor. Digital PCR observed that this point mutation frequency dropped post-transplantation but remained low during maintenance therapy when the patient was leukemia-free. CONCLUSION: This suspected Li-Fraumeni syndrome case report with a likely pathogenic heterozygous TP53 variant expands the cancer genetic spectrum. Screening her family members for mutations facilitates identifying the optimal relative donor and avoids unnecessary treatment by monitoring TP53 germline mutations for minimal residual disease following hematopoietic stem cell transplantation. Its potential roles in hematological malignant tumor development and clinical pathogenic implications necessitate further probing.
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Mutação em Linhagem Germinativa , Síndrome de Li-Fraumeni , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteína Supressora de Tumor p53 , Humanos , Feminino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/genética , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/diagnóstico , LinhagemRESUMO
Chronic myeloid leukaemia (CML) is a haematological malignancy characterized by the constitutive tyrosine kinase activity of the BCR-ABL1 fusion protein. Flumatinib, a second-generation tyrosine kinase inhibitor, has exhibited superior clinical efficacy compared to its precursor, imatinib. However, with increased clinical use, resistance to flumatinib has emerged as a significant challenge. To investigate the mechanisms of flumatinib resistance in CML, we induced the human CML cell line K562 using a flumatinib concentration gradient method in vitro, successfully establishing a flumatinib-resistant K562/FLM cell line. This cell line exhibited cross-resistance to imatinib and doxorubicin, but remained sensitive to the antiparasitic agent ivermectin, which possesses antitumoural effects. Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins. Moreover, it was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. Collectively, the increased autophagy, higher expression of drug-efflux proteins and hyperactivation of the EGFR/ERK/STAT3 signalling pathway were identified as pivotal elements promoting resistance to flumatinib. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML.
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Resistencia a Medicamentos Antineoplásicos , Ivermectina , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ivermectina/farmacologia , Células K562 , Autofagia/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mesilato de Imatinib/farmacologia , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Linhagem Celular TumoralRESUMO
Spinal cord injury (SCI) is a severe traumatic condition in spinal surgery characterized by nerve damage in and below the injured area. Despite advancements in understanding the pathophysiology of SCI, effective clinical treatments remain elusive. Selenium compounds have become a research hotspot due to their diverse medicinal activities. Previously, our group synthesized a selenium-containing Compound 34# with significant anti-inflammatory activity. This study aimed to explore the anti-SCI effects of selenium-containing compounds using network pharmacology, molecular docking (MD), and ADMET methods. To identify SCI-related targets and those associated with 34#, GeneCards, NCBI, and SEA databases were employed. Eight overlapping targets were considered candidate targets, and molecular docking was performed using the PDB database and AutoDock software. The STRING database was used to obtain protein-protein interactions (PPI). Molecular dynamics simulation, MM/GBSA binding free energy score, and ADMET prediction were used to evaluate the potential targets and drug properties of 34#. Finally, experiments on NSC34 cells and mice were to verify the effects of 34# on SCI. Our results revealed eight candidate targets for 34# in the treatment of SCI. PPI and MD identified ADRB2 and HTR1F as the highest connectivity with 34#. ADMET analysis confirmed the low toxicity and safety of 34#. In vitro and in vivo models validated the anti-SCI effects. Our study elucidated candidate targets for alleviating SCI with 34#, explored PPI and target-related signaling pathways, and validated its anti-SCI effects. These findings enhance our understanding of 34#'s mechanism in treating SCI, positioning it as a potential candidate for SCI prevention.
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ETHNOPHARMACOLOGICAL RELEVANCE: Abrus cantoniensis Hance (ACH), known as Jigucao (Chinese: ) has been used in ethnopharmacology for a long history with therapeutic effects for clearing heat, soothing the liver, especially in treating acute and chronic hepatitis which was very effective. In southern China, such as Guangdong and Guangxi, people often use ACH in soup or herbal tea as dietetic therapy. AIM OF THE REVIEW: This paper aims to review ACH's ethnopharmacology, phytochemistry, and pharmacological activity systematically, at the same time, we also hope to provide more research avenues between traditional uses and pharmacological properties. MATERIAL AND METHODS: Through PubMed, Wan Fang Database, CNKI, Web of Science, EBSCO Database, and Google Scholar search for relevant literature in both Chinese and English, the keywords "Abrus cantoniensis, Abrus cantoniensis Hance, Jigucao, pharmacology, chemical constituents, clinical application, network pharmacology" were used alone or combination. RESULTS: Traditionally, ACH was believed to have the effect of soothing the liver, clearing heat, and detoxifying, often used to treat diseases of the liver and inflammation. Modern pharmacological research indicates that ACH has liver protection, anti-inflammation, anti-oxidant, immunomodulation, anti-tumor effects and so on. Whether it was a single chemical compound or an extract from ACH, studies have found that it has abundant pharmacological activities, these were the fundamental sources of traditional uses, like liver protection and anti-inflammation. CONCLUSIONS: A systematic review found that modern phytochemistry and pharmacodynamic research reports on ACH are closely related to its traditional uses, especially its hepatoprotective and anti-inflammatory effects. Modern research has also further explored and expanded the effects of ACH, such as its anti-tumor effect. And all these efforts are gradually filling the gap between traditional uses and modern pharmacology. In general, the current research on the pharmacodynamic mechanism of ACH still needs further in-depth research, and the strategies adopted must also be further strengthened.
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Abrus , Etnofarmacologia , Medicina Tradicional Chinesa , Compostos Fitoquímicos , Humanos , Medicina Tradicional Chinesa/métodos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Animais , Abrus/química , Fitoterapia , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/uso terapêuticoRESUMO
Glioma, a malignant and infiltrative neoplasm of the central nervous system, poses a significant threat due to its high mortality rates. Branched-chain amino acid transaminase 1 (BCAT1), a key enzyme in branched-chain amino acid (BCAA) catabolism, exhibits elevated expression in gliomas and correlates strongly with poor prognosis. Nonetheless, the regulatory mechanisms underlying this increased BCAT1 expression remains incompletely understood. In this study, we reveal that ubiquitination at Lys360 facilitates BCAT1 degradation, with low ubiquitination levels contributing to high BCAT1 expression in glioma cells. The Carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, interacts with BCAT1 via its coiled-coil (CC) domain, promoting its K48-linkage ubiquitin degradation through proteasomal pathway. Moreover, CHIP-mediated BCAT1 degradation induces metabolic reprogramming, and impedes glioma cell proliferation and tumor growth both in vitro and in vivo. Furthermore, a positive correlation is observed between low CHIP expression, elevated BCAT1 levels, and unfavorable prognosis among glioma patients. Additionally, we show that the CHIP/BCAT1 axis enhances glioma sensitivity to temozolomide by reducing glutathione (GSH) synthesis and increasing oxidative stress. These findings underscore the critical role of CHIP/BCAT1 axis in glioma cell proliferation and temozolomide sensitivity, highlighting its potential as a diagnostic marker and therapeutic target in glioma treatment.
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Proliferação de Células , Glioma , Temozolomida , Transaminases , Ubiquitina-Proteína Ligases , Ubiquitinação , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proliferação de Células/efeitos dos fármacos , Glioma/metabolismo , Glioma/patologia , Glioma/genética , Glioma/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Transaminases/metabolismo , Transaminases/genética , Camundongos , Camundongos Nus , Ubiquitina/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamento farmacológico , Proteólise/efeitos dos fármacos , Masculino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , FemininoRESUMO
This study aimed to explore the moderating role of socioeconomic status (SES) in the association between multimorbidity and health-related quality of life (HRQOL) among cancer patients in Anhui China. A total of 560 cancer patients were recruited for the cross-section study. Socio-demographic and clinical characteristics were analyzed using descriptive statistics. Tobit regression analysis was employed to investigate the relationship between multimorbidity and HRQOL as well as to assess the moderating effect of SES. The research findings indicated that 76.61% of cancer patients experienced multimorbidity, with psychological multimorbidity being the most prevalent (45.54%), followed by physical-psychological multimorbidity (20.89%). Moreover, physical-psychological multimorbidity had the most substantial adverse effect on HRQOL (P < .001). The presence of multimorbidity was correlated with a significant decline in HRQOL, with a 17.5% (P < .001) decrease in HRQOL for each additional multimorbidity. Additionally, SES played a significant role in moderating the impact of multimorbidity on HRQOL in cancer patients. (Marginal effect = -0.022, P < .01). The high SES group exhibited a higher overall HRQOL than the low SES group (Marginal effect = 0.068, P < .001). And with the increase of multimorbidity, HRQOL in the higher SES showed a more pronounced downward trend, compared with the lower SES (ß = -.270 vs ß = -.201, P < .001). Our findings underscore the importance of preventing and managing multimorbidity in cancer patients, particularly those with low SES. Furthermore, it is essential to consider the impact of the rapid decline in HRQOL as the number of multimorbidity increases in individuals with higher SES. It is imperative to explore interdisciplinary and continuous collaborative management models.
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Multimorbidade , Neoplasias , Qualidade de Vida , Classe Social , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , China/epidemiologia , Estudos Transversais , Idoso , Adulto , Fatores SocioeconômicosRESUMO
Aberrant activation of thioredoxin reductase (TrxR) is correlated with tumor occurrence and progression, suggesting that TrxR inhibitors can be used as antitumor agents. In this study, we evaluated the anticancer efficacy of eupalinilides B on colorectal cancer cells. Eupalinilides B primarily targeted the conserved selenocysteine 498 residues in TrxR. Besides, it inhibited the enzyme activity in an irreversible manner. After eupalinilides B was used to pharmacologically inhibit TrxR, reactive oxygen species accumulated, and the intracellular redox balance was broken, finally causing oxidative stress-induced tumor cell apoptosis. Significantly, eupalinilides B treatment inhibited in vivo tumor growth. Targeting TrxR by eupalinilides B reveals the new mechanism underlying eupalinilides B and provides insight in developing eupalinilides B as the candidate antitumor chemotherapeutic agent for the treatment of cancer.
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Antineoplásicos , Apoptose , Neoplasias Colorretais , Espécies Reativas de Oxigênio , Tiorredoxina Dissulfeto Redutase , Apoptose/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/metabolismo , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Humanos , Animais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Estresse Oxidativo/efeitos dos fármacosRESUMO
BACKGROUND: Tertiary lymphoid structures (TLSs) exert a crucial role in the tumor microenvironment (TME), impacting tumor development, immune escape, and drug resistance. Nonetheless, the heterogeneity of TLSs in colorectal cancer (CRC) and their impact on prognosis and treatment response remain unclear. METHODS: We collected genome, transcriptome, clinicopathological information, and digital pathology images from multiple sources. An unsupervised clustering algorithm was implemented to determine diverse TLS patterns in CRC based on the expression levels of 39 TLS signature genes (TSGs). Comprehensive explorations of heterogeneity encompassing mutation landscape, TME, biological characteristics, response to immunotherapy, and drug resistance were conducted using multi-omics data. TLSscore was then developed to quantitatively assess TLS patterns of individuals for further clinical applicability. RESULTS: Three distinct TLS patterns were identified in CRC. Cluster 1 exhibited upregulation of proliferation-related pathways, high metabolic activity, and intermediate prognosis, while Cluster 2 displayed activation of stromal and carcinogenic pathways and a worse prognosis. Both Cluster 1 and Cluster 2 may potentially benefit from adjuvant chemotherapy. Cluster 3, characterized by the activation of immune regulation and activation pathways, demonstrated a favorable prognosis and enhanced responsiveness to immunotherapy. We subsequently employed a regularization algorithm to construct the TLSscore based on 9 core genes. Patients with lower TLSscore trended to prolonged prognosis and a more prominent presence of TLSs, which may benefit from immunotherapy. Conversely, those with higher TLSscore exhibited increased benefits from adjuvant chemotherapy. CONCLUSIONS: We identified distinct TLS patterns in CRC and characterized their heterogeneity through multi-omics analyses. The TLSscore held promise for guiding clinical decision-making and further advancing the field of personalized medicine in CRC.
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Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an important role in the occurrence and development of human tumors. However, the function and mechanism of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an RNA-binding protein and m6A reader in gliomas remains to be comprehensively and extensively explored. Herein, we found that HNRNPC mRNA and protein overexpression were associated with a poor prognosis for patients with gliomas, based on the data from TCGA, the CGGA, and the TMAs. Biologically, HNRNPC knockdown markedly repressed malignant phenotypes of glioma in vitro and in vivo, whereas ectopic HNRNPC expression had the opposite effect. Integrative RNA sequencing and MeRIP sequencing analyses identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a downstream target of HNRNPC. The glioma public datasets and tissue microarrays (TMAs) data indicated that IRAK1 overexpression was associated with poor prognosis, and IRAK1 knockdown significantly repressed malignant biological behavior in vitro. Mechanistically, HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which was necessary for the malignant behavior of glioma. Our findings demonstrate the HNRNPC-IRAK1-MAPK axis as a crucial carcinogenic factor for glioma and the novel underlying mechanism of IRAK1 upregulation, which provides a rationale for therapeutically targeting epitranscriptomic modulators in glioma.
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Progressão da Doença , Glioma , Ribonucleoproteínas Nucleares Heterogêneas Grupo C , Quinases Associadas a Receptores de Interleucina-1 , Sistema de Sinalização das MAP Quinases , RNA Mensageiro , Humanos , Glioma/genética , Glioma/patologia , Glioma/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Quinases Associadas a Receptores de Interleucina-1/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Linhagem Celular Tumoral , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Estabilidade de RNA/genética , Camundongos Nus , Animais , Regulação Neoplásica da Expressão Gênica , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Feminino , Masculino , Adenosina/análogos & derivados , Adenosina/metabolismo , PrognósticoRESUMO
INTRODUCTION: We conducted analyses of the association between smoking and osteoporosis and osteoporotic fractures using a secondary dataset analysis of the National Health and Nutrition Examination Survey (NHANES) database and the two-sample Mendelian randomization (MR) method. METHODS: The associations between smoking and osteoporosis or osteoporotic fractures were analyzed using weighted logistic regression models for both univariate and multivariable analyses using pooled 1999-2018 NHANES data. The summary-level data of genome-wide association studies (GWAS) of smoking and osteoporosis were extracted from the IEU Open GWAS project. The inverse variance weighted method was used as the main method for the two-sample MR analysis. RESULTS: We obtained the following main findings based on the NHANES data: smoking was associated with osteoporosis according to the analyses of 30856 participants (OR=1.21; 95% CI: 1.06-1.39, p=0.004); smoking was associated with hip osteoporotic fracture according to the analyses of 30928 participants (OR=1.47; 95% CI: 1.14-1.90, p=0.004); smoking was associated with wrist osteoporotic fracture according to the analyses of 30923 participants (OR=1.33; 95% CI: 1.18-1.49, p<0.001); and smoking was associated with spine osteoporotic fracture according to the analyses of 30910 participants (OR=1.43, 95% CI: 1.18-1.73, p<0.001). In addition, we confirmed the potential causal effect of smoking on the risk of osteoporotic fracture (OR=24.5; 95% CI: 1.11-539, p=0.043) by conducting two-sample MR analyses. CONCLUSIONS: Smoking was associated with increased risks of both osteoporosis and osteoporotic fracture. Smoking showed a potential causal effect on the risk of osteoporotic fracture.
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In the realm of large-area trauma flap transplantation, averting ischaemic necrosis emerges as a pivotal concern. Several key mechanisms, including the promotion of angiogenesis, the inhibition of oxidative stress, the suppression of cell death, and the mitigation of inflammation, are crucial for enhancing skin flap survival. Apoptotic bodies (ABs), arising from cell apoptosis, have recently emerged as significant contributors to these functions. This study engineered three-dimensional (3D)-ABs using tissue-like mouse adipose-derived stem cells (mADSCs) cultured in a 3D environment to compare their superior biological effects against 2D-ABs in bolstering skin flap survival. The findings reveal that 3D-ABs (85.74 ± 4.51) % outperform 2D-ABs (76.48 ± 5.04) % in enhancing the survival rate of ischaemic skin flaps (60.45 ± 8.95) % (all p < 0.05). Mechanistically, they stimulated angiogenesis, mitigated oxidative stress, suppressed apoptosis, and facilitated the transition of macrophages from M1 to M2 polarization (all p < 0.05). A comparative analysis of microRNA (miRNA) profiles in 3D- and 2D-ABs identified several specific miRNAs (miR-423-5p-up, miR30b-5p-down, etc.) with pertinent roles. In summary, ABs derived from mADSCs cultured in a 3D spheroid-like arrangement exhibit heightened biological activity compared to those from 2D-cultured mADSCs and are more effective in promoting ischaemic skin flap survival. These effects are attributed to their influence on specific miRNAs.
Assuntos
Tecido Adiposo , Apoptose , Técnicas de Cultura de Células , Isquemia , Células-Tronco , Células Cultivadas , Humanos , Animais , Camundongos , Células-Tronco/citologia , Células-Tronco/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Células/métodos , Separação Celular/métodos , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Isquemia/genética , Isquemia/patologia , Hipóxia Celular , Sobrevivência Celular , MicroRNAs/genética , Estresse Oxidativo , Neovascularização Patológica , Perfilação da Expressão GênicaRESUMO
A smartphone-based electrochemical aptasensing platform was developed for the point-of-care testing (POCT) of carcinoembryonic antigen (CEA) based on the ferrocene (Fc) and PdPt@PCN-224 dual-signal labeled strategy. The prepared PdPt@PCN-224 nanocomposite showed a strong catalytic property for the reduction of H2O2. Phosphate group-labeled aptamer could capture PdPt@PCN-224 by Zr-O-P bonds to form PdPt@PCN-224-P-Apt. Therefore, a dual signal labeled probe was formed by the hybridization between Fc-DNA and PdPt@PCN-224-P-Apt. The presence of CEA forced PdPt@PCN-224-P-Apt to leave the electrode surface due to the specific affinity, leading to the decrease of the reduction current of H2O2. At the same time, the Fc-DNA strand changed to hairpin structure, which made Fc closer to the electrode and resulted in the increase of the oxidation current of Fc. Thus, CEA can be accurately determined through both signals: the decrease of H2O2 reduction current and the increase of Fc oxidation current, which could avoid the false positive signal. Under the optimal conditions, the prepared aptasensor exhibited a wide linear range from 1 pg·mL-1 to 100 ng·mL-1 and low detection limits of 0.98 pg·mL-1 and 0.27 pg·mL-1 with Fc and PdPt@PCN-224 as signal labels, respectively. The aptasensor developed in this study has successfully demonstrated its capability to detect CEA in real human serum samples. These findings suggest that the proposed sensing platform will hold great potential for clinical tumor diagnosis and monitoring.
Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Antígeno Carcinoembrionário , Técnicas Eletroquímicas , Compostos Ferrosos , Peróxido de Hidrogênio , Limite de Detecção , Paládio , Testes Imediatos , Smartphone , Antígeno Carcinoembrionário/sangue , Antígeno Carcinoembrionário/análise , Aptâmeros de Nucleotídeos/química , Técnicas Eletroquímicas/métodos , Técnicas Eletroquímicas/instrumentação , Humanos , Técnicas Biossensoriais/métodos , Peróxido de Hidrogênio/química , Paládio/química , Compostos Ferrosos/química , Metalocenos/química , Platina/químicaRESUMO
In this editorial we comment on the review by Wang et al published in the recent issue of the World Journal of Gastroenterology in 2023. Small extracellular vesicles (exosomes) play important roles in the tumor microenvironment. In this review, the authors introduce the following points: (1) The composition and function of exosomal microRNAs (miRNAs) of different cell origins in hepatocellular carcinoma (HCC); (2) the crosstalk between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC; and (3) the potential applicability of exosomal miRNAs derived from mesen-chymal stem cells in the treatment of HCC. In addition, the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC was introduced. In this review, the authors give us an overview of the exosomal RNA and summarize the function of exosomal RNA in HCC, which provides a deeper understanding of exosomal miRNAs to the readers.