Current pharmaceutical design最新文献

Background: Synthetic cannabinoids are one of the most identified abused drugs nowadays. Their popularity is due to their psychoactive effects, which resemble delta 9 tetrahydrocannabinol. This study investigates the genotoxic potential of three synthetic cannabinoids of indazole-passed drugs, AB-Fubinaca, AMBFubinaca, and EMB-Fubinaca (at a final concentration of 200 nM).

Methods: Genotoxicity was examined using Sister Chromatid Exchanges (SCEs) and Chromosomal Aberrations (CAs) assays in cultured human lymphocytes. Blood for lymphocyte cultures was obtained from healthy adult young males.

Results: A significant increase in the frequency of SCEs was detected for all examined drugs (range: 5.4-6.1, p < 0.05) compared to the control group (4.70 ± 0.31). The order of synthetic cannabinoids in terms of their ability to induce SCEs was EMB-Fubinaca (6.04 ± 0.63) > AMB-Fubinaca (5.65 ± 0.6) > AB-Fubinaca (5.33 ± 0.58). None of the examined drugs induced significant changes to the frequency of CAs (p > 0.05). Additionally, there were no effects of the synthetic cannabinoids at the studied concentration on proliferation and mitotic indices.

Conclusion: Synthetic cannabinoids have been found to increase the frequency of SCEs in cultured human lymphocytes. The results should be confirmed in in vivo studies using lymphocytes derived from synthetic cannabinoid users.

cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway is an natural immune response signaling pathway in the human body that is essential for sensing abnormal DNA aggregation in the cell. When the cGAS protein senses abnormal or damaged DNA, it forms a second messenger called cyclic dinucleotide (cGAMP). The cycled dinucleotide will activate the downstream STING protein, thereby inducing the expression of inflammatory cytokines such as type I interferon, which binds to receptors on its own cell membrane and ultimately initiates multiple immune response pathways. This signaling pathway plays an important immune role in antimicrobial and antitumor functions, etc. so the development of drugs targeting this signaling pathway has important clinical application value. In recent years nanocomplexes based cGAS-STING signaling pathway activation and inhibition treatments have been gradually developed. In this review, on the basis of elaborating the main activation mechanism of the cGAS-STING pathway, we further introduced the nanocomplexes that effectively activate the cGAS-STING pathway, focusing on the composition, types and applications of the nanocomplexes. In addition, we discussed the key challenges and future research directions of the way that stimulating the cGAS-STING signaling pathway in the form of nanocomplexes to activate immuno-tumor therapy. Our work aims to provide a better understanding of the progress of nanotherapeutics in the cGAS-STING pathway, providing a promising anti-tumor therapeutic strategy.

Aims: This study aims to elucidate the relationship between potential MI targets and SFA's mechanism of action, providing a theoretical basis for clinical development of new drugs.

Background: Myocardial infarction (MI) has been identified as one of the major cardiovascular diseases with adverse consequences. Sophora flavescens Aiton (SFA) is indicated for the therapeutic treatment of MI. However, there is no systematic research on the new therapeutic targets for MI and the exact action mechanism of SFA.

Objective: This study explores the potential mechanisms of SFA in treating MI by integrating bioinformatics, network pharmacology analyses and experimental verification.

Methods: New MI targets were predicted using bioinformatics techniques. Network pharmacology and molecular docking jointly served for predicting the key targets and underlying mechanisms of SFA. A machine learning model was developed to identify the core MI targets. Subsequently, H9c2 cardiomyocytes hypoxia model was established for experimental verification.

Results: 140 active components were ascertained in SFA and 59 differentially expressed genes (DEGs) were screened for MI. Eighty-seven shared genes were obtained by WGCAN. Eighty proteins and 413 interactions were identified by PPI network. After building the machine model, three core targets were identified (STAT1, TNFRSF1A and MCL1). According to in vitro experiments, SFA exerts a protective effect relying on three core targets and biological processes, including cell viability, the inflammatory response, and antiapoptotic effects, etc. Conclusion: This study finds new core targets for MI and the therapeutic activity of SFA against MI, of which the experimental verification provides valuable insights into the molecular mechanisms underlying SFA's efficacy in MI treatment and paves the way for targeted drug development strategies.

Introduction: The COVID-19 pandemic has necessitated rapid advancements in therapeutic discovery. This study presents an integrated approach combining machine learning (ML) and network pharmacology to identify potential non-covalent inhibitors against pivotal proteins in COVID-19 pathogenesis, specifically B-cell lymphoma 2 (BCL2) and Epidermal Growth Factor Receptor (EGFR).

Method: Employing a dataset of 13,107 compounds, ML algorithms such as k-Nearest Neighbors (kNN), Support Vector Machine (SVM), Random Forest (RF), and Naïve Bayes (NB) were utilized for screening and predicting active inhibitors based on molecular features. Molecular docking and molecular dynamics simulations, conducted over a 100 nanosecond period, enhanced the ML-based screening by providing insights into the binding affinities and interaction dynamics with BCL2 and EGFR. Network pharmacology analysis identified these proteins as hub targets within the COVID-19 protein-protein interaction network, highlighting their roles in apoptosis regulation and cellular signaling.

Results: The identified inhibitors exhibited strong binding affinities, suggesting potential efficacy in disrupting viral life cycles and impeding disease progression. Comparative analysis with existing literature affirmed the relevance of BCL2 and EGFR in COVID-19 therapy and underscored the novelty of integrating network pharmacology with ML. This multidisciplinary approach establishes a framework for emerging pathogen treatments and advocates for subsequent in vitro and in vivo validation, emphasizing a multi-targeted drug design strategy against viral adaptability.

Conclusion: This study's findings are crucial for the ongoing development of therapeutic agents against COVID-19, leveraging computational and network-based strategies.

The ocular nanoemulsions (NE) are biphasic systems mainly composed of oil and water emulsified by surfactants/cosurfactants. The extensive surface area of ocular NE enhances corneal contact, leading to improved drug penetration and making it a preferable delivery system. They can also increase the solubility of drugs across the ocular barrier with improved residence time. Oils, surfactants, and co-surfactants used in formulating ocular NEs present a significant challenge in developing safe, stable, less irritant, more permeable, improved residence time, and highly bioavailable products. The choice of oil, surfactant, and co-surfactant significantly impacts the development of ocular Nano emulsions (NE) with desirable characteristics, such as small globule size, enhanced penetration, high drug content, and prolonged retention in the eye. This mini-review aims to contribute valuable insights into the selection criteria of oils, surfactants, and co-surfactants for ocular NE. Finally, the correlation between the properties of ocular NEs and the choice of oils, surfactants, and co-surfactants with emphasis on sterilization and stability aspects are considered in short.

Background: Nitric oxide (NO) is a low-toxicity and high-efficiency anticancer treatment that can augment the cytotoxicity of doxorubicin (DOX) towards breast cancer cells, thereby exhibiting a favorable effect on chemotherapy sensitization.

Objective: The study aimed to establish a hydrogel that sensitizes chemotherapy by inducing local inflammatory stimulation to change the tumor microenvironment and promote NO production. The purpose of the study was to examine the anti-tumor effect in vivo and in vitro.

Methods: The functional properties of the composite hydrogels were tested by UV spectrophotometry and NO detection kit. CCK8, DCFH-DA fluorescent probe, Calcein-AM/PI detection kit, and confocal detection methods were used for the cytocompatibility and cytotoxicity of the composite hydrogels. The subcutaneous tumor volume, weight, and tumor inhibition rate of 4T1 breast cancer cells were evaluated for pharmacodynamic study in vivo.

Results: Each component of hydrogel has good biocompatibility. The combination of gas therapy and chemotherapy can significantly enhance the effect of inhibiting tumor cell growth. The tumor growth of tumor- bearing mice in the hydrogel administration group was slow, and the tumor inhibition rate was 85.10%. The body weight grew steadily, and no significant pathological changes were observed in the H&E staining of major organs.

Conclusion: A composite hydrogel with alginate as the carrier was successfully established, which was based on improving the tumor microenvironment to trigger gas therapy combined with chemotherapy for tumor treatment.

Alzheimer's disease (AD) is a debilitating condition that significantly affects the elderly. Early diagnosis is not only critical for improving patient outcomes but also directly influences the success of emerging therapeutic interventions. A therapeutic strategy targeting only one pathogenic mechanism is unlikely to be very effective, as there is increasing evidence that AD does not have a single pathogenic cause. Therefore, combining medications or developing therapies that address multiple pathways may be beneficial. Most clinical trials can be classified under added therapy rather than combination therapy. Effective treatment of AD likely requires targeting multiple mechanisms, such as amyloid-beta (Aβ) and tau pathology. However, many medications face challenges, including poor solubility, low permeability, and the inability to cross the blood- -brain barrier (BBB). This is where nanocarriers come into play, as they can be loaded with these medications to facilitate targeted drug delivery. This approach enhances the pharmacokinetic profile of drugs in both the blood and the brain. Therefore, this paper provides a concise overview of the use of various nanocarriers loaded with drug combinations for treating AD.

Introduction: Chronic Kidney Disease (CKD) is recognized as a major global public health problem. Dialysis is the mainstay of treatment for patients with end-stage renal disease and can prolong survival in patients with CKD. As patient survival increases, the treatment of complications becomes more important. CKD-mineral and bone disorders (CKD-MBD) and renal anemia are common complications in patients with CKD. Cinacalcet is a calcimimetic for the treatment of Secondary Hyperparathyroidism (SHPT) in adult dialysis patients, which regulates the synthesis and secretion of parathyroid hormone by increasing the sensitivity of calcium-sensitive receptors. This retrospective study evaluated the efficacy of cinacalcet in dialysis patients.

Method: Forty-seven patients on dialysis with elevated parathyroid hormone were included. The selected patients have regular follow-up visits in our outpatient clinic and regular use of cinacalcet for no less than 6 months.

Result: During the 6-month efficacy evaluation phase, cinacalcet not only reduced the levels of the intact parathyroid hormone (iPTH, P ≤ 0.05), serum calcium (P ≤ 0.01), and Ca×P (P ≤ 0.05) but also reduced weekly erythropoietin dosage (P ≤ 0.01) and erythropoietin resistance index (ERI, P ≤ 0.05).

Conclusion: While controlling SHPT in patients with CKD, cinacalcet reduced EPO resistance and improved renal anemia. In conclusion, cinacalcet not only decreased the levels of the iPTH, serum calcium, and Ca×P but also reduced weekly EPO dosage and ERI levels. Controlling SHPT in patients with CKD, cinacalcet also reduced ERI and improved renal anemia.

Background: In vascular tissue, macrophages and inflammatory cells produce the enzyme lipoprotein- associated phospholipase A2 (Lp-PLA2). Treatment with fibrates decreases Lp-PLA2 levels in individuals with obesity and metabolic syndrome; however, these findings have not been fully clarified.

Objective: The goal of this study was to investigate the possible effects of fibrate therapy on Lp-PLA2 mass and activity through a meta-analysis of clinical trials.

Methods: Web of Science, PubMed, Scopus, Google Scholar, and ClinicalTrials.gov databases were searched using MeSH terms and keywords. Randomized controlled trials (RCT) evaluating the effect of statins on Lp- PLA2 mass and/or activity were included in the meta-analysis. Quantitative data were analyzed using a random- effects model and the generic inverse variance method.

Results: The meta-analysis of 10 clinical trials indicated that fibrate treatment has no significant effect on Lp- PLA2 mass (fibrate vs. placebo/nothing = WMD: -3.29 ng/ml, 95% CI: -21.35, 14.78, p = 0.72; fibrate vs. active control = WMD: -1.08 ng/ml, 95% CI: -51.38, 49.22, p = 0.97); Lp-PLA2 activity (fibrate vs. active control = WMD: 0.84 nmol/ml/min, 95% CI: -0.17, 1.84, p = 0.10); HDL-LpPLA2 activity (fibrate vs. active control = WMD: 0.77 nmol/ml/min, 95% CI: -0.33, 1.88, p = 0.17); and secretory PLA2 (fibrate vs. active control = WMD: 0.37 ng/ml, 95% CI: -1.22, 1.97, p = 0.65). Also, the results of the sensitivity analysis were robust for all these parameters.

Conclusion: In conclusion, fibrate therapy did not reduce the mass and activity of Lp-PLA2.

Aims: This study aims to identify and evaluate promising therapeutic proteins and compounds for breast cancer treatment through a comprehensive database search and molecular docking analysis.

Background: Breast cancer (BC), primarily originating from the terminal ductal-lobular unit of the breast, is the most prevalent form of cancer globally. In 2020, an estimated 2.3 million new cases were reported, resulting in approximately 685,000 deaths. Mutations in the BRCA1 and BRCA2 genes are well-established in hereditary breast cancer. The identification of effective therapeutic proteins for BC remains a complex and evolving area of research.

Objective: This study aims to identify and evaluate promising therapeutic proteins and compounds specific to breast cancer through a comprehensive database search and molecular docking analysis.

Methods: A rigorous search was conducted within the National Cancer Institute (NCI), NCI Metathesaurus, SIGnaling Network Open Resource (SIGNOR), Human Protein Atlas (HPA), and the Human Phenotype Ontology (HPO) to shortlist proteins linked to BC (CUI C0678222). Recent studies were reviewed to understand the administration of CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) combined with endocrine therapy for HR-positive and HER2-negative breast cancer. Anticancer compound libraries available at ZINC and PubChem were analyzed. Compounds were evaluated based on their binding energies with CDK4 protein, a rationally selected druggable target.

Results: Key proteins linked to breast cancer were identified through database searches. Proliferation, apoptosis, and G1/S transition pathways were frequently found dysregulated in breast cancer. ZINC13152284 exhibited the strongest binding energy at -10.9 Kcal/mol, followed by ZINC05492794 with a binding energy of -10.4 Kcal/mol. Preexisting drugs showed lower binding energies with the CDK4 protein.

Conclusion: The study highlights the importance of drug repurposing as a strategy for the safe and effective treatment of breast cancer. Synthetic inhibitors often cause severe side effects, emphasizing the need for novel targets and compounds with better therapeutic profiles. Molecular docking identified promising compounds from the ZINC database, suggesting potential new avenues for breast cancer therapy.