Current pharmaceutical design最新文献

Interventions to reduce smoking prevalence aim to help patients quit smoking to cut down its hazards and related impairments in human beings. Pharmacological treatments are recommended for those with high levels of addiction because of severe physical and psychological dependence. Use of pharmacotherapy can double the odds of successful quitting. Nicotine replacement therapy (NRT), drug treatment regimens including nicotinic receptor agonists (varenicline), dopamine and norepinephrine reuptake inhibitors (bupropion), cytisinicline (cytisine), and combination therapy (NRT + medication) can be employed on a case-by-case basis. Furthermore, varenicline has been found to be more effective than the other agents in most studies. The most common adverse effects of pharmacological agents include depression, nausea, anxiety, abnormal dreams, and insomnia. On the other hand, electronic cigarettes offer another alternative to aid in smoking cessation (SC). Endurance of SC is mostly related to the employment of combined approaches, such as counselling and pharmacotherapy. This study is designed to provide an up-to-date overview of the contemporary approach to interventions aimed at helping patients in SC.

The potential of nanomedicine in cancer treatment is highlighted through the development of novel carriers for delivering anticancer drugs. By using advanced drug delivery techniques, nanomedicine, a rapidly developing therapeutic strategy, aims to maximize therapeutic efficacy while reducing adverse effects on healthy tissues. With significant benefits in targetability, stability, drug loading efficiency, and safety, nanomedicine has great potential to improve treatment outcomes and reduce off-target toxicity. More effective drugs are required for the treatment of cancer, given the annual number of new cases and millions of deaths due to the disease worldwide. Traditional cancer treatments are still not very effective against advanced metastatic cancers, despite their success in treating early-stage cancers. Thus, a vital path towards enhancing patient outcomes and lowering death rates in cancer remains a promising strategy. Porphyrin-derived nanomedicines play a crucial role in cancer treatment. Because of their specific characteristics-such as higher singletoxygen quantum yields and precise targeting-porphyrin-based nanomaterials have attracted significant interest. Such nanomaterials have great potential to maximize therapeutic effectiveness while reducing the side effects of cancer treatment. The most recent advancements in the use of porphyrin-based nanomedicine for drug delivery, imaging, and phototherapy are analyzed in this review. Drawing on a comprehensive analysis of current research, this review offers significant insights into the prospective applications of porphyrin-based nanomedicine as a flexible and potent weapon in the fight against cancer.

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.

Introduction: Despite significant advances in the comprehensive treatment of nasopharyngeal carcinoma (NPC), local recurrence or distant metastasis still occurs in a considerable proportion of patients, leading to poor outcomes and posing a significant clinical challenge. The current therapeutic agent, Triptonide (TN), has shown potential efficacy in modulating cellular autophagy, suggesting its therapeutic promise for treating NPC. However, the precise molecular targets and mechanisms underlying TN's role in NPC remain to be elucidated.

Methods: Initially, relevant targets for TN in the treatment of NPC were identified through public databases. Next, network pharmacology and bioinformatics analyses were employed to pinpoint the top 15 hub targets and critical signaling pathways involved in TN's therapeutic action. Finally, experimental validation, including a range of molecular assays, was conducted to investigate the cellular effects of TN treatment, such as apoptosis induction, migration inhibition, Caspase-3 activation, mitochondrial dysfunction, autophagy-related gene expression, and TFAM level detection, thereby confirming the essential genes and pathways.

Results: A total of 31 potential molecular targets for TN in NPC were identified, with 27 genes confirmed through autophagy-related gene analysis. Among these, the top 15 hub genes included RELA, CASP8, NFKBIA, PPARG, PTGS2, MAPK14, MAPK8, HDAC1, ERBB2, CASP1, TERT, AR, CDK1, PGR, and HDAC6. TN was found to activate the MAPK signaling pathway. In vitro, TN induced NPC cell apoptosis via increased ROS, MAPK14 activation, and Caspase-3 cleavage. It disrupted mitochondrial function (reduced membrane potential, decreased copy number, enhanced fission), inhibited mTOR and RELA phosphorylation, and promoted autophagy. TN also caused S-phase arrest, reduced CDH3, and increased CDH1. Lipoic acid partially reversed TN-induced cytotoxicity.

Discussion: TN exerts anti-NPC effects primarily through MAPK pathway activation and autophagy induction. Key targets mediating these effects include RELA, CASP8, PPARG, MAPK14, MAPK8, HDAC1, ERBB2, and CASP1. The reversal by lipoic acid implicates ROS in TN's mechanism. The disruption of mitochondrial function represents a critical facet of its action.

Conclusion: TN demonstrates potential as a therapeutic agent for NPC, primarily through activation of the MAPK signaling pathway and autophagy. Key targets, including RELA, CASP8, PPARG, MAPK14, MAPK8, HDAC1, ERBB2, and CASP1, have been identified as critical mediators of TN's effects, highlighting its role in promoting autophagy and enhancing NPC treatment.

The aim of this article is to study recent developments in the management of vulvovaginal candidiasis (VVC) with emphasis on overcoming antifungal resistance and recurrent VVC by examining hostmicrobe interaction, new molecular targets, immunotherapeutic interventions, and nanotechnology-based strategies. This review integrates recent VVC pathogenesis, immune response, and therapeutic development literature with a focus on immunomodulation, vaccine development, and nanotechnology interventions. Literature on immunotherapy and nanoparticle-based drug delivery systems was comprehensively reviewed. Immunotherapeutic concepts, such as cytokine modulation and vaccine therapy candidates, hold promise to substitute or supplement current antifungals. Nanoparticles exhibit efficacy in advancing drug solubility, reaching fungal cells, and minimizing unwanted effects. The synergy between nanotechnology and immunotherapy provides combined advantages over the multiple drawbacks of current therapies. Although novel methodologies have shown strong promise, aspects of safety, clinical relevance, and regulatory issues continue to remain key challenges. Nanotechnology-based host-targeted immunotherapy is most probably going to transform the scenario of VVC treatment, especially in drug-resistant cases. Additional research is needed to elucidate molecular host-fungal interaction mechanisms, validate vaccine efficacy in the clinic, and design standardized, reproducible nanotherapeutic platforms. Personalized regimens of treatment through immunological and microbiome profiling can enhance long-term outcomes in VVC treatment.