Drug Research最新文献

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.

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.

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.

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.

Discoloration refers to the alteration of the original color of an object, resulting in an unpleasant or damaged appearance. Tooth discoloration can occur due to trauma, residual intracanal medicaments or obturating materials, as well as extrinsic factors such as tea, coffee, and chromogenic bacteria. To reduce or eliminate discoloration, whether in a vital or non-vital tooth, several treatment options are available. The simplest and most cost-effective treatment is bleaching. The bleaching materials used not only diminish discoloration but also have side effects, including compromised tooth strength and cervical resorption. To mitigate these side effects, natural products have been developed, tested, and refined. This review article emphasizes various bleaching procedures, the mechanisms of action, and the effectiveness of natural bleaching agents.

Cyclophosphamide is known to cause liver dysfunction. This study investigated the protective role of vitamin D supplementation against cyclophosphamide -induced liver dysfunction in adult male rats. The rats receiving cyclophosphamide were treated with vitamin D at doses of 1,000 and 3,000 IU/kg. At the end of the study period, biochemical and histopathological evaluations were conducted after the animals were sacrificed. The levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, nitric oxide, and bilirubin were significantly elevated in the cyclophosphamide group compared to the control group (p<0.001). Conversely, these levels were significantly decreased in the vitamin D treatment groups (p<0.01). Additionally, the activities of the catalase and glutathione peroxidase were significantly lower in the cyclophosphamide group than in controls (p<0.01), while they increased significantly in the vitamin D groups (p<0.001). According to a semi-quantitative scoring system, the highest scores for pathological lesions were observed in the cyclophosphamide group, with lower scores in the vitamin D groups. The differences between the cyclophosphamide group and both treated groups were statistically significant (p<0.05). These results indicate that vitamin D, through its antioxidant properties, positively influenced liver enzyme levels altered by cyclophosphamide.

Alectinib is an effective inhibitor of anaplastic lymphoma kinase utilized in the treatment of anaplastic lymphoma kinase-positive non-small-cell lung cancer. Nonetheless, its limited solubility in water restricts its therapeutic effectiveness. This research seeks to improve the anticancer efficacy of alectinib through the formation of an inclusion complex with hydroxypro-pyl-β-cyclodextrin. The alectinib-hydroxypro-pyl-β-cyclodextrin complex was synthesized via the kneading method and characterized according to established studies. In vitro assays, such as cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay), colony formation, scratch wound healing, and tube formation assays, were conducted to assess the antiproliferative, antimigratory, and antiangiogenic activities of the complex in comparison to free alectinib. The alectinib-hydroxypro-pyl-β-cyclodextrin complex exhibited markedly increased cy-totoxicity, diminished colony formation, inhibited cell migration, and impaired tube formation compared to free alectinib. The findings indicate that hydroxypro-pyl-β-cyclodextrin complexation enhances the solubility and anticancer efficacy of alectinib, presenting a viable strategy for improving its therapeutic potential in the treatment of non-small-cell lung cancer. Alectinib, in conjunction with hydroxypropyl-β-cyclodextrin, was evaluated for its effects on A549 cells, which are representative of non-small-cell lung cancer. This study focused on its anticancer activity and its influence on cell migration. Angiogenesis refers to the physiological process through which new blood vessels form from pre-existing vessels.

Colorectal cancer accounts for about 10% of all cancer diagnoses and is the second leading cause of cancer-related death. Until the cancer has progressed to an advanced stage, colorectal cancer typically shows no symptoms. The medications currently utilized to treat colorectal cancer have serious drawbacks. The aim of the study was to evaluate the ability of newly developed synthetic matrix metalloprotease-2 inhibitors to prevent metastases. This study used computational models to evaluate pharmacokinetic characteristics and ligand-binding affinities for preliminary screening. Later, we used the human colorectal cancer cell line SW620 in an in ovo approach to assess its anti-migratory properties. The chorioallantoic membrane was used to transplant tumor cells. In order to assess migrastatic activity in a preclinical model using an in ovo technique, we measured changes in the chick embryo's total body weight, colon length and body weight, complete blood count and histopathology of the colon, liver and stomach. In addition, the histology of the stomach, liver, colon, and chorioallantoic membrane was taken into account while assessing the activity. We discovered that compound N5 ({4-[(3'-amino[1,1'-biphenyl]-4-carbonyl) amino] phenyl~acetic acid) had the best migrastatic action by blocking matrix metalloprotease-2. The new compound showed potential as a matrix metalloprotease-2 inhibitor compared to doxycycline. A more robust platform was needed for further investigation and progress of novel compound towards clinical setting.