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1.
Mol Pharm ; 21(7): 3186-3203, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38815167

RESUMO

Globally, prostate cancer is the most commonly diagnosed tumor and a cause of death in older men. Abiraterone, an orally administered irreversible CYP17 inhibitor, is employed to treat prostate cancer. However, abiraterone has several clinical limitations, such as poor water solubility, low dissolution rate, low bioavailability, and toxic side effects in the liver and kidney. Therefore, there is a need to identify high-efficiency and low-toxicity water-soluble abiraterone derivatives. In this work, we aimed to design and synthesize a series of abiraterone derivatives by methoxypoly(ethylene glycol) (mPEG) modification. Their antitumor activities and toxicology were analyzed in vitro and in vivo. The most potent compound, 2e, retained the principle of action on the CYP17 enzyme target and significantly improved the abiraterone water solubility, cell permeability, and blood safety. No significant abnormalities were observed in toxicology. mPEG-modification significantly improved abiraterone's antitumor activity and efficiency while reducing the associated toxic effects. The finding will provide a theoretical basis for future clinical application of mPEG-modified abiraterone.


Assuntos
Androstenos , Antineoplásicos , Polietilenoglicóis , Neoplasias da Próstata , Solubilidade , Masculino , Humanos , Androstenos/farmacologia , Androstenos/química , Animais , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Polietilenoglicóis/química , Camundongos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/metabolismo
2.
Plants (Basel) ; 13(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38337970

RESUMO

Tree peony (Paeonia suffruticosa Andr.) is a traditional Chinese flower with significant ornamental and medicinal value. Its growth and development process is regulated by some internal and external factors, and the related regulatory mechanism is largely unknown. Myelocytomatosis transcription factors (MYCs) play significant roles in various processes such as plant growth and development, the phytohormone response, and the stress response. As the identification and understanding of the MYC family in tree peony remains limited, this study aimed to address this gap by identifying a total of 15 PsMYCs in tree peony and categorizing them into six subgroups based on bioinformatics methods. Furthermore, the gene structure, conservative domains, cis-elements, and expression patterns of the PsMYCs were thoroughly analyzed to provide a comprehensive overview of their characteristics. An analysis in terms of gene structure and conserved motif composition suggested that each subtribe had similarities in function. An analysis of the promoter sequence revealed the presence of numerous cis-elements associated with plant growth and development, the hormone response, and the stress response. qRT-PCR results and the protein interaction network further demonstrated the potential functions of PsMYCs in the growth and development process. While in comparison to the control, only PsMYC2 exhibited a statistically significant variation in expression levels in response to exogenous hormone treatments and abiotic stress. A promoter activity analysis of PsMYC2 revealed its sensitivity to Flu and high temperatures, but exhibited no discernible difference under exogenous GA treatment. These findings help establish a basis for comprehending the molecular mechanism by which PsMYCs regulate the growth and development of tree peony.

3.
Small ; 20(3): e2305539, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37699754

RESUMO

Artificial enzymes, as alternatives to natural enzymes, have attracted enormous attention in the fields of catalysis, biosensing, diagnostics, and therapeutics because of their high stability and low cost. Polyoxometalates (POMs), a class of inorganic metal oxides, have recently shown great potential in mimicking enzyme activity due to their well-defined structure, tunable composition, high catalytic efficiency, and easy storage properties. This review focuses on the recent advances in POM-based artificial enzymes. Different types of POMs and their derivatives-based mimetic enzyme functions are covered, as well as the corresponding catalytic mechanisms (where available). An overview of the broad applications of representative POM-based artificial enzymes from biosensing to theragnostic is provided. Insight into the current challenges and the future directions for POMs-based artificial enzymes is discussed.


Assuntos
Ânions , Polieletrólitos , Ânions/química , Polieletrólitos/química , Enzimas
4.
Front Pharmacol ; 14: 1234262, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38074113

RESUMO

Backgrounds: Brain metastases occur in approximately 30% of patients with non-small-cell lung cancer (NSCLC). Therefore, the free drug concentration in cerebrospinal fluid (CSF) is strongly associated with the clinical efficacy. Purpose: The present study aimed to develop physiologically based pharmacokinetic (PBPK) models that can predict the steady-state trough concentration (Ctrough) in plasma and CSF, as well as anaplastic lymphoma kinase (ALK) occupancy (AO), for three inhibitors: crizotinib (CRI), alectinib (ALE), and lorlatinib (LOR). Methods: To achieve this, population PBPK models were successfully developed and validated using multiple clinical pharmacokinetics (PK) and drug-drug interaction (DDI) studies, both in healthy subjects and patients. Results: The prediction-to-observation ratios for plasma AUC, Cmax, and Ctrough in heathy subjects and patients ranged between 0.5 and 2.0. In addition, PK profiles of CRI, ALE, and LOR in CSF aligned well with observed data. Moreover, the AUC and Cmax ratios of the three inhibitors when co-administered with CYP3A4 inhibitors/inducers also matched with clinically observed values. Utilizing PK thresholds for effective plasma Ctrough and AO values on wild-type and four ALK mutations in plasma and CSF, PBPK models were then combined with the mean and 95% confidence interval to predict optimal dosing regimens. Conclusions: Overall, these PBPK models provide valuable insights into determining appropriate dosing regimens for the three ALK inhibitors, understanding their effectiveness in brain metastasis therapy, and analyzing the underlying mechanisms of on-target resistance.

5.
ACS Appl Mater Interfaces ; 15(29): 34497-34504, 2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-37439628

RESUMO

Prion disorders are a group of lethal infectious neurodegenerative diseases caused by the spontaneous aggregation of misfolded prion proteins (PrPSc). The oxidation of such proteins by chemical reagents can significantly modulate their aggregation behavior. Herein, we exploit a series of vanadium-substituted Keggin-type tungsten and molybdenum POMs (W- and Mo-POMs) as chemical tools to oxidize PrP106-126 (denoted as PrP), an ideal model for studying PrPSc. Due to the band gaps being larger than that of Mo-POMs, W-POMs possess higher structural stability and show stronger binding and oxidation effect on PrP. Additionally, the substitution of W/Mo by vanadium elevates the local electron distribution on the bridged O(26) atom, thereby strengthening the hydrogen bonding of POMs with the histidine site. Most importantly, with the number of substituted vanadium increases, the LUMO energy level of POMs decreases, making it easier to accept electrons from methionine. As a result, PW10V2 displays the strongest oxidation on the methionine residue of PrP, leading to an excellent inhibitory effect on PrP aggregation and a significant attenuation on its neurotoxicity.


Assuntos
Proteínas Priônicas , Príons , Príons/química , Príons/metabolismo , Vanádio , Metionina/química , Racemetionina
6.
Front Microbiol ; 14: 1196072, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37362917

RESUMO

For the treatment of bacterial infections, photodynamic antimicrobial chemotherapy (PACT) has the advantage of circumventing multi-drug resistance. In this work, new cationic photosensitizers against multi-drug resistant Proteus mirabilis (MRPM) were designed and synthesized by the conjugation of amino phenyl porphyrin with basic amino acid L-ornithine. Their photoinactivation efficacies against MRPM in vitro were reported and include the influence of laser energy, uptake, MIC and MBC, dose-dependent photoinactivation effects, membrane integrity, and fluorescence imaging. The PACT in vivo was evaluated using a wound mouse model infected by MRPM. Photosensitizer 4d displayed high photo inactivation efficacy against MRPM at 7.81 µM under illumination, and it could accelerate wound healing via bactericidal effect. These ornithine-porphyrin conjugates are potential photosensitizers for PACT in the treatment of MRPM infection.

7.
Small ; 19(24): e2207315, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36929209

RESUMO

Polyoxometalates (POMs) are widely used in catalysis, energy storage, biomedicine, and other research fields due to their unique acidity, photothermal, and redox features. However, the leaching and agglomeration problems of POMs greatly limit their practical applications. Confining POMs in a host material is an efficient tool to address the above-mentioned issues. POM@host materials have received extensive attention in recent years. They not only inherent characteristics of POMs and host, but also play a significant synergistic effect from each component. This review focuses on the recent advances in the development and applications of POM@host materials. Different types of host materials are elaborated in detail, including tubular, layered, and porous materials. Variations in the structures and properties of POMs and hosts before and after confinement are highlighted as well. In addition, an overview of applications for the representative POM@host materials in electrochemical, catalytic, and biological fields is provided. Finally, the challenges and future perspectives of POM@host composites are discussed.

8.
Front Plant Sci ; 13: 1046881, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36407591

RESUMO

The efficient induction of peony embryogenic callus is of great significance to the improvement and establishment of its regeneration technology system. In this study, the in vitro embryos of 'Fengdanbai' at different developmental stages were selected as explants, the effects of different concentrations and types of plant growth regulator combinations on the induction and proliferation of embryonic callus at different developmental stages were investigated, and comparative transcriptome analysis of callus with different differentiation potentials were performed to explore the molecular mechanisms affecting callus differentiation. The results showed that the germination rate of 90d seed embryo was the best, which was 94.17%; the 70d and 80d cotyledon callus induction effect was the best, both reaching 100%, but the 80d callus proliferation rate was higher, the proliferation rate reached 5.31, and the optimal induction medium was MS+0.1 mg·L-1NAA+0.3 mg·L-1TDZ+3 mg·L-12,4-D, the callus proliferation multiple was 4.77. Based on the comparative transcriptomic analysis, we identified 3470 differentially expressed genes (DEGs) in the callus with high differentiation rate and low differentiation rate, including 1767 up-regulated genes and 1703 down-regulated genes. Pathway enrichment analysis showed that the "Phenylpropanoid biosynthesis" metabolic pathway was significantly enriched, which is associated with promoting further development of callus shoots and roots. This study can provide reference for genetic improvement and the improvement of regeneration technology system of peony.

9.
Biomed Pharmacother ; 153: 113509, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36076596

RESUMO

BACKGROUND: This study aimed to build a mathematical model of physiologically based pharmacokinetic combined DPP-4 occupancy (PBPK-DO) in humans to provide some recommendations for dosing adjustment in patients with renal impairment. METHODS: The PBPK-DO model was built using physicochemical and biochemical properties and binding kinetics data of TRE and OMA, and then validated by the clinically observed pharmacokinetics (PK) and pharmacodynamics (PD). Finally, the model was applied to determine dose adjustment in patients with renal impairment. RESULTS: The predicted PK and DPP-4 occupancy matched well with the clinically observed data, and all absolute average-folding errors (AAFEs) were within 2. The simulations showed that TRE and OMA were both suggested to only support dose reduction by half in patients with severe renal impairment based on this PBPK-DO model, which is different from the commendations only in terms of their AUC0-336 changes. These simulation results were in good agreement with clinical recommendations about dosage adjustment in patients. CONCLUSION: The present PBPK-DO model can simultaneously predict PK and PD of TRE and OMA in humans and also provide valuable recommendations for dosing adjustment in renal impairment patients, which cannot be achieved by alone depending on PK change.


Assuntos
Compostos Heterocíclicos com 2 Anéis , Insuficiência Renal , Simulação por Computador , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Humanos , Modelos Biológicos , Piranos , Insuficiência Renal/tratamento farmacológico , Uracila/análogos & derivados
10.
Front Pharmacol ; 13: 963311, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36172188

RESUMO

This study aimed to apply a physiologically based pharmacokinetic (PBPK) model to predict optimal dosing regimens of pazopanib (PAZ) for safe and effective administration when co-administered with CYP3A4 inhibitors, acid-reducing agents, food, and administered in patients with hepatic impairment. Here, we have successfully developed the population PBPK model and the predicted PK variables by this model matched well with the clinically observed data. Most ratios of prediction to observation were between 0.5 and 2.0. Suitable dosage modifications of PAZ have been identified using the PBPK simulations in various situations, i.e., 200 mg once daily (OD) or 100 mg twice daily (BID) when co-administered with the two CYP3A4 inhibitors, 200 mg BID when simultaneously administered with food or 800 mg OD when avoiding food uptake simultaneously. Additionally, the PBPK model also suggested that dosing does not need to be adjusted when co-administered with esomeprazole and administration in patients with wild hepatic impairment. Furthermore, the PBPK model also suggested that PAZ is not recommended to be administered in patients with severe hepatic impairment. In summary, the present PBPK model can determine the optimal dosing adjustment recommendations in multiple clinical uses, which cannot be achieved by only focusing on AUC linear change of PK.

11.
Artigo em Inglês | MEDLINE | ID: mdl-35873637

RESUMO

Background: Postmenopausal osteoporosis (PMO) is the most prevalent metabolic bone disease in women. Yishen Zhuanggu (YSZG) decoction and Caltrate D600 reportedly affects bone formation. This study aimed to investigate the efficacy and mechanism of YSZG decoction combined with Caltrate D600 in PMO treatment. Methods: Ovariectomy-induced PMO rat model was treated with YSZG or/and Caltrate D600 for 12 weeks. Femur bone mineral density (BMD), osteoporosis-related protein expression, and serum parameters were measured. Pathological features of femur bone tissues were observed using hematoxylin and eosin staining. Serum levels of oxidative stress parameters were measured using corresponding commercial kits. The mRNA and protein expression of FoxO3a, Wnt, and ß-catenin was detected using qRT-PCR and western blotting. Results: The BMD and ultimate load of PMO rats were increased after treatment with YSZG. YSZG treatment promoted the bone trabeculae formation of PMO rats. YSZG treatment also induced bone differentiation and suppress oxidative stress in PMO rats, evidenced by the increased BALP, Runx2, OPG, SOD, and CAT levels, as well as the decreased TRACP 5b, RANKL, ROS, and MDA levels. Additionally, YSZG treatment downregulated the FoxO3a expression and upregulated the levels of Wnt and ß-catenin in PMO rats. Caltrate D600 addition showed an auxiliary effect for YSZG. Conclusion: YSZG decoction exerts the antiosteoporotic effect on PMO by restraining the FoxO3a expression and activating the Wnt/ß-catenin pathway, which has an impressive synergistic effect with Caltrate D600.

12.
BMC Cancer ; 21(1): 401, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849479

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has high morbidity and mortality rates. It is essential to search new biomarkers to improve the accuracy of early HCC diagnosis. Therefore, we evaluated the diagnostic value of prothrombin induced by vitamin K deficiency or antagonist- II (PIVKA-II) as a potential biomarker that complements α-fetoprotein (AFP) in HCC by detecting the serum PIVKA-II levels. METHODS: Serum PIVKA-II levels were compared in 168 HCC patients, 150 benign liver disease patients and 153 healthy controls to investigate the PIVKA-II potential to be a HCC biomarker. Receiver operating characteristic curve (ROC) analysis was used to evaluate the value of PIVKA-II in the diagnosis of HCC and its complementary role of AFP. The correlation between serum PIVKA-II levels and clinicopathological characteristics was analyzed to study the value of PIVKA-II in assessing HCC progression and prognosis. Finally, the ability of PIVKA-II in assessing the surgical treatment effects of HCC was studied by comparing the pre- and post-operative serum PIVKA-II levels in 89 HCC patients. RESULTS: Serum PIVKA-II levels in HCC patients were significantly higher than that in patients with benign liver disease and healthy controls. The PIVKA-II performance in the diagnosing HCC as an individual biomarker was remarkable. The combined detection of PIVKA-II and AFP improved the diagnostic efficiency of HCC. PIVKA-II retained significant diagnosis capabilities for AFP-negative HCC patients. Significant correlations were found between PIVKA-II expression levels and some clinicopathological characteristics, including tumor size, tumor stage, tumor metastasis, differentiation degree and complications. PIVKA-II expression obviously decreased after surgical resection. CONCLUSIONS: PIVKA-II is a promising serum biomarker for the HCC diagnosis that can be used as a supplement for AFP. The combined diagnosis of the two markers greatly improved the diagnostic efficiency of HCC. The PIVKA-II levels in HCC patients were widely associated with clinicopathological characteristics representing tumor cell dissemination and/or poor prognosis. PIVKA-II can be used to evaluate the curative effects of HCC resection.


Assuntos
Biomarcadores Tumorais , Biomarcadores/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Precursores de Proteínas/sangue , alfa-Fetoproteínas , Carcinoma Hepatocelular/terapia , Gerenciamento Clínico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Biópsia Líquida , Neoplasias Hepáticas/terapia , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Protrombina , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento
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