Effects of hesperetin on the production of inflammatory mediators in IL-1β treated human synovial cells

This study was conducted to evaluate the efficacy of hesperetin in regulating interleukin-1β (IL-1β)-induced production of the matrix metalloproteinase (MMP)-3 and IL-6 in human synovial cell line, SW982. Treatment with hesperetin at 1 or 10 μM significantly (P < 0.05) inhibited IL-1β-induced MMP-3 and IL-6 production when measured by enzyme-linked immunosorbent assay (ELISA). The effects of hesperetin on the activation of mitogen-activated protein kinases (MAPKs) were also examined in SW982 cells by ELISA assay. IL-1β-induced JNK activation was inhibited by hesperetin. These results suggest that hesperetin reduces the production of MMP and IL-6 in SW982 synovial cells by inhibiting JNK.     

Synthesis and biological evaluation of hesperetin derivatives as agents inducing apoptosis

A flavanone, hesperetin, has been known to exert antitumor activity by inducing apoptosis. To find hesperetin derivatives showing better antitumor activity, 12 derivatives were designed and synthesized. Their antitumor activities were measured using a long-term survival clonogenic assay. Among the compounds, K-5b, hesperetin-7-butyrate, showed the half-maximal cell growth inhibitory concentration three times as low as that of hesperetin. To compare the cytotoxicity of hesperetin and K-5b, the HCT116 human colon cancer cell line was treated with various concentrations of each compound. K-5b decreased the cell viability to a larger extent than hesperetin and triggered apoptosis more efficiently than hesperetin in an apoptosis detection assay using fluorescein isothiocyanate-labeled annexin V. Immunoblotting analysis showed that K-5b promoted caspase-mediated apoptosis more efficiently than hesperetin. Because hesperetin has been reported to induce apoptosis through the activation of the c-Jun N-terminal kinase (JNK) pathway, we tested whether K-5b activates JNKs. K-5b stimulated JNK1 and JNK2 more efficiently than hesperetin as shown by western blot analysis. In conclusion, hesperetin derivatives exerting better antitumor activity than hesperetin by inducing apoptosis were found.     

Hesperidin and its aglycone hesperetin in breast cancer therapy: A review of recent developments and future prospects

Breast cancer (BC) has high incidence and mortality rates, making it a major global health issue. BC treatment has been challenging due to the presence of drug resistance and the limited availability of therapeutic options for triple-negative and metastatic BC, thereby urging the exploration of more effective anti-cancer agents. Hesperidin and its aglycone hesperetin, two flavonoids from citrus species, have been extensively evaluated for their anti-cancer potentials. In this review, available literatures on the chemotherapeutic and chemosensitising activities of hesperidin and hesperetin in preclinical BC models are reported. The safety and bioavailability of hesperidin and hesperetin as well as the strategies to enhance their bioavailability are also discussed. Overall, hesperidin and hesperetin can inhibit cell proliferation, migration and BC stem cells as well as induce apoptosis and cell cycle arrest in vitro. They can also inhibit tumour growth, metastasis and neoplastic changes in tissue architecture in vivo. Moreover, the co-administration of hesperidin or hesperetin with doxorubicin, letrozole or tamoxifen can enhance the efficacies of these clinically available agents. These chemotherapeutic and chemosensitising activities of hesperidin and hesperetin have been linked to several mechanisms, including the modulation of signalling pathways, glucose uptake, enzymes, miRNA expression, oxidative status, cell cycle regulatory proteins, tumour suppressor p53, plasma and liver lipid profiles as well as DNA repair mechanisms. However, poor water solubility, extensive phase II metabolism and apical efflux have posed limitations to the bioavailability of hesperidin and hesperetin. Various strategies for bioavailability enhancement have been studied, including the utilisation of nano-based drug delivery systems and the co-administration of hesperetin with other flavonoids. In particular, nanoformulated hesperidin and hesperetin possess greater chemotherapeutic and chemosensitising activities than free compounds. Despite promising preclinical results, further safety and efficacy evaluation of hesperidin and hesperetin as well as their nanoformulations in clinical trials is required to ascertain their potentials to be developed as clinically useful agents for BC treatment.     

Effects of supplemental levels of hesperetin and naringenin on egg quality, serum traits and antioxidant activity of laying hens

Hesperetin and naringenin phytochemicals are naturally occurring flavanoids in citrus fruits. The purpose of this study was to evaluate the effects of supplementing different levels of extracted hesperetin and naringenin on egg quality, serum traits and antioxidant activity in laying hens. Two experiments were conducted, each for 10 weeks, in a completely randomized experiment design. Each had 100 Leghorn laying hens (26 weeks old) randomly assigned into five groups (n = 20) based on dietary categories of hesperetin 0, 0.5, 1, 2, 4 g/kg and naringenin 0, 0.5, 1, 2, 4 g/kg. Experimental results indicated that there was increased (P<0.05) egg production in the 1 g/kg naringenin-supplemented group, but lower (P<0.05) egg production in the hesperetin- and naringenin-supplemented groups given 4 g/kg. Cholesterol content (per gram yolk) and total cholesterol content (per egg) were lower (P<0.05) in the hesperetin- and naringenin-supplemented groups as compared to the control group, and the 2 g/kg hesperetin- and naringenin-supplemented groups showed the most significant difference. Both serum cholesterol and triglyceride concentrations were lower (P<0.05) in the 2 g/kg hesperetin- and naringenin-supplemented groups. The SOD and catalase activities, scavenging O₂⁻ and iron-chelating abilities were higher (P<0.05) in the 2 g/kg hesperetin- and naringenin-supplemented groups, and the trolox equivalent antioxidant capacity was higher (P<0.05) in the 2 g/kg naringenin-supplemented group. The results confirmed that both hesperetin and naringenin could lower serum and egg yolk cholesterol levels, and improve the antioxidant activities, however the measured variables generally showed significant quadratic responses to increasing amounts of the compounds. The recommended supplementation level of hesperetin and naringenin is 2 g/kg of the basal diet for reduced serum and yolk cholesterols contents and increased antioxidant capacity.     

Hesperetin: A Potent Antioxidant Against Peroxynitrite

Peroxynitrite (ONOO^-) is a reactive oxidant formed from superoxide (?O_2-) and nitric oxide (?NO), that can oxidize several cellular components, including essential protein, non-protein thiols, DNA, low-density lipoproteins (LDL), and membrane phospholipids. ONOO^- has contributed to the pathogenesis of diseases such as stroke, heart disease, Alzheimer's disease, and atherosclerosis. Because of the lack of endogenous enzymes to thwart ONOO^- activation, developing a specific ONOO^- scavenger is remarkably important. In this study, the ability of hesperetin (3′,5,7-trihydroxy-4-methoxyflavanone) to scavenge ONOO^- and to protect cells against ONOO^- and ROS was investigated. The data gained show that hesperetin can efficiently scavenge authentic ONOO^-. In spectrophotometric analysis, the data revealed that hesperetin led to declined ONOO^--mediated nitration of tyrosine through electron donation. Hesperetin exhibited significant inhibition on the nitration of bovine serum albumin (BSA) by ONOO^- in a dose-dependent manner. Hesperetin also manifested cytoprotection from cell damage induced by ONOO^- and ROS. The present study suggests that hesperetin is a powerful ONOO^- scavenger and promotes cellular defense activity in the protection against ONOO^- involved diseases.     

Peroxynitrite induced formation of the neurotoxins 5-S-cysteinyl-dopamine and DHBT-1: implications for Parkinson's disease and protection by polyphenols

Mechanisms of nigral cell injury in Parkinson’s disease remain unclear, although a combination of increased oxidative stress, the formation of catecholamine-quinones and the subsequent formation of neurotoxic cysteinyl-catecholamine conjugates may contribute. In the present study, peroxynitrite was observed to generate both 2-S- and 5-S-cysteinyl-dopamine and a dihydrobenzothiazine species, DHBT-1, following the reaction of dopamine with l-cysteine. The formation of 5-S-cysteinyl-dopamine and DHBT-1 in the presence of peroxynitrite induced significant neuronal injury. Pre-treatment of cortical neurons with pelargonidin, quercetin, hesperetin, caffeic acid, the 4′-O-Me derivatives of catechin and epicatechin (0.1-3.0 μM) resulted in concentration dependant protection against 5-S-cysteinyl-dopamine-induced neurotoxicity. These data suggest that polyphenols may protect against neuronal injury induced by endogenous neurotoxins relevant to the aetiology of the Parkinson disease.     

Hesperetin attenuates the highly reducing sugar-triggered inhibition of osteoblast differentiation

Diabetic bone disease is associated with increased oxidative damage and 2-deoxy-d-ribose (dRib) is used to induce oxidative damage similar to that observed in diabetics. To determine if hesperetin (3′,5,7-trihydroxy-4-methoxyflavanone) could influence osteoblast dysfunction induced by dRib, osteoblastic MC3T3-E1 cells were treated with dRib and hesperetin. Then, markers of osteoblast function and oxidative damage were examined. Hesperetin (10⁻⁷–10⁻⁵ M) caused a significant elevation of alkaline phosphatase (ALP) activity, collagen content, and total antioxidant potential of MC3T3-E1 cells in the presence of 20 mM dRib (p < 0.05). Moreover, hesperetin (10⁻⁷ M) decreased cellular protein carbonyl (PCO), advanced oxidation protein products (AOPP), and malondialdehyde (MDA) contents of osteoblastic MC3T3-E1 cells in the presence of 20 mM dRib. These results demonstrate that hesperetin attenuates dRib-induced damage, suggesting that hesperetin may be a useful dietary supplement for minimizing oxidative injury in diabetes related bone diseases.     

Hesperetin: a potent antioxidant against peroxynitrite

Peroxynitrite (ONOO_-) is a reactive oxidant formed from superoxide (•O₂^-) and nitric oxide (•NO), that can oxidize several cellular components, including essential protein, non-protein thiols, DNA, low-density lipoproteins (LDL), and membrane phospholipids. ONOO_- has contributed to the pathogenesis of diseases such as stroke, heart disease, Alzheimer's disease, and atherosclerosis. Because of the lack of endogenous enzymes to thwart ONOO_- activation, developing a specific ONOO_- scavenger is remarkably important. In this study, the ability of hesperetin (3',5,7-trihydroxy-4-methoxyflavanone) to scavenge ONOO_- and to protect cells against ONOO_- and ROS was investigated. The data gained show that hesperetin can efficiently scavenge authentic ONOO_-. In spectrophotometric analysis, the data revealed that hesperetin led to declined ONOO_--mediated nitration of tyrosine through electron donation. Hesperetin exhibited significant inhibition on the nitration of bovine serum albumin (BSA) by ONOO_- in a dose-dependent manner. Hesperetin also manifested cytoprotection from cell damage induced by ONOO_- and ROS. The present study suggests that hesperetin is a powerful ONOO_- scavenger and promotes cellular defense activity in the protection against ONOO_- involved diseases.     

Oral consumption of α-glucosyl-hesperidin could prevent lens hardening,which causes presbyopia

Presbyopia is one of the most well-known diseases of the eye, predominantly affecting the adult population after 50 years’. Due to hardening of the lens and failure of accommodative change, patients lose the ability to focus on near objects. This eye symptom is reported to be an early symptom of age-related nuclear cataract, and we have previously reported that hesperetin treatment could delay the onset of nuclear cataractogenesis induced by sodium selenite. In this study, we examined whether oral intake of α-glucosyl-hesperidin (G-Hsd), which has greater water solubility than hesperetin, could delay the onset of presbyopia. G-Hsd treatment protected lens elasticity, upregulated the mRNA expression of anti-oxidative enzymes like glutathione reductase and thioredoxin reductase 1 in the plasma and lens, and prevented premature cataract symptoms in selenite-induced cataract rat lens. Thus, the anti-presbyopic effects of G-Hsd were attributed, at least in part, to its antioxidant effects. G-Hsd represents the first oral treatment agent with anti-presbyopia and/or anti-cataract properties.