Luteolin target HSPB1 regulates endothelial cell ferroptosis to protect against radiation vascular injury.

Vascular endothelial damage due to ionizing radiation is the main pathological process of radiation injury and the main cause of damage to various organs in nuclear accidents. Ferroptosis plays an important role in ionizing radiation-induced cell death. We have previously reported that luteolin is highly resistant to ferroptosis. In the present study, body weight, microvessel count, H&E, and Masson staining results showed that luteolin rescued radial vascular injury in vivo. Cell Counting Kit 8 (CCK8), Giemsa staining clarified the anti-ferroptosis ability of luteolin with low toxicity. Malondialdehyde (MDA), superoxide dismutase (SOD), NADP+/NADPH, Fe2+ staining, dihydroethidium (DHE) and MitoTracker assays for ferroptosis-related metrics, we found that luteolin enhances human umbilical vein endothelial cells (HUVECs) antioxidant damage capacity. Drug affinity responsive target stability (DARTS), surface plasmon resonance (SPR), computer simulated docking and western blot showed that heat shock protein beta-1 (HSPB1) is one of the targets of luteolin action. Luteolin inhibits ferroptosis by promoting the protein expression of HSPB1/solute carrier family 7 member 11 (SLC7A11)/ glutathione peroxidase 4 (GPX4). In conclusion, we have preliminarily elucidated the antioxidant damage ferroptosis ability and the target of action of luteolin to provide a theoretical basis for the application of luteolin in radiation injury diseases.

Exploration of the potential mechanism of Yiyi Tongfeng Formula in the treatment of acute gouty arthritis based on network pharmacology and molecular docking: A review.

The global prevalence of gout is on the rise. Yiyi Tongfeng Formula (YTF), a traditional herbal compound, has gained recognition for its efficacy in managing acute gouty arthritis (AGA). Despite its widespread use, the underlying mechanisms of YTF in AGA treatment remain largely undefined. This study employed network pharmacology and molecular docking to elucidate these mechanisms. We utilized the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, SymMap database, and various literature sources to identify active components and corresponding targets of YTF. Relevant AGA-associated targets were identified through the Genecards, Drugbank, Therapeutic Target Database, and Online Mendelian Inheritance in Man databases. A protein-protein interaction network was constructed to delineate interactions between YTF targets and AGA. Key ingredients and central targets were further analyzed using Cytoscape. Functional enrichment analyses, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, were conducted via Metascape. Additionally, molecular docking studies were performed using PyMOL and AutoDock4. It was found that quercetin, kaempferol, and luteolin may be the main active components of YTF for AGA treatment. Gene Ontology enrichment analysis shows that the main biological processes involved are cellular responses to lipids, and inflammatory responses. Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggests the involvement of the IL-17 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, and so on. The findings suggest a multi-faceted therapeutic approach of YTF in treating AGA, involving multiple components, targets, biological processes, and signaling pathways. This comprehensive mechanism offers a foundation for further experimental validation.

High-Throughput Screening of Antioxidant Drug Candidates from Natural Antioxidants with a "Zero" Intrinsic Fluorescence Peroxynitrite Sensing Precursor.

The fluorescence high-throughput screening method is of importance for new antioxidant drug candidate discovery for the treatment of serious hepatorenal syndrome, which displayed an obvious upregulated peroxynitrite level. However, most of the current ONOO- probes possessed incomplete fluorescence quenching efficiency, which can result in non-negligible probe inherent fluorescence. Hence, we utilized the probe conjugated structure disruption strategy to construct hydrogenation phosphorus-substituted rhodamine (H-PRh) with "zero" probe inherent fluorescence character. Based on the precursor, a series of natural products were screened for identifying antioxidant drug candidates. Luteolin was screened out by activating the Sirt1-Nrf2-HO-1 signaling pathway to regulate the accumulation of ONOO- in the hepatorenal syndrome. Overall, the "zero" probe inherent fluorescence ONOO- sensor constructed here applies for a promising and versatile toolbox for illuminating the ONOO--related pathological process in the hepatorenal syndrome. Besides, this strategy of constructing highly sensitive sensors could serve as a valuable reference for further fluorescent probes.

The protective effect of luteolin on cadmium induced liver intestinal toxicity in chicken by Gut-liver axis regulation.

Environmental pollution poses a significant challenge to the poultry industry, leading to substantial losses and adverse effects on the health, production, and performance of avian species. In recent years, there has been growing interest in exploring natural compounds with potential protective effects against cadmium (Cd)-induced toxicity. Luteolin (LUT), a flavonoid found in various plants, has been studied for its antioxidant, anti-inflammatory, and cytoprotective properties. In this study, Su green shell grass chickens were divided into 4 groups: control, LUT (150 mg LUT), Cd (100 mg CdCl2), and Cd + LUT (100 mg CdCl2 + 150 mg LUT) groups for 1 month, respectively. The present study revealed that LUT maintained the morphology and functional activity of the liver and intestine. LUT alleviated Cd-induced impairment in the liver and intestinal biochemical indicators, suppressed Cd-induced liver fibrosis, mitigated liver and intestinal tissue damage. Additionally, LUT reduced oxidative stress and regulated the Cd-induced impairment in trace elements of the liver and intestine. Furthermore, LUT reduced Cd-induced liver inflammation, restored Cd-induced intestinal barrier function, and normalized Cd-induced serum proteins, including changes in the content of glutamyltranspeptidase. Moreover, LUT maintained Cd-induced disruption of gut microbiota and alleviated bacterial dysbiosis. Overall, these findings suggest that LUT holds promise as a potential therapeutic agent for mitigating the adverse effects of Cd-induced toxicity in poultry, by preserving liver and intestinal health, reducing oxidative stress, inflammation, and restoring gut microbiota balance.

Isoorientin alleviates ovalbumin-stimulated allergic rhinitis in mice by restoring Th1/Th2 balance.

Allergic rhinitis (AR) is a chronic, non-infectious inflammatory condition of the nasal mucosa mediated by IgE. There is a need for the development of novel medications to treat this ailment. Isoorientin is a naturally occurring flavonoid that possesses antioxidant, anti--inflammatory, and various other advantageous characteristics. However, its potential effects on AR remain unclear. This study evaluates the therapeutic effects of isoorientin on ovalbumin (OVA)-induced allergic rhinitis (AR) in mice and explores the underlying mechanism. Our study revealed that isoorientin administration effectively decreased the frequency of nose rubbing and sneezing in AR mice. The groups treated with isoorientin showed a significant decrease in serum levels of IgE and histamine, with reductions of 40% and 30%, respectively. Isoorientin ameliorated inflammation of the nasal mucosa and restored the Th1/Th2 balance. In addition, isoorientin inhibited the activation of the NF-κB pathway in nasal tissues. In summary, Isoorientin alleviates OVA-stimulated AR in mice by restoring Th1/Th2 balance and blocking the NF-κB pathway. Thus, isoorientin exhibits promise as a natural therapeutic agent for allergic rhinitis.

Mechanism of luteolin induces ferroptosis in nasopharyngeal carcinoma cells.

Nasopharyngeal carcinoma (NPC) originates from the nasopharynx epithelium, and luteolin is recognized as an important anti-cancer agent. This study investigated the effects of luteolin on ferroptosis in NPC cells. NPC cells were cultured and exposed to varying concentrations of luteolin. Cell viability, malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity, glutathione (GSH) levels, Fe2+ concentration, and glutathione peroxidase 4 (GPX4) protein level were assessed. Additionally, SRY-related high-mobility-group box 4 (SOX4) expression was measured. Subsequently, the binding of SOX4 to the growth differentiation factor-15 (GDF15) promoter and GDF15 mRNA levels were evaluated. The impact of the SOX4/GDF15 axis on luteolin-induced ferroptosis in NPC cells was assayed. Luteolin treatment induced cell ferroptosis, evidenced by decreased cell viability, increased MDA and Fe2+ levels, and reduced SOD, GSH, and GPX4 levels. Furthermore, luteolin downregulated SOX4 expression, while overexpression of SOX4 reversed luteolin's pro-ferroptotic effects in NPC cells. SOX4 was found to up-regulate GDF15 transcription by directly binding to its promoter. Conversely, overexpression of GDF15 mitigated the ferroptotic effects induced by luteolin in NPC cells. Therefore, luteolin induces ferroptosis in NPC cells via modulation of the SOX4/GDF15 axis. In conclusion, luteolin reduces the binding of SOX4 to the GDF15 promoter by suppressing SOX4 expression, thereby down-regulating GDF15 transcription levels and inducing ferroptosis in NPC cells.

Luteolin as potential treatment for Huntington's disease: Insights from a transgenic mouse model.

AIMS: The study aimed to evaluate the potential benefits of luteolin treatment in Huntington's disease (HD), an inherited progressive neurodegenerative disorder. METHODS: HD N171-82Q transgenic and WT mice received luteolin or vehicle for treatment at 6 weeks of age. The mice's body weight changes and survival rates were monitored throughout the study, and a series of motor functional tests were conducted. Serum level of the marker NfL was also determined. Immunohistochemical staining and western blotting were utilized to assess the expression of huntingtin aggregates. RESULTS: Luteolin treatment enhanced survival and prevented weight loss in HD mice compared to the vehicle-treated HD group. Furthermore, the luteolin-treated HD mice exhibited enhanced motor coordination and balance and significantly reduced motor dysfunction. Also, luteolin decreased serum NfL levels in HD mice. Notably, the accumulation of huntingtin aggregates was significantly reduced in the brain's cortex, hippocampus, and striatum of luteolin-treated HD mice compared to the vehicle-treated HD group. CONCLUSION: Luteolin holds promise as a therapeutic agent for improving survival outcomes, managing motor dysfunction, and reducing huntingtin aggregates in HD. The findings are of significance as currently, there are no approved therapeutic interventions that reverse HD pathology or slow down its progression.

Luteolin exerts anti-tumour immunity in hepatocellular carcinoma by accelerating CD8+ T lymphocyte infiltration.

Luteolin, a commonly used traditional Chinese medicine, has been utilized for several decades in the treatment of hepatocellular carcinoma (HCC). Previous research has demonstrated its anti-tumour efficacy, but its underlying mechanism remains unclear. This study aimed to assess the therapeutic effects of luteolin in H22 tumour-bearing mice. luteolin effectively inhibited the growth of solid tumours in a well-established mouse model of HCC. High-throughput sequencing revealed that luteolin treatment could enhance T-cell activation, cell chemotaxis and cytokine production. In addition, luteolin helped sustain a high ratio of CD8+ T lymphocytes in the spleen, peripheral blood and tumour tissues. The effects of luteolin on the phenotypic and functional changes in tumour-infiltrating CD8+ T lymphocytes were also investigated. Luteolin restored the cytotoxicity of tumour-infiltrating CD8+ T lymphocytes in H22 tumour-bearing mice. The CD8+ T lymphocytes exhibited intensified phenotype activation and increased production of granzyme B, IFN-γ and TNF-α in serum. The combined administration of luteolin and the PD-1 inhibitor enhanced the anti-tumour effects in H22 tumour-bearing mice. Luteolin could exert an anti-tumour immune response by inducing CD8+ T lymphocyte infiltration and enhance the anti-tumour effects of the PD-1 inhibitor on H22 tumour-bearing mice.

Three-dimensional cell spheroid culture and cell viability study of uveal melanoma cell line C918 with luteolin treatment.

OBJECTIVE: This study aims to investigate the morphological and histological characteristics of three-dimensional cell spheroids derived from the uveal melanoma (UM) cell line C918 and assess the impact of luteolin on their cell viability. METHODS: C918 cells were cultured in ultra-low adsorption 96-well plates, and morphological changes in C918 three-dimensional cell spheroids were observed over varying time intervals. Histological features of C918 multicellular spheroids cultured in ultra-low adsorption 6-well plates were examined using both HE staining and immunohistochemical staining. The CCK8 reagent was employed to measure the optical density at a 450 nm wavelength after 72-h treatments with varying luteolin concentrations in both two-dimensional and three-dimensional cultured C918 cells. The IC50 values were compared between the two culture conditions. RESULTS: Over time in culture, the volume of C918 three-dimensional cell spheroids gradually increased, and an ischemic- and hypoxic-like region became evident within the spheroids on days 4 to 6 of culture. Histological staining demonstrated positive expression of cell viability marker antibodies (Ki67) and melanoma marker antibodies (MelanA, HMB45, S-100) in the multicellular spheroids from three-dimensional culture. CCK-8 experiments revealed that the IC50 values for luteolin in C918 cells were 183.50 µmol/L in three-dimensional culture and 16.19 µmol/L in two-dimensional culture after 72 h. Three-dimensional cultured C918 cells, treated with varying luteolin concentrations for 72 h, were observed under a microscope. The maximum cross-sectional area showed no statistically significant differences between the groups, but it was reduced in comparison to the control group. CONCLUSION: Three-dimensional cultured C918 cell spheroids exhibit histological characteristics similar to real tumors and are less responsive to luteolin than their two-dimensional counterparts. They offer a valuable model for anti-tumor drug screening.

An in silico molecular docking and simulation study to identify potential anticancer phytochemicals targeting the RAS signaling pathway.

The dysregulation of the rat sarcoma (RAS) signaling pathway, particularly the MAPK/ERK cascade, is a hallmark of many cancers, leading to uncontrolled cellular proliferation and resistance to apoptosis-inducing treatments. Dysregulation of the MAPK/ERK pathway is common in various cancers including pancreatic, lung, and colon cancers, making it a critical target for therapeutic intervention. Natural compounds, especially phytochemicals, offer a promising avenue for developing new anticancer therapies due to their potential to interfere with these signaling pathways. This study investigates the potential of anticancer phytochemicals to inhibit the MAPK/ERK pathway through molecular docking and simulation techniques. A total of 26 phytochemicals were screened from an initial set of 340 phytochemicals which were retrieved from Dr. Duke's database using in silico methods for their binding affinity and stability. Molecular docking was performed to identify key interactions with ERK2, followed by molecular dynamics (MD) simulations to evaluate the stability of these interactions. The study identified several phytochemicals, including luteolin, hispidulin, and isorhamnetin with a binding score of -10.1±0 Kcal/mol, -9.86±0.15 Kcal/mol, -9.76±0.025 Kcal/mol, respectively as promising inhibitors of the ERK2 protein. These compounds demonstrated significant binding affinities and stable interactions with ERK2 in MD simulation studies up to 200ns, particularly at the active site. The radius of gyration analysis confirmed the stability of these phytochemical-protein complexes' compactness, indicating their potential to inhibit ERK activity. The stability and binding affinity of these compounds suggest that they can effectively inhibit ERK2 activity, potentially leading to more effective and less toxic cancer treatments. The findings underscore the therapeutic promise of these phytochemicals, which could serve as a basis for developing new cancer therapies.

In vitro and in vivo evaluation of antibacterial activity and mechanism of luteolin from Humulus scandens against Escherichia coli from chicken.

Resistance of Escherichia coli (E.coli) to antibiotics has steadily increased over time; hence, there is an urgent need to develop safer alternatives to antibiotics. The present study aimed to evaluate the effect of luteolin (Lut) on E. coli from chicken. The bioactive compound Lut from Humulus scandens was selected by network pharmacology and molecular docking analyses. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and confocal laser scanning microscopy (CLSM) were used to observe the effects of Lut on the morphology and structure of E. coli cells. The data-independent acquisition (DIA) method was used to analyze protein expression level of E. coli before and after Lut treatment. The in vivo evaluation of the antibacterial, anti-inflammatory, and oxidative effects of Lut on E.coli was conducted using E.coli isolated strains infected the SPF chicken model. The network pharmacology analysis revealed 19 distinctive bioactive compounds such as Lut and ß-sitosterol in H. scandens; furthermore, 30 core targets were selected from H. scandens. The KEGG enrichment analysis showed that the PI3K-Akt, TNF, MAPK, IL-17, JAK-STAT, and HIF-1 pathways were related from H. scandens. Based on the results of the network pharmacology analysis, Lut was subjected to screening by molecular docking analysis to determine its antibacterial effect on E. coli and the associated mechanism of action. The minimum inhibitory concentration (MIC) of Lut against E. coli standard strains was 500 µg/mL. SEM, TEM, and CLSM results indicated that Lut damaged the cell wall and cell membrane of E. coli strains and destroyed the cell structure, leading to cell death.The expression level of membrane structure, Phenylalanine metabolism and some other metabolic pathways in E.coli changed after treatment with Lut (P < 0.05). In vivo experiments in the SPF chicken model showed that Lut treatment alleviated the decline in the growth performance of chickens (P < 0.05), prevented pathological changes in the correspond ding organs and suppressed the inflammatory response induced by E. coli infection (P < 0.05), improved the immunity and antioxidant capacity of chickens (P < 0.05), and protected them against infection with E. coli strains. To summarize, Lut from H. scandens can inhibit E. coli growth by damaging the cell membrane structureand affecting the expression level of some metabolic proteins. In vivo experiments also showed that Lut can significantly reduce the damage caused by E. coli isolates on SPF chickens, improve their antioxidant capacity and immunity, and reduce inflammatory responses following E. coli infection.

Luteolin Inhibits Indoxyl Sulfate-Induced ICAM-1 and MCP-1 Expression by Inducing HO-1 Expression in EA.hy926 Human Endothelial Cells.

In patients with chronic kidney disease, the uremic toxin indoxyl sulfate (IS) accelerates kidney damage and the progression of cardiovascular disease. IS may contribute to vascular diseases by inducing inflammation in endothelial cells. Luteolin has documented antioxidant and anti-inflammatory properties. This study aimed to investigate the effect of luteolin on IS-mediated reactive oxygen species (ROS) production and intercellular adhesion molecule (ICAM-1) and monocyte chemoattractant protein (MCP-1) expression in EA.hy926 cells and the possible mechanisms involved. IS significantly induced ROS production (by 6.03-fold, p < 0.05), ICAM-1 (by 2.19-fold, p < 0.05) and MCP-1 protein expression (by 2.18-fold, p < 0.05), and HL-60 cell adhesion (by 31%, p < 0.05), whereas, luteolin significantly decreased IS-induced ROS production, ICAM-1 and MCP-1 protein expression, and HL-60 cell adhesion. Moreover, luteolin attenuated IS-induced nuclear accumulation of p65 and c-jun. Luteolin dose-dependently increased heme oxygenase-1 (HO-1) expression and the maximum fold induction of HO-1 by luteolin was 3.68-fold (p < 0.05), whereas, HO-1 knockdown abolished the suppression of ICAM-1 and MCP-1 expression by luteolin. Luteolin may protect against IS-induced vessel damage by inducing HO-1 expression in vascular endothelial cells, which suppresses nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) mediated ICAM-1 and MCP-1 expression.

Progress, pharmacokinetics and future perspectives of luteolin modulating signaling pathways to exert anticancer effects: A review.

Luteolin (3, 4, 5, 7-tetrahydroxyflavone) are natural flavonoids widely found in vegetables, fruits and herbs, with anti-tumor, anti-inflammatory and antioxidant effects, and also play an anti-cancer effect in various cancers such as lung, breast, prostate, and liver cancer, etc. Specifically, the anti-cancer mechanism includes regulation of various signaling pathways to induce apoptosis of tumor cells, inhibition of tumor cell proliferation and metastasis, anti-angiogenesis, regulation of immune function, synergistic anti-cancer drugs and regulation of reactive oxygen species levels of tumor cells. Specific anti-cancer mechanisms include regulation of various signaling pathways to induce apoptosis, inhibition of tumor cell proliferation and metastasis, anti-angiogenesis, reversal of epithelial-mesenchymal transition, regulation of immune function, synergism with anti-cancer drugs and regulation of reactive oxygen species levels in tumor cells. This paper integrates the latest cutting-edge research on luteolin and combines it with the prospect of future clinical applications, aiming to explore the mechanism of luteolin exerting different anticancer effects through the regulation of different signaling pathways, so as to provide a practical theoretical basis for the use of luteolin in clinical treatment and hopefully provide some reference for the future research direction of luteolin.

Network pharmacology and molecular docking analysis predict the mechanisms of Huangbai liniment in treating oral lichen planus.

This study explored the mechanism of Huangbai liniment (HB) for the treatment of oral lichen planus (OLP) through network pharmacology and molecular docking techniques. The study identified HB' active ingredients, therapeutic targets for OLP, and associated signaling pathways. The chemical composition of HB was screened using the HERB database. The disease targets of OLP were obtained through the GeneCards and OMIM databases. A protein-protein interactions network was constructed with the String platform. Topological analysis was performed using Cytoscape software to identify core targets. Gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analysis were performed using the Hiplot database, and the active ingredients and core targets were verified by molecular docking. Date analysis showed that the active composition of HB in the treatment of OLP were quercetin, wogonin, kaempferol, and luteolin. This survey identified 10 potential therapeutic targets, including TNF, CXCL8, IL-6, IL1B, PIK3R1, ESR1, JUN, AKT1, PIK3CA, and CTNNB1. Molecular docking revealed stable interactions between OLP' key targets and HB. These key targets were predominantly involved in the PI3K-Akt signaling pathway, AGE-RAGE signaling pathway, TNF signaling pathway, and HIF-1 signaling pathway. HB plays a crucial role in the treatment of OLP, acting on multiple targets and pathways, particularly the PI3K-Akt signaling pathway. It regulated biological processes like the proliferation of epithelial cells and lymphocytes and mediates the expression of transcription factors, cytokines, and chemokines. Therefore, this study provides a theoretical basis for the clinical trial and application of HB in the therapy of OLP.

Induction of luteolin on postharvest color change and phenylpropanoid metabolism pathway in winter jujube fruit (Ziziphus jujuba Mill. cv. Dongzao).

The postharvest quality of winter jujubes is prone to deterioration, including inevitable pericarp reddening and rapid nutrient loss from the flesh, significantly impacting its edible quality and commercial value. As a crucial metabolic pathway in plants, phenylpropane metabolism not only regulates plant stress resistance but also closely relates to various coloration effects. In this study, we investigated the effects of luteolin solutions on postharvest color changes and phenylpropanoid metabolism in winter jujube. The results indicated that compared to the control group, winter jujube fruit treated with 200 mg L-1 luteolin exhibited improved quality indexes, increased antioxidant capacity (capability of eliminating ABTS and DPPH radicals), and higher activities of antioxidant enzymes(superoxide dismutase (SOD), and catalase (CAT)). This led to a reduction in the oxidation of phenolic substances in winter jujube. Furthermore, luteolin treatment inhibited phenylpropanoid metabolism by suppressing the activities of 4-Coumarate: coenzyme A ligase (4CL), phenylalanine ammonilyase (PAL), and cinnamate 4 hydroxylase (C4H), as well as the expression of ZjUFGT, ZjDFT, and ZjPAL genes. Consequently, anthocyanin and quercetin synthesis were limited while the degradation rate of chlorophyll and carotenoid synthesis were slowed down after luteolin treatment. This resulted in delayed reddening of winter jujube following luteolin treatment. In conclusion, luteolin exhibits potential application prospects as a preservative for inhibiting reddening and browning in winter jujubes.

Combining luteolin and curcumin synergistically suppresses triple-negative breast cancer by regulating IFN and TGF-ß signaling pathways.

Combining two or more chemicals in chemotherapy is rapidly increasing because of its higher efficacy, lower toxicity, lower dosages, and lower drug resistance. Here, we identified a novel combination of luteolin (LUT) and curcumin (CUR), two bioactive compounds from foods, synergistically suppressed triple-negative breast cancer (TNBC) cell proliferation (LUT 30 µM + CUR 20 µM), colony formation (LUT 1 µM + CUR 2 µM), and tumor growth in xenograft mice (LUT 10 mg/kg body weight/day + CUR 20 mg/kg body weight/day, i.p. injection every other day, 5 weeks), while the individual chemical alone did not show these inhibitory effects significantly at the selected concentrations/dosages. Our total RNA transcriptome analysis in xenograft tumors revealed that combining LUT and CUR synergistically activated type I interferon (IFN) signaling and suppressed transforming growth factor-beta (TGF-ß) signaling pathways, which was further confirmed by the expression/activity of several proteins of the pathways in tumors. In addition, this combination of LUT and CUR also synergistically decreased oncoprotein levels of c-Myc and Notch1, the critical molecules required to maintain stem cell properties, tumor clonal evolution, and drug resistance. These results suggest that the combination of LUT and CUR synergistically inhibits TNBC by suppressing multiple cellular mechanisms, such as proliferation, colony formation, and transformation, as well as tumor migration, invasion, and metastasis, via regulating IFN and TGF-ß signaling pathways. Therefore, combining LUT and CUR may be an effective therapeutic agent to treat highly aggressive, drug-resistant TNBC patients after clinical trials.

The role of DPYD and the effects of DPYD suppressor luteolin combined with 5-FU in pancreatic cancer.

BACKGROUND: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5-fluorouracil (5-FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5-FU with Lut in PDACs. METHODS AND RESULTS: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5-FU. The xenograft tumors of DPYD-overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA-seq analysis of the DPYD-overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity-MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5-FU on DPYD-overexpressing xenograft tumors and PDAC of Pdx1-Cre; LSL-KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5-FU nor Lut showed significant inhibitory effects; however, the combined administration of 5-FU and Lut exhibited a significant tumor-suppressive effect in both the xenograft tumors and KPPC models. CONCLUSION: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5-FU resistance, in PDACs. The combination therapy of Lut and 5-FU holds the potential for enhanced efficacy against PDACs.

Elucidation of the anti-colorectal cancer mechanism of Atractylodes lancea by network pharmacology and experimental verification.

Atractylodes lancea which was listed in "Shennong's Materia Medica" and could be used to treat gastrointestinal-associated diseases. However, its roles, core and active ingredients, and mechanisms in treatment of colorectal cancer (CRC) were still unknown. Therefore, network pharmacology and experimental validation were used to clarify the effects, core active ingredients and molecular mechanisms of Atractylodes lancea. We found that Atractylodes lancea has 28 effective active components and 213 potential targets. Seventy-three genes which demonstrate interaction between the Atractylodes lancea and CRC were confirmed. Enrichment analysis showed that 2033 GO biological process items and 144 KEGG pathways. Survival and molecular docking analysis revealed that luteolin as the core component interacted with these genes (Matrix metalloproteinase 3 (MMP3), Matrix metalloproteinase 9 (MMP9), Tissue inhibitor of metalloproteinases 1 (TIMP1), Vascular endothelial growth factor A (VEGFA)) with the lowest binding energy, and these genes were involved in building a prognostic model for CRC. Cellular phenotyping experiments showed that luteolin could inhibit the proliferation and migration of CRC cells and downregulate the expression of MMP3, MMP9, TIMP1, VEGFA probably by Phosphoinositide 3-kinase/ serine/threonine kinase Akt (PI3K/AKT) pathway. To conclude, Atractylodes lancea could inhibit proliferation and migration of CRC cells through its core active ingredient (luteolin) to suppress the expression of MMP3, MMP9, TIMP1, VEGFA probably by PI3K/AKT pathway.

Apoptosis induction and inhibition of invasion and migration in gastric cancer cells by Isoorientin studied using network pharmacology.

BACKGROUND: To investigate the effects of Isoorientin on the apoptosis, proliferation, invasion, and migration of human gastric cancer cells (HGC27 cells). METHODS: We used network pharmacology to predict the targets of drugs and diseases. The CCK-8 assay was used to determine the effects of Isoorientin on the proliferation of HGC27 cells. Flow cytometry was employed to analyze the effects of Isoorientin on cell apoptosis and cell cycle distribution of HGC27 cells. Scratch test and transwell chamber test were conducted to assess the effects of Isoorientin on invasion and migration, respectively. Additionally, qPCR and western blot were performed to examine the impact of Isoorientin on apoptosis-related genes and protein expression, respectively. RESULTS: The Isoorientin significantly inhibited the proliferation, migration, and invasion of HGC27 cells compared to the control group. Furthermore, Isoorientin induced apoptosis in HGC27 cells by upregulating the relative expression of Bax and caspase-3 while downregulating the relative expression of p-PI3K, p-AKT, and Bcl-2 proteins. CONCLUSION: The Isoorientin exhibits inhibitory effects on the proliferation, invasion, and migration of HGC27 cells, and induces apoptosis in gastric cancer cells.

Long-term effects of luteolin in a mouse model of nephropathic cystinosis.

In infantile nephropathic cystinosis, variants of the CTNS gene cause accumulation of cystine in lysosomes, causing progressive damage to most organs. Patients usually present before 1 year of age with signs of renal Fanconi syndrome. Cysteamine therapy allows cystine clearance from lysosomes and delays kidney damage but does not prevent progression to end-stage kidney disease, suggesting that pathways unrelated to cystine accumulation are also involved. Among these, impaired autophagy, altered endolysosomal trafficking, and increased apoptosis have emerged in recent years as potential targets for new therapies. We previously showed that luteolin, a flavonoid compound, improves these abnormal pathways in cystinotic cells and in zebrafish models of the disease. Herein, we have investigated if prolonged luteolin treatment ameliorates kidney damage in a murine model of cystinosis. To this end, we have treated Ctns-/- mice from 2 to 8 months with 150 mg/kg/day of luteolin. No significant side effects were observed. Compared to untreated animals, analyses of kidney cortex samples obtained after sacrifice showed that luteolin decreased p62/SQSTM1 levels (p <0.001), improved the number, size, and distribution of LAMP1-positive structures (p <0.02), and decreased tissue expression of cleaved caspase 3 (p <0.001). However, we did not observe improvements in renal Fanconi syndrome and kidney inflammation. Kidney function remained normal during the time of the study. These results indicate that luteolin has positive effects on the apoptosis and endo-lysosomal defects of cystinotic proximal tubular cells. However, these beneficial effects did not translate into improvement of renal Fanconi syndrome.