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Fulltext Platanosides, a Potential Botanical Drug Combination, Decrease Liver Injury Caused by Acetaminophen Overdose in Mice

Samuvel DJ, Nguyen NT, Jaeschke H, Lemasters JJ, Wang X, Choo YM, et al.

J Nat Prod, 2022 Jul 22;85(7):1779-1788.
PMID: 35815804 DOI: 10.1021/acs.jnatprod.2c00324

Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. Platanosides (PTSs) isolated from the American sycamore tree (Platanus occidentalis) represent a potential new four-molecule botanical drug class of antibiotics active against drug-resistant infectious disease. Preliminary studies have suggested that PTSs are safe and well tolerated and have antioxidant properties. The potential utility of PTSs in decreasing APAP hepatotoxicity in mice in addition to an assessment of their potential with APAP for the control of infectious diseases along with pain and pyrexia associated with a bacterial infection was investigated. On PTS treatment in mice, serum alanine aminotransferase (ALT) release, hepatic centrilobular necrosis, and 4-hydroxynonenal (4-HNE) were markedly decreased. In addition, inducible nitric oxide synthase (iNOS) expression and c-Jun-N-terminal kinase (JNK) activation decreased when mice overdosed with APAP were treated with PTSs. Computational studies suggested that PTSs may act as JNK-1/2 and Keap1-Nrf2 inhibitors and that the isomeric mixture could provide greater efficacy than the individual molecules. Overall, PTSs represent promising botanical drugs for hepatoprotection and drug-resistant bacterial infections and are effective in protecting against APAP-related hepatotoxicity, which decreases liver necrosis and inflammation, iNOS expression, and oxidative and nitrative stresses, possibly by preventing persistent JNK activation.

Matched MeSH terms: Kelch-Like ECH-Associated Protein 1/metabolism
Fulltext Effect of Administration of an Equal Dose of Selected Dietary Chemicals on Nrf2 Nuclear Translocation in the Mouse Liver

Alrawaiq NS, Atia A, Abdullah A

Oxid Med Cell Longev, 2023;2023:9291417.
PMID: 37077659 DOI: 10.1155/2023/9291417

Certain dietary chemicals influenced the expression of chemopreventive genes through the Nrf2-Keap1 pathway. However, the difference in Nrf2 activation potency of these chemicals is not well studied. This study is aimed at determining the difference in the potency of liver Nrf2 nuclear translocation induced by the administration of equal doses of selected dietary chemicals in mice. Male ICR white mice were administered 50 mg/kg of sulforaphane, quercetin, curcumin, butylated hydroxyanisole, and indole-3-carbinol for 14 days. On day 15, the animals were sacrificed, and their livers were isolated. Liver nuclear extracts were prepared, and Nrf2 nuclear translocation was detected through Western blotting. To determine the implication of the Nrf2 nuclear translocation on the expression levels of several Nrf2-regulated genes, liver RNA was extracted for qPCR assay. Equal doses of sulforaphane, quercetin, curcumin, butylated hydroxyanisole, and indole-3-carbinol significantly induced the nuclear translocation of Nrf2 with different intensities and subsequently increased the expression of Nrf2-regulated genes with an almost similar pattern as the Nrf2 nuclear translocation intensities (sulforaphane > butylated hydroxyanisole = indole-3-carbinol > curcumin > quercetin). In conclusion, sulforaphane is the most potent dietary chemical that induces the Nrf2 translocation into the nuclear fraction in the mouse liver.

Matched MeSH terms: Kelch-Like ECH-Associated Protein 1/metabolism
Fulltext Stingless Bee (Heterotrigona Itama) Honey and Its Phenolic-Rich Extract Ameliorate Oxidant-Antioxidant Balance via KEAP1-NRF2 Signalling Pathway

Cheng MZSZ, Amin FAZ, Zawawi N, Chan KW, Ismail N, Ishak NA, et al.

Nutrients, 2023 Jun 22;15(13).
PMID: 37447162 DOI: 10.3390/nu15132835

Diabetes is associated with an imbalance between oxidants and antioxidants, leading to oxidative stress. This imbalance contributes to the development and progression of diabetic complications. Similarly, renal and liver diseases are characterised by oxidative stress, where an excess of oxidants overwhelms the antioxidant defense mechanisms, causing tissue damage and dysfunction. Restoring the oxidant-antioxidant balance is essential for mitigating oxidative stress-related damage under these conditions. In this current study, the efficacy of stingless bee honey (SBH) and its phenolic-rich extract (PRE) in controlling the oxidant-antioxidant balance in high-fat diet- and streptozotocin/nicotinamide-induced diabetic rats was investigated. The administration of SBH and PRE improved systemic antioxidant defense and oxidative stress-related measures without compromising liver and renal functioning. Analyses of the liver, skeletal muscle and adipose tissues revealed differences in their capacities to scavenge free radicals and halt lipid peroxidation. Transcriptional alterations hypothesised tissue-specific control of KEAP1-NRF2 signalling by upregulation of Nrf2, Ho1 and Sod1 in a tissue-specific manner. In addition, hepatic translational studies demonstrated the stimulation of downstream antioxidant-related protein with upregulated expression of SOD-1 and HOD-1 protein. Overall, the results indicated that PRE and SBH can be exploited to restore the oxidant-antioxidant imbalance generated by diabetes via regulating the KEAP1-NRF2 signalling pathway.

Matched MeSH terms: Kelch-Like ECH-Associated Protein 1/metabolism
Demethylnobiletin ameliorates cerebral ischemia-reperfusion injury in rats through Nrf2/HO-1 signaling pathway

Huang D, Awad ACA, Tang C, Chen Y

Environ Toxicol, 2024 Mar;39(3):1335-1349.
PMID: 37955318 DOI: 10.1002/tox.24036

BACKGROUND: Demethylnobiletin (DN), with a variety of biological activities, is a polymethoxy-flavanone (PMF) found in citrus. In the present study, we explored the biological activities and potential mechanism of DN to improve cerebral ischemia reperfusion injury (CIRI) in rats, and identified DN as a novel neuroprotective agent for patients with ischemic brain injury.
METHODS: Rat CIRI models were established via middle cerebral artery occlusion (MCAO). Primary nerve cells were isolated and cultured in fetal rat cerebral cortex in vitro, and oxygen-glucose deprivation/reperfusion (OGD/R) models of primary nerve cells were induced. After intervention with DN with different concentrations in MCAO rats and OGD/R nerve cells, 2,3,5-triphenyltetrazolium chloride staining was used to quantify cerebral infarction size in CIRI rats. Modified neurological severity score was utilized to assess neurological performance. Histopathologic staining and live/dead cell-viability staining was used to observe apoptosis. Levels of glutathione (GSH), superoxide dismutase (SOD), reactive oxygen species (ROS) and malondialdehyde (MDA) in tissues and cells were detected using commercial kits. DN level in serum and cerebrospinal fluid of MCAO rats were measured by liquid chromatography tandem mass spectrometry. In addition, expression levels of proteins like Kelch like ECH associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nfr2) and heme oxygenase 1 (HO-1) in the Nrf2/HO-1 pathway, and apoptosis-related proteins like Cleaved caspase-3, BCL-2-associated X protein (Bax) and B-cell lymphoma-2 (Bcl-2) were determined by Western blot and immunofluorescence.
RESULTS: DN can significantly enhance neurological function recovery by reducing cerebral infarction size and weakening neurocytes apoptosis in MCAO rats. It was further found that DN could improve oxidative stress (OS) injury of nerve cells by bringing down MDA and ROS levels and increasing SOD and GSH levels. Notably, DN exerts its pharmacological influences through entering blood-brain barrier. Mechanically, DN can reduce Keap1 expression while activate Nrf2 and HO-1 expression in neurocytes.
CONCLUSIONS: The protective effect of DN on neurocytes have been demonstrated in both in vitro and in vivo circumstances. It deserves to be developed as a potential neuroprotective agent through regulating the Nrf2/HO-1 signaling pathway to ameliorate neurocytes impairment caused by OS.

Matched MeSH terms: Kelch-Like ECH-Associated Protein 1/metabolism
Fulltext Computational Screening for the Anticancer Potential of Seed-Derived Antioxidant Peptides: A Cheminformatic Approach

Chai TT, Koh JA, Wong CC, Sabri MZ, Wong FC

Molecules, 2021 Dec 06;26(23).
PMID: 34885982 DOI: 10.3390/molecules26237396

Some seed-derived antioxidant peptides are known to regulate cellular modulators of ROS production, including those proposed to be promising targets of anticancer therapy. Nevertheless, research in this direction is relatively slow owing to the inevitable time-consuming nature of wet-lab experimentations. To help expedite such explorations, we performed structure-based virtual screening on seed-derived antioxidant peptides in the literature for anticancer potential. The ability of the peptides to interact with myeloperoxidase, xanthine oxidase, Keap1, and p47phox was examined. We generated a virtual library of 677 peptides based on a database and literature search. Screening for anticancer potential, non-toxicity, non-allergenicity, non-hemolyticity narrowed down the collection to five candidates. Molecular docking found LYSPH as the most promising in targeting myeloperoxidase, xanthine oxidase, and Keap1, whereas PSYLNTPLL was the best candidate to bind stably to key residues in p47phox. Stability of the four peptide-target complexes was supported by molecular dynamics simulation. LYSPH and PSYLNTPLL were predicted to have cell- and blood-brain barrier penetrating potential, although intolerant to gastrointestinal digestion. Computational alanine scanning found tyrosine residues in both peptides as crucial to stable binding to the targets. Overall, LYSPH and PSYLNTPLL are two potential anticancer peptides that deserve deeper exploration in future.

Matched MeSH terms: Kelch-Like ECH-Associated Protein 1/metabolism
Bee bread attenuates the progression of atherosclerosis by activating Nrf2/Keap1 and modulating TNF-α/NF-κβ-associated mast cell migration and a mitochondrial-dependent apoptotic pathway in the obese rat model

Othman ZA, Zakaria Z, Suleiman JB, Che Jalil NA, Wan Ghazali WS, Mohamed M

Food Funct, 2022 Aug 01;13(15):8119-8130.
PMID: 35796099 DOI: 10.1039/d2fo00949h

This study explores the anti-atherosclerotic effects of bee bread in the context of oxidative stress, inflammation, and apoptosis phenomena in an obesity animal model, and its vitamin composition. Forty male Sprague-Dawley rats were administered with a normal diet (Normal group) and a high-fat diet (HFD) to induce obesity. After 6 weeks, obese rats that received the HFD were treated either with distilled water (Ob group), bee bread at 0.5 g per kg per day (Ob + Bb group), or orlistat at 10 mg per kg per day (Ob + Or group) concomitant with the HFD for another 6 weeks. Bee bread significantly improved atherosclerotic changes by enhancing the immunoexpressions of Nrf2/Keap1, impeding the immunoexpressions of NF-κβ downstream proteins, and intensifying Bcl-2 upregulation, attributed to the improvement in mast cell adherence and collagen deposition in the aortic wall of the Ob + Bb group. We have demonstrated that the treatment with bee bread attenuates the progression of atherosclerosis through its inhibition of vascular oxidative stress, and retardation of inflammatory reaction and apoptosis in obese rats, indicating its potential therapeutic targets for obesity-related vascular diseases. This could be partly attributed to the components of vitamins such as vitamins A, C and E that are present in bee bread, which need further study for the exact molecular mechanism of action.

Matched MeSH terms: Kelch-Like ECH-Associated Protein 1/metabolism
Fulltext Synthesis and Anti-Inflammatory Activity of 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-Derived NRF2 Activators

Mak KK, Shiming Z, Epemolu O, Dinkova-Kostova AT, Wells G, Gazaryan IG, et al.

ChemistryOpen, 2022 Oct;11(10):e202200181.
PMID: 36284193 DOI: 10.1002/open.202200181

This is the first study investigating the nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity of compounds containing a new scaffold, tetrahydrobenzo[b]thiophene. Eighteen compounds were synthesised and confirmed their NRF2 activation through NQO1 enzymatic activity and mRNA expression of NQO1 and HO-1 in Hepa-1c1c7 cells. The compounds disrupted the interaction between Kelch-like ECH-associated protein 1 (KEAP1) and NRF2 via interfering with the KEAP1's Kelch domain. The compounds exhibited anti-inflammatory activity in Escherichia coli Lipopolysaccharide (LPSEc )-stimulated RAW 264.7 cells. The anti-inflammatory activity of the compounds was associated with their ability to activate NRF2. The compounds reversed the elevated levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IFN-γ) and inflammatory mediators (PGE2, COX-2, and NF-κB). The compounds were metabolically stable in human, rat, and mouse liver microsomes and showed optimum half-life (T1/2 ) and intrinsic clearance (Clint ). The binding mode of the compounds and physicochemical properties were predicted via in silico studies.

Matched MeSH terms: Kelch-Like ECH-Associated Protein 1/metabolism