Search Results (8)

Sophora flavescens is a medicinal herb distributed widely in Japan and it has been used to treat various diseases and symptoms. To explore its pharmacological use, we examined the estrogenic activity of four prenylated flavonoids, namely kurarinone, kushenols A and I, and sophoraflavanone G, which are characterized by the lavandulyl group at position 8 of ring A, but have variations in the hydroxyl group at positions 3 (ring C), 5 (ring A) and 4’ (ring B). These prenylated flavonoids were examined via cell proliferation assays using sulforhodamine B, Western blotting, and RT-PCR, corresponding to cell, protein, and transcription assays, respectively, based on estrogen action mechanisms. All the assays employed here found weak but clear estrogenic activities for the prenylated flavonoids examined. Furthermore, the activities were inhibited by an estrogen receptor antagonist, suggesting that the activities were likely being mediated by the estrogen receptors. However, there were differences in the activity, attributable to the hydroxyl group at position 4’, which is absent in kushenol A. While the estrogenic activity of kurarinone and sophoraflavanone G has been reported before, to the best of our knowledge, there are no such reports on kushenols A and I. Therefore, this study represents the first report of their estrogenic activity. Full article

The regulation of matrix metalloproteinases (MMPs), especially MMP-9, has a critical role in both physiological and pathological events in the central nervous system (CNS). MMP-9 is an indicator of inflammation that triggers several CNS disorders, including neurodegeneration. Tumor necrosis factor-α (TNF-α) has the ability to stimulate the production of different inflammatory factors, including MMP-9, in several conditions. Numerous phytochemicals are hypothesized to mitigate inflammation, including the CNS. Among them, a flavonoid compound, sophoraflavanone G (SG), found in Sophora flavescens has been found to possess several medicinal properties, including anti-bacterial and anti-inflammatory effects. In this study, mouse brain microvascular endothelial cells (bMECs) were used to explore TNF-α-induced MMP-9 signaling. The effects of SG on TNF-α-induced MMP-9 expression and its mechanisms were further evaluated. Our study revealed that the expression of MMP-9 in bMECs was stimulated by TNF-α through the activation of ERK1/2, p38 MAPK, and JNK1/2 via the TNF receptor (TNFR) with a connection to the NF-κB signaling pathway. Moreover, we found that SG can interact with the TNFR. The upregulation of MMP-9 by TNF-α may lead to the disruption of zonula occludens-1 (ZO-1), which can be mitigated by SG administration. These findings provide evidence that SG may possess neuroprotective properties by inhibiting the signaling pathways associated with TNFR-mediated MMP-9 expression and the subsequent disruption of tight junctions in brain microvascular endothelial cells. Full article

Anthyllis henoniana stems were harvested in two seasons: winter and spring (February and May 2021). In this study, we investigated the antioxidant (DPPH, ABTS, FRAP and TAC) and antimicrobial activities, total phenolic contents and total flavonoid contents of the obtained extracts (hexane, ethyl acetate and methanol). The results showed that ethyl acetate extract from stems harvested in winter exhibited the highest antioxidant activity, while ethyl acetate extract from the stems harvested in spring showed the most potent antibacterial and antifungal activities. To explain these differences, we investigated the phytochemical composition of these two extracts using liquid chromatography coupled with mass spectrometry. Therefore, 45 compounds were detected, from which we identified 20 compounds (flavonoids, triterpenoids, chalcones and phenolic acids); some were specific to the harvest month while others were common for both periods. Some of the major compounds detected in ethyl acetate (spring) were dihydrochalcone (Kanzonol Y, 8.2%) and flavanone (sophoraflavanone G, 5.9%), previously recognized for their antimicrobial effects. We therefore concluded that the difference in activities observed for the two harvest periods depends on the chemical composition of the extracts and the relative abundance of each compound. Full article

The review presents prenylated flavonoids as potential therapeutic agents for the treatment of topical skin infections and wounds, as they can restore the balance in the wound microenvironment. A thorough two-stage search of scientific papers published between 2000 and 2022 was conducted, with independent assessment of results by two reviewers. The main criteria were an MIC (minimum inhibitory concentration) of up to 32 µg/mL, a microdilution/macrodilution broth method according to CLSI (Clinical and Laboratory Standards Institute) or EUCAST (European Committee on Antimicrobial Susceptibility Testing), pathogens responsible for skin infections, and additional antioxidant, anti-inflammatory, and low cytotoxic effects. A total of 127 structurally diverse flavonoids showed promising antimicrobial activity against pathogens affecting wound healing, predominantly Staphylococcus aureus strains, but only artocarpin, diplacone, isobavachalcone, licochalcone A, sophoraflavanone G, and xanthohumol showed multiple activity, including antimicrobial, antioxidant, and anti-inflammatory along with low cytotoxicity important for wound healing. Although prenylated flavonoids appear to be promising in wound therapy of humans, and also animals, their activity was measured only in vitro and in vivo. Future studies are, therefore, needed to establish rational dosing according to MIC and MBC (minimum bactericidal concentration) values, test potential toxicity to human cells, measure healing kinetics, and consider formulation in smart drug release systems and/or delivery technologies to increase their bioavailability. Full article

Sophoraflavanone G (SG), isolated from Sophora flavescens, has anti-inflammatory and anti-tumor bioactive properties. We previously showed that SG promotes apoptosis in human breast cancer cells and leukemia cells and reduces the inflammatory response in lipopolysaccharide-stimulated macrophages. We investigated whether SG attenuates airway hyper-responsiveness (AHR) and airway inflammation in asthmatic mice. We also assessed its effects on the anti-inflammatory response in human tracheal epithelial cells. Female BALB/c mice were sensitized with ovalbumin, and asthmatic mice were treated with SG by intraperitoneal injection. We also exposed human bronchial epithelial BEAS-2B cells to different concentrations of SG to evaluate its effects on inflammatory cytokine levels. SG treatment significantly reduced AHR, eosinophil infiltration, goblet cell hyperplasia, and airway inflammation in the lungs of asthmatic mice. In the lungs of ovalbumin-sensitized mice, SG significantly promoted superoxide dismutase and glutathione expression and attenuated malondialdehyde levels. SG also suppressed levels of Th2 cytokines and chemokines in lung and bronchoalveolar lavage samples. In addition, we confirmed that SG decreased pro-inflammatory cytokine, chemokine, and eotaxin expression in inflammatory BEAS-2B cells. Taken together, our data demonstrate that SG shows potential as an immunomodulator that can improve asthma symptoms by decreasing airway-inflammation-related oxidative stress. Full article

The roots of Sophora flavescens (SF) are clinically used as a traditional Chinese medicine for the treatment of various lung diseases. In this study, we investigated the mechanism by which SF inhibits proliferation and induces apoptosis in non-small-cell lung cancer (NSCLC) cells. A new compound, kushenol Z (KZ), and 14 known flavonoids were isolated from SF. KZ, sophoraflavanone G, and kushenol A demonstrated potent cytotoxicity against NSCLC cells in a dose- and time-dependent manner; KZ showed a wide therapeutic window. We also found that KZ induced NSCLC cell apoptosis by increasing the Bax/Bcl-2 ratio and by activating caspase-3 and caspase-9 leading to mitochondrial apoptosis, and upregulated CHOP and activatedcaspase-7 and caspase-12, which triggered the endoplasmic reticulum stress pathway. After KZ treatment, we observed cAMP accumulation, which reflected the inhibition of cAMP-phosphodiesterase (PDE), along with the increase in PKA activity; additionally, phospho-p70 S6 kinase was downregulated. KZ also attenuated the phosphorylation of Akt and PRAS40, which was partially rescued by an Akt activator. This suggested that KZ mediated the antiproliferative activity in NSCLC cells by inhibiting the mTOR pathway through the inhibition of cAMP-PDE and Akt. These findings suggested that KZ may be used as a promising cAMP-PDE and Akt inhibitor in targeted chemotherapeutic drug development. Full article

In a continuation of our computational efforts to find new natural inhibitors of a variety of target enzymes from parasites causing neglected tropical diseases (NTDs), we now report on 15 natural products (NPs) that we have identified as inhibitors of Leishmania major pteridine reductase I (LmPTR1) through a combination of in silico and in vitro investigations. Pteridine reductase (PTR1) is an enzyme of the trypanosomatid parasites’ peculiar folate metabolism, and has previously been validated as a drug target. Initially, pharmacophore queries were created based on four 3D structures of LmPTR1 using co-crystallized known inhibitors as templates. Each of the pharmacophore queries was used to virtually screen a database of 1100 commercially available natural products. The resulting hits were submitted to molecular docking analyses in the substrate binding site of the respective protein structures used for the pharmacophore design. This approach led to the in silico identification of a total of 18 NPs with predicted binding affinity to LmPTR1. These compounds were subsequently tested in vitro for inhibitory activity towards recombinant LmPTR1 in a spectrophotometric inhibition assay. Fifteen out of the 18 tested compounds (hit rate = 83%) showed significant inhibitory activity against LmPTR1 when tested at a concentration of 50 µM. The IC₅₀ values were determined for the six NPs that inhibited the target enzyme by more than 50% at 50 µM, with sophoraflavanone G being the most active compound tested (IC₅₀ = 19.2 µM). The NPs identified and evaluated in the present study may represent promising lead structures for the further rational drug design of more potent inhibitors against LmPTR1. Full article

Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis. It has been the focus of target based drug discovery in recent years. We have identified two components in RD, Kushennol F and Sophoraflavanone G, that can potentially interact with Ctsk. Biological studies were performed to verify the effects of these compounds on Ctsk and its related bone resorption process, which include the use of in vitro fluorescence-based Ctsk enzyme assay, bone resorption pit formation assay, as well as Receptor Activator of Nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis using murine RAW264.7 cells. Finally, the binding mode and stability of these two compounds that interact with Ctsk were determined by molecular docking and dynamics methods. The results showed that the in silico target fishing method could successfully identify two components from RD that show inhibitory effects on the bone resorption process related to protease Ctsk. Full article