Post-modification of covalent organic framework functionalized aminated carbon nanotubes with active site (Fe) for the sensitive detection of luteolin.

In this research, the TT-COF(Fe)@NH2-CNTs was innovatively prepared through a post-modification synthetic process functionalized TT-COF@NH2-CNTs with active site (Fe), where TT-COF@NH2-CNTs was prepared via a one-pot strategy using 5,10,15,20-tetrakis (para-aminophenyl) porphyrin (TTAP), 2,3,6,7-tetra (4-formylphenyl) tetrathiafulvalene (TTF) and aminated carbon nanotubes (NH2-CNTs) as raw materials. The complex TT-COF(Fe)@NH2-CNTs material possessed porous structures, outstanding conductivity and rich catalytic sites. Thus, it can be adopted to construct electrochemical sensor with glassy carbon electrode (GCE). The TT-COF(Fe)@NH2-CNTs/GCE can selectively detect luteolin (Lu) with a wide linear plot ranging from 0.005 to 3 µM and a low limit of detection (LOD) of 1.45 nM (S/N = 3). The Lu residues in carrot samples were determined using TT-COF(Fe)@NH2-CNTs sensor and UV-visible (UV-Vis) approach. This TT-COF(Fe)@NH2-CNTs/GCE sensor paves the way for the quantification of Lu through a cost-efficient and sensitive electrochemical approach, which can make a significant step in the sensing field based on crystalline COFs.

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.

Fabrication of Luteolin Nanoemulsion by Box-Behnken Design to Enhance its Oral Absorption Via Lymphatic Transport.

Intestinal lymphatic transport offers an alternative and effective way to deliver drugs, such as avoiding first-pass metabolism, enhancing oral bioavailability, and facilitating the treatment of targeted lymphoid-related diseases. However, the clinical use of luteolin (LUT) is limited by its poor water solubility and low bioavailability, and enhancing lymphatic transport by nanoemulsion may be an efficient way to enhance its oral bioavailability. The objective of this work is to prepare the luteolin nanoemulsions (LUT NEs), optimized its preparation parameters by using Box-Behnken design optimization (BBD) and evaluated it in vitro and in vivo. An Caco-2 / Raji B cell co-incubation monolayer model was established to simulate the M-cell pathway, and the differences in the transmembrane transport of LUT and NEs were compared. Cycloheximide (CHX) was utilized to establish rat chylomicron (CM) blocking model, and for investigating the influence of pharmacokinetic parameters in rats thereafter. The results showed that LUT NEs have good stability, the particle sizes were about 23.87 ± 0.57 nm. Compared with LUT suspension, The Papp of LUT NEs was enhanced for 3.5-folds, the oral bioavailability was increased by about 2.97-folds. In addition, after binding with chylomicron, the oral bioavailability of LUT NEs was decreased for about 30% (AUC 0-∞ (µg/L*h): 5.356 ± 1.144 vs 3.753 ± 0.188). These results demonstrated that NEs could enhance the oral absorption of luteolin via lymphatic transport routes.

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.

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.

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.

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.

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.

Luteolin-loaded Invasomes Gel for Transdermal Delivery: Development, Optimization, in-vitro, and Preclinical Evaluation.

Luteolin (LN), is an herbal bioactive flavone and exhibits many pharmacological activities. However, the bioavailability of LN is limited due to its inadequate solubility and significant first-pass metabolism. The present study developed transdermal LN-loaded invasomes (IVM) gel to improve the therapeutic efficacy. The LN-IVM was prepared and optimized by 2 3 factorial designs. LN-IVM was characterized for physicochemical parameters. The optimized LN-IVM (LN-IVMopt) was incorporated into HPMC-K4M gel and evaluated for viscosity, spreadability, and irritation. Further LN-IVM gel was evaluated for drug release, ex-vivo permeation, pharmacokinetic and pharmacodynamics study. LN-IVMopt showed 300.8±2.67 nm of VS, 0.258 of PDI, 89.92±1.29% of EE, and a zeta potential of -18.2 mV. LN-IVM exhibited spherical morphology. FTIR and XRD results demonstrated that LN was encapsulated into IVM matrix. The optimized IVM gel (LN-IVMoptG2) exhibited excellent viscosity, spreadability, and sustained release of LN (91.32±2.95% in 24 h). LN-IVMoptG2 exhibited statistically significant (p < 0.05) higher flux (5.79 µg/h/cm2 ) than LN-gel (2.09 µg/h/cm2 ). The apparent permeability coefficient of plain LN gel and LN- IVMoptG was 1.15×10-5 cm/min and 3.22×10-5 cm/min respectively. LN-IVMoptG2 showed no irritation (score 0.0) throughout the study (60 min). The relative bioavailability of LN from LN-IVMopt-G2 (transdermal) was 2.38±0.19 fold as compared to LN-Sus (oral) and 1.81±0.15-fold than plain LN-gel (transdermal). The LN-IVMoptG2 showed a substantial lessening in the paw volume up to 12 h (17.48±1.94% swelling) than plain LN-gel (44.77±2.82% swelling). The finding concluded that the IVM gel is a novel, effective, and safe approach for the delivery of LN transdermally to improve its therapeutic efficacy.

Cloning and Direct Evolution of a Novel 7-O-Glycosyltransferase from Cucurbita moschata and Its Application in the Efficient Biocatalytic Synthesis of Luteolin-7-O-glucoside.

Luteolin-7-O-glucoside(L7G), a glycosylation product of luteolin, is present in a variety of foods, vegetables, and medicinal herbs and is commonly used in dietary supplements due to its health benefits. Meanwhile, luteolin-7-O-glucoside is an indicator component for the quality control of honeysuckle in the pharmacopoeia. However, its low content in plants has hindered its use in animal pharmacological studies and clinical practice. In this study, a novel 7-O-glycosyltransferase CmGT from Cucurbita moschata was cloned, which could efficiently convert luteolin into luteolin-7-O-glucoside under optimal conditions (40 °C and pH 8.5). To further improve the catalytic efficiency of CmGT, a 3D structure of CmGT was constructed, and directed evolution was performed. The mutant CmGT-S16A-T80W was obtained by using alanine scanning and iterative saturation mutagenesis. This mutant exhibited a kcat/Km value of 772 s-1·M-1, which was 3.16-fold of the wild-type enzyme CmGT. Finally, by introducing a soluble tag and UDPG synthesis pathway, the strain BXC was able to convert 1.25 g/L of luteolin into 1.91 g/L of luteolin-7-O-glucoside under optimal conditions, achieving a molar conversion rate of 96% and a space-time yield of 27.08 mg/L/h. This study provides an efficient method for the biosynthesis of luteolin-7-O-glucoside, which holds broad application prospects in the food and pharmaceutical industry.

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.

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.

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.

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.

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.

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.

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.

Luteolin promotes neuronogenesis in hippocampus of chronic unpredictable mild stress rats and primary hippocampus of fetal rats.

OBJECTIVE: To investigate the effects of luteolin on chronic unpredictable mild stress (CUMS)-induced depressive rats and corticosterone (CORT)-induced depressive primary hippocampal neurons, and to elucidate the mechanism behind the action. METHODS: The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats. In vivo, novelty suppressed feeding, open-field and sucrose preference tests as well as Morris water maze were evaluated. The content of brain derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in serum were detected by enzyme-linked immunosorbent assay. The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis, and proliferation. Survival of the septo-temporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine (BrdU), the expression of BDNF, neurotrophin-3 (NT-3), and nerve growth factor (NGF) in hippocampus dentate gyrus region were measured by Western-blotting. In vitro, BDNF, NT-3, tropomyosin receptor kinase B (TrkB), and phosphorylated cyclic adenosine monophosphate responsive element binding protein (p-CREB) were detected through the high content analysis (HCA) to investigate neurotrophin and apoptosis. RESULTS: Induction of CUMS in rats induced depressive symptoms, while luteolin significantly enhanced sucrose consumption, decreased feeding latency, increased locomotor activity, escape latency, distance of target quadrant and regulated the content of depressive-like biomarkers. Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU, BrdU + neuronal nuclear antigen, and BrdU + doublecortin in septo-temporal axis of S2 (mid-septal) and T3 (mid-temporal). Moreover, expression of BDNF, NT-3, and NGF increased significantly in the septo-temporal axis of S2 and T3. HCA showed increased expression of BDNF, NT-3, TrkB and p-CREB in primary hippocampal neurons. CONCLUSION: The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition, which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.