Hesperidin as a Species-Specific Modifier of Aphid Behavior.

Hesperidin is a highly bioactive natural flavonoid whose role in ecological interactions is poorly known. In particular, the effects of hesperidin on herbivores are rarely reported. Flavonoids have been considered as prospective biopesticides; therefore, the aim of the present study was to examine the influence of hesperidin on the host plant selection behavior of three aphid (Hemiptera: Aphididae) species: Acyrthosiphon pisum Harrris, Rhopalosiphum padi (L.), and Myzus persicae (Sulz.). The aphid host plants were treated with 0.1% and 0.5% ethanolic solutions of hesperidin. Aphid probing behavior in the no-choice experiment was monitored using electropenetrography and aphid settling on plants in the choice experiment was recorded. The results demonstrated that hesperidin can be applied as a pre-ingestive, ingestive, and post-ingestive deterrent against A. pisum, as an ingestive deterrent against R. padi, and as a post-ingestive deterrent against M. persicae using the relatively low 0.1% concentration. While in A. pisum the deterrent effects of hesperidin were manifested as early as during aphid probing in peripheral plant tissues, in M. persicae, the avoidance of plants was probably the consequence of consuming the hesperidin-containing phloem sap.

Hesperidin nanoparticles for prostate cancer therapy: preparation, characterization and cytotoxic activity.

Hesperidin, a phytochemical renowned for its therapeutic effects including anticancer, antioxidant, and anti-inflammatory properties, encounters a significant limitation in its application due to its low bioavailability and restricted solubility in water. To surmount these challenges, we employed a spontaneous emulsification method to produce hesperidin nanoparticles. These nanoparticles, averaging 197.2 ± 2.8 nm, exhibited uniform dispersion (polydispersity index: 0.13), a zeta potential (ZP) of -28 mV, encapsulation efficiency of 84.04 ± 1.3%, and demonstrated stable and controlled release across various environments. Assessment of the nanoemulsions stability revealed remarkably high stability levels. Cytotoxicity evaluations (3-(4,5-dimethylthiazol-2-yl)-2,5diphenyl-2-H-tetrazolium bromide, neutral red, trypan blue, and lactate dehydrogenase) indicated that cancer cell viability following treatment with hesperidin nanoemulsion was concentration and time-dependent, significantly lower compared to cells treated with free hesperidin. The colony formation assay and cell morphology evaluation further corroborated the heightened efficacy of hesperidin in its nano form compared to the free form. In summary, hesperidin nanoparticles not only exhibited more potent anticancer activity than free hesperidin but also demonstrated high biocompatibility with minimal cytotoxic effects on healthy cells. These findings underscore the potential for further exploration of hesperidin nanoparticles as an adjunctive therapy in prostate cancer therapy.

Formation of Hesperetin-Methylglyoxal Adducts in Food and In Vivo, and Their Metabolism In Vivo and Potential Health Impacts.

Polyphenols with a typical meta-phenol structure have been intensively investigated for scavenging of methylglyoxal (MGO) to reduce harmful substances in food. However, less attention has been paid to the formation level of polyphenol-MGO adducts in foods and in vivo and their absorption, metabolism, and health impacts. In this study, hesperitin (HPT) was found to scavenge MGO by forming two adducts, namely, 8-(1-hydroxyacetone)-hesperetin (HPT-mono-MGO) and 6-(1-hydroxyacetone)-8-(1-hydroxyacetone)-hesperetin (HPT-di-MGO). These two adducts were detected (1.6-15.9 mg/kg in total) in cookies incorporated with 0.01%-0.5% HPT. HPT-di-MGO was the main adduct detected in rat plasma after HPT consumption. The adducts were absorbed 8-30 times faster than HPT, and they underwent glucuronidation and sulfation in vivo. HPT-mono-MGO would continue to react with endogenous MGO in vivo to produce HPT-di-MGO, which effectively reduced the cytotoxicity of HPT and HPT-mono-MGO. This study provided data on the safety of employing HPT as a dietary supplement to scavenge MGO in foods.

Hesperidin - loaded PVA/alginate hydrogel: targeting NFκB/iNOS/COX-2/TNF-α inflammatory signaling pathway.

Introduction: Skin injuries represent a prevalent form of physical trauma, necessitating effective therapeutic strategies to expedite the wound healing process. Hesperidin, a bioflavonoid naturally occurring in citrus fruits, exhibits a range of pharmacological attributes, including antimicrobial, antioxidant, anti-inflammatory, anticoagulant, and analgesic properties. The main objective of the study was to formulate a hydrogel with the intention of addressing skin conditions, particularly wound healing. Methods: This research introduces a methodology for the fabrication of a membrane composed of a Polyvinyl alcohol - Sodium Alginate (PVA/A) blend, along with the inclusion of an anti-inflammatory agent, Hesperidin (H), which exhibits promising wound healing capabilities. A uniform layer of a homogeneous solution comprising PVA/A was cast. The process of crosslinking and the enhancement of hydrogel characteristics were achieved through the application of gamma irradiation at a dosage of 30 kGy. The membrane was immersed in a Hesperidin (H) solution, facilitating the permeation and absorption of the drug. The resultant system is designed to deliver H in a controlled and sustained manner, which is crucial for promoting efficient wound healing. The obtained PVA/AH hydrogel was evaluated for cytotoxicity, antioxidant and free radical scavenging activities, anti-inflammatory and membrane stability effect. In addition, its action on oxidative stress, and inflammatory markers was evaluated on BJ-1 human normal skin cell line. Results and Discussion: We determined the effect of radical scavenging activity PVA/A (49 %) and PVA/AH (87%), the inhibition of Human red blood cell membrane hemolysis by PVA/AH (81.97 and 84.34 %), hypotonicity (83.68 and 76.48 %) and protein denaturation (83.17 and 85.8 %) as compared to 250 µg/ml diclofenac (Dic.) and aspirin (Asp.), respectively. Furthermore, gene expression analysis revealed an increased expression of genes associated with anti-oxidant and anti-inflammatory properties and downregulated TNFα, NFκB, iNOS, and COX2 by 67, 52, 58 and 60%, respectively, by PVA/AH hydrogel compared to LPS-stimulated BJ-1 cells. The advantages associated with Hesperidin can be ascribed to its antioxidant and anti-inflammatory attributes. The incorporation of Hesperidin into hydrogels offers promise for the development of a novel, secure, and efficient strategy for wound healing. This innovative approach holds potential as a solution for wound healing, capitalizing on the collaborative qualities of PVA/AH and gamma irradiation, which can be combined to establish a drug delivery platform for Hesperidin.

Natural flavonoid hesperetin blocks amyloid ß-protein fibrillogenesis, depolymerizes preformed fibrils and alleviates cytotoxicity caused by amyloids.

The aggregation of ß-amyloid (Aß) peptides to form amyloid plaques is one of the primary hallmarks for Alzheimer's disease (AD). Dietary flavonoid supplements containing hesperetin have an ability to decline the risk of developing AD, but the molecular mechanism is still unclear. In this work, hesperetin, a flavanone abundant in citrus fruits, has been proven to prevent the formation of Aß aggregates and depolymerized preformed fibrils in a concentration-dependent fashion. Hesperetin inhibited the conformational conversion from the natural structure to a ß-sheet-rich conformation. It was found that hesperetin significantly reduced the cytotoxicity and relieved oxidative stress eventuated by Aß aggregates in a concentration-dependent manner. Additionally, the beneficial effects of hesperetin were confirmed in Caenorhabditis elegans, including the inhibition of the formation and deposition of Aß aggregates and extension of their lifespan. Finally, the results of molecular dynamics simulations showed that hesperetin directly interacted with an Aß42 pentamer mainly through strong non-polar and electrostatic interactions, which destroyed the structural stability of the preformed pentamer. To summarize, hesperetin exhibits great potential as a prospective dietary supplement for preventing and improving AD.

Acremonium sp. diglycosidase-aid chemical diversification: valorization of industry by-products.

The fungal diglycosidase α-rhamnosyl-ß-glucosidase I (αRßG I) from Acremonium sp. DSM 24697 catalyzes the glycosylation of various OH-acceptors using the citrus flavanone hesperidin. We successfully applied a one-pot biocatalysis process to synthesize 4-methylumbellipheryl rutinoside (4-MUR) and glyceryl rutinoside using a citrus peel residue as sugar donor. This residue, which contained 3.5 % [w/w] hesperidin, is the remaining of citrus processing after producing orange juice, essential oil, and peel-juice. The low-cost compound glycerol was utilized in the synthesis of glyceryl rutinoside. We implemented a simple method for the obtention of glyceryl rutinoside with 99 % yield, and its purification involving activated charcoal, which also facilitated the recovery of the by-product hesperetin through liquid-liquid extraction. This process presents a promising alternative for biorefinery operations, highlighting the valuable role of αRßG I in valorizing glycerol and agricultural by-products. KEYPOINTS: • αRßG I catalyzed the synthesis of rutinosides using a suspension of OPW as sugar donor. • The glycosylation of aliphatic polyalcohols by the αRßG I resulted in products bearing a single rutinose moiety. • αRßG I catalyzed the synthesis of glyceryl rutinoside with high glycosylation/hydrolysis selectivity (99 % yield).

Microbial-Driven Synthesis and Hydrolysis of Neohesperidin Dihydrochalcone: Biotransformation Process and Feasibility Investigation.

A novel yeast-mediated hydrogenation was developed for the synthesis of neohesperidin dihydrochalcone (NHDC) in high yields (over 83%). Moreover, whole-cell catalytic hydrolysis was also designed to hydrolyze NHDC into potential sweeteners, hesperetin dihydrochalcone-7-O-glucoside (HDC-G) and hesperetin dihydrochalcone (HDC). The biohydrogenation was further combined with whole-cell hydrolysis to achieve a one-pot two-step biosynthesis, utilizing yeast to hydrogenate C═C in the structure, while Aspergillus niger cells hydrolyze glycosides. The conversion of NHDC and the proportion of hydrolysis products could be controlled by adjusting the catalysts, the components of the reaction system, and the addition of glucose. Furthermore, yeast-mediated biotransformation demonstrated superior reaction stability and enhanced safety and employed more cost-effective catalysts compared to the traditional chemical hydrogenation of NHDC synthesis. This research not only provides a new route for NHDC production but also offers a safe and flexible one-pot cascade biosynthetic platform for the production of high-value compounds from citrus processing wastes.

Unveiling the flavone-solubilizing effects of α-glucosyl rutin and hesperidin: probing structural differences through NMR and SAXS analyses.

Flavonoids often exhibit broad bioactivity but low solubility and bioavailability, limiting their practical applications. The transglycosylated materials α-glucosyl rutin (Rutin-G) and α-glucosyl hesperidin (Hsp-G) are known to enhance the dissolution of hydrophobic compounds, such as flavonoids and other polyphenols. In this study, the effects of these materials on flavone solubilization were investigated by probing their interactions with flavone in aqueous solutions. Rutin-G and Hsp-G prepared via solvent evaporation and spray-drying methods were evaluated for their ability to dissolve flavones. Rutin-G had a stronger flavone-solubilizing effect than Hsp-G in both types of composite particles. The origin of this difference in behavior was elucidated by small-angle X-ray scattering (SAXS) and nuclear magnetic resonance analyses. The different self-association structures of Rutin-G and Hsp-G were supported by SAXS analysis, which proved that Rutin-G formed polydisperse aggregates, whereas Hsp-G formed core-shell micelles. The observation of nuclear Overhauser effects (NOEs) between flavone and α-glucosyl materials suggested the existence of intermolecular hydrophobic interactions. However, flavone interacted with different regions of Rutin-G and Hsp-G. In particular, NOE correlations were observed between the protons of flavone and the α-glucosyl protons of Rutin-G. The different molecular association states of Rutin-G or Hsp-G could be responsible for their different effects on the solubility of flavone. A better understanding of the mechanism of flavone solubility enhancement via association with α-glucosyl materials would permit the application of α-glucosyl materials to the solubilization of other hydrophobic compounds including polyphenols such as flavonoids.

Effects of hesperidin combined with synephrine on the capture of acrolein in a mouse model, or in humans by citrus consumption.

Acrolein (ACR) is a highly reactive α,ß-unsaturated aldehyde that plays a key role in the pathogenesis of human diseases, such as atherosclerosis and pulmonary, cardiovascular, and neurodegenerative disorders. We investigated the capture capacity of hesperidin (HES) and synephrine (SYN) on ACR by individual and combined means in vitro, in vivo (utilizing a mouse model), and via a human study. After proving that HES and SYN could efficiently capture ACR by generating ACR adducts in vitro, we further detected the adducts of SYN-2ACR, HES-ACR-1, and hesperetin (HESP)-ACR in mouse urine by ultraperformance liquid chromatography-tandem mass spectrometry. Quantitative assays revealed that adduct formation occurred in a dose-dependent manner, and that there was a synergistic effect of HES and SYN on capturing ACR in vivo. Moreover, quantitative analysis suggested that SYN-2ACR, HES-ACR-1, and HESP-ACR were formed and excreted through the urine of healthy volunteers consuming citrus. The maximum excretions of SYN-2ACR, HES-ACR-1, and HESP-ACR were at 2-4, 8-10, and 10-12 h, respectively, after dosing. Our findings propose a novel strategy for eliminating ACR from the human body via the simultaneous consumption of a flavonoid and an alkaloid.

Improving Solubility and Permeability of Hesperidin through Electrospun Orange-Peel-Extract-Loaded Nanofibers.

Orange peel, which is a rich source of polyphenolic compounds, including hesperidin, is produced as waste in production. Therefore, optimization of the extraction of hesperidin was performed to obtain its highest content. The influence of process parameters such as the kind of extraction mixture, its temperature and the number of repetitions of the cycles on hesperidin content, the total content of phenolic compounds and antioxidant (DPPH scavenging assay) as well as anti-inflammation activities (inhibition of hyaluronidase activity) was checked. Methanol and temperature were key parameters determining the efficiency of extraction in terms of the possibility of extracting compounds with the highest biological activity. The optimal parameters of the orange peel extraction process were 70% of methanol in the extraction mixture, a temperature of 70 °C and 4 cycles per 20 min. The second part of the work focuses on developing electrospinning technology to synthesize nanofibers of polyvinylpyrrolidone (PVP) and hydroxypropyl-ß-cyclodextrin (HPßCD) loaded with hesperidin-rich orange peel extract. This is a response to the circumvention of restrictions in the use of hesperidin due to its poor bioavailability resulting from low solubility and permeability. Dissolution studies showed improved hesperidin solubility (over eight-fold), while the PAMPA-GIT assay confirmed significantly better transmucosal penetration (over nine-fold). A DPPH scavenging assay of antioxidant activity as well as inhibition of hyaluronidase to express anti-inflammation activity was established for hesperidin in prepared electrospun nanofibers, especially those based on HPßCD and PVP. Thus, hesperidin-rich orange peel nanofibers may have potential buccal applications to induce improved systemic effects with pro-health biological activity.

Metabolomic Analysis of Phytochemical Compounds from Ethanolic Extract of Lime (Citrus aurantifolia) Peel and Its Anti-Cancer Effects against Human Hepatocellular Carcinoma Cells.

Lime peels are food waste from lime product manufacturing. We previously developed and optimized a green extraction method for hesperidin-limonin-rich lime peel extract. This study aimed to identify the metabolomics profile of phytochemicals and the anti-cancer effects of ethanolic extract of lime (Citrus aurantifolia) peel against liver cancer cells PLC/PRF/5. The extract's metabolomics profile was analyzed by using LC-qTOF/MS and GC-HRMS. The anti-cancer effects were studied by using MTT assay, Annexin-PI assay, and Transwell-invasion assay. Results show that the average IC50(s) of hesperidin, limonin, and the extract on cancer cells' viability were 165.615, 188.073, and 503.004 µg/mL, respectively. At the IC50 levels, the extract induced more apoptosis than those of pure compounds when incubating for 24 and 48 h (p < 0.0001). A combination of limonin and hesperidin showed a synergistic effect on apoptosis induction (p < 0.001), but the effect of the combination was still less than that of the extract at 48 h. Furthermore, the extract significantly inhibited cancer cell invasion better than limonin but equal to hesperidin. At the IC50 level, the extract contains many folds lower amounts of hesperidin and limonin than the IC50 doses of the pure compounds. Besides limonin and hesperidin, there were another 60 and 22 compounds detected from the LCMS and GCMS analyses, respectively. Taken altogether, the superior effect of the ethanolic extract against liver cancer cells compared to pure compound likely results from the combinatorial effects of limonin, hesperidin, and other phytochemical components in the extract.

Chiral Separation, Configuration Confirmation and Bioactivity Determination of the Stereoisomers of Hesperidin and Narirutin in Citrus reticulata Blanco.

Hesperidin and narirutin are a class of flavanone glycosides, which are the main active constituents in Citrus reticulata Blanco. In the present study, a chiral HPLC-UV method with amylose tris(3,5-dimethylphenylcarbamate) as a stationary phase under a normal-phase mode was used to achieve the stereoselective separation of the C-2 diastereomers of hesperidin and narirutin simultaneously. The single epimer was then successfully prepared by applying semi-preparative chromatography, whose absolute configuration (R/S) was characterized by combining the experimental electronic circular dichroism (ECD) detection with time-dependent density functional theory (TDDFT) calculations. The epimer composition of these two chiral flavanone glycosides in Citrus reticulata Blanco was then determined, which was found to be slightly different in the herbs from different production regions. The anti-inflammatory activity of each prepared single epimer was further evaluated, and some differences between one pair of epimers of hesperidin and narirutin were observed, which suggested that the presence of different epimers should be considered in the quality evaluation and control of natural medicine.

A review of transglycosylated compounds as food additives to enhance the solubility and oral absorption of hydrophobic compounds in nutraceuticals and pharmaceuticals.

Transglycosylation has been used to modify the physicochemical properties of original compounds. As a result, transglycosylated compounds can form molecular aggregates in size ranges of a few nanometers in an aqueous medium when their concentrations exceed a specific level. Incorporating these hydrophobic compounds has been observed to enhance the solubility of hydrophobic compounds into aggregate structures. Thus, this review introduces four transglycosylated compounds as food additives that can enhance the solubility and oral absorption of hydrophobic compounds. Here, transglycosylated hesperidin, transglycosylated rutin, transglycosylated naringin, and transglycosylated stevia are the focus as representative substances. Significantly, we observed that amorphous formations containing hydrophobic compounds with transglycosylated compounds improved solubility and oral absorption compared to untreated hydrophobic compounds. Moreover, combining transglycosylated compounds with hydrophilic polymers or surfactants enhanced the solubilizing effects on hydrophobic compounds. Furthermore, the enhanced solubility of hydrophobic compounds improved their oral absorption. Transglycosylated compounds also influenced nanoparticle preparation of hydrophobic compounds as a dispersant. This study demonstrated the benefits of transglycosylated compounds in developing supplements and nutraceuticals of hydrophobic compounds with poor aqueous solubility.

Hesperidin hexosomal loaded nanodispersion: insights of its antimycobacterial, cytotoxic and anti-HCoV effects.

Fruits of Citrus sinensis L. Osbeck var. Valencia contain hesperidin as a major flavanone glycoside. Hesperidin (H) was isolated from the peels of Valencia orange and formulated as hexosomal nanodispersions (F1) adopting the hot emulsification method. The antimycobacterial activity(anti-TB) was evaluated through a microplate Alamar blue (MABA) assay where F1 showed significant activity with MIC = 0.19 µM. To unravel the potential mechanism of the anti-TB, a molecular docking study of H using the Mycobacterial Dihydrofolate reductase (Mtb. DHFR) enzyme was performed. Hesperidin exhibited significant interactions with Mtb. DHFR active site. Sulforhodamine B assay was applied to evaluate cytotoxic activity against the lung cancer cell line (A-549). F1 showed a cytotoxic effect at IC50= 33 µM. It also has potent antiviral activity against Human Coronavirus 229E with IC50= 258.8 µM utilising crystal violet assay. Peels of Valencia orange could be a source of bioactive metabolites to control significant diseases.

Nanophytosomes of hesperidin and of hesperetin: Preparation, characterization, and in vivo evaluation.

Hesperidin and hesperetin are two important plant flavanones abundantly found in citrus fruit. They have discovered many biological activities to treat diseases, including cancer, diabetes, and Alzheimer's disease. Despite their various benefits, they have poor solubility, which reduces their bioavailability and absorption. In this study, nanophytosomes have been utilized to improve their payload's solubility and bioavailability. In the current study, hesperetin or hesperidin was complexed with Phospholipon 90G with a 2:1 or 3:1 molar ratio, respectively. The formation of associations between active compounds and phospholipid were confirmed by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and nuclear magnetic resonance (NMR) techniques. Dynamic light scattering data show that the prepared associations in the presence of body fluids can make nanoparticles in the range of 200-250 nm. In addition, oral administration demonstrated that Cmax of hesperidin and hesperetin was increased (up to four times) after complexation with the lipid. It is concluded that phospholipid association may be used as a suitable and straightforward strategy to improve therapeutic activities of hesperidin and hesperetin by increasing their solubility and bioavailability.

Recent Progress in the Hesperetin Delivery Regimes: Significance of Pleiotropic Actions and Synergistic Anticancer Efficacy.

BACKGROUND: In the plant kingdom, flavonoids are widely distributed with multifunctional immunomodulatory actions. Hesperetin (HST) remains one of the well-studied compounds in this domain, initially perceived in citrus plants as an aglycone derivative of hesperidin (HDN). OBSERVATIONS: Natural origin, low in vivo toxicity, and pleiotropic functional essence are the foremost fascinations for HST use as an anticancer drug. However, low aqueous solubility accompanied with a prompt degradation by intestinal and hepatocellular enzymes impairs HST physiological absorption. MOTIVATION: Remedies attempted herein comprise the synthesis of derivatives and nanocarrier (NC)-mediated delivery. As the derivative synthesis aggravates the structural complexity, NC-driven HST delivery has emerged as a sustainable approach for its sustained release. Recent interest in HST has been due to its significant anticancer potential, characterized via inhibited cell division (proliferation), new blood vessel formation (angiogenesis), forceful occupation of neighboring cell's space (invasion), migration to erstwhile physiological locations (metastasis) and apoptotic induction. The sensitization of chemotherapeutic drugs (CDs) by HST is driven via stoichiometrically regulated synergistic actions. Purpose and Conclusion: This article sheds light on HST structure-function correlation and pleiotropic anticancer mechanisms, in unaided and NC-administered delivery in singular and with CDs synergy. The discussion could streamline the HST usefulness and long-term anticancer efficacy.

Hesperidin: A Review on Extraction Methods, Stability and Biological Activities.

Hesperidin is a bioflavonoid occurring in high concentrations in citrus fruits. Its use has been associated with a great number of health benefits, including antioxidant, antibacterial, antimicrobial, anti-inflammatory and anticarcinogenic properties. The food industry uses large quantities of citrus fruit, especially for the production of juice. It results in the accumulation of huge amounts of by-products such as peels, seeds, cell and membrane residues, which are also a good source of hesperidin. Thus, its extraction from these by-products has attracted considerable scientific interest with aim to use as natural antioxidants. In this review, the extraction and determination methods for quantification of hesperidin in fruits and by-products are presented and discussed as well as its stability and biological activities.

Extraction of potential bioactive compounds from industrial Tahiti lime (Citrus latifólia Tan.) by-product using pressurized liquids and ultrasound-assisted extraction.

This work evaluated two emerging techniques in extracting phenolic compounds from Tahiti lime pomace - pressurized liquid extraction (PLE) and ultrasound-assisted extraction (UAE). PLE was performed at different temperatures (60 - 110 °C) and times (5 - 40 min), and UAE was carried out varying ultrasound power (160 - 792 W), time (2 - 10 min), and solvent to feed mass ratio (20 - 40 kg solvent/kg dried pomace). Both used ethanol and water (3:1, wt.) as the solvent. The effects of these variables were evaluated on global extraction yield, polyphenols, hesperidin, narirutin yields, and antioxidant capacity. PLE was strongly affected by temperature and extraction time, and the highest temperature (110 °C) provided the best results for global yield, total phenolic, and ORAC, except for hesperidin and narirutin, which were not significative affected by temperature. UAE revealed a weak dependency on power, S/F, and time; however, the lowest power level significantly increased the yields compared to no power application. Thus, P = 480 W, t = 6 min, and S/F = 30 was chosen as the best condition in the UAE in terms of overall extraction yield, total phenolics, specific phenolics, antioxidant capacities, and solvent and energy expenditures. UAE mechanisms were investigated by comparing with heated and stirred maceration, and scanning electron microscopy suggested that total phenolic yield was influenced by mechanisms that only ultrasound can provide. Micrographics confirmed the cavitation effect on Tahiti lime pomace particles' surface. To sum up, PLE resulted in the highest yields and antioxidant capacity, followed by UAE.

Experimental, molecular docking and molecular dynamic studies of natural products targeting overexpressed receptors in breast cancer.

Natural compounds are proper tools for inhibiting cancer cell proliferation. Hence, the search for these ligands of overexpressed receptors in breast cancer has been a competitive challenge recently and opens new avenues for drug discovery. In this research, we have investigated molecular interactions between natural products and overexpressed receptors in breast cancer using molecular docking and dynamic simulation approaches followed by extraction of the best ligand from Citrus limetta and developing for nanoscale encapsulation composed of soy lecithin using a sonicator machine. The encapsulation process was confirmed by DLS and TEM analyses. Anticancer activity was also examined using MTT method. Among the investigated natural compounds, hesperidin was found to bind to specific targets with stronger binding energy. The molecular dynamics results indicated that the hesperidin-MCL-1 complex is very stable at 310.15 K for 200 ns. The RP-HPLC analysis revealed that the purity of extracted hesperidin was 98.8% with a yield of 1.72%. The results of DLS and TEM showed a strong interaction between hesperidin and lecithin with an entrapped efficiency of 92.02 ± 1.08%. Finally, the cytotoxicity effect of hesperidin was increased against the MDA-MB-231 cell line with an IC50 value of 62.93 µg/mL after encapsulation, whereas no significant effect against the MCF10A cell line. We showed for the first time that hesperidin is a flexible and strong ligand for the MCL-1 receptor. Also, it has the in vitro ability to kill the MDA-MB-231 cell lines without having a significant effect on the MCF10A cell lines. Therefore, hesperidin could be used as a food ingredient to generate functional foods.

Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors.

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)-a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer-particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.