Archives of Pharmacal Research最新文献

In recent years, covalent organic frameworks (COFs) have garnered considerable attention in the field of onco-nanotechnology as a new type of nanoporous construct due to their promising physicochemical properties, ease of modification, and ability to be coupled with several moieties and therapeutic molecules. They can not only be used as biocompatible nanocarriers to deliver therapeutic payloads to the tumor zone selectively but can also be combined with a variety of therapeutic modalities to achieve the desired treatments. This review comprehensively presented recent achievements and progress in COF-based cancer diagnosis, detection, and cancer therapy to provide a better prospect for further research. Herein our primary emphasis lies on exploring the application of COFs as potential sensors for cancer-derived biomarkers that have received comparatively less attention in previous discussions. While the utilization of COFs in solid tumor therapy has faced significant challenges in scientific research and clinical applications, we reviewed the most promising features that underscore their potential in cancer theranostics.

Numerous studies have examined the pathophysiological changes induced by chronic alcohol (ethanol) consumption and the underlying mechanisms, while much less attention has been devoted to understanding the health impacts of binge drinking. Binge drinking is defined as the excessive consumption of alcohol within a single drinking episode, and is the typical consumption pattern among young people in Western countries. While most young binge drinkers are not clinically alcohol dependent, binge drinking has emerged as a significant social and public health concern. The circulating alcohol consumed during binge episodes permeates cellular membranes throughout the body, exerting profound effects on multiple organs, and signaling pathways. Regular binge drinking eventually induces hepatic steatosis (fatty liver), initiates acute inflammation, and accelerates neutrophil infiltration, de novo lipogenesis, adipocyte death/lipolysis, and the production of nonoxidative alcohol metabolites, processes that synergize to damage liver tissue and impair liver function. Metabolic abnormalities such as diabetes and obesity can also exacerbate the progression of alcohol-related liver disease among binge drinkers. Several animal models have been developed to evaluate the pathophysiological changes resulting from binge drinking; however, the pathogenesis of binge drinking is not fully understood due to differences in alcohol metabolism between animal models and humans. Thus, given the high prevalence and severe health implications of binge drinking, there is an urgent need for comprehensive experimental and clinical investigations to unravel the associated pathophysiological changes. This review summarizes recent research findings on the impact of binge drinking, specifically focusing on its contributions to alcoholic liver injury.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates hepatic glucose output and is implicated in liver fibrosis. We aimed to investigate the anti-fibrotic effect of a novel 11β-HSD1 inhibitor in a thioacetamide (TAA)-induced liver fibrosis mouse model. Mice were administered TAA for 19 weeks and treated with 11β-HSD1 inhibitor for the last 9 weeks. Treatment with 11β-HSD1 inhibitor significantly reduced fibrosis area, alanine aminotransferase, and aspartate aminotransferase levels compared to the TAA-only group. Inhibition of 11β-HSD1 led to a decrease in intracellular cortisol levels, which suppressed the activation of hepatic stellate cells. RNA sequencing revealed significant downregulation of the Notch signaling pathway, including reduced expression of Notch ligands and receptors, as well as downstream genes. Furthermore, 11β-HSD1 inhibition enhanced NK cell-mediated immune responses, as indicated by the upregulation of NK cell-related genes and increased NK cell populations confirmed by mass cytometry. This increase in NK cell activity contributed to the clearance of activated HSCs and the attenuation of fibrosis. These findings suggest that 11β-HSD1 inhibition alleviates liver fibrosis through Notch pathway suppression and enhancement of NK cell-mediated immune responses. Our results support the therapeutic potential of a novel 11β-HSD1 inhibitor for treating liver fibrosis.

Raf kinase enzymes are often dysregulated in melanoma. While sorafenib demonstrates strong activity against wild-type B-Raf, it fails to effectively inhibit the mutated form of B-Raf. In this study, sorafenib served as a lead compound for the development of new derivatives designed to enhance inhibitory activity across multiple Raf isoforms (pan-Raf inhibitors). Novel naphthalene-based diarylamide derivatives were subsequently designed, synthesized, and evaluated for their biological activity against various Raf kinase isoforms and the melanoma A375 cell line. Among these, compound 9a, containing a difluoromethoxy group, demonstrated strong inhibitory activity across B-Raf^WT, B-Raf^V600E, and c-Raf. Additionally, it induced G2/M phase arrest and triggered dose-dependent apoptosis, effectively suppressing both cell proliferation and survival. Compound 9a also exhibited high selectivity for Raf isoforms with minimal off-target effects, underscoring its specificity and therapeutic potential for Raf-driven malignancies.

Tumor microenvironment (TME) is composed of diverse cell types whose interactions, both direct and indirect, significantly influence tumorigenesis and therapeutic outcomes. Within TME, reactive oxygen species (ROS) are produced by various cells and exhibit a dual role: moderate ROS levels promote tumor initiation and progression, whereas excessive levels induce cancer cell death, influencing the efficacy of anticancer therapies. Inflammasomes, cytosolic multiprotein complexes, are pivotal in multiple stages of tumorigenesis and play a crucial role in establishing the inflammatory TME. By releasing cytokines such as IL-1β and IL-18, inflammasomes contribute to immune cell recruitment and sustain a chronic inflammatory state that supports tumor growth. ROS are critical regulators of inflammasome activation, with the impact of ROS-mediated activation differing across cell types, leading to distinct influences on tumor progression and therapeutic responses. This review explores how ROS drive inflammasome activation in various TME-associated cells and the reciprocal ROS generation induced by inflammasomes, examining their multifaceted impact on tumorigenesis and therapeutic efficacy. By elucidating the complex interplay between ROS and inflammasomes in TME, we provide insights into potential therapeutic approaches that could modulate cancer progression and enhance treatment outcomes.

Gliclazide is a sulfonylurea hypoglycemic agent used to treat type 2 diabetes. Cytochrome P450 (CYP) 2C9 and CYP2C19 are primarily involved in the hepatic metabolism of gliclazide. The two CYP isozymes are highly polymorphic, and their genetic polymorphisms are known to significantly impact the pharmacokinetics of gliclazide. In the present study, the physiologically based pharmacokinetic (PBPK) model was developed using data from subjects whose pharmacokinetic parameters were influenced by the genetic polymorphisms of the CYP metabolic enzymes. All predicted plasma concentration–time profiles generated by the model showed visual agreement with the observed data, and the pharmacokinetic results were within the twofold error range. Individual simulation results showed additional metrics: average fold error (− 0.19 to 0.07), geometric mean fold error (1.13–1.56), and mean relative deviation (1.18–1.58) for AUC, C_max, T_1/2, T_max, CL/F, and V_d values. These results met the standard evaluation criteria. The validation across a total of 8 studies and 7 races also satisfied the twofold error range for AUC, C_max, and T_1/2. Therefore, variations in gliclazide exposure according to individuals’ CYP2C9 and CYP2C19 genotypes were properly captured through PBPK modeling in this study. This PBPK model may allow us to predict the gliclazide pharmacokinetics of patients with genetic polymorphisms in CYP2C9 and CYPC19 under various conditions, ultimately contributing to the realization of individualized drug therapy.

Despite significant progress in the field of human breast cancer research and treatment, there is a consistent increase in the incidence rate of 0.5 percent annually, posing challenges in the development of effective novel therapeutic strategies. The failure rate of drugs in clinical trials stands at approximately 95%, primarily attributed to the limitations and lack of reliability of existing preclinical models, such as mice, which do not mimic human tumor biology. This article examines the potential utility of canine mammary tumors as an adjunct preclinical model for investigating human breast cancer. Given the numerous similarities between canine and human breast cancer, canines present a promising alternative model. The discussion delves into the intricate molecular and clinical aspects of human breast cancer and canine mammary tumors, shedding light on the tumors' molecular profiles, identifying specific molecular markers, and the application of radiological imaging modalities. Furthermore, the manuscript addresses the current constraints of preclinical cancer studies, the benefits of using canines as models, and the obstacles linked to the canine mammary tumors model. By concentrating on these elements, this review aims to highlight the viability of canine models in enhancing our understanding and management of human breast cancer.

This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes. A total of thirty-nine healthy Korean male volunteers were divided into three different CYP2C9 genotype groups (CYP2C9*1/*1, *1/*3 and *3/*3 genotypes) and were enrolled in the celecoxib alone trial, celecoxib with fluconazole trial, or both. In the celecoxib alone trial, participants received a single oral dose of 200 mg celecoxib. In the celecoxib with fluconazole trial, participants received 300 mg fluconazole on day 1, 150 mg fluconazole once daily for four consecutive days (day 2–5), and a coadministration of 200 mg celecoxib with 150 mg fluconazole on day 6. Plasma concentrations of celecoxib and celecoxib carboxylic acid were determined by using HPLC–MS/MS. In the CYP2C9*1/*1 genotype group, fluconazole treatment increased AUC_inf of celecoxib by 2.61-fold, and decreased CL/F by 60.4% (both p < 0.001). In the CYP2C9*1/*3 genotype group, fluconazole treatment increased AUC_inf of celecoxib by 2.44-fold (p < 0.001), prolonged t_1/2 by 1.36-fold (p < 0.05), and decreased CL/F by 60.4% (p < 0.001). Fluconazole treatment increased AUC_inf of celecoxib by 2.23-fold, prolonged t_1/2 by 1.64-fold, and decreased CL/F by 53.8% in the subject with CYP2C9*3/*3 genotype. C_max of celecoxib carboxylic acid significantly decreased in CYP2C9*1/*1 and *1/*3 genotypes (p < 0.01 and p < 0.05, respectively), following fluconazole treatment, whereas AUC_inf showed no significant changes in any CYP2C9 genotype group. In conclusion, fluconazole affected the pharmacokinetics of celecoxib in different CYP2C9 genotypes.