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1.
Phytopathology ; 2024 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-39244657

RESUMO

The commercialized genetically modified (GM) papaya cultivars have protected papaya from the devastating disease caused by papaya ringspot virus (PRSV). However, papaya leaf distortion mosaic virus (PLDMV), which causes similar infection symptoms but is serologically distinct from PRSV, was found as a competitive threat to the papaya industry. Our study surveyed the occurrence of PRSV and PLDMV as well as the transgenic markers of the 35S promoter from cauliflower mosaic virus (CaMV 35S) and the neomycin phosphotransferase II (NPT II) gene in feral papaya plants, which were found frequently growing outside of cultivated papaya fields on Hainan Island. In total, 123 feral papayas, comprising 62 (50.4%) GM plants and 61 (49.6%) non-GM ones, were sampled. Among them, 23 (18.7%) were positive for PRSV, 49 (39.8%) were positive for PLDMV, including 5 plants co-infected by PRSV and PLDMV, and 56 (45.5%) plants were free of either virus. In traditional papaya growing regions, we detected fewer PRSV-infected plants (2 in 33, 6%) than in other regions (21 in 90, 23%). But overall, whether transgenic or not made no significance in PRSV incidence (P=0.230), with 9 PRSV-infected plants among 62 GM papayas and 14 among 61 non-GM papayas. Phylogenetic and genetic differentiation analysis showed a clear correlation between PRSV and PLDMV populations and their geographical origins. Negative selection was estimated for the selected gene regions of both viruses. Notably, PLDMV has deviated from neutral evolution and experienced population expansion, exhibiting increased genetic diversity and is becoming the predominant threat to papaya in Hainan.

2.
Acta Pharmacol Sin ; 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39227736

RESUMO

Emerging evidence shows that psychological stress promotes the progression of Parkinson's disease (PD) and the onset of dyskinesia in non-PD individuals, highlighting a potential avenue for therapeutic intervention. We previously reported that chronic restraint-induced psychological stress precipitated the onset of parkinsonism in 10-month-old transgenic mice expressing mutant human α-synuclein (αSyn) (hαSyn A53T). We refer to these as chronic stress-genetic susceptibility (CSGS) PD model mice. In this study we investigated whether ginsenoside Rg1, a principal compound in ginseng notable for soothing the mind, could alleviate PD deterioration induced by psychological stress. Ten-month-old transgenic hαSyn A53T mice were subjected to 4 weeks' restraint stress to simulate chronic stress conditions that worsen PD, meanwhile the mice were treated with Rg1 (40 mg· kg-1 ·d-1, i.g.), and followed by functional magnetic resonance imaging (fMRI) and a variety of neurobehavioral tests. We showed that treatment with Rg1 significantly alleviated both motor and non-motor symptoms associated with PD. Functional MRI revealed that Rg1 treatment enhanced connectivity between brain regions implicated in PD, and in vivo multi-channel electrophysiological assay showed improvements in dyskinesia-related electrical activity. In addition, Rg1 treatment significantly attenuated the degeneration of dopaminergic neurons and reduced the pathological aggregation of αSyn in the striatum and SNc. We revealed that Rg1 treatment selectively reduced the level of the stress-sensitive protein RTP801 in SNc under chronic stress conditions, without impacting the acute stress response. HPLC-MS/MS analysis coupled with site-directed mutation showed that Rg1 promoted the ubiquitination and subsequent degradation of RTP801 at residues K188 and K218, a process mediated by the Parkin RING2 domain. Utilizing αSyn A53T+; RTP801-/- mice, we confirmed the critical role of RTP801 in stress-aggravated PD and its necessity for Rg1's protective effects. Moreover, Rg1 alleviated obstacles in αSyn autophagic degradation by ameliorating the RTP801-TXNIP-mediated deficiency of ATP13A2. Collectively, our results suggest that ginsenoside Rg1 holds promise as a therapeutic choice for treating PD-sensitive individuals who especially experience high levels of stress and self-imposed expectations.

3.
J Neuroinflammation ; 21(1): 222, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39272155

RESUMO

Gulf War Illness (GWI) is a chronic multisymptom disorder that affects approximately 25-32% of Gulf War veterans and is characterized by a number of symptoms such as cognitive impairment, psychiatric disturbances, chronic fatigue and gastrointestinal distress, among others. While the exact etiology of GWI is unknown, it is believed to have been caused by toxic exposures encountered during deployment in combination with other factors such as stress. In the present study we sought to evaluate the hypothesis that exposure to the toxin permethrin could prime neuroinflammatory stress response and elicit psychiatric symptoms associated with GWI. Specifically, we developed a mouse model of GWI, to evaluate the effects of chronic permethrin exposure followed by unpredictable stress. We found that subjecting mice to 14 days of chronic permethrin exposure followed by 7 days of unpredictable stress resulted in the development of depression-like behavior. This behavioral change coincided with distinct alterations in the microglia phenotype, indicating microglial activation in the hippocampus. We revealed that blocking microglial activation through Gi inhibitory DREADD receptors in microglia effectively prevented the behavioral change associated with permethrin and stress exposure. To elucidate the transcriptional networks impacted within distinct microglia populations linked to depression-like behavior in mice exposed to both permethrin and stress, we conducted a single-cell RNA sequencing analysis using 21,566 single nuclei collected from the hippocampus of mice. For bioinformatics, UniCell Deconvolve was a pre-trained, interpretable, deep learning model used to deconvolve cell type fractions and predict cell identity across spatial datasets. Our bioinformatics analysis identified significant alterations in permethrin exposure followed by stress-associated microglia population, notably pathways related to neuronal development, neuronal communication, and neuronal morphogenesis, all of which are associated with neural synaptic plasticity. Additionally, we observed permethrin exposure followed by stress-mediated changes in signal transduction, including modulation of chemical synaptic transmission, regulation of neurotransmitter receptors, and regulation of postsynaptic neurotransmitter receptor activity, a known contributor to the pathophysiology of depression in a subset of the hippocampal pyramidal neurons in CA3 subregions. Our findings tentatively suggest that permethrin may prime microglia towards a state of inflammatory activation that can be triggered by psychological stressors, resulting in depression-like behavior and alterations of neural plasticity. These findings underscore the significance of synergistic interactions between multi-causal factors associated with GWI.


Assuntos
Depressão , Modelos Animais de Doenças , Microglia , Doenças Neuroinflamatórias , Permetrina , Síndrome do Golfo Pérsico , Animais , Permetrina/toxicidade , Camundongos , Síndrome do Golfo Pérsico/induzido quimicamente , Síndrome do Golfo Pérsico/patologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Depressão/induzido quimicamente , Depressão/etiologia , Doenças Neuroinflamatórias/induzido quimicamente , Doenças Neuroinflamatórias/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Estresse Psicológico
4.
Water Res ; 267: 122417, 2024 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-39299138

RESUMO

The higher efficiency of electro-fermentation in synthesizing medium-chain fatty acids (MCFAs) compared to traditional fermentation has been acknowledged. However, the functional mechanisms of electrode-biofilm enhancing MCFAs synthesis remain research gaps. To address this, this study proposed a continuous flow electrode-biofilm reactor for chain elongation (CE). After 225 days of operation, stable electrode-biofilms formed and notably improved caproate yield by more than 38 %. The electrode-biofilm was enriched with more CE microorganisms and electroactive bacteria compared to the suspended sludge microorganisms, including Caproicibacterium, Oscillibacter and Pseudoramibacter. Besides, the upregulated CE pathways were evaluated by metagenomic analysis, and the results indicated that the pathways such as acetyl-CoA and malonyl-[acp] formation, reverse beta-oxidation, and fatty acid biosynthesis pathway were all markedly enhanced in cathodic biofilm, more than anodic biofilm and suspended microorganisms. Moreover, microbial community regulated processes like bacterial chemotaxis, flagellar assembly and quorum sensing, crucial for electrode-biofilm formation. Electron transfer, energy metabolism, and microbial interactions were found to be prominently upregulated in the cathodic biofilm, surpassing levels observed in anodic biofilm and suspended sludge microorganisms, which further enhanced CE efficiency. In addition, the statistical analyses further highlighted key microbial functions and interactions within the cathodic biofilm. Oscillospiraceae_bacterium was identified to be the most active microbe, alongside pivotal roles played by Caproiciproducens_sp._NJN-50, Clostridiales_bacterium, Prevotella_sp. and Pseudoclavibacter_caeni. Eventually, the proposed microbial collaboration mechanisms of cathodic biofilm were ascertained. Overall, this study uncovered the biological effects of the electrode-biofilm on MCFAs electrosynthesis, thereby advancing biochemicals production and filling the knowledge gaps in CE electroactive biofilm reactors.

5.
Nat Biomed Eng ; 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271933

RESUMO

Biomolecular condensates, which arise from liquid-liquid phase separation within cells, may provide a means of enriching and prolonging the retention of small-molecule drugs within cells. Here we report a method for the controlled in situ formation of biomolecular condensates as reservoirs for the enrichment and retention of chemotherapeutics in cancer cells, and show that the approach can be leveraged to enhance antitumour efficacies in mice with drug-resistant tumours. The method involves histones as positively charged proteins and doxorubicin-intercalated DNA strands bioorthogonally linked via a click-to-release reaction between trans-cyclooctene and tetrazine groups. The reaction temporarily impaired the phase separation of histones in vitro, favoured the initiation of liquid-liquid phase separation within cells and led to the formation of biomolecular condensates that were sufficiently large to be retained within tumour cells. The controlled formation of biomolecular condensates as drug reservoirs within cells may offer new options for boosting the efficacies of cancer therapies.

6.
Am J Transl Res ; 16(8): 4071-4082, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39262759

RESUMO

Medical device research and development are characterized by high costs, extended timelines, inherent risks, and the necessity for interdisciplinary knowledge and skills. It is significantly influenced by policies, making the understanding of medical device innovation both important and challenging. This paper takes a dual approach to analyze medical device innovation. We reviewed representative clinical product of bougie and stylet and summarized the common characteristics and trend of these product. Innovations in these products often involve adding depth markings, replacing material and design structure, enhancing visualization, deciding between reusable or disposable designs, and integrating multi-functional features. This underscores the delicate balance between technological advancements and medical costs for widespread clinical applicability. We explored the guiding role of policy in medical device innovation, emphasizing its impact through an analysis of medical device regulations and policies in China. By offering insights from the perspectives of medical device companies and regulators, this paper aims to elucidate the critical aspects of medical device innovation, assisting researchers in mitigating risks during product development.

7.
Nat Commun ; 15(1): 7769, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39237515

RESUMO

Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse models tested. We show these myeloid populations communicate with H3-mutant cells, mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients.


Assuntos
Neoplasias Encefálicas , Glioma , Histonas , Mutação , Células Mieloides , Microambiente Tumoral , Animais , Glioma/genética , Glioma/imunologia , Glioma/patologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Células Mieloides/metabolismo , Células Mieloides/imunologia , Histonas/metabolismo , Histonas/genética , Camundongos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Humanos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Regulação Neoplásica da Expressão Gênica , Análise de Célula Única
8.
Crit Rev Anal Chem ; : 1-23, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39264749

RESUMO

Hypochlorous acid (HClO) is widely used in everyday life for bleaching and disinfecting tap water, and also in human metabolism, where it plays an important role in destroying foreign bacterial invaders and pathogens as well as immune defense and cellular functioning maintenance. Abnormal levels of hypochlorous acid have the potential to cause joint inflammation, neuronal degeneration, and even life-threatening cancer. Specific identification and effective detection of hypochlorous acid are important for monitoring human health and the environment. In recent years, organic fluorescent probes have attracted much attention because of their simple synthesis, easy operation, high sensitivity, and high specificity, and a variety of hypochlorous acid fluorescent probes based on low-cost, easy-to-operate, and rapid identification have been developed. In this paper, we review the fluorescent probes that have been developed in the past five years for the specific recognition of hypochlorous acid based on different fluorophores, such as triphenylamine, coumarin, 1,8-naphthalize, etc., as well as recognition units, such as N-N dimethyl thiosemicarbazone, and describe how the probes and hypochlorous acid interact for identification in the same manner as other fluorescent probes. In addition, the reaction mechanism between the probe and hypochlorous acid, the fluorescence change of the probe, and the detection limit are described to illustrate the progress in the detection of hypochlorous acid in recent years and to provide ideas for the development of hypochlorous acid fluorescent probes in the future.

10.
BMC Cancer ; 24(1): 1087, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39223584

RESUMO

BACKGROUND: Our research endeavored to develop a robust predictive signature grounded in super-enhancer-related genes (SERGs), with the dual objectives of forecasting survival outcomes and evaluating the tumor immune microenvironment (TiME) in hepatocellular carcinoma (HCC). METHODS: HCC RNA-sequencing data were retrieved from The Cancer Genome Atlas (TCGA), and 365 patients were randomly assigned to training or testing sets in 1:1 ratio. SERGs of HCC were downloaded from Super-Enhancer Database (SEdb). On the basis of training set, a SERGs signature was identified, and its prognostic value was confirmed by internal and external validation (GSE14520) sets. We subsequently examined the model for potential functional enrichment and the degree of tumor immune infiltration. Additionally, we carried out in vitro experiments to delve into the biological functions of CBX2 gene. RESULTS: An SE-related prognostic model including CBX2, TPX2, EFNA3, DNASE1L3 and SOCS2 was established and validated. According to this risk model, patients in the high-risk group had a significantly worse prognosis, and their immune cell infiltration was significantly different from that of low-risk group. Moreover, the high-risk group exhibited a significant enrichment of tumor-associated pathological pathways. The SERGs signature can generally be utilized to screen HCC patients who are likely to respond to immunotherapy, as there is a positive correlation between the risk score and the Tumor Immune Dysfunction and Exclusion (TIDE) score. Furthermore, the downregulation of the CBX2 gene expression was found to inhibit HCC cell viability, migration, and cell cycle progression, while simultaneously promoting apoptosis. CONCLUSIONS: We developed a novel HCC prognostic model utilizing SERGs, indicating that patients with high-risk score not only face a poorer prognosis but also may exhibit a diminished therapeutic response to immune checkpoint inhibitors (ICIs). This model is designed to tailor personalized treatment strategies to the individual needs of each patient, thereby improving the overall clinical outcomes for HCC patients. Furthermore, CBX2 is a promising candidate for therapeutic intervention in HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Medicina de Precisão , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Prognóstico , Medicina de Precisão/métodos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Feminino , Masculino , Elementos Facilitadores Genéticos , Linhagem Celular Tumoral , Proliferação de Células
11.
Diabetes Metab Syndr Obes ; 17: 3053-3061, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39170901

RESUMO

Purpose: The co-morbidity of non-alcoholic fatty liver disease (NAFLD) in patients with bipolar disorder (BD) has a negative impact on patient treatment and prognosis. This study aimed to identify the prevalence of NAFLD in patients with BD and investigate the risk factors of NAFLD. Patients and Methods: A total of 678 patients with BD were included in the study. Clinical data were obtained from the hospital's electronic health record system. Data included fasting blood glucose, alanine aminotransferase, triglycerides, aspartate aminotransferase, high-density lipoprotein cholesterol (HDL), alkaline phosphatase, total cholesterol, glutamine transpeptidase, uric acid, apolipoprotein A1, apolipoprotein B, and liver ultrasound findings. Results: The prevalence of NAFLD was 43.66% in patients with BD. Significant differences in body mass index (BMI), mean age, diabetes prevalence, course of BD, fasting blood glucose, alanine aminotransferase, HDL, alkaline phosphatase, triglycerides, aspartate aminotransferase, uric acid, glutamine transpeptidase, apolipoprotein B, total cholesterol, and apolipoprotein A1 were seen between the groups (all P<0.01). Male sex, age, BMI, course of BD, alanine aminotransferase, fasting blood glucose, aspartate aminotransferase, diabetes, glutamine transpeptidase, total cholesterol, alkaline phosphatase, triglycerides, uric acid, apolipoprotein B, HDL, and apolipoprotein A1 levels were correlated with NAFLD (all P<0.05). In patients with BD, diabetes (OR=6.412, 95% CI=1.049-39.21), BMI (OR=1.398, 95% CI=1.306-1.497), triglycerides (OR=1.456, 95% CI=1.036-2.045), and apolipoprotein A1 (OR=0.272, 95% CI=0.110-0.672) were risk factors for NAFLD (all P<0.05). Conclusion: Risk factors for NAFLD in patients with BD include diabetes, BMI, course of BD, and a low level of apolipoprotein A1. A proactive approach to disease management, such as appropriate physical activity and adoption of a healthy diet, and regular monitoring of changes in patient markers should be adopted to reduce the prevalence of NAFLD.

12.
ChemSusChem ; : e202401337, 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39177729

RESUMO

α-SnWO4 is a promising semiconductor for solar water splitting, however, its performance is limited by weak water oxidation and poor charge transfer. In this study, we employ a vapor deposition method to uniformly implement a carbon layer onto the surface of SnWO4 coupled with a CoNiP cocatalyst, successfully constructing the integrated CoNiP/C/SnWO4 film photoanode and alleviating the oxidation of Sn2+ when loading electrocatalyst. Incorporating the carbon layer enhances the interface charge conduction behavior between the SnWO4 substrate and the CoNiP cocatalyst, thereby mitigating charge recombination. The synergistic interplay between the carbon layer and CoNiP leads to a remarkable achievement, as evidenced by the photocurrent of 1.72 mA cm-2 (1.23 V vs. RHE) observed for SnWO4 film measured in 0.2 M potassium phosphate buffer solution. In this work, we demonstrate the viability of tailoring SnWO4 photoanode and provide valuable insights for prospective advancements in modifying SnWO4 photoanode.

13.
Angew Chem Int Ed Engl ; : e202409160, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39113640

RESUMO

Flexible and high-performance aqueous Zn-ion batteries (ZIBs), coupled with low cost and safe, are considered as one of the most promising energy storage candidates for wearable electronics. However, most of hydrogel electrolytes suffer from poor mechanical properties and interfacial chemistry, which limits them to suppressed performance levels in flexible ZIBs, especially under harsh mechanical strains. Herein, a bio-inspired multifunctional hydrogel electrolyte network (polyacrylamide (PAM)/trehalose) with improved mechanical and adhesive properties was developed via a simple trehalose network-repairing strategy to stabilize the interfacial chemistry for highly reversible flexible ZIBs. As a result, the trehalose-modified PAM hydrogel exhibits a superior strength and stretchability up to 100 kPa and 5338%, respectively, as well as strong adhesive properties to various substrates. Also, the PAM/trehalose hydrogel electrolyte provides superior anti-corrosion capability for Zn anode and regulates Zn nucleation/growth, resulting in achieving a high Coulombic efficiency of 98.8%, and long-term stability over 2400 h. Importantly, the flexible Zn//MnO2 pouch cell exhibits excellent cycling performance under different bending conditions, which offers a great potential in flexible energy-related applications and beyond.

14.
Adv Sci (Weinh) ; : e2406381, 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39206871

RESUMO

Traditional light-driven metal-organic-frameworks (MOFs)-based micromotors (MOFtors) are typically constrained to two-dimensional (2D) motion under ultraviolet or near-infrared light and often demonstrate instability and susceptibility to ions in high-saline environments. This limitation is particularly relevant to employing micromotors in water purification, as real wastewater is frequently coupled with high salinity. In response to these challenges, ultrastable MOFtors capable of three-dimensional (3D) motion under a broad spectrum of light through thermophoresis and electrophoresis are successfully synthesized. The MOFtors integrated photocatalytic porphyrin MOFs (PCN-224) with a photothermal component made of polypyrrole (PPy) by three distinct methodologies, resulting in micromotors with different motion behavior and catalytic performance. Impressively, the optimized MOFtors display exceptional maximum velocity of 1305 ± 327 µm s-1 under blue light and 2357 ± 453 µm s-1 under UV light. In harsh saline environments, these MOFtors are not only maintain high motility but also exhibit superior tetracycline hydrochloride (TCH) removal efficiency of 3578 ± 510 mg g-1, coupling with sulfate radical-based advanced oxidation processes and peroxymonosulfate. This research underscores the significant potential of highly efficient MOFtors with robust photocatalytic activity in effectively removing TCH in challenging saline conditions, representing a substantial advancement in applying MOFtors within real-world water treatment technologies.

15.
J Cancer Res Ther ; 20(4): 1124-1129, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39206973

RESUMO

ABSTRACT: The incidence of pancreatic cancer is increasing worldwide. Approximately, 60% of patients with pancreatic cancer have distant metastases at the time of diagnosis, of which only 10% can be removed using standard resection. Further, patients derive limited benefits from chemotherapy or radiotherapy. As such, alternative methods to achieve local control have emerged, including permanent iodine-125 seed interstitial brachytherapy. In 2023, the Chinese College of Interventionalists, affiliated with the Chinese Medical Doctor Association, organized a group of multi-disciplinary experts to compose guidelines for this treatment modality. The aim of this conference was to standardize the procedure for permanent iodine-125 seed interstitial brachytherapy, including indications, contraindications, pre-procedural preparation, procedural operations, complications, efficacy evaluation, and follow-up.


Assuntos
Braquiterapia , Radioisótopos do Iodo , Neoplasias Pancreáticas , Humanos , Braquiterapia/métodos , Radioisótopos do Iodo/uso terapêutico , Radioisótopos do Iodo/administração & dosagem , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/patologia , China , Consenso , Guias de Prática Clínica como Assunto
16.
Drug Metab Dispos ; 2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39187385

RESUMO

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are important hepatic transporters. We previously identified OATP1B3 being critically implicated in the disposition of abiraterone. We aimed to further investigate the effects of abiraterone on the activities of OATP1B1 and OATP1B3 utilizing a validated endogenous biomarker coproporphyrin I (CP-I). We utilized OATP1B-transfected cells to characterize the inhibitory potential of abiraterone against OATP1B-mediated uptake of CP-I. Inhibition constant (Ki) was incorporated into our physiologically based pharmacokinetic (PBPK) modeling to simulate the systemic exposures of CP-I among cancer populations receiving either our model-informed 500 mg or clinically approved 1000 mg abiraterone acetate (AA) dosage. Simulated data were compared with clinical CP-I concentrations determined among our 9 metastatic prostate cancer patients receiving 500 mg AA treatment. Abiraterone inhibited OATP1B3- but not OATP1B1-mediated uptake of CP-I in vitro, with an estimated Ki of 3.93 µM. Baseline CP-I concentrations were simulated to be 0.81 {plus minus} 0.26 ng/mL, and determined to be 0.72 {plus minus} 0.16 ng/mL among metastatic prostate cancer patients, both of which were higher than those observed for healthy subjects. PBPK simulations revealed an absence of OATP1B3-mediated interaction between abiraterone and CP-I. Our clinical observations confirmed that CP-I concentrations remained comparable to baseline levels up to 12 weeks post 500 mg AA treatment. Using CP-I as an endogenous biomarker, we identified the inhibition of abiraterone on OATP1B3 but not OATP1B1 in vitro, which was predicted and observed to be clinically insignificant. We concluded that the interaction risk between AA and substrates of OATP1Bs is low. Significance Statement We utilized the endogenous biomarker coproporphyrin I (CP-I) and identified abiraterone as a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B3 in vitro. Subsequent physiologically based pharmacokinetic (PBPK) simulations and clinical observations suggested an absence of OATP1B-mediated interaction between abiraterone and CP-I among prostate cancer patients. This multi-pronged study concluded that the interaction risk between abiraterone acetate and substrates of OATP1Bs is low, demonstrating the application of PBPK-CP-I modelling in predicting OATP1B-mediated interaction implicating abiraterone.

17.
Am J Cancer Res ; 14(7): 3468-3482, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39113875

RESUMO

Altered protein ubiquitination is associated with cancer. The novel tripartite motif (TRIM) family of E3 ubiquitin ligases have been reported to play crucial roles in the development, growth, and metastasis of various tumors. The TRIM family member TRIM27 acts as a potential promoter of tumor development in a wide range of cancers. However, little is known regarding the biological features and clinical relevance of TRIM27 in glioblastoma (GBM). Here, we report findings of elevated TRIM27 expression in GBM tissues and GBM cell lines. Further functional analysis showed that TRIM27 deletion inhibited GBM cell growth both in vitro and in vivo. Furthermore, we found that TRIM27 promoted the growth of GBM cells by enhancing the Warburg effect. Additionally, the inactivation of the LKB1/AMPK/mTOR pathway was critical for the oncogenic effects of TRIM27 in GBM. Mechanistically, TRIM27 could directly bind to LKB1 and promote the ubiquitination and degradation of LKB1, which in turn enhanced the Warburg effect and GBM progression. Collectively, these data suggest that TRIM27 contributes to GNM pathogenesis by inhibiting the LKB1/AMPK/mTOR axis and may be a promising candidate as a potential diagnostic and therapeutic marker for patients with GBM.

18.
World J Gastroenterol ; 30(26): 3229-3246, 2024 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-39086630

RESUMO

BACKGROUND: Monopolar spindle-binding protein 3B (MOB3B) functions as a signal transducer and altered MOB3B expression is associated with the development of human cancers. AIM: To investigate the role of MOB3B in colorectal cancer (CRC). METHODS: This study collected 102 CRC tissue samples for immunohistochemical detection of MOB3B expression for association with CRC prognosis. After overexpression and knockdown of MOB3B expression were induced in CRC cell lines, changes in cell viability, migration, invasion, and gene expression were assayed. Tumor cell autophagy was detected using transmission electron microscopy, while nude mouse xenograft experiments were performed to confirm the in-vitro results. RESULTS: MOB3B expression was reduced in CRC vs normal tissues and loss of MOB3B expression was associated with poor CRC prognosis. Overexpression of MOB3B protein in vitro attenuated the cell viability as well as the migration and invasion capacities of CRC cells, whereas knockdown of MOB3B expression had the opposite effects in CRC cells. At the molecular level, microtubule-associated protein light chain 3 II/I expression was elevated, whereas the expression of matrix metalloproteinase (MMP)2, MMP9, sequestosome 1, and phosphorylated mechanistic target of rapamycin kinase (mTOR) was downregulated in MOB3B-overexpressing RKO cells. In contrast, the opposite results were observed in tumor cells with MOB3B knockdown. The nude mouse data confirmed these in-vitro findings, i.e., MOB3B expression suppressed CRC cell xenograft growth, whereas knockdown of MOB3B expression promoted the growth of CRC cell xenografts. CONCLUSION: Loss of MOB3B expression promotes CRC development and malignant behaviors, suggesting a potential tumor suppressive role of MOB3B in CRC by inhibition of mTOR/autophagy signaling.


Assuntos
Autofagia , Movimento Celular , Neoplasias Colorretais , Invasividade Neoplásica , Transdução de Sinais , Serina-Treonina Quinases TOR , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Serina-Treonina Quinases TOR/metabolismo
19.
Mar Pollut Bull ; 207: 116878, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39173475

RESUMO

In the context of carbon emission reduction in the shipping industry, CCUS technology can modify ships to reduce carbon emissions, providing a new direction for the green development of the shipping industry. Based on this, this paper investigates the technology related to carbon capture on ships, firstly puts forward the applicable requirements of carbon capture technology; and analyses the adaptability of the existing carbon capture solutions to the shipping industry; and discusses the development prospect of carbon capture on ships through the three challenges of space utilisation, safety, and economy; and finally analyses the related policies. After analysis and discussion, this paper concludes that the alcohol-amine method is the most suitable carbon capture solution for ships, but there are challenges in economics and space utilisation. The future research direction lies in optimising the performance of the absorber, improving the energy efficiency of the system and solving the CO2 storage problem.


Assuntos
Sequestro de Carbono , Navios , Carbono , Dióxido de Carbono/análise , Indústrias
20.
Rev Sci Instrum ; 95(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38984882

RESUMO

Due to the limited maximum output power of the pulsers based on avalanche transistors, high-power ultrawideband (UWB) radiation systems usually synthesize plenty of modules simultaneously to achieve a high peak effective potential (rEp). However, this would lead to an increased aperture size as well as a narrower beam, which would limit their applications in intentional electromagnetic interference fields. In this paper, a high-power UWB radiation system with beam broadening capacity is developed. To achieve beam broadening in the time domain, a power-law time delay distribution method is proposed and studied by simulation, and then the relative excitation time delays of the modules are optimized to achieve higher rEp and avoid beam splitting in the beam broadening mode. In order to avoid false triggering of the pulser elements when implementing the beam broadening, the mutual coupling effect in the system is analyzed and suppressed by employing onboard high-pass filters, since the mutual coupling effect is much more severe in the low-frequency range. Finally, a radiation system with 36 modules is developed. Measuring results indicate that in the high-rEp mode, the developed system could achieve a maximum effective potential rEp of 313.6 kV and a maximum pulse-repetition-rate of 20 kHz. In the beam broadening mode, its half-peak-power beam width in the H-plane is broadened from the original value of 3.9° to 7.9°, with a maximum rEp of 272.9 kV. The polarization direction of the system could be flexibly adjusted by a built-in motor.

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