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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.

The co-administration of luteolin (LUT) and atorvastatin (ATV) may drive synergetic effects on against atherosclerotic cardiovascular disease (ASCVD). This study aims to explore the pharmacokinetic (PK) drug-drug interactions (DDIs) of LUT toward ATV and the influencing mechanisms involving CYP450s and OATPs, and using the physiologically based pharmacokinetic (PBPK) models extrapolated to humans to optimize the DDIs dosage regimens for subsequent research. Luteolin nanosuspensions lyophilized powder (LUT-NS-LP) were prepared for improving LUT's solubility and bioavailability, the effects of both LUT on the ATV CYP450s enzyme kinetics and LUT-NS-LP/LUT on the PK behavior of ATV in rats were further studied by UPLC. The DDI PBPK model of ATV and LUT-NS-LP was established with the hepatic CYP450s, OATPs, and enterohepatic circulation, and extrapolated to humans through a physiological allometric scaling process with parameter optimization and verified using clinical datasets obtained from various dosage regimens. LUT inhibited ATV as the non-competitive form in rat liver microsomes (RLMs). The and AUC of ATV in the group receiving combined administration of LUT and LUT-NS-LP increased by 1.87-fold and 2.29-fold, 5.42-fold and 10.35-fold, respectively. The constructed PBPK models successfully predicted the PK DDIs between ATV and LUT in rats, demonstrating excellent performance. LUT might inhibit the hepatic CYP450s and OATPs activities to influence the PK behavior of ATV. The extrapolated human model could adequately describe and predict the systemic exposure of ATV in DDIs. LUT nanosuspensions could significantly increase systemic exposure to ATV by inhibiting CYP450s and OATPs activities. The combined application strategy is suggested to run ATV in half of the highest dosage by guidelines. This study offers a valuable experimental foundation for the combined administration of statins with natural drugs and their nanoformulations, providing significant insights into the investigation of underlying mechanisms and potential clinical applications.

The early, precise, and safe management of vulnerable atherosclerotic plaques (VAPs) remains a formidable clinical challenge. Here, we present a targeted nanotherapeutic approach in which osteopontin-targeted nanoparticles encapsulate luteolin (NPs-Lut) for the precise delivery and treatment of VAPs. This engineered system enables site-specific accumulation and sustained release of luteolin at plaque sites. We innovatively constructed an osteopontin-targeted drug delivery system designed for vulnerable atherosclerotic plaques, in which luteolin and atorvastatin were successfully encapsulated. The system demonstrated sustained-release capability in vitro, and its biosafety and histocompatibility were comprehensively evaluated both in vitro and in vivo. Moreover, therapeutic efficacy was further assessed in ApoE mice, confirming its potential for treating atherosclerotic lesions. In vivo evaluation in ApoE mice demonstrated that NPs-Lut markedly outperformed atorvastatin-loaded nanoparticles (NPs-AST) in attenuating plaque-associated inflammation, alleviating endoplasmic reticulum stress and foam cell apoptosis, and enhancing plaque stability. Histological analysis revealed a significant reduction in plaque and necrotic core area, accompanied by increased fibrous cap thickness and collagen deposition. By improving the aqueous solubility and bioavailability of luteolin, NPs-Lut achieved potent therapeutic efficacy at low doses while minimizing systemic toxicity. This work provides a robust and translationally promising nanoplatform for the precision treatment of VAPs, offering a novel strategy for safe and effective intervention in atherosclerotic cardiovascular disease.

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. 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. 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. 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.

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.

Traumatic brain injury (TBI) occurs in response to an acute insult to the head and is recognized as a major risk factor for Alzheimer’s disease (AD). Indeed, recent studies have suggested a pathological overlap between TBI and AD, with both conditions exhibiting amyloid-beta (Aβ) deposits, tauopathy, and neuroinflammation. Additional studies involving animal models of AD indicate that some AD-related genotypic determinants may be critical factors enhancing temporal and phenotypic symptoms of TBI. Thus in the present study, we examined sub-acute effects of moderate TBI delivered by a gas-driven shock tube device in Aβ depositing Tg2576 mice. Three days later, significant increases in b-amyloid deposition, glycogen synthase-3 (GSK-3) activation, phospho-tau, and pro-inflammatory cytokines were observed. Importantly, peripheral treatment with the naturally occurring flavonoid, luteolin, significantly abolished these accelerated pathologies. This study lays the groundwork for a safe and natural compound that could prevent or treat TBI with minimal or no deleterious side effects in combat personnel and others at risk or who have experienced TBI.

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 P app 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. Graphical Abstract

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. 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. 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. These results suggested Lut/Fa-PEG-PCL may be used as an excellent intravenously injectable formulation for the treatment and chemoprevention.

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 is a falconoid compound that is present in various types of plants and possesses remarkable potential as a chemopreventive agent. However, the poor aqueous solubility of luteolin limits its clinical application. In the present study, an approach towards chemoprevention was explored using liposomes to deliver luteolin, and the antitumor efficacy was investigated in colorectal carcinoma. The present findings demonstrated that luteolin was efficiently encapsulated into liposomes with an encapsulation efficiency as high as 90%. The particle size of the liposomal luteolin (Lipo‑Lut) and ζ‑potential were optimized. In vitro studies demonstrated that, Lipo‑Lut had a significant inhibitory effect on the growth on the CT26 colorectal carcinoma cell line compared with free luteolin (Free‑Lut). The in vivo study indicated that Lipo‑Lut could achieve superior antitumor effects against CT26 tumor compared with luteolin alone. The present results suggested that liposome delivery of luteolin improved solubility, bioavailability and may have potential applications in chemoprevention in clinical settings.