Protective effect of soloxolone derivatives in carrageenan- and LPS-driven acute inflammation: Pharmacological profiling and their effects on key inflammation-related processes

Sen’kova, Aleksandra V.; Savin, Innokenty A.; Odarenko, Kirill V.; Salomatina, Oksana V.; Салахутдинов, Н. Ф.; Зенкова, М. А.; Markov, Andrey

doi:10.1016/j.biopha.2023.114231

Cited by 4 publications

(3 citation statements)

References 90 publications

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“…Additionally, the substituents at the C-30 position of the explored triterpenoids have little to no impact on this effect. The last finding is in accordance with recently reported similar potencies of SM, S, and SAO in relation to murine macrophages [46]. The obtained results provide valuable information for the further structural optimization of cyanoenone-containing triterpenoids.…”

Section: Discussionsupporting

confidence: 91%

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Soloxolone Methyl Reduces the Stimulatory Effect of Leptin on the Aggressive Phenotype of Murine Neuro2a Neuroblastoma Cells via the MAPK/ERK1/2 Pathway

Odarenko,

Salomatina,

Chernikov

et al. 2023

Pharmaceuticals

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Despite the proven tumorigenic effect of leptin on epithelial-derived cancers, its impact on the aggressiveness of neural crest-derived cancers, notably neuroblastoma, remains largely unexplored. In our study, for the first time, transcriptome analysis of neuroblastoma tissue demonstrated that the level of leptin is elevated in neuroblastoma patients along with the severity of the disease and is inversely correlated with patient survival. The treatment of murine Neuro2a neuroblastoma cells with leptin significantly stimulated their proliferation and motility and reduced cell adhesion, thus rendering the phenotype of neuroblastoma cells more aggressive. Given the proven efficacy of cyanoenone-bearing semisynthetic triterpenoids in inhibiting the growth of neuroblastoma and preventing obesity in vivo, the effect of soloxolone methyl (SM) on leptin-stimulated Neuro2a cells was further investigated. We found that SM effectively abolished leptin-induced proliferation of Neuro2a cells by inducing G1/S cell cycle arrest and restored their adhesiveness to extracellular matrix (ECM) proteins to near control levels through the upregulation of vimentin, zonula occludens protein 1 (ZO-1), cell adhesion molecule L1 (L1cam), and neural cell adhesion molecule 1 (Ncam1). Moreover, SM significantly suppressed the leptin-associated phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and ribosomal protein S6 kinase A1 (p90RSK), which are key kinases that ensure the survival and proliferation of cancer cells. Further molecular modeling studies demonstrated that the inhibitory effect of SM on the mitogen-activated protein kinase (MAPK)/ERK1/2 signaling pathway can be mediated by its direct interaction with ERK2 and its upstream regulators, son of sevenless homolog 1 (SOS) and mitogen-activated protein kinase kinase 1 (MEK1). Taken together, our findings in murine Neuro2a cells provide novel evidence of the stimulatory effect of leptin on the aggressiveness of neuroblastoma, which requires further detailed studies in human neuroblastoma cells and relevant animal models. The obtained results indicate that SM can be considered a promising drug candidate capable of reducing the impact of adipokines on tumor progression.

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Section: Discussionsupporting

confidence: 91%

“…The chemical synthesis and characterization of soloxolone methyl (SM), soloxolone (S), and soloxolone amidoxime (SAO) by chemical and nucleic magnetic resonance analysis have been previously reported [46,59]. The compounds were dissolved at a concentration of 10 mM in DMSO and were stored at −20 • C until use.…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

Soloxolone Methyl Reduces the Stimulatory Effect of Leptin on the Aggressive Phenotype of Murine Neuro2a Neuroblastoma Cells via the MAPK/ERK1/2 Pathway

Odarenko,

Salomatina,

Chernikov

et al. 2023

Pharmaceuticals

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“…In each group, inflammation was induced by administering a sub-plantar injection of 50 µL of 1% carrageenan (Sigma-Aldrich Cat. 22049, St. Louis, MO, USA) into the right paw, as earlier described by Winter et al [49][50][51]. Simultaneously, in the left paw, distilled water was being administered.…”

Section: Animal Carementioning

confidence: 99%

Selection of Mexican Medicinal Plants by Identification of Potential Phytochemicals with Anti-Aging, Anti-Inflammatory, and Anti-Oxidant Properties through Network Analysis and Chemoinformatic Screening

Barrera-Vázquez,

Montenegro-Herrera,

Martínez-Enríquez

et al. 2023

Biomolecules

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Many natural products have been acquired from plants for their helpful properties. Medicinal plants are used for treating a variety of pathologies or symptoms. The axes of many pathological processes are inflammation, oxidative stress, and senescence. This work is focused on identifying Mexican medicinal plants with potential anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence effects through network analysis and chemoinformatic screening of their phytochemicals. We used computational methods to analyze drug-like phytochemicals in Mexican medicinal plants, multi-target compounds, and signaling pathways related to anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence mechanisms. A total of 1373 phytochemicals are found in 1025 Mexican medicinal plants, and 148 compounds showed no harmful functionalities. These compounds displayed comparable structures with reference molecules. Based on their capacity to interact with pharmacological targets, three clusters of Mexican medicinal plants have been established. Curatella americana, Ximenia americana, Malvastrum coromandelianum, and Manilkara zapota all have anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence effects. Plumeria rubra, Lonchocarpus yucatanensis, and Salvia polystachya contained phytochemicals with anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence reported activity. Lonchocarpus guatemalensis, Vallesia glabra, Erythrina oaxacana, and Erythrina sousae have drug-like phytochemicals with potential anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence effects. Between the drug-like phytochemicals, lonchocarpin, vallesine, and erysotrine exhibit potential anti-oxidant, anti-inflammatory, anti-aging, and anti-senescence effects. For the first time, we conducted an initial virtual screening of selected Mexican medicinal plants, which was subsequently confirmed in vivo, evaluating the anti-inflammatory activity of Lonchocarpus guatemalensis Benth in mice.

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Evaluation of the Antitumor Potential of Soloxolone Tryptamide against Glioblastoma Multiforme Using in silico, in vitro, and in vivo Approaches

Markov

Odarenko

Sen’kova

et al. 2023

Biochemistry Moscow

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Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by uncontrollable diffusive growth, resistance to chemo- and radiotherapy, and a high recurrence rate leading to a low survival rate of patients with GBM. Due to a large number of signaling pathways regulating GBM pathogenesis, one of the promising directions is development of novel anti-glioblastoma compounds based on natural metabolites capable of affecting multiple targets. Here, we investigated the antitumor potential of the semisynthetic triterpenoid soloxolone tryptamide (STA) against human glioblastoma U87 cells. STA efficiently blocked the growth of U87 cells in 2D and 3D cultures, enhanced adhesiveness of tumor cells, and displayed synergistic cytotoxicity with temozolomide. In silico analysis suggested that the anti-glioblastoma activity of STA can be explained by its direct interaction with EGFR, ERBB2, and AKT1 which play an important role in the regulation of GBM malignancy. Along with direct effect on U87 cells, STA normalized tumor microenvironment in murine heterotopic U87 xenograft model by suppressing the development of immature blood vessels and elastin production in the tumor tissue. Taken together, our results clearly demonstrate that STA can be a novel promising antitumor candidate for GMB treatment.

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Protective effect of soloxolone derivatives in carrageenan- and LPS-driven acute inflammation: Pharmacological profiling and their effects on key inflammation-related processes

Cited by 4 publications

References 90 publications

Soloxolone Methyl Reduces the Stimulatory Effect of Leptin on the Aggressive Phenotype of Murine Neuro2a Neuroblastoma Cells via the MAPK/ERK1/2 Pathway

Soloxolone Methyl Reduces the Stimulatory Effect of Leptin on the Aggressive Phenotype of Murine Neuro2a Neuroblastoma Cells via the MAPK/ERK1/2 Pathway

Selection of Mexican Medicinal Plants by Identification of Potential Phytochemicals with Anti-Aging, Anti-Inflammatory, and Anti-Oxidant Properties through Network Analysis and Chemoinformatic Screening

Evaluation of the Antitumor Potential of Soloxolone Tryptamide against Glioblastoma Multiforme Using in silico, in vitro, and in vivo Approaches

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