The apigenin-phospholipid phytosome (APLC) was developed to improve the aqueous solubility, dissolution, in vivo bioavailability, and antioxidant activity of apigenin. The APLC synthesis was guided ...by a full factorial design strategy, incorporating specific formulation and process variables to deliver an optimized product. The design-optimized formulation was assayed for aqueous solubility, in vitro dissolution, pharmacokinetics, and antioxidant activity. The pharmacological evaluation was carried out by assessing its effects on carbon tetrachloride-induced elevation of liver function marker enzymes in a rat model. The antioxidant activity was assessed by studying its effects on the liver antioxidant marker enzymes. The developed model was validated using the design-optimized levels of formulation and process variables. The physical-chemical characterization confirmed the formation of phytosomes. The optimized formulation demonstrated over 36-fold higher aqueous solubility of apigenin, compared to that of pure apigenin. The formulation also exhibited a significantly higher rate and extent of apigenin release in dissolution studies. The pharmacokinetic analysis revealed a significant enhancement in the oral bioavailability of apigenin from the prepared formulation, compared to pure apigenin. The liver function tests indicated that the prepared phytosome showed a significantly improved restoration of all carbon tetrachloride-elevated rat liver function marker enzymes. The prepared formulation also exhibited antioxidant potential by significantly increasing the levels of glutathione, superoxide dismutase, catalase, and decreasing the levels of lipid peroxidase. The study shows that phospholipid-based phytosome is a promising and viable strategy for improving the delivery of apigenin and similar phytoconstituents with low aqueous solubility.
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Neurodegenerative disorders (NDDs) such as Alzheimer’s and Parkinson’s diseases are the most common age-related pathologies that affect millions of people all over the world. To date, ...effective therapy for NDDs is not available and current approaches to disease management include neuroprotection strategy with a hope of maintaining and enhancing the function of survising neurons. Of course, such an approach by its own will not offer a cure but is likely to delay the disease progression by ameliorating the increase of neurotoxic agents such reactive oxygen species (ROS) as well as the associated inflammatory cascades. In this regard, natural products including flavonods that offer neuroprotection through multiple mechanisms have gained a lot of interest in recent years. In this communication, evidences from the various experimental models and clinical trials on the therapeutic potential of one promising flavonod, apigenin, is presented. Its chemistry, mechanism of action and potential benefits in the various examples of NDDs are discussed in the light of drug discovery aspects.
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•Nanoparticles exhibited suitable physicochemical parameters and sustained release.•Nanoparticles were internalized inside ocular cells.•Nanoparticles decreased ocular inflammation in ...vivo.•Nanoparticles were able to revert dry eye symptoms and ameliorate corneal lesions.
Dry eye disease (DED) is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction and constitutes one of the most common ocular conditions worldwide. However, its treatment remains unsatisfactory. While artificial tears are commonly used to moisturize the ocular surface, they do not address the underlying causes of DED. Apigenin (APG) is a natural product with anti-inflammatory properties, but its low solubility and bioavailability limit its efficacy. Therefore, a novel formulation of APG loaded into biodegradable and biocompatible nanoparticles (APG-NLC) was developed to overcome the restricted APG stability, improve its therapeutic efficacy, and prolong its retention time on the ocular surface by extending its release. APG-NLC optimization, characterization, biopharmaceutical properties and therapeutic efficacy were evaluated. The optimized APG-NLC exhibited an average particle size below 200 nm, a positive surface charge, and an encapsulation efficiency over 99 %. APG-NLC exhibited sustained release of APG, and stability studies demonstrated that the formulation retained its integrity for over 25 months. In vitro and in vivo ocular tolerance studies indicated that APG-NLC did not cause any irritation, rendering them suitable for ocular topical administration. Furthermore, APG-NLC showed non-toxicity in an epithelial corneal cell line and exhibited fast cell internalization. Therapeutic benefits were demonstrated using an in vivo model of DED, where APG-NLC effectively reversed DED by reducing ocular surface cellular damage and increasing tear volume. Anti-inflammatory assays in vivo also showcased its potential to treat and prevent ocular inflammation, particularly relevant in DED patients. Hence, APG-NLC represent a promising system for the treatment and prevention of DED and its associated inflammation.
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Protein glycation in the body can lead to malfunction of intracellular and extracellular proteins. Reactive carbonyl species (RCS) have been identified to be key intermediates in the ...reactions. The reaction products, generally termed as advanced glycation end products (AGEs), have been implicated in the development of diabetic complications. In this study, the activity of apigenin (API), a natural flavone in scavenging RCS and the molecular mechanism involved in its protective effect against AGEs-induced oxidative stress and inflammation were examined in vitro. Results showed that API could directly trap methylglyoxal (MGO) to form API-MGO adducts, thus inhibiting AGEs formation. API and di-apigenin adduct (DMA) were found to inhibit AGEs-induced oxidative stress and inflammation in human umbilical vein endothelial cells (HUVECs) by significantly suppressing reactive oxygen species (ROS) production (30% relative to control) and decreasing the protein expression of pro-inflammatory cytokines and adhesion molecules by 30–70%. Further mechanistic investigation revealed that the protective effect was likely mediated via suppression of the extracellular-signal-regulated kinase 1/2 (ERK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway initiated by AGEs-RAGE (receptor for AGEs) interaction and induction of ERK/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway with subsequent up-regulation of antioxidant defense molecules. In summary, our results suggest that API possesses great potential to protect against AGEs-associated health disorders by modulating cellular inflammatory and antioxidant defense signaling pathways.
Here we reported novel apigenin-rivastigmine hybrids were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, their activity in vitro results revealed that ...compound 3d showed significant antioxidant potency (ORAC = 1.3 eq), and it was a reversible huAChE (IC50 = 6.8 μM) and huBChE (IC50 = 16.1 μM) inhibitor. 3d also served as a selective metal chelator, and it significantly inhibited and disaggregated self-mediated and Cu2+-mediated Aβ1-42 aggregation, and also inhibited hAChE-mediated induced Aβ1-40 aggregation. Compound 3d exhibited remarkable neuroprotective effect and hepatoprotective activity. In addition, compound 3d presented favourable blood-brain barrier penetration in vitro and drug-like property. Further, the in vivo assay displayed that 3d indicated remarkable dyskinesia recovery rate and response efficiency on AD zebrafish, and exhibited surprising protective effect on Aβ1-40-mediated zebrafish vascular injury. More importantly, 3d did not indicate obvious acute toxicity at dose up to 2000 mg/kg, and could improve scopolamine-induced memory impairment. Subsequently, the regulation of multi-targets for 3d were further confirmed through transcriptome sequencing of brain hippocampi, which also offered novel potential targets and opened a new way to treat Alzheimer’s disease. More interestingly, the metabolism of 3din vitro indicated that 4 metabolites in rat liver microsome metabolism, 2 metabolites in human liver microsome metabolism, and 4 metabolites in intestinal flora metabolism, which offered supports for the preclinical study of 3d. Overall, this study exhibited that compound 3d was a promising advanced compound targeted multiple factors associated with AD.
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•Novel apigenin-rivastigmine hybrids was rationally designed.•3d was a promising multi-function agent.•3d could improve AlCl3-induced zebrafish AD.•3d could protect Aβ1-40-mediated zebrafish vascular injury.•3d could improve scopolamine-induced memory impairment.
Eclipta alba (Bhringraj) in ayurveda has been widely used as a traditional medicine for its multi-therapeutic properties for ages. Luteolin (LTL), wedelolactone (WDL) and apigenin (APG) are the three ...main bioactive phytochemicals present in Eclipta alba extract. However there was a lack of sensitive bioanalytical method for the pharmacokinetics of these free compounds in plasma which majorly contributes for their activities after oral administration of Eclipta alba. The present study aims to develop a sensitive, rapid and reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous estimation of mice plasma concentrations of LTL, WDL and APG using quercetin as an internal standard for the pharmacokinetic analysis. Analytes were separated on Phenomenex Luna C18 (150 × 4.6 mm, 3.0 μm) column with mobile phase containing methanol: acetonitrile (90: 10, v/v) and 0.1% formic acid in 10 mM ammonium formate buffer in the ratio of 70: 30 (v/v) in isocratic mode. Liquid-liquid extraction was optimized using Hansen solubility parameters and diethyl ether finalized as an extraction solvent for the recovery ranging from 61 to 76% for all analytes in mice plasma. The validated method has an accuracy and precision over the linearity range of 0.1–200 ng/mL with a correlation coefficient (r2) of ≥0.997. The intra and inter-day assay accuracy was between 98.17 and 107% and 95.83–107.89% respectively and the intra and inter day assay precision ranged from 0.37–6.05% and 1.85–10.76%, respectively for all the analytes. This validated method can be used for future clinical investigation studies of Eclipta alba extracts.
•Bio-analytical method validation of WDL is reported for the first time.•First time, PK of Eclipta alba extract having LTL, APG & WDL are reported.•Quantification of LTL, APG & WDL in mice plasma was done using sensitive LC-MS/MS method.•Simple LLE was optimized for simultaneous analytes recovery from the mice plasma.•Diethyl ether was optimized for LLE using Hansen solubility parameters (HSP)
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Lipid metabolic disorders and oxidative stress in the liver are key steps in the progression of nonalcoholic fatty liver disease (NAFLD), which is a major risk factor for the ...development of metabolic syndrome. To date, no pharmacological treatment for this condition has been approved. Our previous study has found that the food-derived compound apigenin (Api) significantly attenuates obesity-induced metabolic syndrome by acting as a peroxisome proliferator-activated receptor gamma modulator (PPARM). Herein, a high fat diet (HFD) induced NAFLD model was used to dig out whether Api had the effect on NAFLD. The results showed that Api had obvious effect in restraining NAFLD progression, including attenuating HFD induced lipid accumulation and oxidative stress in vivo. As a PPARM, although Api did significantly inhibit the expression of PPARγ target genes encoding the protein associated with lipid metabolism, it had no obvious activating effect on PPARγ. Interestingly, we found that Api promoted Nrf2 into the nucleus, thereby markedly activating Nrf2 to inhibit the lipid metabolism related genes and increase the oxidative stress related genes. Further Nrf2 knockdown/knockout and overexpression experiments showed that Api regulating PPARγ target genes was dependent on Nrf2 activation and the activation of Nrf2 counteracted the activation effect of PPARγ by Api. Importantly, we also found that Api might bind with Nrf2 via auto dock and ITC assay. Therefore, our results indicate that Api ameliorates NAFLD by a novel regulating mode of Nrf2 and PPARγ in inhibiting lipid metabolism and oxidative stress abnormity.
Glucosylation is a well-known approach to improve the solubility, pharmacological, and biological properties of flavonoids, making flavonoid glucosides a target for large-scale biosynthesis. However, ...the low yield of products coupled with the requirement of expensive UDP-sugars limits the application of enzymatic systems for large-scale. C. glutamicum is a Gram-positive and generally regarded as safe (GRAS) bacteria frequently employed for the large-scale production of amino acids and biofuels. Due to the versatility of its cell factory system and its non-endotoxin producing properties, it has become an attractive system for the industrial-scale biosynthesis of alternate products. Here, we explored the cell factory of C. glutamicum for efficient glucosylation of flavonoids using apigenin as a model flavonoid, with the heterologous expression of a promiscuous glycosyltransferase, YdhE from Bacillus licheniformis and the endogenous overexpression of C. glutamicum genes galU1 encoding UDP-glucose pyrophosphorylase and pgm encoding phosphoglucomutase involved in the synthesis of UDP-glucose to create a C. glutamicum cell factory system capable of efficiently glucosylation apigenin with a high yield of glucosides production. Consequently, the production of various apigenin glucosides was controlled under different temperatures yielding almost 4.2 mM of APG1(apigenin-4β-O-β-glucoside) at 25℃, and 0.6 mM of APG2 (apigenin-7-O-β-glucoside), 1.7 mM of APG3 (apigenin-4β,7-O-β-diglucoside) and 2.1 mM of APG4 (apigenin- 4β,5-O-β-diglucoside) after 40 h of incubation with the supplementation of 5 mM of apigenin and 37℃. The cost-effective developed system could be used to modify a wide range of plant secondary metabolites with increased pharmacokinetic activities on a large scale without the use of expensive UDP-sugars.
The aim of the study was to investigate the potential of nanocrystals to enhance the oral bioavailability of apigenin (AP), a bioactive flavonoid with various pharmacological activities but poor ...aqueous solubility. In the present investigation, the AP nanocrystals were prepared by the supercritical antisolvent process. In vitro characterization was performed by scanning electron microscopy, FT-IR, differential scanning calorimetry, X-ray powder diffractometry. In vitro dissolution of prepared nanocrystals was studied and compared with untreated coarse powder. In addition, the pharmacokinetic study of AP nanocrystals, in comparison to coarse powder, was also performed in rats after a single oral dose. The prepared AP nanocrystals, without change in crystalline structure, appeared in spherical shape with particle size of about 400–800nm. The reduction of particle size resulted in a more rapid dissolution of AP from nanocrystals than from coarse powder. In comparison to coarse powder, AP nanocrystals exhibited a significantly decreased tmax, a 3.6-fold higher peak plasma concentration (Cmax) and 3.4-fold higher area under the curve (AUC).
Diabetes is one of the important and growing diseases in the world. Among the most common diabetic complications are renal adverse effects. The use of apigenin may prevent the development and ...progression of diabetes-related injuries. The current study aims to review the effects of apigenin in the treatment of diabetic nephropathy.
In this review, a systematic search was performed based on PRISMA guidelines for obtaining all relevant studies on "the effects of apigenin against diabetic nephropathy" in various electronic databases up to September 2022. Ninety-one articles were obtained and screened in accordance with the predefined inclusion and exclusion criteria. Seven eligible articles were finally included in this review.
The experimental findings revealed that hyperglycemia led to the decreased cell viability of kidney cells and body weight loss and an increased kidney weight of rats; however, apigenin administration had a reverse effect on these evaluated parameters. It was also found that hyperglycemia could induce alterations in the biochemical and renal function-related parameters as well as histopathological injuries in kidney cells or tissue; in contrast, the apigenin administration could ameliorate the hyperglycemia-induced renal adverse effects.
The results indicated that the use of apigenin could mitigate diabetes-induced renal adverse effects, mainly through its antioxidant, anti-apoptotic, and anti-inflammatory activities. Since the findings of this study are based on experimental studies, suggesting the use of apigenin (as a nephroprotective agent) against diabetic nephropathy requires further clinical studies.
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