Current pharmaceutical design最新文献

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.

Introduction: Sepsis-induced acute lung injury (S-ALI) is one of the diseases with a very high fatality rate. However, the traditional Chinese medicine compound Buzhong Yiqi Decoction (BZYQD) has an excellent effect in the treatment of S-ALI. Nevertheless, its mechanism of action is still unclear. In this study, we explored the molecular mechanisms of S-ALI injury treated with buzhong yiqi decoction through network pharmacology, in combination with in vivo experimental validation.

Methods: Traditional Chinese medicine system pharmacology (TCMSP) database was used to screen the chemical composition of BZYQD and its action targets; Multiple databases were used to collect target genes for-S-ALI, including OMIM, TTD, GeneCards, and DrugBank; The STRING database was used for the protein- protein interaction (PPI) analysis of the common targets of the BZYQD and the S-ALI; The DAVID database was used for GO and KEGG analysis; molecular docking was used to detect the binding capacity of core components and targets. HE staining was used to visualize the pathology of lung tissue in each group; ELISA was used to detect the levels of inflammatory factors (IL-1β, IL-6, IL-8, NF-κB and TNF-α) and oxidative stressrelated factors (LDH, CK-MB, SOD, GSH-Px); The qPCR and Western blot were used to examine the mRNA and protein expression of IL-1β, IL-6, TNF-α NF-κB, p-NF-κB, PI3K, p-PI3K, AKT, and IKKα.

Results: 113 chemical components and 226 targets were screened from BZYQD; 9059 S-ALI-related genes were screened out, with a total of 228 intersecting targets between BZYQD and S-ALI. Stigmasterol, quercetin, and isorhamnetin are the core components of BZYQD, PPI analysis shows that AKT1, IL6, TNF, and IL1B are the core targets of BZYQD for treating S-ALI, and molecular docking results show that the core components have high binding activity with the target; Enrichment analysis shows that these core targets are related to the TNF signaling pathway. In vivo experimental studies have found that BZYQD can improve the degree of inflammatory infiltration and edema in lung tissue of S-ALI model mice, reduce the expression of IL-6, IL-1β, IL-8, TNF-α, LDH, CK-MB, and NF-κB in serum (P<0.05), as well as the mRNA and protein expression of IL-6, IL-1β, TNF-α, NF-κB, p-NF-κB, PI3K, p-PI3K, AKT, and IKKα in lung tissue (P<0.05), and levels of SOD and GSH-Px were increased (P<0.05).

Discussion: The action targets of the main chemical components of BZYQD are TNF, AKT, and IL6. These targets can promote the activation of PI3K and TNF pathways and mediate the occurrence of inflammation and oxidative stress, which provides inspiration for the treatment of S-ALI. However, the results of this study still need to be verified in combination with in vitro approaches.

Conclusion: This study suggests that the mechanism of BZYQD in treating S-ALI may be achieved by inhibiting the

Para-probiotics, also referred to as non-viable microbial cells or cell components that confer health benefits, are emerging as promising agents in the prevention and management of inflammation-associated diseases. Unlike traditional probiotics, which require viability for efficacy, these inactivated forms offer significant advantages in terms of safety, stability, and applicability in vulnerable populations, including immunocompromised individuals. Recent studies have highlighted their capacity to modulate immune responses, enhance mucosal defense mechanisms, and reinforce intestinal barrier integrity through interactions involving microbial-associated molecular patterns (MAMPs) and host pattern recognition receptors. Such interactions influence signaling cascades like NF-κB, MAPKs, and inflammasome pathways, contributing to antiinflammatory and immunomodulatory effects. One of the key advantages is the reduced risk of adverse effects and concerns associated with live probiotic use. In addition, their robust physicochemical stability under industrial processing conditions supports their incorporation into a range of functional foods and nutraceuticals. Despite these advantages, their mechanisms of action remain incompletely understood and require further investigation. This review synthesizes current evidence on their anti-inflammatory properties, highlights preclinical and clinical studies, and discusses technological approaches for their production. Overall, these bioactives represent a safe, stable, and efficacious alternative to traditional probiotics in managing inflammatory disorders.