Berberine and lycopene as alternative or add-on therapy to metformin and statins, a review.

Nutraceuticals are principally extracted from natural products that are frequently safe and well-tolerated. Lycopene and berberine are natural plants with a wide range of beneficial effects including protective activities against metabolic disorders such as diabetes and cardiovascular diseases. These compounds might be considered technically more as a drug than a nutraceutical and could be prescribed as a product. However, further studies are needed to understand if these supplements could affect metabolic syndrome outcomes. Even if nutraceuticals exert a prophylactic activity within the body, their bioactivity and bioavailability have high interindividual variation, and precise assessment of biological function of these bioactive compounds in randomized clinical trials is critical. However, these reports must be interpreted with more considerations due to the low quality of the trials. The aim of this paper is to bring evidence about the management of cardiovascular diseases and diabetes through the use of nutraceuticals with particular attention to lycopene and berberine effectiveness.

PEGylated Nanoliposomes Potentiated Oral Combination Therapy for Effective Cancer Treatment.

The conventional treatment regimen for cancer with a single chemotherapeutic agent is far behind the clinical expectations due to the complexity of cancer biology and is also associated with poor Quality of Life (QOL) due to off-site toxicity and multidrug resistance. In recent years, nanopotentiated combination therapy has shown significant improvement in cancer treatment via a synergistic approach. However, being synthetic in nature, nanocarriers have been associated with the activation of the Complement (C) activation system resulting in serious hypersensitivity reactions known as CActivation Related Pseudoallergy (CARPA) effect once given via intravenous injection. On the other hand, nanopotentiated oral drug delivery offers several advantages for the effective and safe delivery of the drug to the target site. This hypothesis aims to put forward wherein Exemestane (chemotherapeutic agent) and lycopene (herbal bioactive) co-laden into PEGylated liposomes and delivered to the breast cancer via the oral route. PEGylation of the liposomes would prevent both molecules from the harsh microenvironment of the Gastrointestinal Tract (GIT) and would eventually promote their intestinal absorption via the lymphatic pathway to the systemic circulation. Lycopene being a potent antioxidant and anti-cancer herbal bioactive would promote the therapeutic efficacy of the Exemestane via a synergistic approach. This nanopotentiated oral combination therapy would pave the path for the safe and effective treatment of cancer.

Lycopene in protection against obesity and diabetes: A mechanistic review.

Lycopene, a natural pigment that mainly exists in the mature fruit of tomatoes, has gained increasing attention due to its protective effects against obesity and diabetes. The aim of this review is to summarize the potential mechanisms in which lycopene exerts protection against obesity and diabetes, along with highlighting its bioavailability, synthesis and safety. Literature sources used in this review were from the PubMed Database, China Knowledge Resource Integrated Database, China Science and Technology Journal Database, National Science and Technology Library, Wanfang Data, and the Web of Science. For the inquiries, keywords such as lycopene, properties, synthesis, diabetes, obesity, and safety were used in various combinations. About 200 articles and reviews were evaluated. Lycopene exhibits anti-obesity and anti-diabetic activities in different organs and/or tissues, including adipose tissue, liver, kidney, pancreas, brain, ovaries, intestine, and eyes. The underlying mechanism may be attributed to its anti-oxidant and anti-inflammatory properties and through its ability to regulate of AGE/RAGE, JNK/MAPK, PI3K/Akt, SIRT1/FoxO1/PPARγ signaling pathways and AchE activity. The epidemiological investigations support that lycopene consumption may contribute to lowering the risk of obesity and diabetes. The cis-isomers of lycopene are more bioavailable and better absorbed than trans-lycopene, and mainly distribute in liver and adipose tissue. Lycopene exhibits a good margin of safety and can be obtained by plant extraction, chemical synthesis and microbial fermentation. In summary, lycopene consumption beneficially contributes to protecting against diabetes and obesity in animal studies and epidemiological investigations, which supports the potential of this compound as a preventive/therapeutic agent against these disorders. Well-designed, prospective clinical studies are warranted to evaluate the potential therapeutic effect of lycopene against common metabolic diseases.

Impact of onions in tomato-based sauces on isomerization and bioaccessibility of colorless carotenes: phytoene and phytofluene.

Onions as an interesting ingredient have been proved to promote Z-isomerization of lycopene and increase bioaccessibility of total-lycopene. Phytoene (PT) and phytofluene (PTF), the precursors of lycopene, are colorless carotenes, which are attracting much attention and are also abundant in tomatoes. Therefore, onions might also affect the distribution and bioaccessibility of PT and PTF isomers during heating tomato (hot-break and cold-break purees)-onion-extra virgin olive oil (EVOO) sauces. The addition of onions (or diallyl disulfide present in onions) into tomato purees did not cause degradation of PT or PTF; however it favored E/Z-isomerization of PT and PTF by reducing the proportions of their natural Z-isomers (Z-15-PT and Z2,3-PTF) and decreased the bioaccessibility of total-PT and total-PTF. Simultaneously, a complex picture was obtained for the effect of onions on the bioaccessibility of individual PT and PTF isomers, depending on the precise isomer. Bioaccessibility of PT and PTF isomers in tomato-based sauces decreased in the order: 15-Z-PT > all-E-PT; Z2,3-PTF > all-E-PTF > Z4 or Z5-PTF; total-PT > total-PTF. E-isomerization of PT and PTF enhanced by onions during heating tomato-onion purees decreased their bioaccessibility.

Sialic acid-conjugated PLGA nanoparticles enhance the protective effect of lycopene in chemotherapeutic drug-induced kidney injury.

Lycopene (LYC) is known to protect cells from oxidative damage caused by free radicals in human tissues. In the present study, the authors designed a LYC-loaded sialic acid (SA)-conjugated poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle (LYC-NP) to enhance the therapeutic efficacy of LYC in acute kidney injury. The characteristics of the LYC-NPs were defined according to particle size, morphology, and in vitro drug release. The LYC-NPs exhibited a controlled release of LYC over 48 h. Confocal laser scanning microscopy clearly highlighted the targeting potential of SA. Enhanced green fluorescence was observed for the LYC-NPs in H2O2-treated human umbilical vein endothelial cells, indicating enhanced internalisation of NPs. The LYC-NPs showed significantly greater cell viability than H2O2-treated cells. In addition, the LYC-NPs remarkably reduced proinflammatory cytokine levels, attributable mainly to the increased cellular internalisation of the SA-based carrier delivery system. Furthermore, protein levels of caspase-3 and -9 were significantly down-regulated after treatment with the LYC-NPs. Overall, they have demonstrated that SA-conjugated PLGA-NPs containing LYC could be used to treat kidney injury.

Encapsulation of lycopene within oil-in-water nanoemulsions using lactoferrin: Impact of carrier oils on physicochemical stability and bioaccessibility.

The influence of physicochemical properties of carrier oils on nanoemulsion stability and the bioaccessibility of lycopene were studied. Lycopene-loaded nanoemulsions were prepared by using sesame oil, linseed oil or walnut oil as the oil phase and lactoferrin as the emulsifier. The stability was investigated by particle size, zeta potential, pH sensitivity, thermal stability and lycopene retention. Results showed that the stability was positively correlated with oil density but negatively related to oil viscosity and unsaturation degree; the lycopene nanoemulsion prepared by sesame oil exhibited greater stability and a slower degradation rate of lycopene compared to the other nanoemulsions. In addition, the lycopene retention in sesame oil-nanoemulsions was significantly higher during the first three weeks of storage. The bioaccessibility of lycopene, as measured by a simulated gastrointestinal model, was greatly improved in the nanoemulsion system. The lycopene bioaccessibility was around 25% in sesame oil- and linseed oil-nanoemulsions, and 18% in walnut oil-nanoemulsions, showing a similar trend with their stability. This information may facilitate the design of more efficacious lycopene-fortified delivery systems.

Z-Isomers of lycopene exhibit greater liver accumulation than the all-E-isomer in mice.

The effect of oral administration of all-E-isomer-rich and Z-isomer-rich lycopene on liver accumulation in mice was investigated. When a diet rich in the Z-isomers was administered for 4 weeks, the total lycopene concentration in the liver was more than 3 times higher than that of all-E-isomer administration. This result clearly indicates that lycopene Z-isomers show greater bioavailability and/or liver accumulation than the all-E-isomer in mice.

Oral delivery of lycopene-loaded microemulsion for brain-targeting: preparation, characterization, pharmacokinetic evaluation and tissue distribution.

Lycopene is considered as a promising neuroprotector with multiple bioactivities, while its therapeutic use in neurological disorders is restricted due to low solubility, instability and limited bioavailability. Our work aimed to develop lycopene-loaded microemulsion (LME) and investigate its potentials in improving bioavailability and brain-targeting efficiency following oral administration. The blank microemulsion (ME) excipients were selected based on orthogonal design and pseudo-ternary phase diagrams, and LME was prepared using the water titration method and characterized in terms of stability, droplet size distribution, zeta potential, shape and lycopene content. The optimized LME encompassed lycopene, (R)-(+)-limonene, Tween 80, Transcutol HP and water and lycopene content was 463.03 ± 8.96 µg/mL. This novel formulation displayed transparent appearance and satisfactory physical and chemical stabilities. It was spherical and uniform in morphology with an average droplet size of 12.61 ± 0.46 nm and a polydispersity index (PDI) of 0.086 ± 0.028. The pharmacokinetics and tissue distributions of optimized LME were evaluated in rats and mice, respectively. The pharmacokinetic study revealed a dramatic 2.10-fold enhancement of relative bioavailability with LME against the control lycopene dissolved in olive oil (LOO) dosage form in rats. Moreover, LME showed a preferential targeting distribution of lycopene toward brain in mice, with the value of drug targeting index (DTI) up to 3.45. In conclusion, the optimized LME system demonstrated excellent physicochemical properties, enhanced oral bioavailability and superior brain-targeting capability. These findings provide a basis for the applications of ME-based strategy in brain-targeted delivery via oral route, especially for poorly water-soluble drugs.

Comparison of the bioavailability and intestinal absorption sites of phytoene, phytofluene, lycopene and ß-carotene.

The mechanisms of main tomato carotenes (phytoene, phytofluene, lycopene and ß-carotene) intestinal absorption are still only partly understood. We thus compared carotene bioavailability in mice after gavage with carotene-rich oil-in-water emulsions. We also determined each carotene absorption profile along the duodenal-ileal axis of the intestine to identify their respective absorption sites and compared these profiles with the gene expression sites of their identified transporters, i.e. SR-BI and CD36. Our data show that phytofluene presented a significantly higher bioavailability compared to lycopene and ß-carotene (areas under the curve of 0.76 ±â€¯0.09 vs. 0.30 ±â€¯0.05, 0.09 ±â€¯0.05 and 0.08 ±â€¯0.01 µmol/L·h for phytofluene, phytoene, lycopene and ß-carotene, respectively). ß-Carotene was mostly converted in the proximal and median intestine. Phytoene and phytofluene accumulation tended to be more important in the distal intestine, which did not correlate with the proximal expression of both Scarb1 and CD36. Overall, these results highlight the high bioavailability of phytofluene.

Acute Effect of a Single Dose of Tomato Sofrito on Plasmatic Inflammatory Biomarkers in Healthy Men.

Sofrito is a Mediterranean tomato-based sauce that typically also contains olive oil, onion, and garlic. The preparation of sofrito modifies the bioactive compounds (carotenoids and polyphenols) in the ingredients to more bioavailable forms, promoting cis-lycopene formation and polyphenol bioaccessibility. To evaluate the health benefits of this cooking technique, the effect of consuming an acute dose of sofrito on the inflammatory status was studied. In a clinical trial, 22 healthy male subjects consumed a single dose of sofrito (240 g/70 kg) after three days without ingesting any tomato products and following a low-antioxidant diet the day before the intervention. Plasma carotenoids and total polyphenol excretion (TPE) were evaluated, as well as the inflammatory biomarkers C-reactive protein (CRP), interleukin-6 (IL-6), interleukin 1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). After the sofrito intake, a significant decrease in CRP (p = 0.010) and TNF-α (p = 0.011) was observed, but only TNF-α was inversely correlated with an increase in TPE and plasma ß-carotene (not the major carotenoid, lycopene). The positive health effects of this tomato-based product may be attributed not only to lycopene, but to the bioactive compounds of all the ingredients.

Effects on intestinal cellular bioaccessibility of carotenoids and cellular biological activity as a consequence of co-ingestion of anthocyanin- and carotenoid-rich vegetables.

The effects of co-digestion of a carotenoid-rich vegetable such as carrot, cherry tomato or baby spinach with an anthocyanin-rich vegetable such as red cabbage with and without salad dressing on the intestinal cellular bioaccessibility (cBAC) of carotenoids and the resultant cellular antioxidant and anti-inflammatory activities were investigated. The % cBAC of lutein from the tested vegetables was 0.23-1.42%, lycopene 0.07-0.39%, α-carotene 0.01-0.12% and ß-carotene 0.03-0.61% respectively. The % cBAC of each of these carotenoids from the co-digested vegetables was significantly higher (p < 0.05) than from carrot, cherry tomato or baby spinach digested alone. % cBAC of total carotenoids was significantly increased by 46-191% (p < 0.05) as a result of the co-digestion. The vegetable co-digestion did not result in any impairment on the resultant cellular anti-oxidation and anti-inflammation (NO, IL-8 secretion). Among the tested vegetables, baby spinach co-digested with red cabbage showed synergistic bioactivities in all tested assays.

Watermelon Juice: a Novel Functional Food to Increase Circulating Lycopene in Older Adult Women.

Because of accruing oxidative stress with advancing age, older adults may benefit from increased dietary intake of lycopene, a lipophilic carotenoid with potent antioxidant properties. Yet, intake of dietary lycopene as well as circulating lycopene levels are known to decrease with aging. Watermelon is one of the few food sources of dietary lycopene. Because heat treatment increases lycopene bioavailability, ingestion of watermelon in pasteurized juice form may be an optimal delivery vehicle to increase lycopene levels in older adults. However, due to its lipophilic nature, there are concerns that co-ingestion of dietary fat may be necessary for efficient intestinal absorption of lycopene. Thus, this feasibility study aimed to examine the effects of a one-time dose of 100% pasteurized watermelon juice on circulating lycopene concentrations of postmenopausal women after a 10-h overnight fast. Blood was sampled from eight women before and 2 h after ingestion of 360 ml of juice, and serum lycopene was measured by ultra-high performance liquid chromatography. Circulating lycopene levels increased by three-fold (p < 0.001) with increases observed for every participant. Results demonstrate that 100% watermelon juice is a palatable, effective means of increasing serum lycopene in older adult women, a group at risk for low carotenoid intake. Trial registration: Clinicaltrials.gov identifier: NCT03608254 .

Increased release of carotenoids and delayed in vitro lipid digestion of high pressure homogenized tomato and pepper emulsions.

Carotenoids are lipophilic compounds that are digested and absorbed along with lipids. Emulsions based on a mixture of plum tomato and red sweet pepper, with 5% or 10% rapeseed oil, were obtained by high pressure homogenization, and the concentration of carotenoids in the emulsion oil droplets was quantified. The fraction of lycopene and beta-carotene released from the plant matrix into the oil droplets was highest in the 10% emulsion, which had larger oil droplets than the 5% emulsion. Xanthophylls were easily released into oil droplets in both 5% and 10% emulsions. The results suggest that the release of carotenoids made available for intestinal absorption depends on carotenoid type and can be significantly improved by increasing the homogenization pressure and oil content. However, in vitro gastrointestinal digestion indicated the presence of constituents or structures in the emulsions, originating from tomato, that reduced pancreatic activity, which may delay micellarization and uptake of carotenoids.

Lycopene solid lipid microparticles with enhanced effect on gingival crevicular fluid protein carbonyl as a biomarker of oxidative stress in patients with chronic periodontitis.

Lycopene (LP), a naturally occurring carotenoid in red-coloured fruits, especially tomatoes, has a pivotal role in counteracting the deleterious effect of oxidative stress on periodontal tissues. The aim of this study is to prepare solid lipid microparticles (SLMs) encapsulating LP and to assess their biochemical and clinical effects in the management of chronic periodontitis. Optimization of SLMs was performed by assessing particle size and LP entrapment efficiency. Clinical study included 16 chronic periodontitis patients allocated into two groups, Group I was managed by scaling and root planing (SRP) and local delivery of LP loaded SLMs, while Group II was managed by SRP only. Protein carbonyl (PC) levels as a biomarker of oxidative stress and drug concentration in gingival crevicular fluid (GCF) were assessed at different time intervals. Results revealed that optimum formula of SLMs had a particle size of 77.28 µm and entrapped 98.03% of LP. SLMs recorded 30 d of drug release with no burst effect. Patients treated with LP SLMs showed significantly lower levels of PC after SRP compared to those treated with SRP only, in addition to improvement in the measured clinical parameters. In conclusion, locally delivered LP SLMs along with SRP could have a protective effect over periodontal tissues and it has the ability to decrease oxidative damage of proteins in diseased periodontium.

Genetic factors involved in the bioavailability of tomato carotenoids.

PURPOSE OF REVIEW: To provide an update on the genetic factors recently associated with the interindividual variability of tomato carotenoid bioavailability. RECENT FINDINGS: Several clinical studies have demonstrated that the main carotenoids found in tomatoes (lycopene, phytoene, phytofluene, ß-carotene, lutein) all display relatively large interindividual variabilities of their bioavailability, with coefficients of variations more than 70%. The bioavailability of the parent molecules, and the blood/tissue appearance of their metabolites, is modulated by numerous proteins, involved in intestinal absorption and metabolism, blood lipoprotein transport or tissue uptake. Several single nucleotide polymorphisms (SNPs) have been associated with the interindividual variability of lycopene, lutein and ß-carotene bioavailability, with six genes consistently shared between the three carotenoids, and in particular one SNP in ELOVL fatty acid elongase 2. The effects of the genetic variants taken separately are relatively low, that is each variant is usually associated with only a few percentage of the variability but multivariate analyses suggest that the additive effect of several genetic variants can explain a significant fraction of tomato carotenoid bioavailability. SUMMARY: Additional studies are needed to improve our knowledge of the genetic determinants of tomato carotenoid bioavailability but progress in this field could one day allow nutritionists to provide more personalized dietary recommendations.

Phytoene and Phytofluene Isolated from a Tomato Extract are Readily Incorporated in Mixed Micelles and Absorbed by Caco-2 Cells, as Compared to Lycopene, and SR-BI is Involved in their Cellular Uptake.

SCOPE: Absorption mechanisms of phytoene (PT) and phytofluene (PTF) are poorly known. The main objectives of the study are to measure their micellization and intestinal cell uptake efficiencies and to compare them to those of commonly consumed carotenoids. Other objectives are to assess the involvement of protein(s) in their cellular uptake and whether they compete with other carotenoids for micellization and cellular uptake. METHODS AND RESULTS: Tomato-extract-purified PT and PTF, mainly present as cis-isomers, are much better incorporated in synthetic mixed micelles than pure all-trans lycopene. PT impairs lycopene micellization (-56%, P < 0.05) while PT and PTF do not significantly affect the micellization of other carotenoids, and vice versa. At low concentration, Caco-2 PTF uptake is higher (P < 0.05) than that of PT and lycopene (29%, 21%, and not detectable). SR-BI, but not CD36 neither NPC1L1, is involved in PT and PTF uptake. PT and PTF impair (p < 0.05) ß-carotene uptake (-13 and -22%, respectively). CONCLUSIONS: The high bioaccessibility of PT and PTF can be partly explained by their high micellization efficiency, which is likely due to their natural cis isomerization and/or to their high molecular flexibility. SR-BI is involved in their cellular uptake, which can explain competitions with other carotenoids.