Current pharmaceutical design最新文献

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.

Parkinson's disease (PD) is one of the severe neurodegenerative disorders characterized by a deficiency of dopamine in the substantia nigra. The implicated factors for this include mitochondrial dysfunction, gut dysbiosis, and alteration in the signaling pathways. Overall, these events lead to the generation and aggregation of misfolding proteins, i.e., Lewy bodies. These aggregates contribute to the production of oxidative stress, inflammation, and neurotransmission imbalance. Hence, impaired cognition and body movements in the PD patients. There are several conventional treatments, such as synthetic drugs and herbal drugs, used to mitigate PD. Despite having enormous potential, their use is limited due to their low permeability, low solubility, and complexation in standardization. However, with the advancement in technology, different NDDS (Novel drug delivery systems) such as vesicular drug delivery systems, SNEDDS (Self-Nanoemulsifying Drug Delivery System), NPs (Nanoparticles), NLCs (Nano-structure lipid carrier), SLN (Solid lipid nanoparticles), quantum dots, and dendrimers have been explored to overcome the limitations of conventional treatments. Hence, the present review emphasizes a brief introduction to PD, pathogenesis of PD, signaling pathways, biomarkers, conventional treatments, need for NDDS, and Applications of NDDS in PD. Additionally, patents, clinical trials, and ongoing clinical trials are also covered in the present manuscript.

Introduction: Jiaotai Pill (JTP) is a Traditional Chinese Medicine (TCM) prescription that has demonstrated therapeutic effects against Type 2 Diabetes Mellitus (T2DM). However, its active antidiabetic components and underlying mechanism of action remain unclear. This study aimed to identify the bioactive components in JTP and elucidate their molecular targets and therapeutic pathways in T2DM.

Methods: Chemical components of JTP were identified using ultra-high performance liquid chromatography coupled with Q-Exactive Orbitrap high-resolution mass spectrometer (UHPLC-Q-Exactive Orbitrap-HRMS) in both positive and negative ion modes. Data were processed with Compound Discoverer 3.2 (CD 3.2) data software and validated using literature sources. Network pharmacology analysis was performed via multiple databases, including the Traditional Chinese Medicine Systems Pharmacology Database, Uniport, PubChem, GenCards, String, and Cytoscape, to predict potential bioactive compounds and therapeutic targets. Key interactions were validated using molecular docking and molecular dynamics simulations.

Results: A total of 104 compounds were identified in JTP. Network pharmacology analysis revealed 5 key antidiabetic components and 5 core targets. These targets are involved in biological processes including apoptosis regulation, cell proliferation, and protein phosphorylation, and are enriched in pathways such as neuroactive ligand-receptor interaction, PI3K-AKT signaling, and AGE-RAGE signaling. Molecular docking indicated strong binding affinity between dihydrochelerythrine and AKT1(-9.0 kcal/mol) and TNF-α (-6.7 kcal/mol). Molecular dynamics simulation demonstrated stable and sustained hydrogen bonding between dihydrochelerythrine and AKT1.

Discussion: Dihydrochelerythrine, as an active ingredient in JTP, may exert its antidiabetic mechanism by binding with AKT1, but it needs to be verified by subsequent animal or cell experiments.

Conclusion: Dihydrochelerythrine, a key active component of JTP, may exert antidiabetic effects in T2DM through stable interaction with AKT1, highlighting a potential therapeutic mechanism.

Background: The COVID-19 pandemic, caused by SARS-CoV-2, has highlighted the urgent need for effective antiviral and anti-inflammatory therapies. Spiropyridine derivatives containing a chalcone moiety have shown potential in targeting key enzymes involved in viral replication and inflammation.

Objective: To evaluate the inhibitory effects of synthesized spiropyridine derivatives on SARS-CoV-2 main protease (Mpro), secreted phospholipase A2 (sPLA2), and cytosolic phospholipase A2 (cPLA2), and to assess their impact on inflammatory and oxidative stress markers in LPS-treated lung cells.

Aim: To develop novel therapeutic agents that can effectively manage COVID-19 and related inflammatory conditions.

Methods: The synthesized compounds (1-3) were tested for their inhibitory activity against SARS-CoV-2 Mpro, sPLA2, and cPLA2 using in vitro assays to determine IC50 values. Inflammatory markers (COX-2, IL- 2, IL-4, TGF-1β, TNF-α) and oxidative stress markers (GSH, SOD, GR, MDA) were measured in LPS-treated lung cells. Gene expression levels of sPLA2 and cPLA2 were also assessed. Molecular docking studies were conducted to analyze the binding affinities and interactions of the compounds with the target enzymes.

Results: Compounds 1-3 showed significant inhibitory activity against SARS-CoV-2 Mpro with IC50 values of 19.85 μM, 7.31 μM, and 3.73 μM, respectively. For comparison, baicalein's IC50 value was 13.63 μM. Additionally, these compounds inhibited sPLA2 with IC50 values of 8.36 μM, 7.31 μM, and 3.73 μM, and cPLA2 with IC50 values of 20.44 μM, 6.02 μM, and 4.61 μM, respectively. Baicalein's IC50 values for sPLA2 and cPLA2 were 11.73 μM and 5.89 μM, respectively. In LPS-treated lung cells, compounds 1-3 significantly reduced COX-2 by up to 90.12%, IL-2 by 74.19%, IL-4 by 79.51%, TGF-1β by 44.57%, and TNF-α by 68.49%. They enhanced GSH by up to 194%, SOD by 357.19%, and GR by 445.87%, while reducing MDA by 77.90%. Gene expression of sPLA2 and cPLA2 was significantly downregulated by up to 82.31% and 64.59%, respectively. Molecular docking studies revealed binding affinities of -28.20, -28.20, and -28.07 kcal/mol for SARS-CoV-2 Mpro; -16.72, -17.21, and -15.89 kcal/mol for sPLA2; and -65.66, -66.95, and - 79.24 kcal/mol for cPLA2, respectively.

Conclusion: The synthesized spiropyridine derivatives containing a chalcone moiety exhibit potent antiviral, anti-inflammatory, and antioxidant properties. These findings suggest that these compounds could be promising therapeutic agents for managing COVID-19 and related inflammatory conditions. Future studies should focus on in vivo experiments, clinical trials, and structural optimization to further develop these compounds for clinical use.