Current pharmaceutical design最新文献

Introduction: Hepatitis C virus (HCV) remains a major global health challenge, driving chronic hepatitis C (CHC) progression to severe liver diseases, including hepatocellular carcinoma (HCC). Directacting antivirals (DAAs) have transformed HCV treatment by achieving high sustained virological response (SVR) rates. However, limitations such as resistance, reinfection, and restricted accessibility emphasize the urgent need for novel therapeutic approaches. Among HCV therapeutic targets, the NS3/4A protease is critical for viral replication and immune evasion, positioning it as a prime focus for innovative drug discovery.

Methods: A comprehensive computational approach was adopted to evaluate flavonoids, natural compounds with known antiviral and anticancer properties, as potential inhibitors of the HCV NS3/4A protease. A curated flavonoid library was subjected to virtual screening using molecular docking techniques. Top-ranked flavonoids were further assessed based on binding affinity, dissociation constants, and key protein-ligand interactions. Pharmacokinetic profiling, molecular dynamics simulations, MM/PBSA energy calculations, and principal component analysis were performed to validate the most promising candidate.

Results: The top ten scoring flavonoids demonstrated strong binding affinities and stable interactions with key catalytic residues of the NS3/4A protease. CID 100943380 emerged as the most promising candidate, exhibiting favorable pharmacokinetic properties and sustained stability throughout molecular dynamics simulations. MM/PBSA and PCA analyses further confirmed its robust binding and conformational stability.

Discussion: The findings highlight flavonoids as promising inhibitors of NS3/4A protease, supporting their potential for further antiviral development.

Conclusion: This investigation identifies 10 flavonoids with high potential as NS3/4A protease inhibitors, providing a basis for future biological validation and safer drug development.

As the body's main metabolic organ, the liver performs many crucial functions. Liver diseases such as hepatitis and liver cancer are chronic diseases that can seriously damage health. Currently, effective therapeutic strategies remain limited. In recent years, ferroptosis has become an emerging therapeutic target in the diagnosis and treatment of human diseases. Initially identified in tumor cells linked to neurological disorders, it has recently been acknowledged as a crucial element in the advancement of hepatic ailments. Acyl-CoA synthetase long-chain family member 4 (ACSL4) could be a target for ferroptosis driven by unsaturated fatty acid (FA). More specifically, overexpression of ACSL4 causes reactive oxygen species (ROS) and lipid peroxidation (LPO) products to accumulate, therefore aggravating the course of liver cell ferroptosis. Given that ACSL4 has a complex involvement in liver pathophysiology, its targeted control may represent a novel therapeutic approach for liver illnesses. Even so, more research is required to better understand the molecular mechanisms of ACSL4 and its clinical implications. This article will focus on elucidating the key regulatory molecular mechanisms of ACSL4 in ferroptosis and liver disease progression, aiming to highlight ACSL4 as a potential therapeutic target and provide deep insights into the molecular basis of liver pathology.

Central nervous system (CNS) disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Schizophrenia (Sch) present significant challenges for healthcare systems, both in terms of prevalence and the complexity of pharmacological treatment. While current therapies offer symptomatic relief, there is a high rate of failure in addressing the full spectrum of clinical symptoms and patient adherence issues, especially in long-term care. Since ancient times, various civilizations, including the Chinese, Egyptians, and indigenous South African cultures, have investigated and utilized the transdermal route for therapeutic and medicinal applications. Recent advances in transdermal drug delivery systems (TDS) offer a promising alternative to traditional routes of administration, enhancing drug absorption and minimizing side effects, such as gastrointestinal distress. This review explores the potential of TDS for improving the pharmacotherapy of AD, PD, and Sch. We also highlight the ongoing challenges in optimizing TDS formulations, such as drug absorption through the skin, skin irritation, and maintaining therapeutic efficacy. Furthermore, the review discusses the progress in prodrug design strategies aimed at enhancing skin permeation and bioavailability, particularly in the context of CNS-targeted drugs. The need for continued research into TDS technology is emphasized, as it holds promise for improving treatment adherence, patient quality of life, and caregiver burden, thereby advancing therapeutic options for CNS disorders.

Drug development is expensive and time-consuming, and current efforts to lower the process's financial and temporal costs rely increasingly on computational methodologies. Specifically, during emergencies such as the coronavirus 2019 pandemic, the time needed for vaccine and medical research is increased. Computer-aided drug design (CADD) is a powerful tool for discovering potential therapeutic compounds in traditional drug discovery, having surpassed other high-throughput screening methods commonly used in drug development. The advancement of numerous clinically utilized medications has been significantly aided by CADD. CADD can be approached in two main ways: (1) ligand-based (analogue-based) and (2) structurebased (target-based). Both methods utilize molecular mechanics (MM) force fields to represent atomic-level interactions and define molecular shapes, energy, and motion. The two predominant approaches in drug design are structure-based drug design and ligand-based drug design, both of which provide insights into drugreceptor interactions. Therefore, CADD plays a crucial role in identifying suitable pharmacological properties and compatibility, providing a significant advantage in pre-clinical trials. In this review, we reported the use of the computer-aided drug discovery (CADD) technique to suggest new therapeutic targets and possible inhibitor ligands for M. tuberculosis, S. aureus, and H. pylori. The results of the review may be useful in managing the treatment problems brought on by the higher incidence of antibiotic resistance in the aforementioned bacteria.

Essential oils (EOs) are plant-derived bioactive compounds, primarily made up of terpenoids, which possess various biological and pharmacological effects. Lavender essential oil (LEO) is one of the most extensively studied options. LEO contains terpenes, ketones, alcohols, polyphenols, and flavonoids. Aromatherapy, a practice dating back to ancient civilizations such as the Egyptians, Romans, and Chinese, involved the use of incense, baths, and embalming rituals. Anxiety disorders have gained significant attention in understanding both physical and mental health. Many people are turning to complementary and alternative therapies for the management of anxiety due to the side effects of pharmacological treatments. Several preclinical studies suggest that LEO may alleviate anxiety-like behaviors in experimental models. This review examines the chemical composition, pharmacological properties, and mechanisms of LEO that contribute to its role in managing anxiety in humans. The literature indicates that LEO-based aromatherapy may effectively reduce anxiety in various groups, such as nursing students, patients undergoing surgery, and those involved in clinical procedures. While the exact mechanisms behind LEO's anxiolytic effects remaining unclear, active compounds in EOs may influence the production and release of neurotransmitters through pathways involving γ-aminobutyric acid, dopamine, and serotonin. More extensive preclinical and clinical studies with diverse subject groups are needed to better understand the molecular mechanisms of LEO's anxiolytic properties, which could ultimately help in developing optimized treatments for managing anxiety disorders.

Cancer remains a major global health challenge, with conventional treatments such as chemotherapy and radiotherapy often lacking specificity and causing significant side effects. Hinokitiol, a natural tropolone derivative from the Cupressaceae family, has emerged as a promising anticancer agent due to its broadspectrum activity. This review provides a comprehensive overview of hinokitiol's anticancer properties, mechanisms of action, and safety profile. Hinokitiol has demonstrated potent effects across various cancer types, including breast, lung, prostate, colorectal, and melanoma. Its mechanisms include apoptosis induction, cell cycle arrest at the G1/S and G2/M checkpoints, inhibition of Epithelial-Mesenchymal Transition (EMT), suppression of metastasis, and iron chelation. Additionally, it may enhance chemosensitivity in cancer cells that are resistant to treatment. Importantly, this review identifies and discusses key research gaps limiting hinokitiol's clinical translation. These include the absence of human clinical trials, limited pharmacokinetic and pharmacodynamic data, insufficient toxicity profiling, and context-dependent effects on cellular pathways such as ferroptosis and autophagy. We also highlight its unexplored potential in combination therapies aimed at overcoming multidrug resistance. By synthesizing current preclinical findings and outlining future research directions such as optimizing delivery systems, clarifying mechanisms in specific cancer contexts, and initiating clinical evaluation, this review contributes a critical perspective on the steps needed to develop hinokitiol as a viable anticancer therapeutic. Addressing these gaps could significantly enhance its therapeutic utility and integration into modern oncology.

Nanotechnology has significantly improved drug delivery and targeting in central nervous system diseases and neurodegenerative diseases. Intranasal drug delivery has emerged as a promising approach for enhancing therapeutic outcomes by leveraging the unique anatomical and physiological characteristics of the nasal cavity. This route offers several advantages, including rapid absorption, bypassing the blood-brain barrier for central nervous system targeting, and improved patient compliance. The highly vascularized nasal mucosa facilitates efficient systemic drug absorption, making it an attractive option for both local and systemic treatments. This article explores the principles of intranasal drug delivery, the influence of nasal anatomy on drug bioavailability, and advancements in formulation strategies to optimize efficacy. Additionally, it addresses current challenges, including mucociliary clearance and enzymatic degradation, as well as innovative solutions designed to enhance drug stability and absorption. Understanding the interplay between nasal anatomy and drug delivery mechanisms can pave the way for novel therapeutic interventions and enhance the effectiveness of intranasal medications in various clinical applications. It also highlights challenges in the nasal delivery of therapeutics.

Diabetic foot ulcer (DFU) is one of the most common serious complications of diabetes mellitus and often results in amputation. This complication affects 15% of individuals with diabetes over their lifetime. This review investigates the role of epigenetic modifications in DFUs, as many epigenetic mechanisms contribute to the underlying pathogenesis of diabetes and its complications, including DFUs. Therefore, initiatives aimed at understanding these epigenetic mechanisms may represent a paradigm shift in diagnosing and treating DFUs. Molecular-level studies have been conducted to identify the clinical manifestations of epigenetics in diabetes and its associated complications, such as DFU. This review synthesizes recent literature on epigenetic mechanisms contributing to diabetic foot ulcer (DFU) pathogenesis and explores the therapeutic potential of natural compounds targeting these mechanisms. Through a structured search of databases including PubMed and Scopus, we identified key natural agents, such as curcumin and resveratrol, that modulate DNA methylation, histone modifications, and non-coding RNAs. Natural compounds, which are bioactive ingredients derived from natural organisms, may serve as lead molecules and promising drug candidates, offering an excellent alternative to synthetic drugs for managing and alleviating DFUs and related complications. These natural compounds exhibit pleiotropic activities, including anti-inflammatory and antimicrobial effects, stimulation of angiogenesis, antioxidant activity, facilitation of fibroblast migration, as well as the promotion of cytokines and growth factors; therefore, they hold significant potential as valuable adjuncts to conventional therapy.

Wound healing is a dynamic and multifactorial biological process involving complex interactions among cells, cytokines, and growth factors. The development of advanced therapeutic dressings has become essential to accelerate healing, prevent infections, and minimize scar formation. Among the various biomaterials investigated, poly(ε-caprolactone) (PCL)-based nanocomposites have attracted significant attention due to their excellent biocompatibility, controllable biodegradability, mechanical strength, and high drugloading efficiency. This review provides a comprehensive overview of the characteristics that make PCL a promising material for wound healing applications and presents an integrated analysis of various PCL-based strategies for delivering therapeutic agents across acute and chronic wound models. It covers multiple fabrication approaches, including electrospinning, nanoparticle incorporation, and surface modification, with a focus on enhancing biological performance and functional outcomes. The review also addresses key limitations associated with PCL systems, such as their inherently slow degradation rate, potential for burst drug release, and challenges related to large-scale manufacturing. Future directions emphasize the development of stimuliresponsive and multifunctional dressings, the blending of PCL with other natural or synthetic polymers, and the application of advanced technologies, such as three-dimensional bioprinting, to create patient-specific solutions. By consolidating findings from a broad spectrum of preclinical and translational studies, this review aims to offer a thorough and current understanding of the biomedical potential of PCL, the existing challenges, and the innovations required for its successful clinical application in wound care.

Cholesterol transport within the brain represents a highly regulated process essential for maintaining neuronal function and central nervous system (CNS) homeostasis. Unlike peripheral tissues, the brain relies on in situ cholesterol synthesis, primarily by astrocytes and other glial cells, which supply neurons via high-density lipoprotein (HDL)-like particles, identified in the human cerebrospinal fluid (CSF). The major component of HDL-like lipoproteins is the apolipoprotein E (ApoE), whose E4 isoform represents the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Growing evidence suggests that impaired cholesterol transport contributes to the pathogenesis of various neurodegenerative disorders, particularly AD, a major public health concern due to increasing prevalence and the lack of effective treatments. Indeed, the unconvincing outcomes of the amyloid-targeting monoclonal antibodies underscore the urgency of identifying alternative therapeutic strategies. This review provides a comprehensive analysis of cholesterol transport mechanisms within the brain and their dysregulation in AD by examining the astrocyte-to-neuron cholesterol supply pathways, including endogenous biosynthesis, cholesterol efflux from astrocytes, neuronal uptake, and intracellular processing. Key molecular players involved in each step are discussed, focusing on their roles in AD pathophysiology and potential as therapeutic targets. Furthermore, the review critically evaluates recent preclinical studies exploring pharmacological interventions able to modulate cerebral cholesterol homeostasis. These emerging approaches offer promising alternatives to amyloid-based treatments and may open new perspectives for preventing or mitigating neurodegeneration in AD. By providing an integrated overview of cholesterol transport in the brain, this review highlights novel directions for research and drug development targeting CNS cholesterol metabolism.