Current pharmaceutical design最新文献

Background: Osteoporosis is a prevalent bone disorder resulting from imbalanced bone remodeling, characterized by excessive bone resorption and insufficient bone formation. Physcion, a natural anthraquinone, exhibits diverse pharmacological activities; however, its effects on bone remodeling remain unclear.

Objective: This study aimed to investigate the potential of physcion in mitigating osteoporotic bone loss by regulating the differentiation and activity of osteoclasts and osteoblasts.

Methods: In vitro, the effects of physcion on osteoclastogenesis and osteoblast differentiation were assessed using bone marrow-derived monocytes (BMMs) and bone marrow mesenchymal stem cells (MSCs) treated with various non-cytotoxic doses (0, 0.1, 1, and 10 µM). Osteoclast formation and function were evaluated using tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assays. Osteoblast differentiation was assessed by alkaline phosphatase (ALP) staining and activity measurement. Expression of key markers and activation of signaling pathways associated with osteoclasts and osteoblasts were analyzed by Western blotting and quantitative real-time PCR (qPCR). In vivo, ovariectomy (OVX)-induced osteoporotic mice were treated with physcion (5 mg/kg, twice weekly) for 8 weeks, and bone microarchitecture was analyzed using micro-CT.

Results: Physcion dose-dependently inhibited receptor activator of nuclear factor κB ligand (RANKL)- induced osteoclast formation and bone resorption by suppressing the nuclear factor κB (NF-κB) and p38 MAPK pathways and downregulating osteoclast-specific genes (e.g., NFATc1 and CTSK). Simultaneously, it promoted osteoblast differentiation and increased the expression of osteogenic markers (RUNX2, OSX, and COL1), associated with activation of SMAD1/5/9 and ERK1/2 signaling pathways. In vivo administration of physcion significantly attenuated OVX-induced bone loss.

Discussion: These findings indicate that physcion holds promise as a natural agent for preventing bone loss.

Conclusion: Physcion exhibits dual osteoprotective effects by inhibiting osteoclast differentiation and enhancing osteoblast formation, suggesting its potential as a therapeutic agent for osteoporosis.

Quantitative Structure-Activity Relationship (QSAR) is a computer-based tool that depicts empirical aspects in drug modeling. While it was limited to physical organic chemistry for the past fifty years, QSAR modeling has been diversified and has become more challenging, especially in drug design. From physicochemical property prediction to toxicity predictions, ADME properties, and data mining, it has changed the perspective in drug designing. This innovation was much needed in drug design due to the increasing complexity of the process, which demands more proficient tools and a lower probability of errors. However, when it comes to challenges like predicting potency, fast structure-activity generation, and series design, QSAR has much to offer in the near future. This article aims to give an overview of modern drug chemistry and the importance of various QSAR approaches in drug designing across various fields. The present manuscript discusses the application of QSAR methods in drug design and development, along with a historical overview of various QSAR approaches, supported by relevant examples.

Background: Depression is a serious mental health problem, leading to low mood, loss of interest, and even extreme behaviors. Anle tablets are commonly used in the clinical treatment of depression; however, their mechanism of action is still unclear.

Methods: Components and targets of Anle tablets were identified using Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), PubChem, and SwissTargetPrediction. Depression-related targets were searched from the Genecards, Online Mendelian Inheritance in Man (OMIM), and the Therapeutic Target Database (TTD). A network diagram was constructed to screen the core components. We conducted enrichment analysis to demonstrate the underlying molecular mechanisms. Feature targets were identified utilizing the Gene Expression Omnibus (GEO), machine learning, and a nomogram. We subsequently performed preliminary validation using molecular docking and another GEO dataset. Finally, we performed a dynamic analysis of drug-target protein binding using molecular dynamics simulations.

Results: IGF1R, HSD11B1, GABRA1, and OPRK1 were screened as the feature targets. The core components were screened, such as 3,22-Dihydroxy-11-oxo-delta(12)-oleanene-27-alpha-methoxycarbonyl-29-oic acid (MOL004905), (+)-Anomalin, and 7-Acetoxy-2-methylisoflavone. The primary mechanisms of action were associated with synaptic function and neurotransmitter transmission. The drug component MOL004905 and the target protein HSD11B1 emerged as the optimal docking pair. Their binding sites and the forces of interaction between them revealed strong stability.

Discussion: This study employed a multifaceted approach, integrating network pharmacology, bioinformatics, molecular docking, and molecular dynamics simulations, to analyze the components, targets, and mechanisms of Anle tablets in the treatment of depression. It also simulated the combination of drug molecules and target proteins and conducted a comprehensive evaluation.

Conclusion: Anle tablets may exert their therapeutic effects by targeting feature targets through their core active components, thereby modulating synaptic function and neurotransmitter transmission.

Breast cancer (BC) continues to be a significant challenge in oncology, primarily due to the emergence of drug resistance, which severely limits treatment efficacy and adversely affects patient outcomes. This review aims to elucidate the mechanisms underlying drug resistance in BC, focusing on the roles of the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) signaling pathways. It identifies advanced therapeutic strategies that effectively target and overcome resistance by analyzing these pathways. This review integrates a comprehensive selection of clinical data and cell lines with known resistance profiles, encompassing both clinical and laboratory settings. It employs cutting-edge techniques such as highthroughput sequencing, proteomics, and advanced imaging. Key measurements include receptor expression levels, pathway activation states, and drug response data, analyzed using bioinformatics tools for genetic and proteomic insights and statistical models to determine the clinical significance of the findings. The review identifies specific mutations and alterations in the ER and HER2 pathways that contribute to drug resistance. Notably, it highlights novel biomarkers and resistance mechanisms, including the upregulation of alternative signaling cascades and mutations in downstream effectors. It also emphasizes promising targeted therapeutic strategies, such as combination therapies and next-generation inhibitors, which have demonstrated encouraging results in preclinical models. In conclusion, this review provides critical insights into the intricate mechanisms of drug resistance in BC, underscoring the pivotal roles of the ER and HER2 signaling pathways. It identifies unique resistance mechanisms and potential therapeutic targets, paving the way for the development of advanced strategies to improve treatment outcomes.

Skin cancer is the most common cancer globally, and BCCs and CSCCs do comprise most of the non-melanoma skin cancer. The review summarises new epidemiological evidence (2020-2025), indicating the dynamics in global incidence, long-term WHO forecasts to 2050 and the interaction of genes and the environment as risk factors. Pathophysiological understanding highlights molecular modulations, escape from immune attack and the effects of chronic ultraviolet exposure on the development of tumours. The causes and mechanisms of action section has been reorganised and includes detailed mechanistic descriptions of current treatment modalities, such as surgery, radiotherapy, chemotherapy, immunotherapy, and targeted therapy, with examples of clinical applications. Particular emphasis is laid on the clinical treatment of BCC and CSCC in the older adult population, with references to the latest international guidelines and consideration of psychological and social support in treating patients. The new treatment methods emerging, like nanocarrier, photodynamic therapy, and personalised medicine, are addressed with the recent data on their application and future outlook. Under the new section of prevention and patient education, there is an outline of community awareness programs, campaigns aimed at reducing the burden of the sun, early detection, and evidence-based approaches to reduce the disease burden. Other approaches in technical methods are also reviewed to determine their translational opportunities, comprising hyaluronic acid delivery methods, ultrasonic-assisted nanoparticle penetration, and microneedle technology. Current publications have been used massively, and they constitute more than 50 percent of the provided circulatory content, with publications from the last five years, which adds to their clinical nature and timeliness. Bringing together current epidemiology, new treatment approaches, and patient-focused prevention, this review presents a complete evidence-based source to assist clinicians, researchers, and public health staff in managing the emerging era of skin cancer treatment.

Colorectal cancer (CRC) continues to be a substantial cause of cancer-related fatality globally, necessitating improved diagnostic and therapeutic strategies. Exosomes, small extracellular vesicles that facilitate intercellular communication, as key mediators in CRC progression by transporting bioactive molecules, including non-coding RNAs (ncRNAs). These exosomal ncRNAs (exo-ncRNAs) participate in regulating gene expression, tumor proliferation, metastasis, chemoresistance, and immune escape. ExoncRNAs show distinct patterns in CRC, making them potential non-invasive indicators for early detection and prognosis. Additionally, the potential of exosome-based therapies, including engineered exosomal RNA delivery, offers new avenues for precision oncology. However, addressing challenges, such as standardization of exosome isolation methods, clinical validation, and mechanistic elucidation, is necessary before their full clinical implementation. This article offers a comprehensive synthesis of the recent knowledge of exo-ncRNAs in CRC, emphasizing their biological functions, molecular mechanisms, and translational potential in diagnostics and therapeutics. Future research integrating artificial intelligence and multi-omics approaches may further enhance the clinical utility of exo-ncRNAs, advancing precision medicine in CRC management.

Cancers characterized by uncontrolled cell proliferation and metastasis remain a major public health challenge worldwide. In Saudi Arabia, the increasing incidence necessitates comprehensive strategies for prevention, early detection, and effective treatment. Drug resistance, often driven by genetic mutations leading to multidrug resistance, remains a major clinical obstacle. The innovative delivery systems such as liposomes, polymeric nanoparticles, and exosomes are required to improve therapeutic efficacy. In this review, data from reputable databases and scientific sources such as Web of Science, PubMed, EMBASE, ScienceDirect, Scopus, and others, are critically compiled and analyzed. Strict inclusion criteria for peerreviewed studies on polymeric nanoparticles in cancer therapy are applied, covering in vitro, in vivo, and clinical applications, while non-English-language, incomplete, or methodologically weak studies are excluded. Biodegradable polymeric nanoparticles such as PLGA, chitosan, and PCL have been shown to improve anticancer drug delivery by enabling precise targeting, reducing systemic toxicity, and overcoming multidrug resistance, with consistent therapeutic benefits observed in all studies. Despite these advances, challenges such as biocompatibility, toxicity, controlled release, tumor heterogeneity, long-term safety, and regulatory hurdles remain unresolved. Overall, nanoparticles represent a promising approach to cancer therapy as they improve drug delivery and minimize side effects, but sustained research and interdisciplinary collaboration are essential to fully exploit their potential in oncology.

Background: Cancer immunotherapy has been a rapidly growing therapeutic approach, with nanovaccines offering new opportunities to improve antigen delivery and activate immune responses. Nevertheless, traditional cancer vaccines are generally under-immunogenic and ineffective in lymphoid targeting. This article reviews progress in nanotechnology-based vaccine platforms, with a special emphasis on lymph node-targeting nanovaccines for cancer management and therapy.

Methods: We systematically reviewed the recent literature on nanovaccine delivery systems, including liposomes, polymeric nanoparticles, and mRNA-based formulations. The emphasis was on immunological mechanisms, antigen presentation pathways, and lymphatic targeting strategies.

Results: Nanovaccines can deliver tumor antigens and adjuvants together to lymphoid tissues, enhancing antigen uptake, dendritic cell activation, and T-cell priming. Systems, such as lipid nanoparticles, artificial dendritic networks, and CpG- or STING-charged nanocarriers, have been shown to exhibit enhanced therapeutic performance in both preclinical and early clinical trials. mRNA-4157 and BNT111 are clinical candidates showing encouraging results in melanoma and other cancer trials.

Conclusion: Nanovaccine platforms can potentially overcome some constraints of conventional vaccines by enhancing lymph node targeting, antigen stability, and immunogenicity. Further research in this field could further advance targeted cancer immunotherapy.

Innovative lipid-based vesicles called transferosomes are designed to improve the delivery of transdermal medications. These ultra-deformable vesicles, comprised of phospholipids and edge activators, can successfully pass through the skin's stratum corneum and overcome conventional obstacles, resulting in better absorption of medications. Transferosomes have potential uses in treating several illnesses, such as cancer, and various skin ailments, and for vaccine delivery. They are also used to improve the bioavailability of poorly absorbed oral medications. Despite wide applications, the transferosomes formulation approach has limitations in scalability, stability, regulatory approval, and patient compliance, which must be addressed in ongoing and future research to maximize their therapeutic applications and establish transferosomes as a breakthrough in non-invasive drug delivery technology. This review covers the technical aspects involving the composition, structure, mechanisms of action, and formulation approach of transferosomes with comparison to other approaches, which will surely be beneficial for exploring novel targeted approaches involving liposomes, niosomes, ethosomes, and pharmacosomes.

Introduction: Autorefraction is fast, yet accommodation can distort pediatric measurements, and cycloplegic refraction minimizes accommodation and therefore could be more suitable for functional eyesight. The correlation between the readings of the autorefractometer, cycloplegic refraction, and the subjective acceptance was systematically reviewed in children aged between 6 and 15 years.

Methods: Following PRISMA, PubMed, Scopus, and Web of Science were searched (20002024) in search of studies comparing the outcomes of autorefraction, cycloplegic refraction, and/or subjective refraction in children. Risk of bias (QUADAS-2) was assessed using duplicate assessment of eligibility and data extraction.

Results: In all the suitable studies, cycloplegic refraction demonstrated the best correlation with the ultimate subjective acceptance and delivered hyperopia estimates that were more accurate in comparison to noncycloplegic cycloplegic autorefractive refraction. Non-cycloplegic autorefraction was more likely to overmyopia/ under-hyperopia in younger children. It was in agreement more when autorefraction was done under cycloplegia and in the old subgroups.

Discussion: Since accommodation is dynamic in the pediatric population, non-cycloplegic autorefraction alone is insufficient to misclassify the refractive status. The association of autorefraction with cycloplegia is enhanced in precision and performance, whereas the subjective refinement is fundamental towards comfort and compliance.

Conclusion: Parents of the 6- to 15-year-old age group children rely most on cycloplegic refraction as a source of prescription, with autorefraction being utilised most optimally under cycloplegia or as a screening measure followed by cycloplegic confirmation and age-adjusted additional subjective refinement.