Investigation of Leoligin Derivatives as NF-κΒ Inhibitory Agents.
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ABSTRACT:
SUBMITTER: Linder T
PROVIDER: S-EPMC8773117 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:(1) Background: Nuclear factor κB (NF-κB) is an important transcriptional regulator that regulates the inflammatory pathway and plays a key role in cellular inflammatory and immune responses. The presence of a high concentration of NF-κB is positively correlated with the severity of inflammation. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation; (2) Methods: we designed and synthesized 23 mollugin derivatives and evaluated their inhibitory activity against NF-κB transcription; (3) Results: Compound 6d exhibited the most promising inhibitory activity (IC50 = 3.81 µM) and did not show any significant cytotoxicity against the tested cell lines. Investigation of the mechanism of action indicated that 6d down-regulated NF-κB expression, possibly by suppressing TNF-α-induced expression of the p65 protein. Most of the compounds exhibited potent anti-inflammatory activity. Compound 4f was the most potent compound with 83.08% inhibition of inflammation after intraperitoneal administration, which was more potent than mollugin and the reference drugs (ibuprofen and mesalazine). ADMET prediction analysis indicated that compounds 6d and 4f had good pharmacokinetics and drug-like behavior; (4) Conclusions: Several series of mollugin derivatives were designed, synthesized, and evaluated for NF-κB inhibitory activity and toxicity. These results provide an initial basis for the development of 4f and 6d as potential anti-inflammatory agents.
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Project description:Twenty-four 14-sulfonamide-tetrandrine derivatives as potential anti-cancer agents were synthesized. The synthetic derivatives were investigated for their cytotoxic activity against human cancer cell lines MDA-MB-231, PC3, WM9, HEL and K562. Initially, the IC50 values (50% inhibitory concentrations) of all of the compounds were determined. These derivatives exhibited potent, but distinct, inhibitory effects on the above-mentioned cell lines. Among them, compound 23, which was modified with a 2-naphthalenesulfonyl group at the 14-amino position, showed impressive inhibition of all five cancer cell lines, and especially of MDA-MB-231 cells with an IC50 value of 1.18 ± 0.14 μM. Further mechanism exploration showed that 23 induced potent apoptotic cell death on MDA-MB-231 cancer cells in a concentration-dependent manner. The results revealed that 23 might be a potential anti-cancer drug candidate.
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Project description:Taxol, a first-line anti-tumour drug, has low effectiveness against colorectal cancer. Combination with other agents is an effective strategy to enhance Taxol cytotoxicity. Kanglaite injection is an extract from Coix lacryma-jobi seed and is usually combined with other agents to treat cancer. The aim of this study was to investigate the treatment effect of Taxol combined with Kanglaite on colorectal cancer cell lines. Kanglaite pretreatment followed by Taxol treatment was found to show the best synergism among all combination strategies. This combination also resulted in the smallest tumour volume in a Balb/c mice model. Kanglaite inhibited the expression of nuclear factor (NF)-κΒ and upregulated that of connexin 43, both of which sensitized cancer cells to Taxol. Moreover, Kanglaite increased many cellular variations caused by Taxol, including tubulin polymerization, caspase-3 cleavage, and upregulated expression of survivin and cyclin B1. These results suggest that Kanglaite pretreatment may increase the effect of Taxol on colorectal cancer.
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Project description:Rosmarinic acid (RA), a natural ester phenolic compound, is known to have antioxidant and anti-inflammatory properties. RA has also been reported to exhibit a hypoglycemic effect; however, the mechanisms underlying this effect have yet to be investigated. Therefore, the present study focused on the anti-diabetic effects and mechanism of RA in INS-1 cells using in vitro model. Streptozotocin (STZ) at a concentration of 3 mM was applied to INS-1 cells for 4 h to create a diabetic model. The cells were pretreated for 24 h with various concentrations (1 and 2.5 μM) of RA. The Cell viability, glucose-stimulated insulin secretion (GSIS), glucose uptake, lipid peroxidation, reactive oxygen species (ROS), apoptosis, and protein expression of Bcl-2, NF-κB, 1L-1β, and PARP were assessed. Results showed that STZ-treated INS-1 cells exhibited reduced cell viability, insulin release, insulin content, glucose uptake, and elevated MDA and ROS levels. Cells pretreated with RA maintained the function and morphology of β-cells against STZ-induced damage. Moreover, RA sustained high protein expression levels of Bcl-2 and low expression levels of NF-κB, IL-1β, and PARP. In conclusion, RA preserved β-cells function against STZ-induced damage by altering NF-κB and Bcl-2 pathways.
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Project description:Glycation of serum albumin and its consequence products were considered as an important factor in drug distribution and diabetic complications, therefore finding the glycation inhibitors and their inhibitory mechanisms became a valuable field of study. In this work, bovine serum albumin (BSA) became a subject as a model protein for analyzing the inhibitory mechanism of flavonoids, known as natural BSA glycation inhibitors in the early stage of glycation.Firstly, for theoretical study, the three-dimensional model of BSA structure was generated by homology modeling and refined through molecular dynamic simulation. Secondly, several validation methods (statistical assessment methods and also neural network methods) by simultaneous docking study were employed for insurance about accuracy of our simulation. Then docking studies were performed for visualizing the relation between flavonoids' binding sites and BSA glycation sites besides, the correlation analyzes between calculated binding energy and reported experimental inhibitory IC50 values of the flavonoids set, was considered to explore their molecular inhibitory mechanism.The quality assessment methods and simultaneous docking studies on interaction of quercetin (as the most studied flavonoids) with BSA and Human serum albumin (HAS), confirm the accuracy of simulation and the second stage of docking results which were in close agreement with experimental observations, suggest that the potential residues in flavonoids binding sites (which were place neighbor of tryptophan 212 within 5?) cannot be considered as one of glycation sites.Based on the results, flavonoids don't participate in inhibitory interference mechanism, and also, the differentiation between complexes of flavonoids with BSA and HSA could destroy the speculation of using them as an exchangeable model protein in study of serum albumin and flavonoids interactions.
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Project description:Enterotoxigenic Bacteroides fragilis (ETBF) is human intestinal commensal bacterium and a potent initiator of colitis through secretion of the metalloprotease Bacteroides fragilis toxin (BFT). BFT induces cleavage of E-cadherin in colon cells, which subsequently leads to NF-κB activation. Zerumbone is a key component of the Zingiber zerumbet (L.) Smith plant and can exhibit anti-bacterial and anti-inflammatory effects. However, whether zerumbone has anti-inflammatory effects in ETBF-induced colitis remains unknown. The aim of this study was to determine the anti-inflammatory effect of orally administered zerumbone in a murine model of ETBF infection. Wild-type C57BL/6 mice were infected with ETBF and orally administered zerumbone (30 or 60 mg/kg) once a day for 7 days. Treatment of ETBF-infected mice with zerumbone prevented weight loss and splenomegaly and reduced colonic inflammation with decreased macrophage infiltration. Zerumbone treatment significantly decreased expression of IL-17A, TNF-α, KC, and inducible nitric oxide synthase (iNOS) in colonic tissues of ETBF-infected mice. In addition, serum levels of KC and nitrite was also diminished. Zerumbone-treated ETBF-infected mice also showed decreased NF-κB signaling in the colon. HT29/C1 colonic epithelial cells treated with zerumbone suppressed BFT-induced NF-κB signaling and IL-8 secretion. However, BFT-mediated E-cadherin cleavage was unaffected. Furthermore, zerumbone did not affect ETBF colonization in mice. In conclusion, zerumbone decreased ETBF-induced colitis through inhibition of NF-κB signaling.
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