Current topics in medicinal chemistry最新文献

Oxidative stress plays a central role in the pathogenesis of liver diseases, including hepatotoxicity, by disrupting the balance between reactive oxygen species (ROS) and the hepatic antioxidant defense system. Excessive ROS production leads to inflammation, fibrosis, and cellular damage. Antioxidants-both endogenous and exogenous-can mitigate these effects by neutralizing ROS and restoring redox homeostasis. This review evaluates the mechanistic role of antioxidants in modulating key oxidative stress-related signaling pathways, such as nuclear factor erythroid 2-related factor 2 (Nrf2), mitogen-activated protein kinases (MAPKs), nuclear factorkappa B (NF-κB), phosphoinositide 3-kinase/Akt (PI3K/Akt), and Janus kinase/signal transducer and activator of transcription (JAK/STAT). Through the regulation of these pathways, antioxidants reduce apoptosis, suppress pro-inflammatory signaling, and enhance the expression of detoxifying enzymes. Natural compounds like flavonoids, polyphenols, and vitamins C and E have shown hepatoprotective effects, while synthetic antioxidants and their combinations with other therapeutic agents represent promising strategies for clinical application. This review underscores the therapeutic potential of antioxidants in combating oxidative stress-induced hepatotoxicity by offering a comprehensive overview of their mechanistic targets.

Introduction: Zika virus (ZIKV), a flavivirus primarily transmitted by Aedes aegypti, became a major global health concern during the 2015-2016 outbreak, particularly in Brazil. Its association with congenital malformations and neurological disorders underscores the urgent need for effective therapeutic interventions. This review explores molecular targets for ZIKV treatment within the Brazilian context.

Method: A systematic search was conducted using PubMed, ScienceDirect, and Scopus for studies published between 2004 and 2024. Inclusion criteria focused on studies identifying druggable molecular targets related to viral replication, immune evasion, or host-virus interactions. Key search terms included "Zika virus," "molecular targets," "Brazil," "antiviral," and "drug discovery."

Results: The review identified several critical viral proteins, NS1, NS3, NS5, and the envelope protein, as potential drug targets. Host cellular factors essential for viral survival were also highlighted. Technologies such as high-throughput screening, molecular docking, and structural genomics contributed significantly to the identification and validation of these targets.

Discussion: Although promising targets have been identified, therapeutic development is hindered by the genetic variability of ZIKV and its antigenic similarity to other flaviviruses, notably the dengue virus. These challenges complicate the specificity and efficacy of drugs. Nevertheless, Brazil has made strides in research infrastructure and collaborations to tackle these obstacles.

Conclusion: This review synthesizes current knowledge on ZIKV molecular targets and ongoing drug discovery efforts. The findings support the strategic development of antivirals and emphasize the necessity for sustained investment in research to mitigate future ZIKV outbreaks in Brazil and globally.

Manassantin, a dineolignan, is a natural compound that has gained significant attention due to its diverse pharmacological properties, including anti-inflammatory, anticancer, neuroprotective, and antimicrobial effects. Its unique polyphenolic scaffold offers a versatile platform for drug development, enabling targeted therapeutic applications. This review explores the molecular mechanisms underlying the bioactivity of manassantin with a focus on its role in modulating key cellular pathways, including NF-κB, MAPK, JAK/STAT, oxidative stress, apoptosis, and inflammatory signaling. Furthermore, it highlights recent advancements in structural modifications aimed at enhancing the pharmacokinetic and pharmacodynamic properties of this compound. By unlocking the full therapeutic potential of manassantin, this study paves the way for its future development as a multifunctional therapeutic agent.

Introduction: Obesity, a widespread health condition marked by excessive body fat, markedly elevates the risk of chronic diseases and has emerged as a major global health issue. Chrysin, a flavonoid with promising health benefits, exhibits potent antioxidant and antiinflammatory properties. This study seeks to examine the impact of chitosan chrysin nanoparticles (Chrysin-CSNPS) on obesity induced by a high-fat diet (HFD) in male rats.

Methods: Rats were fed a high-fat diet for 4 weeks to induce obesity, followed by a 4-week treatment period. Thirty rats were allocated into five groups (six rats per group): control (dist. water, orally), HFD control (dist. water, orally), HFD + chrysin (500 mg/kg, orally), HFD + chitosan-NP (60 mg/kg, orally), and HFD + Chrysin-CSNPS (60 mg/kg, orally).

Results: In silico studies revealed that chrysin has a binding energy value of -8.8 kcal/mol to fat mass and obesity-associated (FTO) protein. Also, Chrysin is identified as an inhibitor of several cytochrome P450 enzymes, specifically CYP1A2, CYP2D6, and CYP3A4. Albumin, high-density lipoprotein cholesterol, glutathione, and nitric oxide levels rose, whereas glucose, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatinine, urea, total cholesterol, triglycerides, malondialdehyde, and nitric oxide levels fell upon Chrysin-CSNPS treatment. The histological examination revealed a significant enhancement in the structures of the liver and kidneys.

Discussion: These findings suggest that chrysin could potentially inhibit FTO activity, thereby contributing to a reduction in obesity-related phenotypes. The compound that satisfied Lipinski's criteria was selected for toxicity prediction.

Conclusion: Chrysin-CSNPS have hypolipidemic properties and an antioxidant role, reducing HFD consequences in the liver and kidney.

Introduction: This study aims to elucidate the mechanisms underlying Dementia using bioinformatics analysis and machine learning algorithms, to identify novel therapeutic targets for its clinical management.

Methods: Gene expression datasets related to dementia were sourced from the GEO database. Differentially expressed genes (DEGs) were identified using R, and key module genes were determined through the Weighted Gene Co-expression Network Analysis (WGCNA) method. Oligodendrocyte (OL) related targets were retrieved from the GeneCards database. The intersecting genes from DEGs, WGCNA, and OL were analyzed using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Subsequently, three machine learning algorithms were employed to pinpoint core genes associated with OL in dementia. The CIBERSORT algorithm was used to evaluate the abundance of 22 immune cell types and their correlation with Dementia-related immune infiltration. Validation was carried out via quantitative reverse transcription polymerase chain reaction (RT-qPCR).

Results: Through bioinformatics and machine learning techniques, six core OL genes associated with Dementia were identified, notably C1QA, CD163, and TGFB2, which showed elevated expression in Dementia. Immune cell infiltration analysis indicated that several immune cell types may contribute to Dementia's pathogenesis, and RT-qPCR results corroborated the bioinformatics findings.

Discussion: The discovered genes may contribute to dementia pathogenesis through oligodendrocyte dysfunction and neuroimmune interactions. Notably, TGFB2 and complement-related genes (C1QA, CD163) suggest involvement in both myelination defects and neuroinflammation, highlighting their therapeutic potential.

Conclusion: The six feature genes: TGFB2, C1QA, CD163, ACTG1, WIF1, and OPALIN are significantly linked to Dementia.

Diabetes mellitus, a chronic metabolic disorder, poses a significant global health challenge, demanding continuous research into effective treatments. With projections of 629 million individuals affected by 2045 and escalating healthcare costs, the need for new anti-diabetic medications is urgent. Current therapies often present limitations, including undesirable side effects and insufficient long-term efficacy. This review explores the development of oral anti-diabetic drugs (OADs), focusing on the structure-activity relationship (SAR) employed to create both established and emerging classes of medications. We examine the six major OAD classes: biguanides, sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, and SGLT2 inhibitors. In addition, a new promising class of OAD, namely metal complexes, is discussed. This review highlights the crucial role of synthetic chemistry in advancing diabetes treatment and improving patient outcomes.

Objective: To explore the molecular mechanism of α7 nicotinic acetylcholine receptor (α7nAChR) mediated by Formononetin (FMN) in inhibiting macrophage inflammatory polarization and stabilizing atherosclerotic plaque.

Methods: SiRNA α7nAChR was transfected into THP-1-induced M0 cells and treated with FMN. Oil Red O staining was used to evaluate macrophage lipid deposition. RT-qPCR was used to detect α7nAChR, COX-2, IL-1β, IL-6, HO-1, and SHIP1 expression in M1 and M2 macrophages. Western blot was used to detect α7nAChR, iNOS, CD206, CD68, p-JAK2, and p-STAT3 protein expression in M1 and M2 macrophages.

Results: Compared with the control group, FMN-mediated α7nAChR reduced lipid deposition in M1 and M2 macrophages. RT-qPCR results showed that FMN intervention significantly downregulated COX-2 and IL-1β expression in M1 (P < 0.05). α7nAChR expression significantly reduced COX-2, IL-6, and IL-1β expression in M2 (P < 0.05) and significantly increased HO-1 and SHIP1 expression (P < 0.05). FMN-mediated α7nAChR significantly decreased the expression of iNOS, CD68, p-JAK2, and p-STAT3 in M1 and M2 macrophages and significantly increased the expression of CD206 protein by Western blot (P < 0.05).

Discussion: This study, for the first time, elucidated the mechanism of FMN regulating macrophage polarization through the α7nAChR/JAK2/STAT3 axis, providing new experimental evidence for the role of the cholinergic anti-inflammatory pathway in cardiovascular diseases. However, there are some limitations, such as the limited applicability of the THP-1 cell line, the need to strengthen the dose correlation study, the bioavailability and solubility limiting clinical translation, and the lack of human toxicological data.

Conclusion: FMN effectively modulates macrophage polarization through inhibition of the JAK/STAT signaling pathway while promoting α7nAChR expression.

Pyridine alkaloids possess important biological activities and are widely used in fields such as medicine and pesticides. This paper comprehensively reviews the research progress in the chemical synthesis and biosynthesis of pyridine alkaloids. In terms of chemical synthesis, there are diverse synthesis methods for arylpyridine compounds. For example, 2,4,6-triarylpyridine can be synthesized by using iron-organic framework materials or other reagents. The 3-ethylsulfone pyridine compounds with aryltriazole structures can be synthesized through specific reactions. And 2- arylpyridine can also be synthesized in this way. Heterocyclic pyridine compounds can be prepared into their corresponding derivatives through multiple approaches. The synthesis of polysubstituted pyridine adopts reactions such as cycloaddition, Diels-Alder, condensation, cyclization, and aromatization. The synthesis of polypyridine focuses on the construction of new complexes. Other synthesis methods such as ultrasound-assisted synthesis are also introduced. The main biosynthesis pathways include the co-synthesis of polyketide synthase and non-ribosomal peptide synthase, the origin of lysine, the participation of aspartate, and the synthesis of thiopeptide antibiotics. Meanwhile, the biosynthesis pathways of pyridomycin, pyridine pigment compounds in functional red yeast rice, and vitamin B6 were also discussed, which provides a theoretical basis for further research and application of pyridine alkaloids.

Introduction: Crohn's disease (CD) is a complex inflammatory bowel disorder with incompletely understood mechanisms. This study aimed to identify novel biomarkers and elucidate macrophage-related pathogenesis in CD.

Methods: Using gene expression data (GSE17928522) from the Gene Expression Omnibus (GEO) database, we compared 1135 CD patients with 180 healthy controls to identify altered gene expression profiles. Immune infiltration analysis was conducted to evaluate changes in immune cell subpopulations. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to construct gene co-expression networks and identify macrophage-associated modules. Mendelian randomization was used to validate the causal role of macrophages. For ex vivo validation, immunohistochemical staining of GBP4 protein expression was performed in colonic tissue samples from 6 CD patients (with ileal or colonic lesions). Non-lesional tissues from the same patients served as intra-individual controls to minimize inter-patient variability.

Results: Our analysis revealed significant changes in immune cell subpopulations, particularly macrophages, within the CD microenvironment. A macrophage-associated module was identified, with GBP4 emerging as a critical gene. Immunohistochemical staining confirmed differential expression of GBP4 in CD tissue samples compared to controls.

Discussion: This multi-modal study establishes GBP4 as a novel macrophage-associated biomarker for CD, supported by causal Mendelian randomization and immunohistochemical validation. The integration of WGCNA and genetic evidence strengthens the role of macrophage dysregulation in CD pathogenesis. Limitations include population bias in genomic data and small validation cohorts, but the consistency across methodologies underscores GBP4's potential as a therapeutic target.

Conclusion: Our findings highlight GBP4 as a novel potential biomarker and therapeutic target in CD, providing insights into the immune-mediated mechanisms underlying the disease. These results contribute to a better understanding of CD pathogenesis and may lead to new therapeutic strategies.