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.

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.

Dissecting the antitumor effects of Scutellaria barbata: Initial insights into the metabolism of scutellarin and luteolin by gut microbiota.

The high prevalence of cancer and detrimental side effects associated with many cancer treatments necessitate the search for effective alternative therapies. Natural products are increasingly being recognized and investigated for their potential therapeutic benefits. Scutellaria barbata D. Don (SBD), a plant with potent antitumor properties, has attracted significant interest from oncology researchers. Its primary flavonoid components-scutellarin and luteolin-which have limited oral bioavailability due to poor absorption. This hinders its application for cancer treatment. The gut microbiota, which is considered a metabolic organ, can modulate the biotransformation of compounds, thereby altering their bioavailability and efficacy. In this study, we employed liquid chromatography tandem mass spectrometry (LC-MS/MS 8060) and ion trap-time of flight (LC-MSn-IT-TOF) analysis to investigate the ex vivo metabolism of scutellarin and luteolin by the gut microbiota. Five metabolites and one potential metabolite were identified. We summarized previous studies on their antitumor effects and performed in vitro tumor cell line studies to prove their antitumor activities. The possible key pathway of gut microbiota metabolism in vitro was validated using molecular docking and pure enzyme metabolic experiments. In addition, we explored the antitumor mechanisms of the two components of SBD through network pharmacology, providing a basis for subsequent target identification. These findings expand our understanding of the antitumor mechanisms of SBD. Notably, this study contributes to the existing body of knowledge regarding flavonoid biotransformation by the gut microbiota, highlighting the therapeutic potential of SBD in cancer treatment. Moreover, our results provide a theoretical basis for future in vivo pharmacokinetic studies, aiming to optimize the clinical efficacy of SBD in oncological applications.

Combined Hydroxyethyl Starch Luteolin Nanocrystals for Effective Anti-Hyperuricemia Effect in Mice Model.

Introduction: Although flavonoid compounds exhibit various pharmacological activities, their clinical applications are restricted by low oral bioavailability owing to their poor solubility. Nanocrystals (NCs) represent an excellent strategy for enhancing the oral bioavailability of flavonoids. Hydroxyethyl starch (HES), a biomaterial compound used as a plasma expander, could be an ideal stabilizer material for preparing flavonoid NCs. Methods: HES was used to stabilize flavonoid nanocrystals (NCs), using luteolin (LUT) as a model drug. After full characterization, the freeze-drying and storage stability, solubility, intestinal absorption, pharmacokinetics, and in vivo anti-hyperuricemic effect of the optimized HES-stabilized LUT NCs (LUT-HES NCs) were investigated. Results: Uniformed LUT-HES NCs were prepared with mean particle size of 191.1±16.8 nm, zeta potential of about -23 mV, drug encapsulation efficiency of 98.52 ± 1.01%, and drug loading of 49.26 ± 0.50%. The freeze-dried LUT-HES NCs powder showed good re-dispersibility and storage stability for 9 months. Notably, compared with the coarse drug, LUT-HES NCs exhibited improved saturation solubility (7.49 times), increased drug dissolution rate, enhanced Caco-2 cellular uptake (2.78 times) and oral bioavailability (Fr=355.7%). Pharmacodynamic studies showed that LUT-HES NCs remarkably lowered serum uric acid levels by 69.93% and ameliorated renal damage in hyperuricemic mice. Conclusion: HES is a potential stabilizer for poorly soluble flavonoid NCs and provides a promising strategy for the clinical application of these compounds. LUT-HES NCs may be an alternative or complementary strategy for hyperuricemia treatment.

Luteolin-incorporated fish collagen hydrogel scaffold: An effective drug delivery strategy for wound healing.

In clinical practice, wound care has always been challenging. Hydrogels play a key role in facilitating active wound recovery by absorbing exudates, maintaining moisture, and alleviating pain through cooling. In this study, type I collagen was isolated from the skin of crucian carp (Carassius carassius) and verified by amino acid analysis, FTIR, and SDS-PAGE. By adopting a new approach, luteolin was added to collagen hydrogels in situ after being dissolved in an alkaline solution. XRD and SEM confirmed the luteolin was incorporated and entirely distributed throughout the hydrogel. The plastic compression improved the young's modulus of hydrogel to 15.24 ± 0.59 kPa, which is adequate for wound protection. The drug loading efficiency was 98 ± 1.47 % in the selected formulation. The luteolin-incorporated hydrogel enabled regulated drug release. We assessed the cytotoxicity using MTT and live-dead assays, as well as examined the hemocompatibility to determine the biocompatibility of the hydrogel. In vivo experiments showed that the hydrogel with luteolin had the highest wound closure rate (94.01 ± 2.1 %) and improved wound healing with granular tissue formation, collagen deposition, and re-epithelialization. These findings indicate that this efficient drug delivery technology can accelerate the process of wound healing.

Preparation and evaluation of luteolin-loaded PLA-based shape memory gastroretentive drug delivery systems.

Luteolin, a natural flavonoid, is gaining growing attention for its potential in the treatment of gastric cancer. However, its clinical application is limited by factors such as poor aqueous solubility. This study aimed to develop a novel gastroretentive drug delivery system (GRDDS) to both enhance the oral bioavailability of luteolin and prolong its release and in vivo circulation time. Out of 10 luteolin-loaded PLA-based shape memory films prepared in this study, the LPC-PLA/PEG(7/3) formulation incorporated with PEG, HPMC, and NaHCO3 exhibited optimal properties in terms of drug release and inhibitory activity against SGC-7901 cells. Moreover, small-animal imaging revealed that LPC-PLA/PEG(7/3) exhibited a prolonged gastric retention time of approximately 8 h. Furthermore, the pharmacokinetic studies indicated a 354 % increase in the oral bioavailability of LPC-PLA/PEG(7/3) in rats compared to luteolin. In sum, a novel GRDDS was developed to enhance the relative bioavailability of luteolin, offering a potential strategy for practical oral administration.

A rapid HPLC-MS/MS method for the simultaneous determination of luteolin, resveratrol and their metabolites in rat plasma and its application to pharmacokinetic interaction studies.

Both luteolin (LUT) and resveratrol (RES) are natural polyphenols that exert therapeutic effects on liver injuries. Extensive glucuronidation by uridine diphosphate-glucuronosyltransferases 1As (UGT1As) results in poor bioavailability of LUT, which limits its clinical application. As an inhibitor of UGT1A1 and UGT1A9, RES may affect the bioavailability of LUT. The purpose of this study was to develop and validate an HPLC-MS/MS method for the simultaneous determination of LUT, luteolin-3'-O-glucuronide (LUT-3'-G), RES and resveratrol-3-O-glucuronide (RES-3-G) in rat plasma to investigate the effects of RES on the bioavailability and metabolism of LUT after coadministration. The samples were extracted by protein precipitation with methanol using daidzein and naringenin as the internal standards. Separation was achieved on an XBridgeTM C18 column by isocratic elution using 88% methanol-12% water with 2 mM ammonium acetate and 0.01% formic acid. Multiple reaction monitoring mode with a negative electrospray ionization interface was used for quantification of the analytes. The calibration curves were linear over the concentration ranges of 1-1000 (r > 0.995), 2-2000 (r > 0.999), 5-5000 (r > 0.998) and 10-40000 ng/mL (r > 0.996) for LUT, LUT-3'-G, RES and RES-3-G, respectively. The method was fully validated in terms of accuracy, precision, matrix effect, recovery and stability. The validated data met the acceptance criteria in FDA guidelines. The method was successfully applied in a pharmacokinetic interaction study of LUT and RES. The results indicated that RES had a significant effect on the enhanced bioavailability of LUT by reducing the major glucuronidation metabolite in rats, which provides a reference for the combination of LUT and RES in liver diseases.

Development and evaluation of luteolin loaded pegylated bilosome: optimization, in vitro characterization, and cytotoxicity study.

The present research was aimed to develop luteolin (LL) loaded pegylated bilosomes (PG-BLs) for oral delivery. The luteolin bilosomes (BLs) were prepared by the thin-film hydration method and further optimized by the Box-Behnken design (four-factors at three-levels). The prepared LL-BLs were evaluated for vesicle size (VS), PDI, zeta potential (ZP), and entrapment efficiency to select the optimized formulation. The optimized formulation was further assessed for surface morphology, drug release, gut permeation, antioxidant, and antimicrobial study. The cytotoxicity study was conducted on breast cancer cell lines (MDA-MB-231 and MCF7). The optimized formulation LL-PG-BLs-opt exhibited a VS of 252.24 ± 3.54 nm, PDI of 0.24, ZP of -32 mV with an encapsulation efficiency of 75.05 ± 0.65%. TEM study revealed spherical shape vesicles without aggregation. The DSC and XRD results revealed that LL was encapsulated into a PG-BLs matrix. LL-PG-BLs-opt exhibited a biphasic release pattern as well as significantly high permeation (p<.05) was achieved vis-a-vis LL-BL-opt and LL dispersion. The antioxidant activity result revealed 70.31 ± 3.22%, 83.76 ± 2.56%, and 96.87 ± 2.11% from LL-dispersion, LL-BLs-opt, and LL-PG-BLs-opt, respectively. Furthermore, LL-PG-BLs-opt exhibited high cell viability on both cell lines than LL-BL-opt and pure LL. The IC50 value was found to be 390 µM and 510 µM against MCF7 and MDA-MB-231 cancer cells, respectively. The antimicrobial activity result exhibited LL-PG-BLs-opt had better antibacterial activity than pure LL against Staphylococcus aureus and Escherichia coli. Hence, PG-BLs might provide an efficient nano oral delivery for the management of the different diseases.

Systems pharmacology to reveal multi-scale mechanisms of traditional Chinese medicine for gastric cancer.

Because of the complex etiology, the treatment of gastric cancer is a formidable challenge for contemporary medical. The current treatment method focuses on traditional surgical procedures, supplemented by other treatments. Among these other treatments, Traditional Chinese Medicine (TCM) plays an important role. Here, we used the systems pharmacology approach to reveal the potential molecular mechanism of PRGRC on gastric cancer which composes of Pinellia ternata (Thunb.) Breit., Rheum palmatum L., Gentiana scabra Bunge, Radix Aucklandiae and Citrus aurantium L. This approach combines pharmacokinetics analysis with pharmacodynamics evaluation for the active compounds screening, targets prediction and pathways assessing. Firstly, through pharmacokinetic evaluation and target prediction models, 83 potential compounds and 184 gastric cancer-related targets were screened out. Then, the results of network analysis suggested that the targets of PRGRC were mainly involved two aspects: apoptosis and inflammation. Finally, we verified the reliability of the above analysis at the cellular level by using naringenin and luteolin with good pharmacokinetic activity as representative compounds. Overall, we found that PRGRC could influence the development of gastric cancer from a multi-scale perspective. This study provided a new direction for analyzing the mechanism of TCM.

Paving Luteolin Therapeutic Potentialities and Agro-Food-Pharma Applications: Emphasis on In Vivo Pharmacological Effects and Bioavailability Traits.

Luteolin is a naturally occurring secondary metabolite belonging to the class of flavones. As many other natural flavonoids, it is often found in combination with glycosides in many fruits, vegetables, and plants, contributing to their biological and pharmacological value. Many preclinical studies report that luteolin present excellent antioxidant, anticancer, antimicrobial, neuroprotective, cardioprotective, antiviral, and anti-inflammatory effects, and as a consequence, various clinical trials have been designed to investigate the therapeutic potential of luteolin in humans. However, luteolin has a very limited bioavailability, which consequently affects its biological properties and efficacy. Several drug delivery strategies have been developed to raise its bioavailability, with nanoformulations and lipid carriers, such as liposomes, being the most intensively explored. Pharmacological potential of luteolin in various disorders has also been underlined, but to some of them, the exact mechanism is still poorly understood. Given the great potential of this natural antioxidant in health, this review is aimed at providing an extensive overview on the in vivo pharmacological action of luteolin and at stressing the main features related to its bioavailability, absorption, and metabolism, while essential steps determine its absolute health benefits and safety profiles. In addition, despite the scarcity of studies on luteolin bioavailability, the different drug delivery formulations developed to increase its bioavailability are also listed here.

Folic acid-modified ROS-responsive nanoparticles encapsulating luteolin for targeted breast cancer treatment.

Luteolin (Lut) is a natural flavonoid polyphenolic compound with multiple pharmacological activities, such as anti-oxidant, anti-inflammatory, and anti-tumor effects. However, the poor aqueous solubility and low bioactivity of Lut restrict its clinical translation. Herein, we developed a reactive oxygen species (ROS)-responsive nanoplatforms to improve the bioactivity of Lut. Folic acid (FA) was employed to decorate the nanoparticles (NPs) to enhance its targeting ability. The size of Lut-loaded ROS-responsive nanoparticles (Lut/Oxi-αCD NPs) and FA-modified Lut/Oxi-αCD NPs (Lut/FA-Oxi-αCD NPs) is 210.5 ± 6.1 and 196.7 ± 1.8 nm, respectively. Both Lut/Oxi-αCD NPs and Lut/FA-Oxi-αCD NPs have high drug loading (14.83 ± 3.50 and 16.37 ± 1.47%, respectively). In vitro cellular assays verified that these NPs could be efficiently internalized by 4T1 cells and the released Lut from NPs could inhibit tumor cells proliferation significantly. Animal experiments demonstrated that Lut/Oxi-αCD NPs, especially Lut/FA-Oxi-αCD NPs obviously accumulated at tumor sites, and inhibited tumor growth ∼3 times compared to the Lut group. In conclusion, the antitumor efficacy of Lut was dramatically improved by targeting delivery with the ROS-responsive nanoplatforms.

Luteolin and cancer metastasis suppression: focus on the role of epithelial to mesenchymal transition.

Epithelial to mesenchymal transition (EMT) is a physiological process that assumes a primary role in the induction of cancer metastasis. This results in increased cell renewal, and resistance to cell death and therapies. EMT, therefore, represents an effective strategy for regulating cancerous cell activity. A need for efficacy and low cytotoxicity epithelial to mesenchymal transition modifying drugs has led to the investigational testing of the efficacy of plethora of different groups of phytonutrients. Luteolin is a natural flavonoid inhibits the growth of cancer cells by various mechanisms, such as the stimulation of cancer cell apoptosis, cell cycle arrest, inhibition of cell replication, tumor growth, improvement of drug resistance, prevention of cancer cell intrusiveness and metastasis. This review article focuses on the anti-cancer and anti-metastatic potential of luteolin targeting various transcription factors, markers and signaling pathways associated with the repression of epithelial to mesenchymal transition.

Improving Oral Bioavailability of Luteolin Nanocrystals by Surface Modification of Sodium Dodecyl Sulfate.

Luteolin suffers from drawbacks like low solubility and bioavailability, thus hindering its application in the clinic. In this study, we employed sodium dodecyl sulfate (SDS), an efficient tight junction opening agent, to modify the surface of luteolin nanocrystals, aiming to enhance the bioavailability of luteolin (LUT) and luteolin nanocrystals (LNC). The particle sizes of SDS-modified luteolin nanocrystals (SLNC) were slightly larger than that of LNC, and the zeta potential of LNC and SLNC was -25.0 ± 0.7 mV and -43.5 ± 0.4 mV, respectively. Both LNC and SLNC exhibited enhanced saturation solubility and high stability in the liquid state. In the cellular study, we found that SDS has cytotoxicity on caco-2 cells and could open the tight junction of the caco-2 monolayer, which could lead to an enhanced transport of luteolin across the intestinal membrane. The bioavailability of luteolin was enhanced for 1.90-fold by luteolin nanocrystals, and after modification with SDS, the bioavailability was enhanced to 3.48-fold. Our experiments demonstrated that SDS could efficiently open the tight junction and enhance the bioavailability of luteolin thereafter, revealing the construction of SDS-modified nanocrystals is a good strategy for enhancing the oral bioavailability of poorly soluble drugs like luteolin.

Dietary Luteolin: A Narrative Review Focusing on Its Pharmacokinetic Properties and Effects on Glycolipid Metabolism.

Luteolin, a flavone subclass of flavonoids, is commonly found in food plants and has multiple biological activities. Recently, evidence is growing with regard to the potential of luteolin intake to beneficially affect glycolipid metabolism disorders (GLMDs), particularly insulin resistance, diabetes, and obesity. The aim of this contribution is to provide an overview of recent advances in identifying and understanding the pharmacokinetic properties (absorption, metabolism, and bioavailability) of luteolin, its regulatory effects on glycolipid metabolism, and the underlying mechanisms of action of luteolin in the brain, liver, adipose tissues, and other tissues/organs. Collectively, luteolin or its principal metabolites may contribute to counteracting GLMDs, especially for human obesity and diabetes.

A network pharmacology strategy to investigate the anti-inflammatory mechanism of luteolin combined with in vitro transcriptomics and proteomics.

Luteolin, a natural flavonoid exists in various medicinal plants, has strong anti-inflammatory effect. However, anti-inflammatory mechanism of luteolin has not been fully explored. Hence, we systematically investigated druggability and anti-inflammatory mechanism of luteolin based on network pharmacology and in vitro experiments. The absorption, distribution, metabolism and excretion of luteolin were evaluated by TCMSP server. Targets associated with luteolin and inflammation were collected from public databases, and the overlapping targets between luteolin and inflammation were analyzed by Draw Venn diagram. Then the protein-protein interaction network of luteolin against inflammation was constructed. Further, gene function and pathway enrichment analysis were performed. Finally, in vitro experiments were carried out to estimate the accuracy of predicted target genes. ADME results indicated that luteolin has great potential to be developed into a drug. 226 overlapping targets were screened by matching 280 targets of luteolin with 9015 targets of inflammation. 9 core targets of luteolin against inflammation were identified, including MMP9, MAPK1, HSP90AA1, CASP3, ALB, EGFR, SRC, HRAS and ESR1. Gene function were mainly involved in metabolism, energy pathways and signal transduction. Metabolic pathways, pathways in cancer, PI3K-AKT signaling pathway, Ras signaling pathway and so on might be the critical pathways of luteolin against inflammation. RT-qPCR and ELISA results indicated that luteolin decreased the expression of most of core genes at protein and mRNA levels (MMP9, MAPK1, HSP90AA1, EGFR, SRC and HRAS). Luteolin is expounded to have great potential to be developed into a drug and target various genes and pathways to perform anti-inflammatory effect.

Analysis of five active ingredients of Er-Zhi-Wan, a traditional Chinese medicine water-honeyed pill, using the biopharmaceutics classification system.

Er-Zhi-Wan (EZW) is a traditional Chinese medicine with many clinical applications and used as a health product in East Asia. Five active ingredients (salidroside, specnuezhenide, nuezhenoside, luteolin, and oleanolic acid) were screened out from EZW to develop an in vitro rapid evaluation method for the classification of in vivo drug absorption behavior by biopharmaceutics classification system (BCS). Ultra-performance liquid chromatography was used for quantitative analysis. Solubility and permeability were assayed by equilibrium solubility and multiple models: everted rat intestinal sac model, cultured Caco-2 cells, octanol-water partition coefficient (LogP) method. The BCS properties of drugs were predicted using software applications, and the correlations of measured and predicted values of factors affecting oral drug absorption were calculated. The results were verified by measuring the absolute bioavailability of the active ingredients. Salidroside, specnuezhenide, and nuezhenoside were classified as BCS class III drugs, and luteolin was classified as a BCS class III/I drug because of the difference in LogP and intestinal permeability. Oleanolic acid was classified as a BCS class II/IV drug in acidic media and BCS class I/III drug in other media. Overall, EZW may be classified as a BCS class III drug, and permeability was identified as the primary factor limiting absorption. The results provide a novel method for the evaluation of the in vivo absorption of oral traditional Chinese medicines.

Delivery luteolin with folacin-modified nanoparticle for glioma therapy.

BACKGROUND: Glioblastoma mutliforme is the most common and has the poorest prognosis of any malignant tumor of the central nervous system. Luteolin, the most abundant xanthone extracted from vegetables and medicinal plants, has been shown to have treatment effects in various cancer cell types. Luteolin is however, hydrophobic and has poor biocompatibility, which leads to low bioavailability. PATIENTS AND METHODS: In this study, folic acid modifiedpoly(ethylene glycol)-poly(e-caprolactone) (Fa-PEG-PCL) nano-micelles was used to encapsulate the luteolin, creating luteolin loaded PEG-PCL (Lut/Fa-PEG-PCL) micelles to treat glioma both in vitro and in vivo. RESULTS: When compared with the free luteolin and Lut/MPEG-PCL, Lut/Fa-PEG-PCL induced a significant cell growth inhibition and more apoptosis of GL261 cells both in vitro and in vivo. The safety assessment also showed no obvious side effects were observed in mice which were administrated with free luteolin or Lut/MPEG-PCL and Lut/Fa-PEG-PCL. CONCLUSION: These results suggested Lut/Fa-PEG-PCL may be used as an excellent intravenously injectable formulation for the treatment and chemoprevention.

Novel extraction techniques and pharmaceutical activities of luteolin and its derivatives.

Luteolin is a 3', 4', 5, 7 tetra hydroxyl flavonoid that exits in many plants, fruits, and vegetable. Many methods of extraction, isolation, and purification are being used, and therapeutic properties are being under discussion due to its valuable role in nutrition and human health. In this review, we have summarized conventional and novel extraction techniques from most recent research on luteolin, its derivatives, and its biological activities. Maceration, soxhlet, reflux, hydrodistillation, ultrasound-assisted extraction, microwave-assisted extraction, ultrasound microwave-assisted extraction, enzyme-assisted extraction, supercritical fluid extraction, and high-speed counter-current chromatography extraction techniques are being used for isolation and purification of these phytochemicals. The anti-inflammatory, anti-cancer, antioxidant, antiviral, heart protective, neurological impairments protection, anti-aging, and whiting properties have been discussed in this review. The literature suggests luteolin and its derivative has many promising health benefits and its therapeutic activity is strongly associated with isolating and purifying solvents and extraction techniques. PRACTICAL APPLICATIONS: This review aims to highlight the sources, novel extraction techniques, and pharmaceutical properties of luteolin. This review provides enough knowledge about how to get maximum extraction yield of luteolin using the novel extraction techniques. Because its therapeutic activity is strongly associated with isolating and purifying solvents and techniques.

Bioavailability and Pharmaco-therapeutic Potential of Luteolin in Overcoming Alzheimer's Disease.

Luteolin is a naturally occurring, yellow crystalline flavonoid found in numerous dietary supplements we frequently have in our meals. Studies in the last 2 decades have revealed its therapeutic potential to reduce the Alzheimer's disease (AD) symptoms in various in vitro and in vivo models. The anti-Alzheimer's potential of luteolin is attributed to its ability to suppress Aß as well as tau aggregation or promote their disaggregation, down-regulate the expression of COX-2, NOS, MMP-9, TNF-α, interleukins and chemokines, reduce oxidative stress by scavenging ROS, modulate the activities of transcription factors CREB, cJun, Nrf-1, NF-κB, p38, p53, AP-1 and ß-catenine and inhibiting the activities of various protein kinases. In several systems, luteolin has been described as a potent antioxidant and anti-inflammatory agent. In addition, we have also discussed about the bio-availability of the luteolin in the plasma. After being metabolized luteolin persists in plasma as glucuronides and sulphate-conjugates. Human clinical trials indicated no dose limiting toxicity when administered at a dose of 100 mg/day. Improvements in the formulations and drug delivery systems may further enhance the bioavailability and potency of luteolin. The current review describes in detail the data supporting these studies.

An HPLC-MS/MS method for the simultaneous determination of luteolin and its major metabolites in rat plasma and its application to a pharmacokinetic study.

A selective and accurate HPLC-MS/MS method was established to simultaneously quantify luteolin and its active metabolites (diosmetin, chryseriol, and luteolin-7-O-glucuronide) in rat plasma. The analytes were separated on a C18 column with a mobile phase of water containing 0.5% formic acid and acetonitrile under gradient elution to shorten the total chromatographic run time and increase the resolution of diosmetin and chryseriol. A triple quadruple mass spectrometer coupled with an electrospray ionization source in the negative ion mode was used to detect the analytes. The multiple reaction monitoring transitions were of m/z 284.9→132.9 for luteolin, m/z 298.9→283.9 for diosmetin and chryseriol, m/z 461.1→284.9 for luteolin-7-O-glucuronide, and m/z 300.9→150.9 for the internal standard. The method was linear within the concentration ranges of 0.06-90 µg/mL for luteolin, 0.03-12 µg/mL for diosmetin, 0.015-4.8 µg/mL for chryseriol, and 0.06-60 µg/mL for luteolin-7-O-glucuronide. The intra- and interday precisions were all within 6.0%. Accuracy ranged from -3.2 to 6.4%. The matrix effect and instability were not observed during bioanalysis. This method was used to study the pharmacokinetic characteristics of luteolin and its metabolites in rats after treatment with luteolin.