Liposomal Resveratrol Research Articles

Cardioprotective effects of liposomal resveratrol in diabetic rats: unveiling antioxidant and anti-inflammatory benefits

ABSTRACT As a consequence of chronic hyperglycemia, diabetes complications and tissue damage are exacerbated. There is evidence that natural phytochemicals, including resveratrol, a bioactive polyphenol, may be able to reduce oxidative stress and improve insulin sensitivity. However, resveratrol's limited bioavailability hampers its therapeutic effectiveness. By using liposomes, resveratrol may be better delivered into the body and be more bioavailable. The objective of this study was to assess the cardioprotective potential of liposome-encapsulated resveratrol (LR) in a streptozotocin-induced (STZ) diabetic rat model. Adult male Wistar rats were categorized into five groups: control, diabetic, resveratrol-treated (40 mg/kg), liposomal resveratrol (LR)-treated (20 mg/kg) and liposomal resveratrol (LR)-treated (40 mg/kg) for a five-week study period. We compared the effects of LR to those of resveratrol (40 mg/kg) on various parameters, including serum levels of cardiac markers, tissue levels of pro-inflammatory cytokines, nuclear transcription factor, oxidative stress markers, and apoptotic markers. LR treatment in STZ-diabetic rats resulted in notable physiological improvements, including blood glucose regulation, inflammation reduction, oxidative stress mitigation, and apoptosis inhibition. LR effectively lowered oxidative stress and enhanced cardiovascular function. It also demonstrated a remarkable ability to suppress NF-kB-mediated inflammation by inhibiting the pro-inflammatory cytokines TNF-α and IL-6. Additionally, LR restored the antioxidant enzymes, catalase and glutathione peroxidase, thereby effectively counteracting oxidative stress. Notably, LR modulated apoptotic regulators, including caspase, Bcl2, and Bax, suggesting a role in regulating programmed cell death. These biochemical alterations were consistent with improved structural integrity of cardiac tissue as revealed by histological examination. In comparison, resveratrol exhibited lower efficacy at an equivalent dosage. Liposomal resveratrol shows promise in alleviating hyperglycemia-induced cardiac damage in diabetes. Further research is warranted to explore its potential as a therapeutic agent for diabetic cardiovascular complications and possible cardioprotective effects.

Implication of MAPK, Lipocalin-2, and Fas in the protective action of liposomal resveratrol against isoproterenol-induced kidney injury

Background and ObjectiveIsoproterenol (ISO) is a non-selective β-adrenergic receptor agonist. It can be used to treat bradycardia and cardiogenic shock. Despite its usefulness, the overstimulation of β-receptors by ISO can cause “cardiorenal syndrome,” a term used to describe heart and kidney damage. Resveratrol (RES), a natural polyphenol, has marked anti-inflammatory and antioxidant activities. The present work was designed to study the protective efficacy of liposomal resveratrol (L-RES) against ISO-induced kidney injury. Materials and MethodsThe kidney injury was induced in rats by administering ISO (50 mg/kg, s.c.) twice a week for 2 weeks. RES and L-RES were administered at a dose (20 mg/kg/ day, p.o.) along with ISO for 2 weeks. Inflammatory and apoptotic biomarkers were analyzed, which were validated using histochemical analysis. ResultsISO caused renal dysfunction, which manifested as elevated urea, creatinine and uric acid, besides cystatin c and MAPK protein overexpression. In addition, ISO induced gene expression of Fas and lipocalin-2 and provoked genomic DNA fragmentation in renal tissues as compared with the control group. Histological examination confirmed morphological alterations of the kidney tissues obtained from the ISO group. Concurrent treatment of either RES or L-RES with ISO significantly ameliorated kidney damage as demonstrated by the improvement of all measured parameters with the best results for L-RES. The histopathological findings were correlated with the above biochemical parameters. ConclusionL-RES could be a promising approach for the prevention of kidney injury induced by ISO, most likely via the downregulation of MAPK, cystatin c, Fas, and lipocalin-2.

The beneficial efficacy of liposomal resveratrol against doxorubicin-induced hepatotoxicity in rats: Role of TGF-β1 and SIRT1

ObjectivesDoxorubicin (DOXR) belongs to the antineoplastic anthracycline antibiotic and despite its prevalent use for various types of cancer, it is associated with side effects that occur even after treatment cessation, particularly on the heart, blood, liver and kidney. This study aimed to study the efficiency of carvedilol (CAR), resveratrol (RES) or liposomal RES (LIPO-RES) and their combination to treat DOXR-induced hepatotoxicity and to investigate other driving mechanisms that are involved. MethodsRats were injected twice weekly with DOXR for five weeks to induce liver injury. A week before DOXR injection commenced, rats were pretreated singly or simultaneously with CAR, RES or LIPO-RES for six weeks. ResultsThe significant elevation in serum alanine aminotransferase (ALT) and the changed the hepatic tissue structure following DOXR administration indicating hepatic injury. Additionally, DOXR injection caused upregulation of the hepatic malondialdehyde (MDA), inflammatory cytokines, and transforming growth factor-β1 (TGF-β1) levels. The endogenous glutathione (GSH) and sirtuin1 (SIRT1) expressions in the liver were downregulated following DOXR administration. CAR, RES or LIPO-RES as their alternative combinations attenuated the liver injury by controlling oxidative stress, inflammation, and fibrosis. These beneficial effects were apparent upon using combined CAR and LIPO-RES, as proved by restoring the balance of MDA and GSH levels, decreasing hepatic cytokines levels of IL-6 and TNF-α, upregulating SIRT1 and downregulating TGF-β1 levels. ConclusionThe current study indicated that the use of CAR, RES or LIPO-RES alone or in combination could prevent DOXR-induced hepatic damage in rats by inhibiting oxidative stress, inflammation, and fibrosis.

Antioxidant, antiapoptotic, and antifibrotic effects of the combination of liposomal resveratrol and carvedilol against doxorubicin-induced cardiomyopathy in rats.

The use of the cytotoxic antibiotic doxorubicin (DOXR) is limited by its dose-dependent cardiotoxicity. The aim of this study was to evaluate the cardioprotective effect of the combination of carvedilol (CARD) and liposomal resveratrol (LIPO RESV) against DOXR-induced cardiomyopathy in rats. The results of the present study showed that DOXR administration significantly increased heart weight/body weight ratio by 35.6%, creatine kinase-MB (CK-MB) by 40.6%, troponin-I levels by 85%, and decreased reduced glutathione level and superoxide dismutase activity by 47% and 52%, respectively compared to the control group. Moreover, cardiac caspase-3 protein expression was upregulated by 51.6% vs the control group. In contrast, treatment of DOXR-administered rats with CARD, RESV, or LIPO RESV and their combination for 6 weeks improved all the above-mentioned measured parameters. In conclusion, concomitant administration of CARD and LIPO RESV exerted additive pharmacological effects in some measured parameters against DOXR-induced cardiomyopathy and this may be a useful cardioprotective strategy.

Liposomal Resveratrol and/or Carvedilol Attenuate Doxorubicin-Induced Cardiotoxicity by Modulating Inflammation, Oxidative Stress and S100A1 in Rats.

Doxorubicin (DOX) is a cytotoxic anthracycline antibiotic and one of the important chemotherapeutic agents for different types of cancers. DOX treatment is associated with adverse effects, particularly cardiac dysfunction. This study examined the cardioprotective effects of carvedilol (CAR) and/or resveratrol (RES) and liposomal RES (LIPO-RES) against DOX-induced cardiomyopathy, pointing to their modulatory effect on oxidative stress, inflammation, S100A1 and sarco/endoplasmic reticulum calcium ATPase2a (SERCA2a). Rats received CAR (30 mg/kg) and/or RES (20 mg/kg) or LIPO-RES (20 mg/kg) for 6 weeks and were challenged with DOX (2 mg/kg) twice per week from week 2 to week 6. DOX-administered rats exhibited a significant increase in serum creatine kinase-MB (CK-MB), troponin-I and lactate dehydrogenase (LDH) along with histological alterations, reflecting cardiac cell injury. Cardiac toll-like receptor 4 (TLR-4), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α and interleukin (IL)-6 protein expression were up-regulated, and lipid peroxidation was increased in DOX-administered rats. Treatment with CAR, RES or LIPO-RES as well as their alternative combinations ameliorated all observed biochemical and histological alterations with the most potent effect exerted by CAR/LIPO-RES. All treatments increased cardiac antioxidants, and the expression of S100A1 and SERCA2a. In conclusion, the present study conferred new evidence on the protective effects of CAR and its combination with either RES or LIPO-RES on DOX-induced inflammation, oxidative stress and calcium dysregulation.

The effects of topical liposomal resveratrol on incisional and excisional wound healing process

The effects of topical liposomal resveratrol on incisional and excisional wound healing process

P 25 Vesicle-based resveratrol formulation for the topical treatment of Trichomonas vaginalis caused vaginal infection and inflammation

Introduction Untreated vaginal inflammation can cause miscarriage, preterm labour, placental dysfunction and perinatal complications. Trichomonas vaginalis infection and inflammation are of serious concerns due to lipophosphoglycan (LPG) which triggers selective up regulation of cytokines, especially IL-8, in the female reproductive tract [1] . There are several anti-inflammatory and anti-microbial drugs currently available on the market, however, there is no general consensus regarding safe formulation especially for use in early pregnancy and considering microbial resistance. Resveratrol, a natural polyphenol, showed promising results comparing to clinically used drug metronidazole [2] . However, due to poor solubility and low bioavailability of resveratrol, its clinical application remains challenging. Our aim was to develop a non-teratogenic and non-toxic formulation which can be used in early pregnancy for the treatment of Trichomonas infection and inflammation. Methods Liposomes carrying resveratrol were characterized for their stability, size and entrapment efficiency. Antioxidant activities were evaluated by DPPH/ABTS+ and SOD activities. Antioxidant and anti-inflammatory activities of resveratrol and their corresponding vesicle-based formulation were compared. Anti-inflammatory activities were evaluated by measuring LPS-induced NO and pro-inflammatory cytokines such as IL-1β, TNF-α, IL-8 in macrophages (J774.1) and LPG-induced cytokines IL-8 in human vaginal cells lines (VK2/E6E7). Results Phospholipid-based vesicles, liposomes, of average size around 100 nm were found to be stable with a high resveratrol load (77%). Liposomal resveratrol was found to be 3 folds more potent than resveratrol in inhibiting NO production and up to 30% pro-inflammatory cytokines in macrophages were inhibited. IL-8 was inhibited up to 36% by the liposomal resveratrol in human vaginal cell lines VK2/E6E7 as compared to resveratrol. Conclusion Standardized liposomal resveratrol might be an appropriate, effective and safe topical formulation for the treatment of vaginal infection and inflammation against trichomoniasis in early pregnancy.

Effect of quercetin and resveratrol co-incorporated in liposomes against inflammatory/oxidative response associated with skin cancer

The present investigation reports the development of liposomes for the co-delivery of naturally occurring polyphenols, namely quercetin and resveratrol. Small, spherical, uni/bilamellar vesicles were produced, as demonstrated by light scattering, cryo-TEM, SAXS. The incorporation of quercetin and resveratrol in liposomes did not affect their intrinsic antioxidant activity, as DPPH radical was almost completely inhibited. The cellular uptake of the polyphenols was higher when they were formulated in liposomes, and especially when co-loaded rather than as single agents, which resulted in a superior ability to scavenge ROS in fibroblasts. The in vivo efficacy of the polyphenols in liposomes was assessed in a mouse model of skin lesion. The topical administration of liposomes led to a remarkable amelioration of the tissue damage, with a significant reduction of oedema and leukocyte infiltration. Therefore, the proposed approach based on polyphenol vesicular formulation may be of value in the treatment of inflammation/oxidative stress associated with pre-cancerous/cancerous skin lesions.

Resveratrol-loaded liposomes for topical treatment of the vaginal inflammation and infections

Resveratrol (RES), chemically known as 3,5,4′-trihydroxy-trans-stilbene, is a promising multi-targeted anti-oxidative and anti-inflammatory natural polyphenol. Preclinical studies showed its biological activities against the pathogens of sexually transmitted diseases causing vaginal inflammation and infections. Due to its low solubility and poor bioavailability, the optimal therapeutic uses are limited. Therefore, a clinically acceptable topical vaginal formulation of RES exhibiting optimal therapeutic effects is highly desirable. For this purpose, we prepared and optimized chitosan-coated liposomes with RES. The coated vesicles (mean diameter 200nm) entrapped up to 77% of RES, a sufficient load to assure required therapeutic outcome. In vitro drug release study showed the ability of liposomes to provide sustained release of RES. In vitro anti-oxidative activities of RES, namely DPPH and ABTS•+ radicals scavenging assays, confirmed RES to be as potent as standard anti-oxidants, vitamins C and E. The anti-oxidative activities of RES and its corresponding liposomal formulation were also compared by measuring enhanced superoxide dismutase (SOD) activities in lipopolysaccharide (LPS)-induced J774A.1 cells. In vitro anti-inflammatory activities were compared by measuring nitric oxide (NO), tumor necrosis factor (TNF)-α and interleukin (IL)-1β production in LPS-induced J774A.1 cells. Liposomal RES was found to exhibit stronger anti-oxidative and anti-inflammatory activities than RES solution.

Liposomes as carriers of the lipid soluble antioxidant resveratrol: Evaluation of amelioration of oxidative stress by additional antioxidant vitamin

AimResveratrol (RES) is a well-known antioxidant, yet in combination with other antioxidant vitamins, it was found to be more effective than any of these antioxidants alone. Present work aims to compare the antioxidant actions of resveratrol with and without vitamin C following delivery as liposomes tested using chemical and cellular antioxidative test systems. Main methodsLiposomes were prepared by the thin film hydration method and characterised for percent drug entrapment (PDE), Z-average mean size (nm), polydispersity index (PDI) and zeta potential. Antioxidative capacity was determined by studying the inhibition of AAPH induced luminol enhanced chemiluminescence and inhibition of ROS production in isolated blood leukocytes. Intracellular oxygen-derived radicals were measured using flow cytometry with buffy coats (BC) and human umbilical vein endothelial cells using H2DCF-DA dye. Key findingsParticle size varied from 134.2±0.265nm to 103.3±1.687nm; PDI ≤0.3; zeta potential values were greater than −30mV and PDE ≥80%. Radical scavenging effect was enhanced with liposomal systems; oxidative burst reaction in BC was inhibited by liposomal formulations, with the effect slightly enhanced in presence of vitamin C. Reduction in reactive oxygen species (ROS) production during spontaneous oxidative burst of BC and incubation of HUVECs with H2O2 further intensified the antioxidative effects of pure RES and liposomal formulations. SignificanceThe present work clearly shows that the antioxidative effects of resveratrol loaded into liposomes are more pronounced when compared to pure resveratrol. Liposomal resveratrol is even active within the intracellular compartments as RES could effectively quench the intracellular accumulation of ROS.

Nanodesign of olein vesicles for the topical delivery of the antioxidant resveratrol

The ex-vivo percutaneous absorption of the natural antioxidant resveratrol in liposomes and niosomes was investigated. The influence of vesicle composition on their physicochemical properties and stability was evaluated. Liposomes containing resveratrol were formulated using soy phosphatidylcholine (Phospholipon90G). Innovative niosomes were formulated using mono- or diglycerides: glycerol monooleate (Peceol) and polyglyceryl-3 dioleate (Plurol OleiqueCC), respectively, two suitable skin-compatible oleins used in pharmaceutical formulations as penetration enhancers. Small, negatively charged vesicles with a mean size of approximately 200 nm were prepared. The accelerated stability of vesicles was evaluated using Turbiscan Lab Expert, and the bilayer deformability was also assessed. Ex-vivo transdermal experiments were carried out in Franz diffusion cells, on newborn pig skin, to study the influence of the different vesicle formulations on resveratrol skin delivery. Results indicated a high cutaneous accumulation and a low transdermal delivery of resveratrol, especially when Peceol niosomes were used. Overall, niosomes formulated with Plurol oleique or Peceol showed a better behaviour than liposomes in the cutaneous delivery of resveratrol.

Improvements of cellular stress response on resveratrol in liposomes

Resveratrol (RSV) has proven potential in prophylaxis and treatment of various disorders mediated by free radicals and oxidative stress. RSV solubility, stability, and cytotoxicity must be regulated for satisfactory bioavailability. Here, RSV was loaded into liposomes, characterized by PCS and TEM and evaluated on HEK293 cell line by metabolic activity assay, electron paramagnetic resonance, and fluorescence microscopy. RSV at 10 microM induced changes in cell metabolic activity and significantly improved antioxidative capacity. At 100 microM it showed concentration-dependent cytotoxicity. Oligolamellar liposomes with mean diameter 84 nm, polydispersity index 0.2, and zeta potential -40 mV showed high entrapment of RSV and rapid cellular internalization. Cell stress caused by UV-B irradiation diminished cell metabolic activity by 50%. RSV loaded into them showed no cytotoxicity at 100 microM and stimulated cellular metabolic and antioxidant activity levels to eliminate the harmful effect of the stress. Localization of RSV within liposomal bilayer is crucial for stimulation of cell-defense system, prevention of RSV cytotoxicity, and its long-term stability. In summary, evidence of different metabolic activity using free RSV and LIP-RSV is presented indicating that liposome-mediated uptake of RSV is more effective for improvement of the cell-stress response.

Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice

Increasing interest in the use of phytochemicals to reduce prostate cancer led us to investigate 2 potential agents, curcumin and resveratrol as preventive agents. However, there is concern about the bioavailability of these agents pertinent to the poor absorption and thereby limiting its clinical use. With the view to improve their bioavailability, we used the liposome encapsulated curcumin, and resveratrol individually and in combination in male B6C3F1/J mice. Further, we examined the chemopreventive effect of liposome encapsulated curcumin and resveratrol in combination in prostate-specific PTEN knockout mice. In vitro assays using PTEN-CaP8 cancer cells were performed to investigate the combined effects curcumin with resveratrol on (i) cell growth, apoptosis and cell cycle (ii) impact on activated p-Akt, cyclin D1, m-TOR and androgen receptor (AR) proteins involved in tumor progression. HPLC analysis of serum and prostate tissues showed a significant increase in curcumin level when liposome encapsulated curcumin coadministered with liposomal resveratrol (p < 0.001). Combination of liposomal forms of curcumin and resveratrol significantly decreased prostatic adenocarcinoma in vivo (p < 0.001). In vitro studies revealed that curcumin plus resveratrol effectively inhibit cell growth and induced apoptosis. Molecular targets activated due to the loss of phosphatase and tensin homolog (PTEN) including p-Akt, cyclin D1, mammalian target of rapamycin and AR were downregulated by these agents in combination. Findings from this study for the first time provide evidence on phytochemicals in combination to enhance chemopreventive efficacy in prostate cancer. These findings clearly suggest that phytochemicals in combination may reduce prostate cancer incidence due to the loss of the tumor suppressor gene PTEN.

Effect of resveratrol incorporated in liposomes on proliferation and UV-B protection of cells

The possibility of improving the efficacy of resveratrol, a polyphenol with strong antioxidant and free-radical scavenging properties, on cell proliferation and photoprotection by liposomal incorporation was investigated. Oligolamellar vesicles of different lipid compositions, loaded with resveratrol, were prepared and characterized by evaluating size, zeta potential, incorporation efficiency, electron microscopy and stability over 60 days. The effect of free and liposomal resveratrol on the viability of HEK 293 cells and their photoprotection after UV-B irradiation was assessed by the MTS method. Resveratrol decreased the cell viability at 100 μM concentration, while at 10 μM increased cell proliferation and also achieved the most effective photoprotection. Photomicrographs of the treated cells from inverted light and fluorescence microscopy demonstrated resveratrol effectiveness at 10 μM, as well as its toxicity at higher concentrations, based on changes in cell shape, detachment and apoptotic features. Interestingly, liposomes prevented the cytotoxicity of resveratrol at high concentrations, even at 100 μM, avoiding its immediate and massive intracellular distribution, and increased the ability of resveratrol to stimulate the proliferation of the cells and their ability to survive under stress conditions caused by UV-B light.