Current pharmaceutical design最新文献

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen and progesterone receptors (ER, PR) and low or absent HER2 expression, limiting treatment options. Quercetin, a flavonoid with anti-cancer properties, has the potential to be a therapeutic intervention.

Objectives: The study aimed to explore the potential of Quercetin derivatives as therapeutic agents for TNBC using several computational methods.

Methods: The study utilized PASS prediction, molecular docking, ADMET prediction, QSAR models, MD simulations, binding free energy, and DFT calculations to evaluate the efficacy of quercetin derivatives.

Results: ADMET analysis confirmed the solubility, non-carcinogenicity, and low toxicity of four quercetin derivatives: LM01, LM02, LM05, and LM10. These derivatives exhibited strong binding affinity against TNBC protein PPAR1, with binding energies of -10.6, -10.7, -11.4, and -10 kcal/mol, respectively. MD simulations confirmed their stability, with consistent RMSD values and favorable RMSF values. Post-simulation calculations and reduced HOMO-LUMO energy gaps further supported their potential as promising candidates.

Conclusion: Our computational findings suggest that quercetin derivatives, particularly LM01, LM02, and LM10, exhibit strong stability and binding affinity, positioning them as promising candidates for TNBC treatment. Further experimental validation is required to confirm their therapeutic potential.

Cancer is one of the leading causes of death worldwide, which involves the uncontrolled growth of body cells. Cytotoxic chemotherapy drugs, such as tamoxifen, doxorubicin, methotrexate, and cisplatin, have shortcomings that have deprived these treatments of the desired efficiency to destroy tumor cells. Poor pharmacokinetics, severe side effects, and low targeting properties are examples of these shortcomings. Meanwhile, in the last few years, the use of nanocarriers in drug delivery systems has grown significantly. Porphyrins, also called life pigments, are classified as organic complexes. Due to their unique electrochemical and photophysical properties, they have been used in various fields, such as photodynamic therapy, fluorescence, and photoacoustic imaging. However, due to the limitations of these compounds in aqueous environments, such as aggregation by surface molecules, weak absorption in the biological spectral window, self-quenching, and poor chemical and optical stability, there are gaps in the clinical applications of porphyrins. To overcome these challenges, researchers have developed porphyrin-based MOFs. Metal-organic frameworks (MOFs), made of metal ions and clusters coupled with organic linkers, such as porphyrins, through self-assembly, retain the properties of porphyrins while offering additional advantages. Several synthetic approaches and significant advances have been made in the development of porphyrin-based MOFs, including combination therapies, advanced drug delivery, cancer therapy, and photodynamic therapy. Porphyrin-based metal-organic frameworks represent a transformative approach in cancer treatment by integrating multiple therapeutic functions, improving targeting mechanisms, ensuring safety, increasing drug delivery efficiency, and overcoming tumor biological barriers, such as hypoxia, and their day-to-day development promises the formation of more personalized and effective strategies.

PDT is a common and minimally invasive treatment used for certain types of cancer. Photodynamic therapy involves the generation of reactive oxygen species, resulting in cellular apoptosis and disruption of the tumor microenvironment. This review presents a comprehensive examination of recent developments in Photodynamic Therapy (PDT), detailing its mechanisms, the importance of photosensitizers, and their applications across various cancer types. Photosensitizers are essential in photodynamic therapy as they generate reactive oxygen species when exposed to light. Advanced photosensitizers demonstrate high conversion efficiency, improved tumor specificity, and reduced adverse effects. Recent advancements have led to the creation of photosensitizers that exhibit enhanced solubility, stability, and the ability to selectively accumulate in tumors. Combination therapies that incorporate PDT exhibit notable therapeutic outcomes, indicating substantial progress in the field. Recent developments in photodynamic therapy, particularly those that boost immune responses, show considerable promise in significantly enhancing the effectiveness of tumor elimination. These advancements have the potential to enhance the therapeutic application of photodynamic therapy, offering new possibilities for cancer treatment.

Antibiotic resistance poses a significant threat to public health, rendering many life-saving medications ineffective as pathogenic microorganisms develop resistance spontaneously. This results in infections that are difficult to treat, with limited or no treatment options. Traditionally, addressing this challenge involves developing new pharmaceuticals, a lengthy and costly process. However, a more efficient approach lies in improving drug delivery methods, which can be quicker and more economical. In recent years, 3D printing technology has emerged as a groundbreaking, industry-accepted technique that enables the affordable, simple, and rapid manufacturing of pharmaceuticals. This technology supports iterative design-build-test cycles, facilitating the development of a wide range of products, from simple 3D-printed tablets to complex medical devices, tailored for diverse applications. This article explores innovative strategies in the search for novel antibiotics, the development of more effective preventative measures, and, crucially, a deeper understanding of the ecology of antibiotics and antibiotic resistance. It provides an overview of these issues' historical and current status, emphasizing the potential of 3D printing to address antibiotic resistance. Additionally, it discusses how to expand conceptual frameworks in response to recent advancements in chemotherapy, antimicrobials, and antibiotic resistance. The article highlights various notable efforts in utilizing 3D printing to develop antimicrobial dosage forms and medical devices, offering insights into future possibilities.

Background: Intestinal permeability plays a crucial role in drug absorption, as it varies across different gastrointestinal regions, affecting the bioavailability of orally administered drugs. This variability, combined with dose-dependent absorption, influences the overall efficacy and pharmacokinetics of the drug.

Objective: This study aimed to investigate the impact of three intestinal regions (jejunum, ileum, and colon) along with two different doses of amlodipine (AML) (5 mg and 10 mg) on its permeability.

Methods: An optimized HPLC method was developed and validated for the simultaneous quantification of AML, metoprolol (MTP), and phenol red (PR), while a modified single-pass intestinal perfusion (SPIP) was used to assess AML permeability across different intestinal segments.

Results: Net Water Flux (NWF) showed significant fluctuations, with high positive values in the colon, indicating distinct physiological responses in this region. The effective permeability (Peff) of AML varied across different intestinal segments and doses. In the jejunum and ileum, the Peff of AML decreased with increasing doses from 5 mg to 10 mg, while in the colon, Peff remained relatively stable. Peff values ranged from 3.50 × 10-4 cm/s for the 5 mg dose to 1.80 × 10-4 cm/s for the 10 mg dose in the jejunum, from 3.30 × 10-4 cm/s (5 mg) to 2.41 × 10-4 cm/s (10 mg) in the ileum, and from 6.65 × 10-4 cm/s (5 mg) to 6.79 × 10-4 cm/s (10 mg) in the colon.

Conclusion: This study demonstrated significant segmental and dose-dependent variations in the intestinal permeability of AML using the SPIP model in rats.

Introduction: Huachansu injection (HCSI), a clinical traditional Chinese medicine (TCM) preparation, is used to treat non-small cell lung cancer (NSCLC), but the mechanisms of its core components (bufadienolides) remain to be further elucidated. The study aims to explore the mechanisms of bufadienolides from HCSI against NSCLC through network pharmacology and molecular docking.

Methods: The bufadienolides components in HCSI were retrieved from relevant literature. By integrating data from public databases, we identified relevant targets of bufadienolides and NSCLC, then constructed a protein- protein interaction (PPI) network and a "drug-components-targets" network. The key targets and the core components were screened via topological analysis of two networks, and their binding affinity was evaluated through molecular docking, with enrichment analysis performed.

Results: A total of 26 bufadienolides components and 5396 NSCLC targets were collected. The PPI network indicated that HCSI treatment of NSCLC primarily through 10 key targets: HSP90AB1, HSP90AA1, SRC, ESR1, EGFR, BCL-2, MTOR, CCND1, STAT3, and AKT1. Enrichment analysis showed that HCSI treatment of NSCLC mainly involves peptidyl serine phosphorylation, protein kinase complex, PI3K-AKT, and MAPK signaling pathway. Additionally, molecular docking showed that CCND1 and HSP90AB1 had the best binding energy with the core components.

Discussion: HCSI therapy for NSCLC has the advantage of multi-component, multi-target, and multipathway synergistic regulation. It primarily inhibits cancer cell proliferation, induces cell cycle arrest and apoptosis through targets such as HSP90, CCND1, and AKT1, and related pathways.

Conclusion: The study provides significant theoretical support for understanding the pharmacological basis and mechanisms of HCSI in the treatment of NSCLC, and lays the foundation for developing new multitargeted treatment strategies for NSCLC based on HCSI.

Alzheimer's disease (AD) is an ongoing progressive neurodegenerative disorder that predominantly affects elderly individuals. A systematic literature search was conducted using electronic databases such as PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trial reports, and experimental studies published in English within the last 15 years were considered. The keywords used for the search included "Alzheimer's disease," "amyloid-beta," "tau protein," "neuroinflammation," "immunotherapy," "drug repurposing," and "experimental treatment strategies." It is the most common form of dementia, ultimately leading to death in advanced stages. Recent advances in AD have featured the expected role of antiamyloid, anti-tau, and anti-inflammatory therapies. Nonetheless, these treatments are still in various stages of preclinical and clinical trials. Moreover, drug repurposing is another promising avenue to identify effective therapeutic alternatives for Alzheimer's disease. This review highlights the underlying pathophysiological mechanisms of AD along with the limits of existing treatments. It also includes two methodologies, specifically; active immunotherapy and passive immunotherapy. Active immunotherapy tactics include the administration of antigens to stimulate antibody production. Additionally, this study discusses several experimental drugs and novel pharmaceutical approaches for AD.

Introduction: Breast cancer remains a critical global health issue, particularly in patients with BRCA1/2 mutations, which lead to genomic instability and increased cancer susceptibility. While PARP inhibitors targeting PARP1 and PARP2 have shown clinical success through synthetic lethality, PARP15, a mono-ADP-ribosyltransferase involved in DNA repair and tumour progression, remains largely understudied.

Method: A structure-based virtual screening approach was applied to identify potential PARP15 inhibitors. The screening was performed on a Bioactive Screening Compound Library consisting of over 12,200 druglike small molecules. Using the MTiOpenScreen platform, 1,500 candidate compounds were initially shortlisted. Molecular docking was then conducted to identify top-binding compounds, followed by 500- nanosecond molecular dynamics simulations to assess complex stability. Principal component analysis (PCA), free energy landscape (FEL) evaluation, and absorption, distribution, metabolism, and excretion (ADME) profiling were also performed to characterise compound behaviour and drug-likeness.

Results: Three compounds, F2002-0551, F2028-0309, and F1495-1822, emerged with docking scores surpassing the known PARP15 inhibitor, Niraparib. Molecular dynamics simulations confirmed their structural stability with low RMSD values and favourable FELs. PCA revealed consistent ligand dynamics, and ADME analysis showed high gastrointestinal absorption and other drug-like characteristics. Superimposition analysis demonstrated minimal deviation in docked poses, indicating strong and stable interactions with PARP15.

Discussion: These results highlight the therapeutic potential of the selected compounds as novel PARP15 inhibitors. Their favourable binding stability and pharmacokinetic profiles support their candidacy for further development against BRCA-mutated breast cancer.

Conclusion: F2002-0551, F2028-0309, and F1495-1822 represent promising leads for PARP15 inhibition. This study offers a computational foundation for future experimental validation and therapeutic exploration in BRCA-associated breast cancer.

Artificial Intelligence (AI) and Machine Learning (ML) are rapidly transforming microbiome and colorectal cancer (CRC) research by enabling high-throughput data analysis and predictive modelling. This review highlights the current applications of AI/ML tools, such as Convolutional Neural Networks, Random Forest classifiers, and Support Vector Machines, in CRC diagnostics and microbiome profiling. It discusses how AI-integrated endoscopic and imaging systems improve polyp detection accuracy and reduce diagnostic delays. The manuscript also introduces the novel use of AI and microbial fingerprints in forensic science, including postmortem interval estimation and individual identification. Lastly, emerging trends in microbiotabased precision medicine and ethical considerations surrounding AI deployment are explored. These insights underscore AI/ML's potential in reshaping clinical diagnostics, prognostics, and forensic practices related to CRC. This review emphasizes the translational impact of AI/ML in CRC, from bench to bedside to the courtroom, highlighting both current challenges and future research directions.

Introduction: Doxorubicin (DOX), a widely used chemotherapeutic agent, is effective against various malignancies, but its clinical application is limited by cumulative dose-dependent cardiotoxicity. The objective of this review is to systematically explore the molecular mechanisms involved in DOX-induced cardiotoxicity (DIC) and evaluate the cardioprotective potential of plant-derived bioactive compounds.

Methods: A comprehensive literature search was conducted using databases, such as PubMed, Scopus, and Web of Science, focusing on studies published in the last two decades. Emphasis was placed on experimental and preclinical models that investigated molecular pathways of DIC and the therapeutic role of phytochemicals.

Results: DOX-induced cardiotoxicity is mediated through a cascade of molecular events, including excessive oxidative and nitrosative stress, mitochondrial damage, apoptosis, impaired autophagy, and altered activity of signaling pathways, such as AMPK, Nrf2, TGF-β1/Smad2, and HIF-1α. Epigenetic dysregulation also contributes to myocardial injury. Phytochemicals, such as flavonoids, polyphenols, and alkaloids, have shown significant cardioprotective effects. These compounds exert their actions by modulating redox homeostasis, preserving mitochondrial function, regulating apoptotic markers, and restoring signaling imbalances.

Discussion: The pleiotropic nature of phytocompounds enables them to target multiple pathological mechanisms associated with DIC. Despite promising in vitro and in vivo evidence, limitations, such as poor bioavailability, lack of standardized dosing, and inadequate clinical data, hinder their translational potential. Novel delivery systems and well-controlled clinical trials are necessary to overcome these challenges.

Conclusion: Plant-derived bioactive compounds show potential in mitigating doxorubicin-induced cardiotoxicity, as supported by preclinical evidence. However, further translational studies are warranted to validate these findings, optimize pharmacokinetics, and evaluate their feasibility in clinical oncology settings.