Drug Research最新文献

Glioblastoma is one of the most frequently seen cancer types in the central nervous system, which is associated with drug resistance and high mortality rates. Curcumin demonstrates significant anticancer potential by inhibiting crucial processes, such as cell proliferation and metastasis, positioning it as a candidate for targeted treatment strategies. In this study, the potential of curcumin to overcome temozolomide resistance in U87 glioblastoma cells was examined, with a focus on elucidating the underlying molecular pathways.U87 and U87/TMZ cells were treated with different concentrations of curcumin, temozolomide, and their combination for 24 and 48 hours, and the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to assess viability. The expression of key genes and proteins of the Bax, Bcl-2, caspase-3, O6-methylguanine-DNA methyltransferase, and DNA repair genes, including MSH2, MSH6, and PARP1, was evaluated by quantitative real-time polymerase chain reaction and western blot. Also, the activity of caspase-3/7 enzymes and the level of apoptosis were measured by fluorometric methods and enzyme-linked immunosorbent assay.Curcumin significantly decreased temozolomide-resistant U87 cell viability in combination with temozolomide in a dose-dependent manner. The expression of O6-methylguanine-DNA methyltransferase, MSH2, MSH6, and PARP1 genes and proteins was decreased. Also, the increase in Bax expression and caspase activity indicated a strong induction of apoptosis by curcumin in resistant cells.Curcumin mitigates temozolomide resistance in glioblastoma by modulating the O6-methylguanine-DNA methyltransferase/MSH2/MSH6 axis and enhancing apoptosis. This natural compound holds promise as a potential agent for the development of targeted glioblastoma therapies.

Nausea and vomiting are commonly reported side effects of long-term linezolid therapy, which is indispensable for tuberculosis and osteoarticular infections. Since the mechanism underlying the development of nausea and vomiting during linezolid treatment is unknown, this study aimed to explore the mechanisms by focusing on the monoamine oxidase-inhibiting effect of linezolid.In vitro serotonin release assays were performed using QGP-1 cells as a surrogate for enterochromaffin cells exposed to linezolid, the monoamine oxidase inhibitor clorgyline, and the known emetogenic agent cisplatin. Serotonin concentrations in the solutions were measured using an enzyme-linked immunosorbent assay. Clorgyline and cisplatin were administered simultaneously with linezolid to elucidate the serotonin release mechanism and confirm the synergistic effects. The intracellular Ca²⁺assays using Fura‑2 were also performed to assess whether serotonin release is mediated by Ca²⁺‑dependent exocytosis.Linezolid exposure significantly increased serotonin release from QGP-1 cells in concentration- and time-dependent manners. Serotonin release also increased in the clorgyline exposure group, and the release of serotonin in the linezolid/clorgyline co-exposure group was higher than that in the single-exposure groups. In contrast, no significant serotonin release or synergistic effects were observed in the cisplatin/linezolid-exposed groups. The Ca²⁺assays demonstrated that linezolid exposure did not change intracellular Ca²⁺levels.Serotonin release was observed when QGP-1 cells were exposed to linezolid, an effect similar to that observed with the potent monoamine oxidase A inhibitor clorgyline. Furthermore, the Ca²⁺assays indicated that linezolid‑induced serotonin release occurs independently of Ca²⁺‑dependent exocytosis.

Vitiligo is a cutaneous autoimmune disease characterized by the destruction of epidermal melanocytes leading to white patches with a global prevalence of about 0.5-2%, and patients' quality of life are greatly affected by the change in appearance and social discrimination caused by the disease. Most of the key cytokines in the pathogenesis of vitiligo act through the Janus kinase/signal transducer and activator of transcription signaling pathway, which is an effective therapeutic target. The first generation Janus kinase inhibitors, i.e., tofacitinib and ruxolitinib, inhibit a variety of Janus kinases, whereas the new generation Janus kinase inhibitors, such as ritlecitinib and upadacitinib, exhibit inhibitory effects only on specific Janus kinases; they are therefore selective as well as safer and more effective. In this review, we aim to provide an up-to-date view of vitiligo pathogenesis at the cellular, molecular, and genetic levels and further to elucidate the relationship between Janus kinase/signal transducer and activator of transcription signaling pathway components and vitiligo. Finally, we summarize currently market-approved and preclinical Janus kinase inhibitors, highlighting the latest advances in their clinical applications.

Several studies have shown that some drugs can slow the growth of cancer cells by inhibiting the c-Abl kinase. However, some of these drugs can cause side effects such as gynecomastia, pulmonary toxicity, and lentiginosis, among others. In the search for a therapeutic alternative, some amide derivatives have been developed to treat cancer. However, their interaction with the c-Abl kinase is not clear.The aim of this study was to evaluate the interaction of 28 amide derivatives with the c-Abl kinase as a therapeutic alternative to treat cancer cells.The theoretical interaction of amide derivatives with the c-Abl kinase was carried out using the 1iep protein as a theoretical model. Besides, bosutinib, dasatinib, imatinib, nilotinib, and radotinib were used as controls in the DockingServer program.The results displayed different types of aminoacid residues involved in the interaction of amide derivatives with the 1iep protein surface compared to the controls. In addition, the inhibition constant (Ki) was lower for compounds 15, 16, and 18 compared to radotinib. Finally, the Ki for amide derivatives 1, 19, and 21 were lower compared with bosutinib, dasatinib, imatinib, and nilotinib.Theoretical data indicate that amide derivatives such as 1, 15, 16, 18, 19, and 21 might have a higher affinity for the 1iep protein surface. This phenomenon could be translated as c-Abl kinase inhibition, resulting in a decrease in cancer cell growth.

ABL kinase inhibitors have transformed the clinical management of chronic myelogenous leukemia; yet, the metabolic consequences of their use remain largely unexplored. In the current study, using K562 cell lines, the metabolic impact of five ABL kinase inhibitors, such as imatinib, dasatinib, nilotinib, ponatinib, and axitinib, was studied. Comparative metabolic profiling revealed both common and inhibitor-specific metabolic alterations. Pathway enrichment analysis identified significant downregulation in starch and sucrose metabolism, nucleotide sugar metabolism and sphingolipid metabolism. These results offered insights to guide the development of treatment strategies for overcoming the drug resistance in chronic myelogenous leukemia as well as managing the associated toxicities.

Both eliglustat and miglustat are substrate reduction therapies targeting glucosylceramide synthase; yet, their safety profile has not been comprehensively analyzed. This study analyzes adverse events associated with both drugs using the U.S. Food and Drug Administration Adverse Event Reporting System to provide insights for clinical safety.Adverse events were classified by MedDRA System Organ Class (SOC, v26.1). Adverse event signals were mined by disproportionality analyses, including the reporting odds ratio, the proportional reporting ratio, the multi-item gamma Poisson shrinker algorithms, and the Bayesian confidence propagation neural network.A total of 1,223 and 980 adverse event reports were retrieved from eliglustat and miglustat, respectively, involving 27 System Organ Class categories each. Some positive signals were consistent with the drug labels, including dyspepsia identified in eliglustat and diarrhoea identified in miglustat. We also identified unexpected signals not listed on the drug labels, such as paresthesia, dry skin, and ichthyosis for eliglustat and dysphagia for miglustat. For patients treated with eliglustat and miglustat, the majority of adverse events manifested more than 1 year after the initiation of therapy. Notably, male patients treated with eliglustat have the significantly higher incidence of weight increase and dry skin. Female patients treated with miglustat have the significantly higher incidence of dysphagia and cognitive disorder.In the clinical administration of eliglustat and miglustat, clinicians need to monitor the effects of adverse events varied by gender and to pay more attention to new adverse event signals.

Liposomes are artificially constructed, phospholipid-based vesicular systems that have emerged as vital components in pharmaceutical nanotechnology and advanced drug delivery. Their flexible bilayered structure enables the encapsulation of a broad spectrum of therapeutic agents, enhancing drug stability and bioavailability. Since their discovery, liposomes have been widely explored as efficient drug carriers and diagnostic tools due to their superior capacity to deliver active pharmaceutical ingredients precisely to target sites. Their inherent advantages including high biocompatibility, the enhanced permeability and retention effect for passive tumor targeting, customizable surface modification for improved targeting efficiency, and enhanced physicochemical stability collectively position them as promising nanocarriers for cancer therapy and other biomedical applications. Liposomes, as synthetic nanoscale vesicles, offer significant promise for immunotherapeutic interventions due to their capability to codeliver antigens and adjuvants while modulating immune cell behavior. Specialized formulations such as immunoliposomes, virosomes, and other immunostimulatory complexes engineered with specific ligands or immune active moieties exhibit unique structural and functional profiles that enhance anticancer immune responses. Furthermore, liposomes facilitate targeted cargo delivery to immune cells, influencing their phenotype and functional activity. This review presents an integrated overview of liposomal composition, structural attributes, mechanisms of drug delivery, therapeutic applications, and clinical progress. The use of liposomes in delivering small molecules, macromolecules, and nucleic acids has demonstrated significant advancements, underscoring their expanding role in modern therapeutics. Overall, this article provides a comprehensive and up-to-date examination of liposome technology and its clinical translational potential.

Benign prostatic hyperplasia is a common public health problem in aging men across the globe. Diarylpropionitrile, a selective estrogen receptor-beta agonist, favorably regulates cell proliferation and inflammation, two major hallmarks of benign prostatic hyperplasia pathology.This study aimed to explore the mitigative impact of diarylpropionitrile on testosterone-induced benign prostatic hyperplasia in rats.Forty male rats were randomly divided into four groups (n=10): a normal control group, a benign prostatic hyperplasia group, a finasteride-treated group, and a diarylpropionitrile-treated group. After 4 weeks of treatment, macroscopic and microscopic features of prostatic hyperplasia and androgenic, proliferative, angiogenic, apoptotic, and inflammatory biomarkers were assessed.Testosterone administration significantly increased prostate weight, prostatic index, and hyperplasia scores. Both diarylpropionitrile and finasteride effectively ameliorated the benign prostatic hyperplasia lesions by reversing these changes. Both treatments significantly lowered elevated prostatic dihydrotestosterone, 5-αR2, β-catenin, and proliferating cell nuclear antigen levels, demonstrating a strong anti-proliferative effect. They also attenuated the increased pro-inflammatory cytokines interleukin-6, interleukin-27, and prostaglandin E2 and growth factors transforming growth factor beta and vascular endothelial growth factor. Furthermore, both agents inhibited testosterone-induced estrogen receptor-beta upregulation, counteracted peroxisome proliferator-activated receptor gamma tissue protein, and boosted the expression of the anti-apoptotic marker B-cell lymphoma 2.Diarylpropionitrile alleviates testosterone-induced benign prostatic hyperplasia in rats by modulating key pathways associated with cellular proliferation and inflammation. Diarylpropionitrile, as an estrogen receptor-beta agonist, represents a promising alternative for the benign prostatic hyperplasia treatment through multi-targeted mechanisms.

Oral squamous cell carcinoma is one of the most common head and neck cancers, which is associated with drug resistance and high mortality rates. The PI3K/AKT/mTOR pathway plays a crucial role in the survival, growth, and metastasis of cancer cells, making it a suitable target for targeted therapy.This study investigated the antitumor effects of gallic acid on CAL-27 cells, with a focus on the aforementioned pathway.CAL-27 cells were treated with different concentrations of gallic acid for 48 hours, and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to assess viability. The expression of key genes and proteins in the PI3K/AKT/mTOR pathway, as well as apoptosis-related genes, was evaluated using the quantitative real-time reverse transcription polymerase chain reaction and western blot. Also, the activity of caspase-3/7 enzymes and the level of apoptosis were measured by fluorometric methods and enzyme-linked immunosorbent assay.Gallic acid significantly decreased oral squamous cell carcinoma cell viability in a dose- and time-dependent manner. The expression of PI3K, AKT, and mTOR genes and proteins was decreased, while PTEN expression was increased. Also, the increase in Bax expression and caspase activity indicated a strong induction of apoptosis by gallic acid.Gallic acid exhibits significant anticancer effects in oral squamous cell carcinoma cells by inhibiting the PI3K/AKT/mTOR pathway and activating apoptotic pathways. This natural compound may contribute to the development of targeted therapies for oral cancer, pending further preclinical validation.

This study investigated the protective effect of alkaloid boldine against diclofenac-induced kidney damage in normotensive female rats. Animals were divided into three groups: naive, vehicle+diclofenac (50 mg/kg), and boldine+diclofenac (boldine 0.1 mg/kg+diclofenac 50 mg/kg). Treatments were administered orally once daily for 2 days. The vehicle+diclofenac group showed reduced urinary volume and sodium excretion. In contrast, the boldine+diclofenac group restored both parameters to levels similar to the naive group. Other urinary electrolytes indicated imbalance in diclofenac-treated animals, regardless of boldine co-treatment. Plasma analysis showed no alterations. Kidney tissue from diclofenac-treated groups revealed increased glutathione and decreased lipid hydroperoxides. Histology showed that vehicle+diclofenac resulted in a reduction in glomerular size, thickening of Bowman's capsule, and mesangial disarray, while these changes were less pronounced with boldine co-treatment. Molecular docking analysis indicated that boldine may interact with important proteins related to renal hemodynamics, sodium regulation, and inflammatory processes pointing to a multi-target mechanism. Boldine attenuated renal damage induced by diclofenac, improving urinary parameters and reducing histological alterations. Further studies are necessary to elucidate its protective mechanisms and impact on renal hemodynamics.