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1.
Cell ; 187(11): 2703-2716.e23, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38657602

RESUMO

Antigen presentation defects in tumors are prevalent mechanisms of adaptive immune evasion and resistance to cancer immunotherapy, whereas how tumors evade innate immunity is less clear. Using CRISPR screens, we discovered that IGSF8 expressed on tumors suppresses NK cell function by interacting with human KIR3DL2 and mouse Klra9 receptors on NK cells. IGSF8 is normally expressed in neuronal tissues and is not required for cell survival in vitro or in vivo. It is overexpressed and associated with low antigen presentation, low immune infiltration, and worse clinical outcomes in many tumors. An antibody that blocks IGSF8-NK receptor interaction enhances NK cell killing of malignant cells in vitro and upregulates antigen presentation, NK cell-mediated cytotoxicity, and T cell signaling in vivo. In syngeneic tumor models, anti-IGSF8 alone, or in combination with anti-PD1, inhibits tumor growth. Our results indicate that IGSF8 is an innate immune checkpoint that could be exploited as a therapeutic target.


Assuntos
Imunidade Inata , Imunoterapia , Células Matadoras Naturais , Neoplasias , Animais , Feminino , Humanos , Camundongos , Apresentação de Antígeno , Linhagem Celular Tumoral , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/terapia
2.
Mol Cell ; 84(2): 202-220.e15, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38103559

RESUMO

Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising anticancer agents. Nevertheless, side effects and drug resistance pose significant obstacles in BET-based therapeutics development. Using high-throughput screening of a 200,000-compound library, we identified small molecules targeting a phosphorylated intrinsically disordered region (IDR) of BRD4 that inhibit phospho-BRD4 (pBRD4)-dependent human papillomavirus (HPV) genome replication in HPV-containing keratinocytes. Proteomic profiling identified two DNA damage response factors-53BP1 and BARD1-crucial for differentiation-associated HPV genome amplification. pBRD4-mediated recruitment of 53BP1 and BARD1 to the HPV origin of replication occurs in a spatiotemporal and BRD4 long (BRD4-L) and short (BRD4-S) isoform-specific manner. This recruitment is disrupted by phospho-IDR-targeting compounds with little perturbation of the global transcriptome and BRD4 chromatin landscape. The discovery of these protein-protein interaction inhibitors (PPIi) not only demonstrates the feasibility of developing PPIi against phospho-IDRs but also uncovers antiviral agents targeting an epigenetic regulator essential for virus-host interaction and cancer development.


Assuntos
Infecções por Papillomavirus , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Papillomavirus Humano , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/genética , Proteômica , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Papillomaviridae/genética , Papillomaviridae/metabolismo , Proteínas Virais/genética , Replicação Viral/fisiologia , Reparo do DNA , Proteínas que Contêm Bromodomínio
3.
Pharmacol Rev ; 76(3): 414-453, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38697854

RESUMO

Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. SIGNIFICANCE STATEMENT: Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.


Assuntos
Antineoplásicos , Neoplasias , Proteínas Proto-Oncogênicas c-mdm2 , Humanos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Terapia de Alvo Molecular
4.
Br J Haematol ; 204(6): 2351-2364, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38613241

RESUMO

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.


Assuntos
Antígenos CD7 , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Indução de Remissão , Humanos , Masculino , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Adolescente , Pessoa de Meia-Idade , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Adulto Jovem , Criança , Recidiva , Transplante Homólogo , Receptores de Antígenos Quiméricos/uso terapêutico , Resultado do Tratamento , Pré-Escolar , Taxa de Sobrevida
5.
Anal Chem ; 96(29): 11890-11896, 2024 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-38987697

RESUMO

Dipeptidyl peptidase 4 (DPP4) plays a key role in glucose metabolism, which has been a close target for diabetes pathology and treatment. It is significant for the evaluation of cellular DPP4 activity in various biological systems. Fluorescence imaging technology is currently a popular method for detecting enzymes in living cells due to its advantages of high selectivity, high sensitivity, high spatiotemporal resolution, and real-time visualization. Herein, a near-infrared (NIR)-emissive probe NEDP with a large Stokes shift (153 nm) was developed for the assay of DPP4 activity. Upon addition of DPP4, NEDP can emit a significant turn-on NIR fluorescence signal (673 nm) with high sensitivity and specificity. Moreover, NEDP can successfully be used for imaging of intracellular DPP4, confirming the regulation of DPP4 expression in hyperglucose and its treatment in living cells. Most importantly, NEDP can not only monitor the changes of DPP4 in vivo but also show that DPP4 in diabetes is mainly up-regulated in the liver, and the level of DPP4 is positively correlated with the pathological damage of the liver. In addition, NEDP can identify the serum of diabetic patients from healthy people through the fluorescence response to DPP4. These results demonstrated that the designed probe NEDP provides a prospective visual tool to explore the relationship between DPP4 and diabetes and would be applied for detecting serum of diabetes in the clinic.


Assuntos
Diabetes Mellitus Experimental , Dipeptidil Peptidase 4 , Corantes Fluorescentes , Fígado , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/sangue , Animais , Humanos , Camundongos , Fígado/metabolismo , Fígado/patologia , Corantes Fluorescentes/química , Diabetes Mellitus Experimental/metabolismo , Imagem Óptica , Raios Infravermelhos , Masculino
6.
J Med Virol ; 96(6): e29757, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38899432

RESUMO

No effective treatments can ameliorate symptoms of long COVID patients. Our study assessed the safety and efficacy of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) in the treatment of long COVID patients. Ten long COVID patients were enrolled and received intravenous infusions of UC-MSCs on Days 0, 7, and 14. Adverse events and clinical symptoms were recorded, and chest-high-resolution CT (HRCT) images and laboratory parameters were analyzed. During UC-MSCs treatment and follow-up, we did not observe serious adverse events, the symptoms of long COVID patients were significantly relieved in a short time, especially sleep difficulty, depression or anxiety, memory issues, and so forth, and the lung lesions were also repaired. The routine laboratory parameters did not exhibit any significant abnormalities following UC-MSCs transplantation (UMSCT). The proportion of regulatory T cells gradually increased, but it was not statistically significant until 12 months. The proportion of naive B cells was elevated, while memory B cells, class-switched B-cells, and nonswitched B-cells decreased at 1 month after infusion. Additionally, we observed a transient elevation in circulating interleukin (IL)-6 after UMSCT, while tumor necrosis factor (TNF)-α, IL-17A, and IL-10 showed no significant changes. The levels of circulating immunoglobulin (Ig) M increased significantly at month 2, while IgA increased significantly at month 6. Furthermore, the SARS-CoV-2 IgG levels remained consistently high in all patients at Month 6, and there was no significant decrease during the subsequent 12-month follow-up. UMSCT was safe and tolerable in long COVID patients. It showed potential in alleviating long COVID symptoms and improving interstitial lung lesions.


Assuntos
COVID-19 , Transplante de Células-Tronco Mesenquimais , Cordão Umbilical , Humanos , COVID-19/terapia , COVID-19/imunologia , Transplante de Células-Tronco Mesenquimais/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Cordão Umbilical/citologia , Células-Tronco Mesenquimais , Idoso , Resultado do Tratamento , Adulto , SARS-CoV-2 , Linfócitos T Reguladores/imunologia , Linfócitos B/imunologia , Interleucina-6/sangue
7.
Rev Cardiovasc Med ; 25(4): 127, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-39076535

RESUMO

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, with its diagnosis being closely tied to higher rates of cardiovascular morbidity and mortality. AF is associated with a range of dangerous complications including stroke and heart failure, making it a key driver of healthcare spending and a major threat to global public health. The precise mechanisms that govern AF incidence and the onset of related complications, however, remain uncertain. Ferroptotic cell death has been the focus of rising interest in the cardiac arrhythmias, and there is recent evidence supporting a role for atrial ferroptosis as a mediator of AF development. Interventional strategies focused on ferroptotic activity, such as novel ferroptosis inhibitors, have also shown promise as a means of protecting against AF through their ability to reduce iron overload. In this review, we provide a summary of the proposed mechanisms whereby ferroptosis contributes to the pathophysiology of AF and their therapeutic implications.

8.
Rev Cardiovasc Med ; 25(3): 85, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-39076944

RESUMO

Background: For individuals with persistent stable chest pain (SCP) and a coronary artery calcium score (CACS) of 0, it might be challenging to establish the best risk assessment method for determining the individuals who will not benefit from further cardiovascular imaging testing (CIT). Thus, we investigated the CACS-weighted clinical likelihood (CACS-CL) model in SCP patients with a CACS of 0. Methods: Thus, to assess SCP, we originally enrolled 14,232 individuals for CACS and coronary computed tomography angiography (CCTA) scans between January 2016 and January 2018. Finally, patients with a CACS of 0 were included and followed up ​until January 2022. According to the established CACS-CL cutoffs of 15% and 5%, the associations between coronary artery disease (CAD) and major adverse cardiovascular events (MACEs) in risk groups were evaluated, alongside the net reclassification improvement (NRI). Results: Of the 6689 patients with a CACS of 0, the prevalence of CAD increased significantly (p < 0.0001) in patients with higher CACS-CL. However, there was no significant difference in the CAD distribution (p = 0.0637) between patients with CACS-CL < 5% and 5-15%. The association between the CACS-CL = 15%-determined risk groups and the occurrence of MACEs was stronger than for a CACS-CL = 5% (adjusted hazard ratio (HR): 7.24 (95% CI: 1.93-16.42) versus 3.68 (95% CI: 1.50-8.26)). Compared with the cutoff for CACS-CL = 5%, the NRI was 10.61% when using a cutoff for CACS-CL = 15%. Conclusions: Among patients with an SCP and CACS of 0, the CACS-CL model provided accurate predictions of CAD and MACEs. Compared to the cutoff for CACS-CL = 5%, the cutoff for CACS-CL = 15% seemed to be more effective and safer for deferring further CIT. Clinical Trial registration: NCT04691037.

9.
Exp Dermatol ; 33(3): e15027, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38514926

RESUMO

Hemangioma is a common benign tumour that usually occurs on the skin of the head and neck, particularly among infants. The current clinical treatment against hemangioma is surgery excision, however, application of drug is a safer and more economical therapy for children suffering from hemangioma. As a natural sulfated polysaccharide rich in brown algae, fucoidan is widely recognized for anti-tumour bioactivity and dosage safety in humans. This study aims to demonstrate the anti-tumour effect and underlying mechanism of fucoidan against hemangioma in vivo and in vitro. We investigated the effects of fucoidan by culturing hemangioma cells in vitro and treating BALB/c mice bearing with hemangioma. At first, we measured the cell proliferation and migration ability through in vitro experiments. Then, we tested the expression of epithelial-mesenchymal transition (EMT) and Wnt/ß-catenin pathway-related biomarkers by western blot and qPCR. Furthermore, we applied ß-catenin-specific inhibitor, XAV939, to determine whether fucoidan suppressed EMT via the Wnt/ß-catenin pathway in hemangioma cells. In vivo experiments, we applied oral gavage of fucoidan to treat EOMA-bearing mice, along with evaluating the safety and efficacy of fucoidan. We found that fucoidan remarkably inhibits the proliferation and EMT ability of hemangioma cells, which is dependent on the Wnt/ß-catenin pathway. These results suggest that fucoidan exhibits tumour inhibitory effect on aggressive hemangioma via regulating the Wnt/ß-catenin signalling pathway both in vitro and in vivo, providing a new potent drug candidate for treating hemangioma.


Assuntos
Hemangioma , Polissacarídeos , Via de Sinalização Wnt , beta Catenina , Animais , Criança , Humanos , Camundongos , beta Catenina/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Hemangioma/tratamento farmacológico , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Via de Sinalização Wnt/efeitos dos fármacos
10.
Phys Rev Lett ; 132(25): 250204, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38996245

RESUMO

The Hamiltonian, which determines the evolution of a quantum system, is fundamental in quantum physics. Therefore, it is crucial to implement high-precision generation and measurement of the Hamiltonian in a practical quantum system. Here, we experimentally demonstrate ultrahigh-precision Hamiltonian parameter estimation with a significant quantum advantage in a superconducting circuit via sequential control. We first observe the commutation relation for noncommuting operations determined by the system Hamiltonian, both with and without adding quantum control, verifying the commuting property of controlled noncommuting operations. Based on this control-induced commuting property, we further demonstrate Hamiltonian parameter estimation for polar and azimuth angles in superconducting circuits, achieving ultrahigh metrological gains in measurement precision exceeding the standard quantum limit by up to 16.0 and 16.1 dB at N=100, respectively.

11.
J Surg Res ; 298: 14-23, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38537450

RESUMO

INTRODUCTION: Activated hepatic stellate cells (HSCs) are the primary effector cells in hepatic fibrosis, over depositing extracellular matrix (ECM) proteins. Our previous work found oridonin analog CYD0682 attenuates proliferation, Transforming Growth Factor ß (TGFß)-induced signaling, and ECM production in immortalized HSCs. The underlying mechanism behind these reductions is unclear. The Signal Transduction and Activator of Transcription 3 (STAT3) pathway plays a central role in HSC activation and has been found to be overexpressed in models of hepatic injury. In this study, we will examine the effect of CYD0682 on STAT3 signaling. METHODS: Immortalized human (LX-2) and rat (HSC-T6) HSC lines were treated with CYD0682 or Tanespimycin (17-AAG) with or without TGF-ß. Nuclear and cytosolic proteins were extracted. Protein expression was analyzed with Western blot. DNA binding activity was assessed with STAT3 DNA Binding ELISA. Cell viability was assessed with Alamar blue assay. RESULTS: CYD0682 treatment inhibited STAT3 phosphorylation at tyrosine 705 in a dose-dependent manner in LX-2 and HSC-T6 cells. STAT3 DNA binding activity and STAT3 regulated protein c-myc were significantly decreased by CYD0682. Notably, TGFß-induced STAT3 phosphorylation and ECM protein expression were inhibited by CYD0682. STAT3 is reported to be a Heat Shock Protein 90 (HSP90) client protein. Notably, CYD0682 attenuated the expression of endogenous STAT3 and other HSP90 client proteins FAK, IKKα, AKT and CDK9. HSP90 specific inhibitor 17-AAG suppressed endogenous and TGFß-induced STAT3 phosphorylation and ECM protein production. CONCLUSIONS: CYD0682 attenuates endogenous and TGFß-induced STAT3 activation and ECM production via an HSP90 dependent pathway in HSCs. Further study of this pathway may present new targets for therapeutic intervention in hepatic fibrosis.


Assuntos
Benzoquinonas , Diterpenos do Tipo Caurano , Proteínas de Choque Térmico HSP90 , Células Estreladas do Fígado , Fator de Transcrição STAT3 , Transdução de Sinais , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Fator de Transcrição STAT3/metabolismo , Humanos , Ratos , Animais , Diterpenos do Tipo Caurano/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Benzoquinonas/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular , Fosforilação/efeitos dos fármacos , Lactamas Macrocíclicas/farmacologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia
12.
BMC Neurol ; 24(1): 254, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39048961

RESUMO

OBJECTIVE: The primary objective of this study was to explore the clinical characteristics of apoplectic intratumoral hemorrhage in gliomas and offer insights for improving the diagnosis and treatment of this disease. METHODS: We analyzed the clinical data of 35 patients with glioma and hemorrhage. There were eight cases of multiple cerebral lobe involvement, and 22 cases involved a single lobe. Twenty-one patients had a preoperative Glasgow Coma Scale (GCS) score of ≥ 9 and had a craniotomy with tumor resection and hematoma evacuation after undergoing preoperative preparation. A total of 14 patients with GCS < 9, including one with thalamic hemorrhage breaking into the ventricles and acute obstructive hydrocephalus, underwent craniotomy for tumor resection after external ventricular drainage (EVD). One patient had combined thrombocytopenia, which was surgically treated after platelet levels were normalized through transfusion. The remaining 12 patients received immediate intervention in the form of craniotomy hematoma evacuation and tumor resection. RESULTS: We performed subtotal resection on three tumors of thalamic origin and two tumors of corpus callosum origin, but we were able to successfully resect all the tumors in other locations that were gross total resection Pathology results showed that 71.43% of cases accounted for WHO-grade 4 tumors. Among the 21 patients with a GCS score of ≥ 9, two died perioperatively. Fourteen patients had a GCS score < 9, of which eight patients died perioperatively. CONCLUSIONS: Patients with a preoperative GCS score ≥ 9 who underwent subemergency surgery and received aggressive treatment showed a reasonable prognosis. We found their long-term outcomes to be correlated with the pathology findings. On the other hand, patients with a preoperative GCS score < 9 required emergency treatment and had a high perioperative mortality rate.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Glioma/complicações , Glioma/cirurgia , Masculino , Feminino , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/complicações , Pessoa de Meia-Idade , Adulto , Idoso , Adulto Jovem , Adolescente , Hemorragia Cerebral/cirurgia , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/complicações , Criança , Craniotomia/métodos , Escala de Coma de Glasgow , Estudos Retrospectivos , Resultado do Tratamento
13.
Environ Sci Technol ; 58(23): 10275-10286, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38825773

RESUMO

The pronounced lethality of N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-quinone or 6PPDQ) toward specific salmonids, while sparing other fish species, has received considerable attention. However, the underlying cause of this species-specific toxicity remains unresolved. This study explored 6PPDQ toxicokinetics and intestinal microbiota composition in adult zebrafish during a 14-day exposure to environmentally realistic concentrations, followed by a 7-day recovery phase. Predominant accumulation occurred in the brain, intestine, and eyes, with the lowest levels in the liver. Six metabolites were found to undergo hydroxylation, with two additionally undergoing O-sulfonation. Semiquantitative analyses revealed that the predominant metabolite featured a hydroxy group situated on the phenyl ring adjacent to the quinone. This was further validated by assessing enzyme activity and determining in silico binding interactions. Notably, the binding affinity between 6PPDQ and zebrafish phase I and II enzymes exceeded that with the corresponding coho salmon enzymes by 1.04-1.53 times, suggesting a higher potential for 6PPDQ detoxification in tolerant species. Whole-genome sequencing revealed significant increases in the genera Nocardioides and Rhodococcus after exposure to 6PPDQ. Functional annotation and pathway enrichment analyses predicted that these two genera would be responsible for the biodegradation and metabolism of xenobiotics. These findings offer crucial data for comprehending 6PPDQ-induced species-specific toxicity.


Assuntos
Biotransformação , Microbioma Gastrointestinal , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo
14.
Epilepsy Behav ; 157: 109870, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38870867

RESUMO

OBJECTIVE: To evaluate the incidence and the independent risk factors of SRS-related epilepsy in patients with supratentorial brain metastases (st-BMs), providing evidences for prevention or reduction secondary epilepsy after SRS. METHODS: Patients with st-BMs from four gamma knife centers who developed secondary epilepsy after SRS were retrospectively studied between January 1, 2017 and June 31, 2023. The incidence and clinical characteristics of the patients with secondary epilepsy were analyzed. The predictive role of baseline clinical-demographic variables was evaluated according to univariate and multivariate logistic regression model. The impact of secondary epilepsy on patients' OS was evaluated as well by log-rank test. RESULTS: 11.3 % (126/1120) of the patients with totally 158 st-BMs experienced secondary epilepsy after SRS in median 21 days. 61.9 % (78/126) of the patients experienced simple partial seizures. 91.3 % (115/126) patients achieved good seizure control after received 1-2 kinds of AEDs for median 90 days, while 7.1 % (9/126) of the patients suffered from refractory epilepsy. Patients had higher risk of secondary epilepsy if the tumor located in cortex and/or hippocampus, peri-tumor edema larger than 20.3 cm3 before SRS, had epilepsy history, and failed to receive bevacizumab prior to SRS. There was no difference in the OS of patients who experience secondary epilepsy or not after SRS. CONCLUSIONS: The incidence of SRS-related secondary epilepsy is 11.3 % in patients with st-BMs in this retrospective study. The risk of secondary epilepsy is higher in patients with st-BM located in cortex and/or hippocampus area, peri-tumor edema larger than 20.3 cm3 before SRS, and epilepsy history. Bevacizumab is suggested prior to SRS therapy, as it could be used for the control of peri-tumor edema and SRS-related damage, hence reduce the risk of secondary epilepsy. However, whether or not patients suffered from secondary epilepsy after SRS does not affect their OS.


Assuntos
Epilepsia , Radiocirurgia , Humanos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Radiocirurgia/efeitos adversos , Idoso , Incidência , Epilepsia/epidemiologia , Epilepsia/etiologia , Adulto , Fatores de Risco , Neoplasias Supratentoriais/complicações , Neoplasias Supratentoriais/cirurgia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/complicações , Complicações Pós-Operatórias/epidemiologia , Anticonvulsivantes/uso terapêutico
15.
Cell Mol Biol (Noisy-le-grand) ; 70(3): 174-181, 2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38650145

RESUMO

Ovarian cancer is a prevalent malignancy in the female reproductive system, representing a significantly fatal and incurable tumor. Chelerythrine (CHE), a natural benzopyridine alkaloid, has demonstrated a broad spectrum of anticancer activities. Nevertheless, the ovarian cancer inhibitory impact of CHE remains unclear. In this study, we investigated the cytotoxic mechanism and potential targets of CHE on in vitro cultures of A2780 and SKOV3 cells derived from ovarian cancer. Additionally, in vivo experiments were conducted to confirm the suppressive impact of CHE on tumor growth in nude mice. The findings revealed that CHE impeded the growth of A2780 and SKOV3 cells in a concentration-time-dependent manner and significantly suppressed the development of tumors in nude mice. CHE elevated the level of oxidative stress in tumor cells, prompted cell cycle halt in the S phase, and increased their mitochondrial membrane potential. Western blotting results demonstrated that CHE could modulate the expression of proteins associated with apoptotic and ferroptosis processes in A2780 and SKOV3 cells. Nrf2 was verified to be an upstream key target mediating the inhibitory impact of CHE on ovarian cancer cells. In summary, CHE exerts its anti-cancer effects on ovarian cancer by modulating Nrf2, inhibiting cellular proliferation, and promoting apoptosis and ferroptosis.


Assuntos
Apoptose , Benzofenantridinas , Proliferação de Células , Ferroptose , Camundongos Nus , Fator 2 Relacionado a NF-E2 , Neoplasias Ovarianas , Feminino , Benzofenantridinas/farmacologia , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Linhagem Celular Tumoral , Ferroptose/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
16.
Philos Trans A Math Phys Eng Sci ; 382(2271): 20230094, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38522461

RESUMO

At the Royal Society meeting in 2023, we have mainly presented our lunar orbit array concept called DSL, and also briefly introduced a concept of a lunar surface array, LARAF. As the DSL concept had been presented before, in this article, we introduce the LARAF. We propose to build an array in the far side of the Moon, with a master station which handles the data collection and processing, and 20 stations with maximum baseline of 10 km. Each station consists of 12 membrane antenna units, and the stations are connected to the master station by power line and optical fibre. The array will make interferometric observation in the 0.1-50 MHz band during the lunar night, powered by regenerated fuel cells. The whole array can be carried to the lunar surface with a heavy rocket mission, and deployed with a rover in eight months. Such an array would be an important step in the long-term development of lunar-based ultralong wavelength radio astronomy. It has a sufficiently high sensitivity to observe many radio sources in the sky, though still short of the dark age fluctuations. We discuss the possible options in the power supply, data communication, deployment etc. This article is part of a discussion meeting issue 'Astronomy from the Moon: the next decades (part 2)'.

17.
Phys Chem Chem Phys ; 26(27): 18854-18864, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38946575

RESUMO

Supported noble metal nanocatalysts typically exhibit strong crystal plane dependent catalytic behavior, but their working mechanism is still unclear. Herein, using anatase TiO2 with well-exposed crystal facets of {101}, {100} and {001} as a prototype support, Pd- and Pt-based supported TiO2 nanocatalysts (TiO2-Pd and TiO2-Pt) were prepared by chemical reduction with NaBH4 as reducer, and they showed a distinct metal-dependent crystal facet effect in the selective hydrogenation of cinamaldehyde (CAL). For Pd-based nanocatalysts, most Pd species on the {100} plane of TiO2 are present in the oxidized form with positive charges and unexpectedly show higher reactivity than the Pd species in the zero-valence state on the {101} and {001} planes. On the contrary, Pt species on all three crystal planes of TiO2 show zero-valence state, with relatively low conversion, but much better selectivity for hydrogenation of a CO bond than Pd-based catalysts. Well-designed experiments manipulating the stability and type of surface oxygen species confirmed that the essence of the crystal facet effect of the catalyst support actually creates a unique nanoconfined interface at the molecular level to construct a surface p-band intermediate state (PBIS), which provides a new alternative channel for surface electron transfer and consequently accelerates the reaction kinetics.

18.
BMC Endocr Disord ; 24(1): 116, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39010034

RESUMO

BACKGROUND: Somatic mutations have been observed to induce aldosterone-producing adenomas (APAs). These may be accelerated during pregnancy. Somatic PRKACA mutations are common in cortisol-producing adenomas (CPAs). However, their role in APAs, particularly aldosterone- and cortisol-producing adenomas (A/CPAs), is not well understood. This study aims to investigate the association between PRKACA mutations and the accelerated development of A/CPAs during pregnancy. CASE PRESENTATION: A patient with primary aldosteronism (PA) associated with severe Cushing's syndrome (CS) underwent surgical resection of an adrenal tumor one year after delivery. Pathologic examination revealed an adrenocortical adenoma characterized primarily by zona glomerulosa hyperplasia. Somatic mutation analysis revealed the presence of the somatic PRKACA mutation, which was validated as a deleterious mutation by various computational databases. Immunohistochemical results showed positive staining for cytochrome P450 family 11 subfamily B member 1 (CYP11B1), cytochrome P450 family 11 subfamily B member 2 (CYP11B2), and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). Our study included a review of 20 previously documented cases of aldosterone- and cortisol-producing adenomas (A/CPAs), two of which were concurrently positive for both CYP11B1 and CYP11B2, consistent with our findings. CONCLUSION: Somatic mutations in PRKACA may correlate with the upregulation of LHCGR, which synergistically drives the accelerated growth of co-secretion tumors during pregnancy, thereby exacerbating disease progression.


Assuntos
Neoplasias do Córtex Suprarrenal , Adenoma Adrenocortical , Aldosterona , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico , Hidrocortisona , Mutação , Complicações Neoplásicas na Gravidez , Humanos , Feminino , Gravidez , Adulto , Hidrocortisona/metabolismo , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/patologia , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/cirurgia , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Aldosterona/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Complicações Neoplásicas na Gravidez/genética , Complicações Neoplásicas na Gravidez/patologia , Hiperaldosteronismo/genética , Hiperaldosteronismo/patologia , Hiperaldosteronismo/cirurgia , Síndrome de Cushing/genética , Síndrome de Cushing/patologia , Adenoma/genética , Adenoma/patologia , Adenoma/metabolismo
19.
Acta Pharmacol Sin ; 45(4): 867-878, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38114644

RESUMO

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.


Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Indóis , Neoplasias Pulmonares , Panobinostat , Inibidores de Proteínas Quinases , Pirimidinas , Humanos , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Lipossomos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Panobinostat/farmacologia , Panobinostat/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
20.
Acta Pharmacol Sin ; 45(8): 1632-1643, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38627462

RESUMO

Despite the effectiveness of antiretroviral therapy (ART) in prolonging the lifespan of individuals infected with HIV-1, it does not offer a cure for acquired immunodeficiency syndrome (AIDS). The "block and lock" approach aims to maintain the provirus in a state of extended transcriptional arrest. By employing the "block and lock" strategy, researchers endeavor to impede disease progression by preventing viral rebound for an extended duration following patient stops receiving ART. The crux of this strategy lies in the utilization of latency-promoting agents (LPAs) that are suitable for impeding HIV-1 provirus transcription. However, previously documented LPAs exhibited limited efficacy in primary cells or samples obtained from patients, underscoring the significance of identifying novel LPAs that yield substantial outcomes. In this study, we performed high-throughput screening of FDA-approved compound library in the J-Lat A2 cell line to discover more efficacious LPAs. We discovered ripretinib being an LPA candidate, which was validated and observed to hinder proviral activation in cell models harboring latent infections, as well as CD4+ T cells derived from infected patients. We demonstrated that ripretinib effectively impeded proviral activation through inhibition of the PI3K-AKT-mTOR signaling pathway in the HIV-1 latent cells, thereby suppressing the opening states of cellular chromatin. The results of this research offer a promising drug candidate for the implementation of the "block and lock" strategy in the pursuit of an HIV-1 cure.


Assuntos
HIV-1 , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Humanos , HIV-1/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transcrição Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Retinoides/farmacologia , Retinoides/uso terapêutico
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