Current pharmaceutical design最新文献

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.

The emergence of virus-like particles (VLPs) in cancer represents a promising research avenue for effective targeted therapies. VLPs structurally resemble viruses but lack genetic material and offer distinct advantages in cancer therapy, including targeting specific cancer cells, inducing immune responses, and delivering therapeutic payloads. Conventionally, VLPs can trigger apoptosis, stimulate immune-mediated cytotoxicity, or transport anticancer agents. Viral and non-viral-based VLPs have shown potential for cancer treatment, exhibiting preclinical efficacy which is observed in animal models. Furthermore, early-phase clinical trials have demonstrated the safety and feasibility of VLP-based therapies, with limited efficacy in some cases. Despite these advancements, challenges such as immunogenicity, scalability, and delivery issues persist, necessitating further research to optimize VLP-based cancer therapies. Future directions encompass innovative strategies such as combination therapies and personalized medicine approaches to enhance the efficacy and clinical utility of VLPs. This review provides a comprehensive overview of the status of VLP-based cancer therapy, elucidating its mechanisms of action, types of VLPs utilized, preclinical and clinical studies, and challenges and future directions in this field. In conclusion, VLP-based cancer therapy has immense potential as a novel therapeutic modality, offering hope for improved outcomes and enhanced quality of life for patients with cancer in the future.

Background: There is increasing evidence that environmental factors play an important role in the pathogenesis of hyperuricemia. However, the relationship between Brominated Flame Retardants (BFRs) and serum uric acid and hyperuricemia remains unclear.

Methods: This study used data from 7996 National Health and Nutrition Examination Survey (NHANES) participants from 2005 to 2016. Ten BFRs, including PBB153 and PBDE28, were included in the analysis. Multivariate logistic regression, subgroup analysis, Spearman correlation analysis, Weighted Quantile Sum (WQS), and Bayesian Kernel Machine Regression (BKMR) were used to assess the association between BFRs and hyperuricemia. We also evaluated the mediating role of the Systemic Immunoinflammatory Index (SII) in the relationship between BFRs and hyperuricemia.

Results: Results show that, after adjusting for all covariates, PBDE47, PBDE99, PBDE100, and PBDE154 were significantly associated with hyperuricemia risk. The results of the WQS regression and BKMR model showed a significant positive correlation between exposure to mixed BFRs and hyperuricemia risk. PBDE183 (weight: 38%) was found to have the highest weight in the mixture. Further mediating analysis showed that the relationship between PBDE28 and PBDE183 exposure and hyperuricemia risk was mediated by SII.

Discussion: Exposure to BFRs increases the risk of hyperuricemia, which may be mediated by inflammation. Therefore, future research should further explore the potential mechanisms underlying the association between BFR exposure and hyperuricemia risk.

Conclusion: Exposure to BFRs may increase the risk of hyperuricemia. Large-scale prospective cohort studies and experimental research are needed to confirm the relationship between BFRs and hyperuricemia.

Leukemia, a heterogeneous group of hematologic malignancies, has significantly benefited from advancements in diagnosis, classification, and treatment, particularly through precision medicine. This review examines the role of genetic and molecular profiling, transcriptomics, and artificial intelligence (AI) in advancing precision medicine for leukemia. Key genetic alterations and molecular abnormalities driving leukemogenesis, along with their implications for targeted therapies, are addressed. Insights from RNA sequencing and single-cell RNA sequencing (scRNA-seq) have facilitated the identification of novel therapeutic targets and enhanced risk stratification. Furthermore, AI-driven models, including machine learning (ML) and deep learning (DL) algorithms, have improved leukemia diagnosis, prognosis, and treatment optimization. Despite these advancements, challenges such as clonal evolution, genetic heterogeneity, and treatment resistance remain. The integration of multi-omics data and emerging technologies holds promise for refining personalized therapeutic strategies, ultimately improving patient survival and quality of life.

Introduction: Metallic nanoparticles are of interest for their potent bactericidal and anti-biofilm effects within a favorable therapeutic index. This study reports the green synthesis of bimetallic nickel-iron (Ni-Fe) nanoparticles using Eugenia jambolana extract and evaluates their antimicrobial, anti-biofilm, antiinflammatory, and antioxidant activities.

Methods: Ni-Fe nanoparticles were synthesized using E. jambolana extract and characterized for crystalline structure, size, stability, zeta potential, and functional groups. Antimicrobial activity was tested against Grampositive (Bacillus subtilis, Staphylococcus aureus), Gram-negative (Escherichia coli, Pseudomonas aeruginosa), and Candida albicans. Anti-biofilm potential was assessed via inhibition and dispersion assays, EPS quantification, and in situ visualization. Anti-inflammatory activity was measured through protein denaturation and nitric oxide scavenging assays, while antioxidant capacity was determined using DPPH and H2O2 scavenging tests.

Results: Crystalline, stable Ni-Fe nanoparticles with favorable functional groups were obtained. At 200 μg/mL, they showed broad-spectrum antimicrobial activity. Biofilm formation was reduced by 50% at 250 μg/mL, and dispersion occurred at 10-50 μg/mL, with S. aureus most susceptible. EPS inhibition at 50 μg/mL was 78% (E. coli), 70% (P. aeruginosa), 73% (B. subtilis), and 91% (S. aureus). Visualization confirmed strong adherence to biofilms. At 250 μg/mL, protein denaturation inhibition reached 45%, nitric oxide scavenging 42.6%, DPPH scavenging 44%, and H2O2 scavenging 49%.

Discussion: Ni-Fe nanoparticles exhibit strong antimicrobial, anti-biofilm, anti-inflammatory, and antioxidant activities, notably against S. aureus. High EPS inhibition and biofilm dispersion suggest potential against biofilm- associated, drug-resistant infections.

Conclusion: Green-synthesized Ni-Fe nanoparticles from E. jambolana show multifunctional bioactivities, offering promise for therapeutic applications targeting resistant and biofilm-related infections.

Introduction: This study aimed to synthesize and characterize copper oxide nanoparticles (CuO NPs) using Rhus punjabensis extract and chemical methodologies. The comparative nephrotoxicity of greensynthesized CuO NPs (G-CuO-NPs) and chemically synthesized CuO NPs (C-CuO NPs) were examined in Sprague-Dawley rats and their offspring following oral administration during pregnancy and lactation.

Methods: Fourier Transform Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and X-ray Diffraction (XRD) were employed to examine the morphology, dimensions, and functional groups of the fabricated CuO NPs. To assess the relative nephrotoxicity of G-CuO-NPs and C-CuO-NPs at doses of 50 and 100 mg/kg, twenty-five rats were randomly allocated to five groups (designated as G1, G2, G3, G4, and G5), with each group comprising one male and four female animals for mating purposes. Nephrotoxicity of both parental and offspring animals was evaluated by examining their antioxidant status, total protein content, lipid peroxidation, genotoxicity, serum biochemistry, and histopathology.

Results: FT-IR confirmed the synthesis of CuO NPs, while TEM and SEM revealed that G-CuO NPs were spherical and C-CuO NPs were oval. The XRD analysis showed that both NPs had a monoclinic structure. The crystalline dimensions of G-CuO NPs were 36.6 nm, and 32.85 nm for C-CuO NPs. C-CuO NPs showed dose-dependent toxicity in both parents and pups, causing a disturbance in the antioxidant balance, reducing protein content, and inducing lipid peroxidation and genotoxicity in the renal tissues. The morphological architecture of the parents' kidneys and renal function were evaluated. G-CuO NPs, on the other hand, showed mild toxicity only in the parents.

Discussion: The findings indicate that G-CuO NPs exhibit biocompatibility and are suitable for biological applications. This study underscores the compatibility of plant-derived metallic nanoparticles with living systems and paves the way for investigating their potential applications in contexts where toxicity limits the use of nanoparticles.

Conclusion: Based on these findings, the biocompatibility of green-synthesized CuO NPs was determined, and they did not induce nephrotoxicity in both parents and their offspring. In contrast, chemically synthesized CuO NPs, when administered at higher concentrations, were found to cause nephrotoxicity, which may also be transmitted to the offspring through lactation.

Chondroitinase ABC (ChABC) is a bacterial enzyme that can potentially address the inhibitory effects of Chondroitin Sulfate Proteoglycans (CSPGs) in various neurological disorders and injuries. CSPGs are key components of the extracellular matrix that, when accumulated after Central Nervous System (CNS) injury or neurodegenerative diseases, inhibit axonal growth and tissue repair. This review explores the therapeutic potential of ChABC in Spinal Cord Injury (SCI), Traumatic Brain Injury (TBI), stroke, Parkinson's Disease (PD), Alzheimer's Disease (AD), and peripheral nerve regeneration. ChABC's mechanism of action involves the degradation of CSPGs, promoting neural plasticity, axonal regeneration, and functional recovery in SCI and other CNS injuries. In stroke and TBI, ChABC treatment has been shown to enhance neurogenesis, reduce glial scar formation, and support neuronal survival. In neurodegenerative conditions like PD and AD, ChABC's ability to modify the inhibitory extracellular environment offers novel strategies for promoting neuronal repair and cognitive function. Additionally, ChABC has been explored in cancer therapy, where its ability to degrade the tumor extracellular matrix facilitates improved drug delivery and tumor infiltration. While ChABC holds promise, challenges remain in its clinical application, particularly regarding stability, targeted delivery, and long-term effects. This review discusses the mechanism of action of ChABC and various delivery strategies, including viral vectors and localized infusion, and emphasizes the need for further research to optimize ChABC's potential. The future of ChABC in regenerative medicine depends on overcoming these barriers, improving delivery methods, and exploring synergistic treatments for enhanced recovery outcomes.

Integrating the most advanced technologies in drug formulation and delivery systems is revolutionizing modern healthcare, leading to improved treatment efficacy and patient outcomes. This study explains how new technologies are transforming the way drugs are manufactured and delivered. They include the use of advanced materials, nanotechnology, and biotechnology. Nanotechnology has also enabled the fabrication of targeted drug-delivery particles. Such particles would guarantee that drugs reach a specific tissue or cell, with notable minimization of side effects. The precise targeting of drugs is found to significantly enhance the effectiveness of treatment in fields, such as oncology and personalized medicine, among others. Breakthroughs can also be observed in the design of biologics, gene therapies, and monoclonal antibodies, resulting in highly targeted treatments for a wide range of diseases. Besides novel drug formulations, smart delivery devices have also been designed that not only control the location and rate of drug release, but also the timing of drug release. These include implantable pumps, which ensure more controlled and sustained drug release, bio-responsive hydrogels, medication-eluting stents, which ensure controlled and sustained drug release, and many more devices. This reduces the number of readjustments and increases the likelihood of patient compliance with the treatment plan. This study also discusses the role of digital technologies, such as wearables and AI-driven drug delivery systems, which continue to track patient responses and dosages to improve the outcomes of therapy. Such developments have marked a significant paradigm shift in pharmaceutical research, bringing highly personalized, secure, and effective treatment options to patients worldwide.