In vitro evaluation of PLGA loaded hesperidin on colorectal cancer cell lines: an insight into nano delivery system.

BACKGROUND: Colorectal cancer is a common disease worldwide with non-specific symptoms such as blood in the stool, bowel movements, weight loss and fatigue. Chemotherapy drugs can cause side effects such as nausea, vomiting and a weakened immune system. The use of antioxidants such as hesperidin could reduce the side effects, but its low bioavailability is a major problem. In this research, we aimed to explore the drug delivery and efficiency of this antioxidant on the HCT116 colorectal cancer cell line by loading hesperidin into PLGA nanoparticles. MATERIALS AND METHODS: Hesperidin loaded PLGA nanoparticles were produced by single emulsion evaporation method. The physicochemical properties of the synthesized hesperidin-loaded nanoparticles were determined using SEM, AFM, FT-IR, DLS and UV-Vis. Subsequently, the effect of the PLGA loaded hesperidin nanoparticles on the HCT116 cell line after 48 h was investigated by MTT assay at three different concentrations of the nanoparticles. RESULT: The study showed that 90% of hesperidin were loaded in PLGA nanoparticles by UV-Vis spectrophotometry and FT-IR spectrum. The nanoparticles were found to be spherical and uniform with a hydrodynamic diameter of 76.2 nm in water. The release rate of the drug was about 93% after 144 h. The lowest percentage of cell viability of cancer cells was observed at a concentration of 10 µg/ml of PLGA nanoparticles loaded with hesperidin. CONCLUSION: The results indicate that PLGA nanoparticles loaded with hesperidin effectively reduce the survival rate of HCT116 colorectal cancer cells. However, further studies are needed to determine the appropriate therapeutic dosage and to conduct animal and clinical studies.

Enhanced Therapeutic Efficacy Against Melanoma through Exosomal Delivery of Hesperidin.

Melanoma, characterized as the most aggressive and metastatic form of skin cancer, currently has limited treatment options, predominantly chemotherapy and radiation therapy. However, the drawbacks associated with parenterally administered chemotherapy underscore the urgent need for alternative compounds to combat melanoma effectively. Hesperidin (HES), a flavonoid present in various citrus fruits, exhibits promising anticancer activity. Nevertheless, the clinical utility of HES is hindered by challenges such as poor water solubility, a short half-life, and low oral bioavailability. In response to these limitations, we introduced a novel approach by formulating HES-loaded exosomes (Exo-HES). Isolation of exosomes was achieved through the ultracentrifugation method, and HES was efficiently loaded using the sonication method. The resulting formulations displayed a desirable particle size (∼106 nm) and exhibited a spherical morphology, as confirmed by scanning electron and atomic force microscopy. In vitro studies conducted on B16F10 cell lines demonstrated higher cytotoxicity of Exo-HES compared to free HES, supported by enhanced cellular uptake validated through coumarin-6-loaded exosomes. This superior cytotoxicity was further evidenced by DNA fragmentation, increased generation of free radicals (ROS), loss of mitochondrial membrane potential, and effective inhibition of colony formation. The antimetastatic properties of Exo-HES were confirmed through wound healing and transwell migration assays. Oral pharmacokinetics studies revealed a remarkable increase of approximately 2.5 times in oral bioavailability and half-life of HES when loaded into exosomes. Subsequent in vivo experiments utilizing a B16F10-induced melanoma model in Swiss mice established that Exo-HES exhibited superior anticancer activity compared to HES after oral administration. Importantly, no biochemical, hematological, or histological toxicities were observed in tumor-bearing mice treated with Exo-HES. These findings suggest that exosomes loaded with HES represent a promising nanocarrier strategy to enhance the therapeutic effectiveness of hesperidin in melanoma treatment.

Hesperidin/Salinomycin Combination; a Natural Product for Deactivation of the PI3K/Akt Signaling Pathway and Anti-Apoptotic Factors in KG1a Cells.

AML is a highly aggressive malignant clonal disease of hematopoietic origin. Hesperidin as a polyphenol glycoside, Activates the apoptotic pathway and salinomycin as a k + selective ionophore. We examined how hesperidin and salinomycin induce pro-apoptotic effects in KG1a cells. Cells were divided into four groups; 1) control cells (CRTL), 2) cells treated with hesperidin 85 µM, 3) cells treated with 2 µM salinomycin, 4) cells treated with combination of salinomycin and hesperidin. The MTT assay was implemented to determine the IC50 of hesperidin and salinomycin in KG1a cell lines. Propidium iodide staining and flow cytometry were used to analyze the distribution of the cell cycle. The level of ROS was evaluated by fluorescent microscopy and spectrophotometry. Additionally, Akt, XIAP, Bad, and FOXO1 gene expression was analyzed by real-time PCR. Hesperidin/Salinomycin decreased the viability of KG1a leukemic cells more than Hesperidin and Salinomycin separately. Changes in the shape of apoptotic cells and rise in ROS levels were detected after Hesperidin/Salinomycin treatment. Our findings showed that following Hesperidin/Salinomycin treatment, the expression of PI3K/AKT signaling pathway related genes (AKT, PTEN and FOXO1), were in line with the destruction of KG-1a cells. Furthermore, XIAP and BAD mRNA were regulated to trigger apoptosis in cancer cells. The study discovered that hesperidin and salinomycin, could effectively hinder the PI3K/Akt signaling pathway in leukemia cancer cells. Also, the combination of hesperidin and salinomycin has the potential to be a treatment option for acute myeloid leukemia.

Hesperidin counteracts chlorpyrifos-induced neurotoxicity by regulating oxidative stress, inflammation, and apoptosis in rats.

Chlorpyrifos (CPF), considered one of the most potent organophosphates, causes a variety of human disorders including neurotoxicity. The current study was designed to evaluate the efficacy of hesperidin (HSP) in ameliorating CPF-induced neurotoxicity in rats. In the study, rats were treated with HSP (orally, 50 and 100 mg/kg) 30 min after giving CPF (orally, 6.75 mg/kg) for 28 consecutive days. Molecular, biochemical, and histological methods were used to investigate cholinergic enzymes, oxidative stress, inflammation, and apoptosis in the brain tissue. CPF intoxication resulted in inhibition of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) enzymes, reduced antioxidant status [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH)], and elevation of malondialdehyde (MDA) levels and carbonic anhydrase (CA) activities. CPF increased histopathological changes and immunohistochemical expressions of 8-OHdG in brain tissue. CPF also increased levels of glial fibrillary acidic protein (GFAP) and nuclear factor kappa B (NF-κB) while decreased levels of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). Furthermore, CPF increased mRNA transcript levels of caspase-3, Bax, PARP-1, and VEGF, which are associated with apoptosis and endothelial damage in rat brain tissues. HSP treatment was found to protect brain tissue by reducing CPF-induced neurotoxicity. Overall, this study supports that HSP can be used to reduce CPF-induced neurotoxicity.

Hesperidin reduces systolic blood pressure in diabetic patients and has no effect on blood pressure in healthy individuals: A systematic review and meta-analysis.

In recent years, there have been a number of studies where hesperidin was administered to modify arterial blood pressure, but the conclusions of each study are contradictory. In order to investigate the effect of hesperidin on blood pressure, we searched the CNKI, Wanfang Database, the VIP database, Sinomed database, Pubmed, Embase and The Cochrane Library databases, and searched the literature on hesperidin and blood pressure published in Chinese and English journals, mainly focusing on patients' systolic blood pressure and diastolic blood pressure. The search time frame was from the inception of the databases until December 2023. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the overall quality and used Cohen's kappa coefficient (κ) to measure agreement. We did preliminary screening of the retrieved literature through Notexpress, 14 articles with a total of 656 patients were included. Cochrance data conversion tool was used for data conversion, and RevMan 5.3 was used for meta-analysis, and finally Stata was used to make the Egger's test for the included study. The results of total population blood pressure showed that hesperidin had no antihypertensive effect on the population, but the conclusions changed when the population was divided into groups. The results of different populations showed that hesperidin had no effect on systolic blood pressure (weighted mean difference [WMD] = -0.50, 95% CI: -3.25 ~ 2.26, Z = 0.35, p = 0.72) and diastolic blood pressure (WMD = -0.51, 95% CI: -2.53 ~ 1.51, Z = 0.50, p = 0.62) in healthy individuals. However, hesperidin reduced systolic blood pressure in patients with type 2 diabetes (WMD = -4.32, 95% CI: - 7.77 ~ - 0.87, Z = 2.45, p = 0.01), and had a tendency to reduce diastolic blood pressure in diabetic patients (WMD = -3.72, 95% CI: -7.63 ~ 0.18, Z = 1.87, p = 0.06). The results in patients with type 2 diabetes needed to be further supported by future research focusing on individuals with diabetes.

Effect of hesperidin on blood pressure and lipid profile: A systematic review and meta-analysis of randomized controlled trials.

The cardioprotective activity of hesperidin has been well demonstrated in several clinical studies. Also, there is a meta-analysis published on this topic in 2019. However, considering the recently published clinical studies, there is a scope for performing a systematic review and meta-analysis of hesperidin to determine its beneficial effect in alleviating alterations in cardiovascular parameters. In this study, the literature search was performed using online databases such as PubMed and Google Scholar till April 2023 involving randomized controlled studies conducted on hesperidin against various cardiovascular disorders including metabolic disorders in healthy/diseased individuals compared to the placebo/control. Based on the inclusion and exclusion criteria, nine clinical studies involving 2414 subjects were included. The meta-analysis revealed that hesperidin has significantly reduced the low-density lipoprotein (LDL) (IV: -0.55 (-0.94 to -0.16) at 95% CI, p = 0.005, I2 = 70%), total cholesterol (TC) (IV: -61 (-0.82 to -0.41) at 95% CI, p < 0.00001, I2 = 69%), and triglycerides (TG) (IV: -0.21 (-0.40 to -0.02) at 95% CI, p = 0.03, I2 = 12%). However, there were no statistically significant changes in the systolic blood pressure (IV: -0.29 (-2.21 to 1.63) at 95% CI, p = 0.77, I2 = 60%), diastolic blood pressure (IV: 0.79 (-0.74 to 2.31) at 95% CI, p = 0.31, I2 = 49%), and high-density lipoprotein (IV: 0.04 (-0.25 to 0.34) at 95% CI, p = 0.78, I2 = 56%) in the hesperidin treatment compared to the placebo/control. In conclusion, the outcomes of this meta-analysis suggest that hesperidin administration could benefit patients with CVD by reducing LDL, TC, and TG. Further high-quality studies are needed to firmly establish the clinical efficacy of hesperidin for its benefits in treating cardiovascular conditions.

Niosomal hesperidin attenuates the M1/M2-macrophage polarization-based hepatotoxicity followed chlorpyrifos -induced toxicities in mice.

Chlorpyrifos(CPF) is a well-known hepatotoxic agent that has side effects on several organs. On the contrary, hepatic macrophages are crucial in maintaining liver tissue integrity. The main objective of this study was to evaluate the effects and possible mechanisms of niosomal hesperidin (Nio + Hesp), a flavanone glycoside found in citrus fruits, on M1-M2 liver macrophage polarization and inflammatory cells in the brain, liver, and ovarian tissues. Forty C57 mice were divided into CPF(3 mg/kg), Sham(Dimethyl sulfoxide 40 µL/kg), CPF + Hesp(100 mg/kg), and CPF + Nio + Hesp (100 mg/kg) groups. The activity of sera superoxide dismutase (SOD) and malondialdehyde (MDA), brain, liver, and ovary tissues changes, and M1-M2 liver macrophage polarization were evaluated by examining the expression of CD163 and CD68 genes. Hepatic lesions consisting of sporadic foci of coagulation necrosis, inflammatory cell reaction, and regenerative fibrosis were seen following CPF injection, reflected by significant overexpression of CD163 and CD68 genes. In comparison, Nio + Hesp declined the amount of cell apoptosis in the liver and downregulated CD163 and CD68 gene expression. Both Nio + Hesp and Hesp alleviated CPF-induced hepatotoxicity, however, Nio + Hesp was superior to hesperidin in the downregulation of the CD163 and CD68 gene expression. Even though a significant difference between hesperidin and Nio + Hesp was observed in the number of Graafian follicles, corpus luteum, and peri-antral follicles, no substantial difference was observed in primary follicles. The ameliorative effects of Hesp and Nio + Hesp may be at least in part due to their antioxidant and anti-inflammatory properties. These findings showed that both M1- and M2-macrophages contributed to the development of hepatic lesions induced by CPF and provided information about macrophage activation, indicating the importance of analysis of macrophage phenotypes for hepatotoxicity based on M1/M2-polarization which can be downregulated by niosomal nesperidin.

Octanal enhances disease resistance in postharvest citrus fruit by the biosynthesis and metabolism of aromatic amino acids.

Octanal was found to be able to reduce green mold incidence in citrus fruit by a defense response mechanism. However, the underlying mechanism remains largely unclear. Herein, the metabolomics, RNA-seq and biochemical analyses were integrated to explore the effect of octanal on disease resistance in harvested citrus fruit. Results showed that octanal fumigation at 40 µL L-1 was effective in controlling citrus green mold. Metabolomics analysis showed that octanal mainly led to the accumulation of some plant hormones including methyl jasmonate, abscisic acid, indole-3-butyric acid, indoleacetic acid (IAA), salicylic acid, and gibberellic acid and many phenylpropanoid metabolites including cinnamyl alcohol, hesperidin, dihydrokaempferol, vanillin, quercetin-3-O-malonylglucoside, curcumin, naringin, chrysin, coniferin, calycosin-7-O-ß-D-glucoside, trans-cinnamaldehyde, and 4',5,7-trihydroxy-3,6-dimethoxyflavone. Particularly, IAA and hesperidin were dramatically accumulated in the peel, which might be the contributors to the resistance response. Additionally, transcriptome analysis showed that octanal greatly activated the biosynthesis and metabolism of aromatic amino acids. This was further verified by the accumulation of some metabolites (shikimic acid, tryptophan, tyrosine, phenylalanine, IAA, total phenolics, flavonoids and lignin), increase in some enzyme activities (phenylalanine ammonia-lyase, tyrosine ammonia-lyase, 4-coumarate CoA ligase, cinnamic acid 4-hydroxylase, polyphenol oxidase, and peroxidase), up-regulation of some genes (tryptophan pyruvate aminotransferase, aldehyde dehydrogenase, shikimate kinase and shikimate dehydrogenase) expressions and molecular docking results. Thus, these results indicate that octanal is an efficient strategy for the control of postharvest green mold by triggering the defense response in citrus fruit.

Protective Effects of Tunisian Orange Co-Product Extract and Oleuropein-Hesperidin Combination on Bleomycin-Induced Pulmonary Fibrosis in Rats.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia that leads to acute lung damage, deterioration of lung function, and increased mortality risk. In this study, we investigated the effects of the orange coproduct extract (OCE) and the combination of pure hesperidin and oleuropein (HO) on an experimental model of pulmonary fibrosis induced by bleomycin (BLM) in Wistar rats. Rats were divided into six groups: the control group (G1), the BLM group (G2), three groups (G3, G4, G5) receiving a single dose of BLM combined with OCE extract at 100, 200, and 300 mg/kg, and group 6 (G6) receiving a single dose of BLM combined with HO: both pure major phenolic compounds of OCE (hesperidin at 50 mg/kg) and olive leaves (oleuropein at 2.5 mg/kg). Oxidative stress in lung tissues was investigated using catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX) assays and the measurement of malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels. Treatment with OCE and HO normalized the disturbance in oxidative markers' levels and showed a significant reduction in fibrosis score with no renal or hepatic toxic effects. In conclusion, OCE and HO exhibit antifibrotic effects on a rat model of pulmonary fibrosis.

Naringenin, Hesperidin and Quercetin Ameliorate Radiation-Induced Damage In Rats: In Vivo And In Silico Evaluations.

In this study, we sought to determine how well naringenin, hesperidin, and quercetin prevented damage brought on by radiotherapy. During the investigation, 48 adult female Sprague Dawley rats were used. Eight groups of eight rats each were formed by randomly assigning the rats to the groups. The normal control group was represented by Group 1. Group 2 rats were those that received a dose of 15 Gray (Gy) of radiotherapy. The rats assigned to Group 3 received only Naringenin, whereas those assigned to Group 4 received only quercetine, and those assigned to Group 5 received only hesperidin. Rats in Group 6, 7 and 8 were received naringenin, quarcetin and hesperidin at a dose of 50 mg/kg daily for one week prior to radiotheraphy exposition. After radiotheraphy and phenolic compounds rats were sacrificed and some metabolic enzyme (aldose reductase (AR), sorbitol dehydrogenase (SDH), paraoxonase-1 (PON1), butyrylcholinesterase (BChE) and glutathione S-transferase (GST)) activity was determined in eye and brain tissues. It was found that phenolic compounds have protective effect against radiation-induced damage because of their anti-diabetic antioxidant and anti-inflammatory properties. In addition, hesperidin was found to be superior to quercetin and naringenin in terms of enzyme activity efficacy. Furthermore, hesperidin exhibited favorable binding affinity for BChE in silico compared to other enzymes.

Exploring In-Silico, In-Vitro Antioxidant, and Cytotoxic Potential of Valerian wallichii by On Cervical Epithelial Carcinoma (HeLa) Cell Lines.

Traditional medicinal practices often utilize herbal remedies for treating various diseases. This study focuses on exploring the phytochemical constituents, in-silico, in-vitro antioxidant, and anticancer activities of Valerian wallichii root extracts on human cervical epithelial carcinoma (HeLa) cell lines. The molecular docking approach was employed to predict the ligand molecule's orientation within the receptor like Epidermal growth factor receptor tyrosine kinase domain (PDB ID: 1M17) using Schrodinger's GLIDE model. Among the selected phytocompounds, hesperidin exhibited promising inhibitory activity against EGFR (Epidermal Growth Factor Receptor) domain with -8.701 kcal/mol docking score and interactions with MET 769, ASP 831, ASP776, LEU694 and ASN818 residues as compared to standard doxorubicin with -7.6 kcal/mol docking score and interactions with ASP 831, ASN818 and ASP776 residues and further, various antioxidant activity was assessed and In-vitro anticancer activity against HeLa cell lines was evaluated by hydroalcoholic root extracts demonstrated antioxidant capacities, and selective cytotoxicity was observed, with IC50 : 45.759±0.42 µg/mL for the overall extract and IC50 : 30.245±0.58 µg/mL for the EAF fraction as compared to standard doxorubicin with IC50 : 25.9891±0.25 µg/mL, respectively. The present study concluded that Valerian wallichii L possesses potential human cervical epithelial carcinoma cell line inhibition properties based on the computer aided drug design models and in-vitro activity.

Enhancement of aqueous solubility of hesperidin and naringenin utilizing hydrotropic solubilization technique: characterization and in vitro evaluation.

The therapeutic potential of two important flavonoids, i.e. hesperidin and naringenin, remains unutilized due to pharmacokinetics issues, especially poor aqueous solubility. Hydrotropic solid dispersions with different agents like sodium salicylate, niacinamide, benzoic acid, and urea etc. can change the solubility profile of poorly soluble drugs. The current study investigated the potential of different hydrotropic agents in improving the solubility of both natural bioactives. The hydrotropic solid dispersion in 1:3 w/w drug: sodium salicylate ratio showed maximum solubility and dissolution amongst all the tested hydrotropes. This novel and economical approach could be explored for other poorly soluble pharmaceuticals.

Anti-inflammatory effects of hesperidin on human gingival fibroblasts stimulated by lipopolysaccharide of Porphyromonas gingivalis in vitro.

Periodontal disease is an inflammatory disease caused by periodontopathogenic bacteria, the inflammatory response generated against them, and host factors. Furthermore, environmental factors can lead to disease progression. Using lipopolysaccharide (LPS)-stimulated human gingival fibroblast (HGF), this study investigated the bioactivity of HGF after exposure to hesperidin (Hesp) and the anti-inflammatory activity of Hesp against early periodontitis. HGF were cultured in Dulbecco's modified Eagle's medium containing 15% fetal bovine serum. They were exposed to LPS for 6 h, followed by Hesp (1, 10, 30, and 50 µM) exposure for 4 h. Cell proliferation was evaluated using reduction staining with alamerBlue™. Inflammatory cytokines [interleukin (IL)-6 and IL-8] and Toll-like receptor 4 (TLR4) levels were assessed using reverse transcription quantitative polymerase chain reaction. Hesp 50 µM + LPS inhibited cell proliferation. The Hesp exposure group inhibited the expression of IL-8 and IL-6. No significant difference in TLR4 expression was observed. Hesp significantly suppressed IL-6 and IL-8 expression by inhibiting downstream signaling without inhibiting TLR4 activation.

Hesperidin from Orange Peel as a Promising Skincare Bioactive: An Overview.

The pursuit for better skin health, driven by collective and individual perceptions, has led to the demand for sustainable skincare products. Environmental factors and lifestyle choices can accelerate skin aging, causing issues like inflammation, wrinkles, elasticity loss, hyperpigmentation, and dryness. The skincare industry is innovating to meet consumers' requests for cleaner and natural options. Simultaneously, environmental issues concerning waste generation have been leading to sustainable strategies based on the circular economy. A noteworthy solution consists of citrus by-product valorization, as such by-products can be used as a source of bioactive molecules. Citrus processing, particularly, generates substantial waste amounts (around 50% of the whole fruit), causing unprecedented environmental burdens. Hesperidin, a flavonoid abundant in orange peels, is considered to hold immense potential for clean skin health product applications due to its antioxidant, anti-inflammatory, and anticarcinogenic properties. This review explores hesperidin extraction and purification methodologies as well as key skincare application areas: (i) antiaging and skin barrier enhancement, (ii) UV radiation-induced damage, (iii) hyperpigmentation and depigmentation conditions, (iv) wound healing, and (v) skin cancer and other cutaneous diseases. This work's novelty lies in the comprehensive coverage of hesperidin's promising skincare applications while also demonstrating its potential as a sustainable ingredient from a circular economy approach.

Formulation of hesperidin-loaded in situ gel for ocular drug delivery: a comprehensive study.

BACKGROUND: Allergic conjunctivitis is one of the most common eye disorders. Different drugs are used for its treatment. Hesperidin is an active substance isolated from Citrus sinensis L. (Rutaceae) fruit peels, with known anti-inflammatory activity but low solubility. It was complexed with cyclodextrin and encapsulated in situ gel to extend its duration in the eye. RESULTS: The optimized formulation comprised 1% hesperidin, 1.5% hydroxyethyl cellulose, and 16% poloxamer 407. The viscosity at 25 °C was 492 ± 82 cP, and at 35 °C it was 8875 ± 248 cP, the pH was 7.01 ± 0.03, gelation temperature was 34 ± 1.3 °C, and gelation time was 33 ± 1.2 s. There was a 66% in vitro release in the initial 2 h, with a burst effect. A lipoxygenase (LOX) inhibition test determined that hesperidin was active at high doses on leukotyrens seen in the body in allergic diseases. In cell-culture studies, the hesperidin cyclodextrin complex loaded in situ gel, BRN9-CD (poloxamer 16%, hydroxy ethyl cellulose (HEC) 1.5%), enhanced cell viability in comparison with the hesperidin solution. It was determined that BRN9-CD did not cause any irritation in the ocular tissues in the Draize test. CONCLUSION: The findings of this study demonstrate the potential of the in situ gel formulation of hesperidin in terms of ease of application and residence time on the ocular surface. Due to its notable LOX inhibition activity and positive outcomes in the in vivo Draize test, it appears promising for incorporation into pharmaceutical formulations. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Pulsed electric field-assisted extraction of hesperidin from tangerine peel and its technological optimization through response surface methodology.

BACKGROUND: Tangerine peel is rich in flavonoids, particularly hesperidin, which has anti-inflammatory, antioxidant and anticancer biological activities. However, it is often wasted during citrus processing. The current common extraction method for hesperidin is solvent extraction, which has the characteristics of low extraction rate and high contamination. The aim of this study was to investigate the effect of pulsed electric field-assisted alkali dissolution extraction, followed by an acidification precipitation method, on the extraction rate and structure of hesperidin from tangerine peel. RESULTS: The results showed that the selected factors (material/liquid ratio, electric field intensity and pulse number) had a significant effect on the extraction yield. An optimum condition of 66.00 mL g-1, 4.00 kV cm-1 and 35.00 pulses gave the maximum amount (669.38 µg mL-1), which was consistent with the theoretically predicted value by software (672.10 µg mL-1), indicating that the extraction process was feasible. In addition, the purified extract was further identified as hesperidin from UV and NMR spectra. CONCLUSION: An appropriate strength of pulsed electric field-assisted alkali dissolution extraction followed by an acidification precipitation method can effectively improve the extraction rate of orange peel, and the purity of the extracted orange peel is higher. Compared with the traditional extraction, the pulsed electric field-assisted extraction method may be a potential technology for hesperidin extraction, which is beneficial for the high-value utilization of citrus resources. © 2024 Society of Chemical Industry.

Co-crystallization of Hesperidin with different co-formers to enhance solubility, antioxidant and anti-inflammatory activities.

Hesperidin (HSP) is a natural flavonoid glycoside with very low aqueous solubility and a slow dissolution rate, limiting its effectiveness. This study aims to address these issues by creating co-crystals of hesperidin with water-soluble small molecules (co-formers) such as L-arginine, glutathione, glycine, and nicotinamide. Using the solvent drop grinding method, we prepared three different molar ratios of hesperidin to co-formers (1:1, 1:3, and 1:5) and conducted in-vitro solubility and dissolution studies. The results demonstrated that the prepared co-crystals exhibited significantly enhanced solubility and dissolution rates compared to untreated hesperidin. Of particular note, the HSP co-crystals formula (HSP: L-arg 1:5) displayed approximately 4.5 times higher dissolution than pure hesperidin. Further analysis using FTIR, powder x-ray diffraction patterns, and DSC thermograms validated the formation of co-crystals between HSP and L-arginine. Additionally, co-crystallization with L-arginine improved the in vitro anti-inflammatory and antioxidant activities of hesperidin compared to the untreated drug. This study highlights the potential of using water-soluble small molecules (co-formers) through co-crystallization to enhance the solubility, dissolution, and biological activities of poorly water-soluble drugs. Furthermore, in vivo studies are crucial to validate these promising results.

Thermoresponsive lipids engineered magnetic nanoparticles for spatiotemporal delivery of hesperidin to inflammatory sites in animal model.

Thermoresponsive nanoparticles are exploited as drug-delivery vehicles that release their payload upon increment in temperature. We prepared and characterized thermoresponsive lipid-anchored folic acid engineered magnetic nanoparticles (LP-HP-FANPs) that combine receptor-based targeting and thermoresponsive sustained release of hesperidin (HP) in response to endogenous inflammation site temperature. The progressive surface engineering of NPs was validated by FTIR analysis. Our LP-HP-FANPs had a particle size of 100.5 ± 1.76 nm and a zeta potential of 14.6 ± 2.65 mV. The HP encapsulation effectiveness of LP-HP-FANPs is around 91 ± 0.78%. AFM scans indicated that our modified nanoparticles were spherical. LP-HP-FANPs exhibit increased drug release (85.8% at pH 4.0, 50.9% at pH 7.0) at 40 °C. Animal studies showed no toxicity from nanoparticles. Compared to conventional drugs and HP, LP-HP-FANPs effectively decreased paw edema, cytokine levels, and total cell recruitment in thioglycollate-induced peritonitis (p < 0.05). LP-HP-FANPs substantially decreased cytokines compared to HP, HP-FA-NPs, and the standard medication (p < 0.05, p < 0.01, and p < 0.001). These findings imply that the synthesized HP-loaded formulation (LP-HP-FANPs) may be a potential anti-inflammatory formulation for clinical development.

Hesperidin, a Potential Antiviral Agent against SARS-CoV-2: The Influence of Citrus Consumption on COVID-19 Incidence and Severity in China.

This review examines hesperidin, a citrus bioflavonoid, as a potential antiviral agent against SARS-CoV-2. The COVID-19 pandemic has demanded an urgent need to search for effective antiviral compounds, including those of natural origin, such as hesperidin. The review provides a comprehensive analysis of the chemical properties, bioavailability and antiviral mechanisms of hesperidin, particularly its potential efficacy against SARS-CoV-2. A review of databases, including PubMedPico, Scopus and Web of Science, was conducted using specific keywords and search criteria in accordance with PRISMA (Re-porting Items for Systematic Reviews and Meta-Analysis) guidelines between 2020 and 2024. Of the 207 articles, 37 were selected for the review. A key aspect is the correlation of in vitro, in silico and clinical studies on the antiviral effects of hesperidin with epidemiological data on citrus consumption in China during 2020-2024. The importance of integrating laboratory findings with actual consumption patterns to better understand the role of hesperidin in mitigating COVID-19 was highlighted, and an attempt was made to analyze epidemiological studies to examine the association between citrus juice consumption as a source of hesperidin and the incidence and severity of COVID-19 using China as an example. The review identifies consistencies and discrepancies between experimental and epidemiological data, highlighting the need to correlate the two fields to better understand the potential of hesperidin as an agent against SARS-CoV-2. Challenges and limitations in interpreting the results and future research perspectives in this area are discussed. The aim of this comprehensive review is to bridge the gap between experimental studies and epidemiological evidence and to contribute to the understanding of their correlation.

Antioxidant and anti-inflammatory activity through inhibition of NF-κB and sEH of some citrus peel and phytoconstituent characteristics.

In Indonesia, there are many types of citrus where parts of the fruit, leaves, and peel can be utilized as food, drinks, spices, and medicine. This research aims to determine the phytochemical characteristics, antioxidant activities, and anti-inflammatory activity through inhibition of NF-κB and sEH, and the main phytoconstituents of three types of citrus fruits that are commonly used as herbs in Indonesia. The flesh and peel of Citrus amblycarpa/CAm, C. aurantiifolia/CAu, and C. hystrix/CH were extracted by Ultrasound-Assisted Extraction (UAE) with 70 % ethanol and then concentrated. All extracts were tested for total flavonoid content (TFC), total polyphenolic content (TPC), chemical constituents using LCMS, and DPPH radical scavenging activity. Molecular docking tests of 33 compounds containing CAm, CAu, and CH fruit peels from the literature study against NF-κB (Nuclear Factor Kappa Beta) and sEH (Soluble Epoxide Hydrolase) were also conducted. The TFC in fruit peels was 13.47-17.34 mg QE/g extract, and in flesh was 1.35-2.51 mg QE/g extract. The TPC in fruit peels was 4.28-6.3 mg GAE/g extract, and in flesh was 0.85-2.09 mg GAE/g extract. The IC50 values of antioxidant activity on fruit peel were 74.01-168.54 µg/mL; and flesh 185.62-2669 µg/mL. CAu peels provided the highest antioxidant activity and polyphenol content. The LC-MS/MS test on citrus peels shows the main chemical compounds: naringin (C27H32O14), naringenin (C15H12O5), hesperidin (C28H34O15), and hesperitin (C16H14O6). Molecular docking shows that naringin and neohesperidin predicted inhibit NF-κB, and hesperidin, neohesperidin, narirutin, naringin, apigenin, kaempferol, quercetin, rutin, eriocitrin, sinensetin, and vitamin A predicted can inhibit sEH enzyme. All citrus peel has stronger antioxidant activity and more flavonoids and phenolics than the flesh. Naringin and neohesperidin can inhibit NF-κB and sEH enzymes. The main flavonoid contents of the citrus peels and presumed to have activity are hesperidin and naringin. These flavonoids and their glycosides can be used as marker phytoconstituents in the quality assurance of pharmaceutical products.