Current medicinal chemistry最新文献

Licochalcone A (Lic A) is a natural chalcone compound extracted from Glycyrrhiza inflata Batal, which exhibits a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anti-tumor, analgesic, hepatoprotective and antibacterial properties. Regarding its pharmacological effects, Lic A demonstrates inhibitory effects on various tumors, such as hepatocellular carcinoma, colorectal carcinoma, and leukemia. These effects are achieved by modulating key signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen- activated protein kinase (MAPK), and phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (Akt). However, the therapeutic potential of Lic A is remarkably hampered by its poor aqueous solubility and low permeation efficiency, which lead to inadequate absorption and poor bioavailability, posing formidable challenges for both oral and transdermal delivery. To address these limitations, advanced technologies such as micelles, mesoporous silica nanoparticles, cell-penetrating peptides, self-microemulsifying drug delivery systems, and eutectogels have been employed to enhance the solubility, permeability, and bioavailability of Lic A, thereby expanding its potential applications. This review aims to summarize the pharmacological effects, signal pathways, and mechanisms of action of Lic A. Moreover, it discusses recent research progress in improving its oral and transdermal delivery efficiency, further summarizing its clinical application and development prospects. Collectively, the work provides a comprehensive reference and methodological guidance for in-depth investigations of Lic A, as well as the exploration and formulation optimization of other flavonoid ingredients.

Introduction: Curcuma longa, commonly known as turmeric, contains curcumin, which is its main compound and has been reported to possess a wide variety of pharmacological activities, such as anti-carcinogenic, anti-malarial, antioxidant, antibacterial, anti-mutagenic, anti-inflammatory, and immunomodulatory effects. Even though it has many strong biological properties, curcumin lacks solubility, which affects its clinical efficacy. DK1 is a curcumin analogue that has been found to possess selective cytotoxicity on breast cancer cells compared to normal breast cells; however, its effectiveness in colon cancer has yet to be validated. This study was performed to investigate the effects of DK1 on colon cancer using an in vivo model in terms of its anti-apoptotic, immunoregulatory, and antioxidant potential. The pathways affected by the DK1 treatment were also evaluated.

Methods: In this study, male BALB/c mice induced with colon cancer were utilized, and the resulting tumours and spleen were subjected to TUNEL, immunophenotyping, and several antioxidant assays, such as nitric oxide, malondialdehyde, and superoxide dismutase, as well as gene and protein expression analyses.

Results: K1 treatment led to tumor shrinkage, an increase in apoptotic tumor cells, and elevated populations of helper and cytotoxic T cells by 5% and 3%, respectively. Besides that, the NO and MDA levels were also significantly reduced. This study also observed dysregulations in several oncogenes in the VEGF pathway, such as CMYC, iNOS, and IL-1β genes, which are involved in angiogenesis and inflammation.

Discussion: The effects of DK1 treatment included antitumor and anti-inflammatory properties against the inoculated CT26 tumour. DK1 showed potential in regulating the inflammation via the VEGF pathway by the significant downregulation of TNF-α and IL-1β pro-inflammatory genes, as well as PTX3, OPN, and serpin-E1 pro-angiogenic proteins.

Conclusion: The results suggested that DK1 may potentially function as an immunoregulator and anti-cancer agent for colon cancer therapy.

Introduction: Ischemic stroke (IS) is a major cause of death and disability worldwide. The transcriptional mechanism of neutrophil extracellular trap-related genes (NRGs) and their diagnostic potential remain unknown. This study aims to explore the mechanism of NRGs in IS through machine learning and Single-cell RNA sequencing (scRNA-seq).

Methods: We conducted differential analysis and functional enrichment analysis on the GEO dataset. Machine learning algorithms were used to identify NRGs related to IS. ScRNA-seq analysis was employed to verify the expression of NRGs in different cell types, and cellchat was used to explore the interactions between cell types in the IS. The expression of Eno1 was also verified in the mouse model of middle cerebral artery occlusion (MCAO).

Results: We identified 26 differentially expressed NRGs (DE-NRGs). The diagnostic models constructed from five DE-NRGs (ENO1, HMGB1, ILK, ORAI1, SUCNR1) demonstrated high predictive ability. Single-cell analysis revealed that NRGs were highly expressed in the IS group. The experiment verified the significant upregulation of Eno1.

Discussion: This study employed machine learning and scRNA-seq to identify the DENRGs- related diagnostic model, providing a certain theoretical basis for IS risk stratification. More experiments are needed to verify the role of DE-NRGs in IS in the future.

Conclusion: This study identified DE-NRGs with diagnostic capabilities in IS and verified their high expression through scRNA and experimental methods. DE-NRGs may be potential therapeutic targets for IS.

Introduction: Neuroinflammation, primarily mediated by activated microglia, is a significant contributor to neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Quercetin (QCT), a dietary flavonoid, has demonstrated anti-inflammatory and neuroprotective properties; however, the detailed molecular mechanisms behind these effects remain unclear. This study aimed to investigate the anti-inflammatory actions of QCT, particularly focusing on its potential to suppress the activation of microglia and subsequent neuroinflammation.

Methods: BV-2 microglial cells were stimulated with lipopolysaccharide (LPS) to induce an inflammatory response and were subsequently treated with various concentrations of QCT. Cell viability was assessed using the MTT assay. Levels of pro-inflammatory cytokines (IL-6, TNF- α) and nitric oxide (NO) were quantified through ELISA and Griess reaction methods, respectively. Western blot analysis was conducted to examine inducible nitric oxide synthase (i- NOS), NF-κB, IκBα, and phosphorylated IκBα protein expressions. In silico approaches, including protein-protein interaction (PPI) network analysis and molecular docking, were employed to explore potential molecular mechanisms involving NF-κB signaling pathways.

Results: Treatment with QCT significantly reduced the secretion of IL-6 (96%) and TNF-α (87%), as well as NO production (42%), in a dose-dependent manner. Western blot results demonstrated a marked reduction in iNOS expression and inhibition of NF-κB activation through reduced phosphorylation of IκBα following QCT treatment. Molecular docking indicated a strong binding affinity between QCT and IKKβ, suggesting inhibition of the NF-κB pathway.

Discussion: The findings indicated QCT to exert potent anti-inflammatory effects in LPS-stimulated BV-2 cells by modulating key proteins involved in the NF-κB signaling pathway. Specifically, the docking results implied QCT's direct interaction with the catalytic subunit IKKβ, inhibiting IκBα phosphorylation and subsequent NF-κB activation. The results have been found to be consistent with previous literature, reinforcing QCT's role in reducing neuroinflammation through specific molecular targets and pathways. Further in vivo studies are necessary to validate the findings.

Conclusion: Quercetin effectively suppressed neuroinflammation in microglial cells through inhibition of the NF-κB signaling pathway, reducing levels of critical pro-inflammatory mediators. The outcomes have highlighted the potential of quercetin as a preventive nutraceutical for neurodegenerative diseases, necessitating future in vivo investigations to confirm its therapeutic efficacy.

Introduction: Clostridium difficile infection (CDI) is a serious global health concern characterized by toxin-induced colonic damage, ranging from diarrhea to life-threatening conditions. Despite improved diagnostics and treatments, recurrence rates of up to 30% underscore persistent gaps in effective disease management.

Methods: CDI pathogenesis is driven by the disruption of the gut microbiota, often due to broad- -spectrum antibiotic use. Risk factors such as advanced age, hospitalization, IBD, and immunosuppression increase the severity and recurrence of the infection. The hypervirulent ribotype 027 strain has been associated with increased mortality and treatment resistance, necessitating targeted therapies.

Results: Emerging treatments such as FMT and monoclonal antibodies show promise for CDI management, with FDA approvals marking progress in microbiome restoration. However, hurdles remain in safety, regulation, and donor screening. Advances in diagnostic and scoring tools have aided in the detection and treatment, but differentiating between colonization and infection remains a challenge. Preventive measures and novel agents such as bacteriocins and bacteriophages offer targeted, microbiome-sparing strategies.

Discussion: Despite recent advances, CDI management remains challenging because of diagnostic uncertainty and frequent recurrences. Innovative treatments such as FMT and monoclonal antibodies are promising but face limitations in safety, access, and cost. Preventive strategies and decision tools help, yet distinguishing colonization from infection remains difficult, underscoring the need for ongoing and multidisciplinary innovation.

Conclusions: This review highlights current approaches to CDI diagnosis, treatment, and prevention, stressing the urgent need for innovative strategies to reduce recurrence. Targeted research and policy efforts are vital to improving outcomes and quality of life for those affected.

Introduction: Ischemic Stroke (IS) represents the most prevalent subtype of cerebrovascular disease, characterized by complex pathophysiological mechanisms that remain inadequately characterized, particularly concerning mitochondrial dysfunctions. These mitochondrial impairments are increasingly recognized as contributory factors in IS pathogenesis, emphasizing the need for further investigation into the underlying molecular mechanisms involved.

Methods: In this study, we integrated transcriptomic datasets from the Gene Expression Omnibus (GEO) with the comprehensive MitoCarta3.0 mitochondrial proteome inventory to elucidate the role of dysregulated Mitochondrial-Related Genes (MRGs) in IS. We employed an advanced bioinformatics and machine learning pipeline, incorporating differential expression profiling alongside network-based prioritization using CytoHubba. Rigorous feature selection was conducted through LASSO regression, Support Vector Machine (SVM), and Random Forest (RF) algorithms to derive a robust core MRG signature. Our methodology included training and validation cohorts to construct diagnostic models, which were critically evaluated via Receiver Operating Characteristic (ROC) curves, nomograms, and calibration analyses.

Results: Our analysis identified a seven-gene signature comprising DNAJA3, ACSL1, HSDL2, ECHDC2, ECHDC3, ALDH2, and PDK4, which demonstrated significant correlation with activated CD8+ T-cell and natural killer cell infiltration. Furthermore, integrative network analyses revealed intricate regulatory interactions among MRGs, microRNAs, and transcription factors. Notably, drug-target predictions indicated Bezafibrate as a promising therapeutic agent for modulating mitochondrial homeostasis in the context of IS.

Discussion: These findings offer a novel framework for ischemic stroke diagnosis and therapy, yet their computational derivation underscores the need for thorough experimental validation of MRGs and drug candidates, along with the integration of diverse clinical data to confirm their real-world applicability.

Conclusion: Our findings underscore mitochondrial dysfunction not only as a critical factor in IS pathogenesis but also as a viable therapeutic target. The identified MRG signature presents potential for clinical application in diagnostic and pharmacological strategies aimed at ameliorating ischemic injury. This study highlights the translational significance of systems biology approaches within cerebrovascular medicine, warranting further mechanistic exploration of mitochondrial-immune interactions in stroke pathology.

Introduction: Heterocyclic compounds remain cornerstones of contemporary drug discovery because their ring-embedded heteroatoms confer adaptable electronics, conformational flexibility, and a broad spectrum of biological activities. The skeleton structure of 4-thiazolidinone is present in many cytotoxically active compounds and is often used in the design of new antitumor agents. This study aimed to synthesize, characterize, and evaluate the anticancer potential of fifteen new (2-imino-4-oxo-1,3-thiazolidin- 5-yl)acetic acid derivatives.

Method: Compounds were synthesized using a consistent synthetic route involving a reaction between a thiourea derivative and maleic anhydride, which formed the thiazolidin- 4-one ring through cyclization. The compounds were then categorized into three sets based on the attached heterocyclic rings (tryptamine, thiazole, and 1,2,4-triazole). The NMR and X-ray analysis followed the synthesis. Apoptotic effects, cell cycle arrest, IL-6 suppression, docking, and dynamics simulations were conducted. Preliminary cytotoxic activity was tested on metastatic colorectal cancer (SW620) and human breast adenocarcinoma (MDA-MB-231) cell lines using the MTT assay.

Result: Compounds 5, 6, and 7 demonstrated notable selectivity indexes (4.73, 2.42, 4.16, respectively) and were further investigated for their mechanisms of action, revealing pro-apoptotic properties and the ability to induce cell cycle arrest. Additionally, compound 5 inhibited IL-6 secretion by 76%. in silico studies revealed the formation of an energetically stable complex between compound 5 and the EGFR crystal structure (min/- max binding affinities of -9.4|-8.0 kcal/mol, compared to the -7.71 kcal/mol for the native ligand).

Discussion: This preliminary study provides compelling data on synthesized derivatives, but more advanced testing is needed to assess their therapeutic value fully. Compared with earlier reports on related thiazolidinone scaffolds, the present derivatives exhibit improved potency, clearer selectivity, and mechanistic features consistent with EGFR inhibition and cytokine modulation.

Conclusion: These findings validate (2-imino-4-oxo-1,3-thiazolidin-5-yl)acetic acid as a privileged core for cytotoxic lead generation and indicate that strategic substitution with either a tryptamine moiety (compound 5) or a 1,2,4-triazole ring (compound 7) is particularly advantageous. These compounds are promising EGFR-targeting anticancer candidates, warranting further investigation.

Diabetes mellitus (DM) significantly impacts systemic and skin health, with advanced glycation end-products (AGEs), metal imbalances, and immune dysfunction emerging as central drivers of skin-related complications. Furthermore, dysregulation of essential metals like zinc, copper, and iron exacerbates oxidative damage and immune dysfunction, fostering a detrimental skin environment. Autoimmune processes, increasingly recognized in both type 1 and type 2 DM, contributes towards dermatological conditions such as bullous pemphigoid and vitiligo. Emerging therapeutic strategies, including AGE inhibitors, chelation therapies, antioxidants, RAGE antagonists, and immune modulators, offers promising avenues for intervention. Advances in diagnostic tools, such as LC-MS/MS and ICP-MS, facilitate precise detection of AGEs and metal imbalances, paving the way for innovative therapies. This review underscores the importance of multidisciplinary approaches to address the rising burden of DM-related skin disorders and improve the quality of life of affected individuals.

Introduction: Gliomas are aggressive brain tumors with a poor prognosis and high recurrence. Oridonin, a traditional Chinese medicine, has shown potential in treating various cancers, but its role in glioma treatment, especially in modulating Epithelial- Mesenchymal Transition (EMT), remains underexplored.

Methods: We identified 371 potential target genes of Oridonin using various bioinformatics databases. Enrichment analyses, including Differential Expression Analysis, Gene Set Enrichment Analysis (GSEA), and Weighted Gene Co-expression Network Analysis (WGCNA), were performed to link these targets to glioma characteristics. in vitro experiments validated Oridonin's impact on EMT-related gene expression in glioma cells.

Results: Enrichment analyses identified 19 common genes between Oridonin and glioma targets, with 12 EMT-related core genes. KEGG enrichment highlighted PI3K-Akt, MAPK pathways, and glioma pathways, while DO enrichment included high-grade gliomas. CCK8 assay showed Oridonin IC50 values of 6.92 μM for H4 and 10.54 μM for SW1783 glioma cell lines. WB results indicated increased E-Cadherin and decreased Vimentin, N-Cadherin, and Snail expression after Oridonin treatment. PPI network and single- cell transcriptome analyses identified key genes linked to glioma progression and immune cell infiltration.

Discussion: Oridonin may inhibit glioma progression by targeting EMT-related pathways like PI3K-Akt and MAPK. The upregulation of E-Cadherin and downregulation of Vimentin, N-Cadherin, and Snail suggest a reversal of the EMT process. Future work should validate these effects in vivo and explore Oridonin's ability to cross the blood- -brain barrier.

Conclusion: Oridonin may provide a novel therapeutic approach for glioma by targeting EMT-related pathways, offering a foundation for further clinical investigation.