Naunyn-Schmiedeberg's archives of pharmacology最新文献

Cancer remains a leading cause of mortality globally, necessitating ongoing research and development of innovative therapeutic strategies. Natural products from plants, herbs, and marine species have shown great promise as anti-cancer therapies due to their bioactive components that alter cellular pathways, particularly apoptosis. This review explores the mechanism by which natural chemicals trigger the apoptosis of cancerous cells, which is crucial for eliminating them and halting tumor growth. These can affect the mitochondrial process by controlling the Bcl-2 protein family, increasing cytochrome c release, and activating caspases. They also activate death receptors like Fas and TRAIL to enhance the extrinsic apoptotic pathway. We focus on the main signaling channels involved, such as the endoplasmic reticulum (ER) stress-mediated apoptosis, extrinsic death receptor, and intrinsic mitochondrial pathways. The review explores the role of natural substances such as polyphenols, terpenoids, alkaloids, and flavonoids in promoting apoptotic cell death and increasing cancer cell susceptibility, potentially aiding in cancer treatments and the potential of combining natural products with traditional chemotherapeutic medicines to combat medication resistance and enhance therapeutic efficacy. Understanding cancer development involves inhibiting cell proliferation, regulating it, targeting apoptosis pathways, and using plant and marine extracts as apoptotic inducers.

Amyloid-beta (Aß) plaques and neurofibrillary tangles are distinctive features of Alzheimer's disease (AD), a progressive disorder that results in considerable memory loss and decline in cognitive function. Presently available therapies, such as donepezil and other medications that inhibit acetylcholinesterase, mainly provide relief from symptoms but do not change the course of the disease. This research article intends to investigate the possible reuse of two FDA-approved medications, doxazosin and dolutegravir, discovered through computerized screening using shape similarity, docking energy, and molecular dynamics stability, for the purpose of targeting human acetylcholinesterase (AChE) in the development of disease-altering treatments. In order to mimic neurotoxicity similar to Alzheimer's disease, zebrafish (Danio rerio) were treated with aluminum chloride (AlCl₃). Various behavioral assessments, such as the open field test, mirror biting test, novel tank test, social preference test, and dark-light preference test, were carried out to assess cognitive function, movement, and anxiety-related behaviors. The results indicated that doxazosin, a drug that blocks alpha-1 adrenergic receptors, successfully decreased neuroinflammation and improved cognitive abilities. Additionally, dolutegravir, which is mainly used as an antiviral medication, showed notable benefits in protecting the nervous system. This study highlights the possibility of using doxazosin and dolutegravir as effective alternative treatments for Alzheimer's disease. Upcoming preclinical and clinical research is necessary to confirm the safety and effectiveness of AD treatment, paving the way for new opportunities in therapeutic intervention.

The expression of glutathione S-transferase P1 (GSTP1) enzyme increases in cancer cells, leading to anticancer drug resistance. The antioxidant chlorophyllin has an inhibitory effect on GSTP1. In this study, we investigated the effect of chlorophyllin and its combined administration with the chemotherapeutic agent docetaxel on metastatic processes. For this purpose, both the 4T1 triple-negative breast cancer cell line and metastatic animal model were used. The MTT, flow cytometry, and wound healing assays were used to investigate cell viability, cell cycle, and cell migration, respectively. Total gelatinase activity, GST activity, and glutathione levels in cell and liver tissue lysates measured by colorimetric methods. Micrometastases were evaluated histochemically in liver tissue sections. As a result, the coadministration of chlorophyllin and docetaxel significantly inhibited cell migration in vitro. There was a significant decrease in the total gelatinase activity in vivo. We found that only combined treatment reduced the micrometastatic lesions in the liver tissues, though this reduction was not statistically significant. In conclusion, the coadministration of chlorophyllin and docetaxel may have a potential role in controlling metastatic processes by suppressing cell migration, gelatinase activity, and micrometastasis formation in triple-negative breast cancers.

Glucagon-like peptide-1 (GLP-1) analogs are synthetic derivatives of the natural incretin hormone GLP-1, which plays a crucial role in glucose metabolism. These analogs mimic the function of endogenous GLP-1 by stimulating insulin secretion, suppressing glucagon release, delaying gastric emptying, and promoting satiety, making them effective for managing type 2 diabetes mellitus (T2DM) and obesity. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, has gained considerable attention for its potential in treating type 2 diabetes mellitus, obesity, and cardiovascular disorders. However, its therapeutic application is significantly hindered by poor absorption, a short biological half-life, and unintended off-target effects, necessitating advanced drug delivery strategies. To address these challenges, various nanocarrier-based systems-such as nanofibers, liposomes, polymeric nanoparticles, exosomes, hydrogels, and lipid nanoparticles-have been explored. These nanocarriers facilitate site-specific and sustained release of liraglutide, improving its bioavailability and therapeutic efficacy. This article provides a comprehensive overview of liraglutide's pharmacological properties, preclinical studies, and the potential of different nanocarrier-based approaches in optimizing its delivery for enhanced clinical outcomes.

Ulcerative colitis (UC), a chronic inflammatory bowel disease with increasing global incidence and limited therapeutic options, underscores the urgent need for novel multi-target agents. Swertiamarin (STM), a secoiridoid glycoside derived from traditional medicine, exhibits anti-inflammatory properties, but its pharmacological mechanisms in UC remain unclear. In this study, we integrated network pharmacology and experimental validation to systematically decipher STM's therapeutic effects. Network analysis identified 67 overlapping targets between STM and UC, which were significantly enriched in key pathways such as Toll-like receptor 4/Nuclear factor-kappa B (TLR4/NF-κB), Interleukin-17 (IL-17), and apoptosis. Molecular docking and protein-protein interaction (PPI) networks prioritized core targets such as TLR4, Caspase-3 (CASP3), and Prostaglandin-endoperoxide synthase (PTGS2). In a dextran sulfate sodium (DSS)-induced murine UC model, STM treatment significantly alleviated colitis severity, evidenced by reduced disease activity index (DAI), attenuated colon shortening (56.5% improvement vs. DSS group, p < 0.01), and restored histological integrity. Mechanistically, STM suppressed TLR4/NF-κB signaling, decreasing phosphorylated Inhibitor of NF-κB alpha (p-IκBα) (1.84 ± 0.33 vs. DSS 2.32 ± 0.28) and NF-κB (1.62 ± 0.39 vs. DSS 2.33 ± 0.38), while downregulating pro-inflammatory mediators (TNF-α, Interleukin-1β) and elevating anti-inflammatory Interleukin10 (IL-10) (98.33 ± 4.13 vs. DSS 61.70 ± 6.70, p < 0.01). Furthermore, STM reduced intestinal epithelial apoptosis (20 ± 2 vs. DSS 55 ± 3, p < 0.01) and modulated systemic immune responses by normalizing lymphocyte/neutrophil ratios. These findings reveal STM's multi-target efficacy in UC, bridging traditional medicine with modern mechanistic insights, and position it as a promising candidate for further clinical development.

Prominin-1, or CD133, is a membrane-bound pentaspan protein that has been utilized recently to identify cancer stem cells (CSCs) in a variety of carcinomas. Today, bioinformatics offers a potent tool for studying the structural and functional relationships of fusion proteins. A structure-activity relationship model based on physicochemical characteristics, biological functions of single-chain antibodies, and molecular conformation can be developed by the integration of biomolecular computer models with biological experiments. In the present study, a mice library of single-chain variable fragment (scFv) antibodies was developed by mRNA extracted from mice immunized for the efficient and specific identification of the N-terminal domain of recombinant CD133 (D-EC1). First, a part of sequences of the scFvs library were cloned in the T.vector and sequenced. Then, bioinformatics was used to select the scFvs with high affinity by molecular dynamics simulations and docking. Based on bioinformatics analysis, three scFvs were cloned and expressed. Finally, the ability of the selected scFv was confirmed with the indirect enzyme-linked immunosorbent assay (ELISA) and immunocytochemistry (ICC). ELISA data showed that scFv3 had a greater affinity for the N-terminal of recombinant CD133, and it was selected for the immunocytochemistry (ICC) analysis. The immunocytochemistry experiments confirmed that the obtained scFv could bind to the CD133-expressing HT-29 cells. Our results suggest that using bioinformatics tools could be applied as a new, rapid, and valid method for the design and development of antibodies with improved properties. The selected scFv may be successfully applied in scFv-based diagnostics and therapeutics.

This study aimed to investigate the potential pharmacological effects of icariin (ICA) in the treatment of spinal cord injury (SCI). Network pharmacology was used to focus on the potential targets and biological processes of ICA in SCI. Molecular docking was used to verify the ability of ICA to bind to its core targets. Finally, valuate the efficacy and potential mechanisms of ICA in treating spinal cord injury through in vitro and in vivo experiments. A total of 37 targets were screened out, and core genes were screened out from the protein‒protein interaction network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that these targets are enriched mainly in response to hypoxia, regulation of the cellular response to stress, and the TGF-beta signaling pathway. Molecular docking analysis showed that ICA has good docking ability with core targets. In animal experiments, Basso, Beattie and Bresnahan scores, catwalk gait analysis, hematoxylin and eosin staining, and RT-qPCR showed that ICA can inhibit spinal cord inflammation and effectively improve the behavioral and histological recovery after SCI rats. Western blot and immunofluorescence showed that ICA can reduce astrocyte activation and downregulate the TGF-beta signaling pathway after SCI. In addition, ICA can promote axonal nerve elongation and promotes angiogenesis after spinal cord injury in rats. In vitro experiments revealed that ICA can inhibit TGFβ1-induced activation of the TGF-beta signaling pathway and astrocyte activation. ICA treats SCI through multiple targets and pathways. ICA plays a major role in protecting nerves, promoting angiogenesis, and inhibiting reactive astrocyte activation in the treatment of SCI.

Flavonoids in fruits, vegetables, and plant-based drinks have potential neuroprotective properties, with clinical research focusing on their role in reducing oxidative stress, controlling inflammation, and preventing apoptosis. Some flavonoids, such as quercetin, kaempferol, fisetin, apigenin, luteolin, chrysin, baicalein, catechin, epigallocatechin gallate, naringenin, naringin, hesperetin, genistein, rutin, silymarin, and daidzein, have been presented to help heal damage to the central nervous system by affecting key signaling pathways including PI3K/Akt and NF-κB. This review systematically analyzed articles on flavonoids, neuroprotection, and brain and spinal cord injury from primary medical databases like Scopus, PubMed, and Web of Science. Flavonoids enhance antioxidant defenses, reduce pro-inflammatory cytokine production, and aid cell survival and repair by focusing on specific molecular pathways. Clinical trials are also exploring the application of preclinical results to therapeutic approaches for patients with spinal cord injury and traumatic brain injury. Flavonoids can enhance injury healing, reduce lesion size, and enhance synaptic plasticity and neurogenesis. The full potential of flavonoids lies in their bioavailability, dose, and administration methods, but there are still challenges to overcome. This review explores flavonoid-induced neuroprotection, its clinical implications, future research opportunities, and molecular mechanisms, highlighting the potential for innovative CNS injury therapies and improved patient health outcomes.

Chicoric acid (CA), a polyphenolic compound found in chicory (Cichorium intybus), shows potential for the management of a number of diseases due to its antioxidant, anticancer, anti-inflammatory, and insulin-sensitizing properties. Chicory, a perennial member of Asteraceae family, is undoubtedly an underestimated vegetable. Currently, its primary usage is concentrated in India, Greece, Italy, and Poland. This review will concentrate on the potential of chicoric acid in different diseases through a study of the literature and in silico research. A comprehensive search of the literature was conducted using specialized and dedicated search engines. Chicoric acid has an impact on several disease types reported in vitro and in vivo. Chicoric acid has surfaced as a promising neuroprotective agent, anticancer, anti-inflammatory, antidiabetics, and antimicrobial exhibiting a broad range of actions that contribute to health and function. Bioactive compound effects on diseases are examined using network pharmacology (ADME, networking, and docking). KEGG analysis and gene ontology demonstrated that chicoric acid works by interfering with many immune system and cancer pathways. Chicoric acid had the best match with receptor proteins 1PXX and 2YCF, which suited the chemical chicoric acid best, with docking scores of - 8.46 and - 9.4, respectively. To sum up, chicoric acid is a new molecule in the medication development process.