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Hesperidin
Hesperidin
Hesperidin
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Hesperidin
Names
IUPAC name
(2S)-3′,5-Dihydroxy-4′-methoxy-7-[α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranosyloxy]flavan-4-one
Systematic IUPAC name
(22S,42S,43R,44S,45S,46R,72R,73R,74R,75R,76S)-13,25,43,44,45,73,74,75-Octahydroxy-14-methoxy-76-methyl-22,23-dihydro-24H-3,6-dioxa-2(2,7)-[1]benzopyrana-4(2,6),7(2)-bis(oxana)-1(1)-benzenaheptaphan-24-one
Other names
Hesperetin, 7-rutinoside,[1] Cirantin, hesperidoside|heperetin, 7-rhamnoglucoside, hesperitin, 7-O-rutinoside
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.007.536 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C28H34O15/c1-10-21(32)23(34)25(36)27(40-10)39-9-19-22(33)24(35)26(37)28(43-19)41-12-6-14(30)20-15(31)8-17(42-18(20)7-12)11-3-4-16(38-2)13(29)5-11/h3-7,10,17,19,21-30,32-37H,8-9H2,1-2H3/t10-,17-,19+,21-,22+,23+,24-,25+,26+,27+,28+/m0/s1 checkY
    Key: QUQPHWDTPGMPEX-QJBIFVCTSA-N checkY
  • InChI=1/C28H34O15/c1-10-21(32)23(34)25(36)27(40-10)39-9-19-22(33)24(35)26(37)28(43-19)41-12-6-14(30)20-15(31)8-17(42-18(20)7-12)11-3-4-16(38-2)13(29)5-11/h3-7,10,17,19,21-30,32-37H,8-9H2,1-2H3/t10-,17-,19+,21-,22+,23+,24-,25+,26+,27+,28+/m0/s1
    Key: QUQPHWDTPGMPEX-QJBIFVCTBQ
  • InChI=1/C28H34O15/c1-10-21(32)23(34)25(36)27(40-10)39-9-19-22(33)24(35)26(37)28(43-19)41-12-6-14(30)20-15(31)8-17(42-18(20)7-12)11-3-4-16(38-2)13(29)5-11/h3-7,10,17,19,21-30,32-37H,8-9H2,1-2H3/t10-,17-,19+,21-,22+,23+,24-,25+,26+,27+,28+/m0/s1
    Key: QUQPHWDTPGMPEX-QJBIFVCTBQ
  • O=C4c5c(O)cc(O[C@@H]2O[C@H](CO[C@@H]1O[C@H]([C@H](O)[C@@H](O)[C@H]1O)C)[C@@H](O)[C@H](O)[C@H]2O)cc5O[C@H](c3ccc(OC)c(O)c3)C4
Properties
C28H34O15
Molar mass 610.565 g·mol−1
Density 1.65 ± 0.1g/mL (predicted)
Melting point 262 °C
Boiling point 930.1 ± 65 °C (predicted)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Hesperidin is a flavanone glycoside found in citrus fruits. Its aglycone is hesperetin. Its name is derived from the word "hesperidium", for fruit produced by citrus trees.

Hesperidin was first isolated in 1828 by French chemist M. Lebreton from the white inner layer of citrus peels (mesocarp, albedo).[2][3]

Hesperidin is believed to play a role in plant defense.

Sources

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Rutaceae

[edit]

Lamiaceae

[edit]

Peppermint contains hesperidin.[7]

Ultraviolet 280 nm chromatogram after UHPLC separation of commercial orange juice. Hesperidin is the peak at 16.44 min.

Content in foods

[edit]

Approximate hesperidin content per 100 ml or 100 g[8]

Metabolism

[edit]

Hesperidin 6-O-α-L-rhamnosyl-β-D-glucosidase, an enzyme that uses hesperidin and water to produce hesperetin and rutinose, is found in the Ascomycetes species.[9]

Research

[edit]

As a flavanone found in the rinds of citrus fruits (such as oranges or lemons), hesperidin is under preliminary research for its possible biological properties in vivo. One review did not find evidence that hesperidin affected blood lipid levels or hypertension.[10] Another review found that hesperidin may improve endothelial function in humans, but the overall results were inconclusive.[11]

Biosynthesis

[edit]
Chemical drawing scheme depicting the successive chemoenzymatic transformations from L-phenylalanine to arrive at hesperidin.
The biosynthesis of hesperidin proceeds from L-phenylalanine in nine steps.

The biosynthesis of hesperidin stems from the phenylpropanoid pathway, in which the natural amino acid L-phenylalanine undergoes a deamination by phenylalanine ammonia lyase to afford (E)-cinnamate.[12] The resulting monocarboxylate undergoes an oxidation by cinnamate 4-hydroxylase to afford (E)-4-coumarate,[13] which is transformed into (E)-4-coumaroyl-CoA by 4-coumarate-CoA ligase.[14] (E)-4-coumaroyl-CoA is then subjected to the type III polyketide synthase naringenin chalcone synthase, undergoing successive condensation reactions and ultimately a ring-closing Claisen condensation to afford naringenin chalcone.[15] The corresponding chalcone undergoes an isomerization by chalcone isomerase to afford (2S)-naringenin,[16] which is oxidized to (2S)-eriodictyol by flavonoid 3′-hydroxylase.[17] After O-methylation by caffeoyl-CoA O-methyltransferase,[18] the hesperitin product undergoes a glycosylation by flavanone 7-O-glucosyltransferase to afford hesperitin-7-O-β-D-glucoside.[19] Finally, a rhamnosyl moiety is introduced to the monoglycosylated product by 1,2-rhamnosyltransferase, forming hesperidin.[20]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Hesperidin

View on Grokipedia
from Grokipedia
Hesperidin is a glycoside, a type of bioflavonoid, that serves as the 7-O-rutinoside of , consisting of a hesperetin aglycone bound to the rutinose. It has the molecular C28H34O15 and a of 610.57 g/mol, appearing as a white to almost white powder that is practically insoluble in water, slightly soluble in alcohols, and soluble in alkaline solutions. Naturally abundant in the peels and of fruits such as oranges (), lemons (Citrus limon), and grapefruits (Citrus paradisi), hesperidin constitutes approximately 5% of the dry weight in orange peels, making citrus byproducts a primary commercial source for its extraction. First isolated in from orange peels, it is biosynthesized in plants via the phenylpropanoid pathway, where it accumulates as a storage form and contributes to defense against . Hesperidin exhibits a wide array of biological activities, primarily attributed to its properties, which involve scavenging free radicals, chelating metal ions, and enhancing endogenous enzymes like and . Its effects are mediated through inhibition of pro-inflammatory cytokines such as TNF-α and IL-6, as well as modulation of pathways like and MAPK, showing potential in alleviating conditions like and . Cardiovascular benefits include improving endothelial function, reducing , and protecting against by lowering LDL oxidation and platelet aggregation. Additionally, hesperidin demonstrates anticancer activity by inducing and arrest in various lines, alongside neuroprotective effects that mitigate oxidative damage in models of Alzheimer's and Parkinson's diseases. In therapeutic applications, hesperidin is commonly used in supplements, often combined with or , to treat , , and capillary fragility, with clinical evidence supporting its efficacy in reducing symptoms like leg swelling and pain. Beyond , it finds use in the as a natural preservative and , enhancing product stability and providing health-promoting effects in functional foods. Ongoing research explores its potential in metabolic disorders, such as , where it improves insulin sensitivity and , underscoring its multifaceted role as a promising .

Chemical Characteristics

Molecular Structure

Hesperidin is a with the molecular formula C₂₈H₃₄O₁₅. It consists of the aglycone , which is bound to a rutinose moiety comprising α-L- and β-D-glucose. The core structure of hesperidin features the backbone, known as 2-phenylchroman-4-one, characterized by two rings (A and B) connected via a heterocyclic ring (C ring) with a phenyl at the 2-position and a at the 4-position. This backbone is glycosylated at the 7-position of the A ring with the rutinose sugar, where the glucose unit links via a β-1 , and the rhamnose attaches to the glucose at the 6-position. The full systematic name is (2S)-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxo-3,4-dihydro-2H-chromen-7-yl 6-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranoside, highlighting the and substitutions. In comparison to related such as , another , hesperidin is distinguished by its unique 5-hydroxy-4'-methoxy substitution pattern on the aglycone, whereas naringin features a 4',5,7-trihydroxy pattern on naringenin. This methoxy group at the 4' position of the B ring contributes to hesperidin's specific biochemical properties. The name hesperidin originates from "hesperidium," a term referring to the of trees, reflecting its primary natural occurrence in these plants.

Physical and Chemical Properties

Hesperidin appears as a white to pale yellow crystalline powder. It exhibits a of 250–255 °C, at which it decomposes. The compound is levorotatory, with a of approximately -76° (c=2, ). Hesperidin demonstrates poor solubility in water, approximately 57 mg/L at 25 °C, and is essentially insoluble in non-polar solvents such as acetone, , and . It shows slight solubility in alcohols like and , as well as in (DMSO), and dissolves readily in alkaline solutions due to its phenolic groups. Regarding stability, hesperidin is sensitive to , , air exposure, and extreme conditions, where it undergoes degradation primarily through to form . It remains stable under neutral to mildly acidic conditions ( 1–7) and moderate temperatures (up to 40 °C) for extended periods, but degrades more rapidly at alkaline above 9, with half-lives of about 23 days at 25 °C and 4.5 days at 40 °C. The pKa values for hesperidin's phenolic hydroxyl groups are approximately 10, reflecting its weak acidity and influencing solubility in basic media; alcoholic hydroxyl groups have higher pKa values exceeding 11.5.

Natural Sources

Plant Families

Hesperidin is predominantly found in members of the Rutaceae family, particularly within the Citrus genus, which includes species such as sweet orange (Citrus sinensis), lemon (Citrus limon), and grapefruit (Citrus paradisi). This flavanone glycoside accumulates in various plant tissues, with the highest concentrations observed in the peels of immature citrus fruits, where it can constitute up to 2–10% of the dry weight in orange peels. Secondary occurrences are noted in the Lamiaceae family, including in peppermint (Mentha × piperita), where hesperidin is present in the leaves alongside other flavonoids. Minor sources include the Ginkgoaceae family, specifically in the leaves of Ginkgo biloba, as identified in phytochemical analyses. Additionally, hesperidin appears in certain Rosaceae species, such as Potentilla erecta. From an evolutionary perspective, hesperidin serves a protective role in these plants by aiding defense against through UVB absorption and contributing to resistance against bacterial and fungal pathogens as a phytoanticipin.

Content in Foods

Hesperidin is most abundant in fruits, where it serves as a primary contributor to dietary intake. In , concentrations typically range from 20 to 60 mg per 100 mL, equivalent to approximately 20–60 mg per 100 g assuming standard . Similar levels are observed in juices from other varieties, such as tangerines (8–46 mg/100 mL) and lemons (4–41 mg/100 mL). peels, often discarded but rich in hesperidin, contain up to 2,000–10,000 mg per 100 g , making them a concentrated source compared to the edible pulp. Beyond citrus, hesperidin occurs in trace amounts in select non-citrus foods. Peppermint tea infusions provide small quantities, with hesperidin levels around 1–5 mg per cup based on extraction from dried leaves containing 60–180 mg per 100 g fresh weight. Apples and berries, while rich in other flavonoids like quercetin, contain only low or negligible hesperidin, typically under 1 mg per 100 g. Food processing significantly influences hesperidin retention; whole fruits preserve higher levels than processed juices, where juicing or peeling can lead to losses of 20–50% due to exposure to air, light, and heat, which degrade the compound. Freeze-drying or minimal processing helps maintain content better than thermal methods. In typical Western diets emphasizing consumption, daily hesperidin intake is estimated at 100–500 mg, varying with fruit and juice intake; for instance, one liter of could contribute 200–600 mg. Hesperidin is not routinely listed on nutritional labels, as it falls under the umbrella of total without specific regulatory requirements.

Biosynthesis

Biosynthetic Pathway

Hesperidin biosynthesis in plants, particularly in species, occurs via the phenylpropanoid-flavonoid pathway, initiating from the . is deaminated by (PAL) to form trans-cinnamic acid, which undergoes successive hydroxylations and activations to yield p-coumaroyl-CoA, the key starter unit for assembly. This involves enzymes such as cinnamate 4-hydroxylase (C4H) and 4-coumarate:CoA ligase (4CL). p-Coumaroyl-CoA condenses with three molecules of through the action of chalcone synthase (CHS), producing naringenin chalcone, a central intermediate in flavanone . Subsequent catalyzed by chalcone isomerase (CHI) converts naringenin chalcone to naringenin, the basic scaffold. To form the hesperetin aglycone specific to hesperidin, naringenin undergoes B-ring modification: flavonoid 3'-hydroxylase (F3'H), a enzyme, introduces a hydroxyl group at the 3' position to yield eriodictyol. Eriodictyol is then methylated at the 4' position by eriodictyol 4'-O-methyltransferase (a caffeoyl-CoA O-methyltransferase homolog) to produce . Unlike branches leading to , this pathway avoids flavanone 3-hydroxylase (F3H) and flavonol synthase (FLS), retaining the flavanone . Glycosylation of hesperetin occurs sequentially at the 7-hydroxyl position. First, 7-O-glucosyltransferase (a UDP-glucosyltransferase, UGT) transfers a β-D-glucose from UDP-glucose to form hesperetin 7-O-glucoside. This is followed by the addition of an α-L-rhamnose unit to the 6'' position of the glucose by a 1,6-rhamnosyltransferase (such as Crc1,6RhaT in Citrus reticulata), resulting in the rutinoside linkage and completion of (hesperetin 7-O-rutinoside). The overall pathway can be summarized as: → p-coumaroyl-CoA → naringenin chalcone → naringenin → eriodictyol → hesperetin → hesperetin 7-O-glucoside → hesperidin. These reactions primarily take place in the , with the glycosylated product transported to vacuoles for storage. Biosynthesis of hesperidin is regulated by environmental stresses and hormones, notably upregulated by and its derivative in fruits. Exogenous application of enhances hesperidin accumulation by activating phenylpropanoid pathway genes, including those for CHS and downstream enzymes, as a defense response to biotic and abiotic stresses.

Key Enzymes

Hesperidin biosynthesis involves several key enzymes that catalyze specific steps in the flavonoid pathway within plants, particularly in species like . synthase (CHS) is the primary enzyme initiating the process by condensing one molecule of p-coumaroyl-CoA with three molecules of to form naringenin chalcone, the first committed intermediate in production. This polyketide synthase-like enzyme operates in the and is rate-limiting for downstream accumulation, with kinetic parameters showing high affinity for its substrates in extracts (Km for p-coumaroyl-CoA approximately 10-20 μM). Following CHS activity, stereospecifically isomerizes the to the naringenin through a stereoselective cyclization, preventing non-enzymatic side reactions and ensuring efficient flux toward hesperidin precursors. In , CHI exhibits broad substrate specificity but prefers citrus-specific chalcones, with optimal activity at pH 7.5-8.0 and temperatures around 30-40°C, contributing to the high content in peels. This enzyme's expression correlates positively with hesperidin levels during fruit development. Later in the pathway, 7-O-glucosyltransferase (F7GT), also known as UDP-glucose: 7-O-glucosyltransferase, catalyzes the transfer of a glucose moiety from UDP-glucose to the 7-hydroxyl position of (derived from naringenin via ), forming 7-O-glucoside as a key intermediate. This enzyme, purified from Citrus paradisi seedlings, displays specificity for like (Km ≈ 40 μM) over , operating optimally at pH 7.0 and 35°C, and is crucial for that enhances and storage in vacuoles. In , multiple F7GT isoforms (Cit7GlcTs) have been identified, with four novel ones functionally validated for 7-O-glucosylation of . The final glycosylation step is mediated by 1,6-rhamnosyltransferase (1,6-RhaT), which transfers an α-L-rhamnose from UDP-rhamnose to the 6''-position of the glucose in 7-O-glucoside, forming the rutinoside linkage characteristic of hesperidin (hesperetin 7-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside). Unlike the 1,2-RhaT for neohesperidosides, 1,6-RhaT ensures the non-bitter in most commercial varieties. Genes encoding these enzymes have been cloned and characterized in . The CHS gene family includes multiple members, with CsCHS-bo (1,512 bp) isolated from blood orange cultivars, showing tissue-specific expression highest in flavedo and regulated by developmental cues. Functional analysis revealed at least three active CitCHS paralogs, with one novel variant influencing total output through differential promoter activity. Similarly, F7GT genes in C. sinensis have been cloned, with Cit7GlcT1-4 demonstrating glycosylation of and contributing to peel-specific hesperidin accumulation. Enzyme activities in hesperidin are modulated by environmental factors, including UV and elicitors. UV induces CHS and CHI transcription via MYB and bHLH regulators, enhancing production as a photoprotective response in leaves and fruits. Fungal elicitors like those from Penicillium spp. upregulate F7GT and 1,6-RhaT expression through signaling, increasing hesperidin levels by 2-5 fold in cell cultures as a defense mechanism. These regulators highlight the plasticity of the pathway in response to stress.

Metabolism

Absorption and Bioavailability

Hesperidin, a , exhibits low oral absorption primarily due to its hydrophilic nature and poor in aqueous environments, limiting its uptake in the intact form. Upon , it reaches the where a portion undergoes limited , but the majority transits to the colon intact. There, , particularly such as species expressing α-rhamnosidase and β-, cleave the rutinoside stepwise—first producing hesperetin-7-glucoside and then the aglycone —which is absorbed via passive across the . The of hesperidin is generally low, estimated at 1–10% when measured as the aglycone or its phase II metabolites in plasma or , reflecting extensive first-pass and rapid . This low systemic availability is attributed to poor aqueous , efflux by transporters, and interindividual variations in composition. Absorption occurs mainly in the for the minor hydrolyzed fraction and in the colon for microbiota-derived , with overall urinary recovery of metabolites typically below 10% of the ingested dose. Several factors influence hesperidin's , including the food matrix in which it is consumed. Co-ingestion with dietary fats can enhance absorption by improving and micellar incorporation of the lipophilic aglycone, while can reduce bioavailability by entrapping hesperidin in the food matrix, slowing release and hindering microbial access in the gut. Formulations such as or encapsulation have been shown to increase bioavailability up to 2–5-fold by overcoming solubility barriers. Pharmacokinetic studies indicate that , the primary absorbable form, reaches peak plasma concentrations (Tmax) of 4–7 hours post-ingestion, with levels typically in the range of 0.1–2 μM following a 500 mg dose of hesperidin. The elimination of hesperetin and its conjugates is approximately 3–7 hours, contributing to its transient presence in circulation before phase II conjugation in the liver and excretion via urine and . These parameters underscore the compound's limited and delayed systemic exposure, emphasizing the role of in modulating its pro-health potential.

Biotransformation

Hesperidin, a , undergoes initial through hydrolysis in the . Specifically, the rutinoside moiety is cleaved by intestinal enzymes, including β-glucosidase activity from lactase-phlorizin and enzymes such as α-rhamnosidase and β-glucosidase, yielding the aglycone , which is subsequently absorbed into the bloodstream. Following absorption, is subject to phase II conjugation in the liver and intestines, primarily through via UDP-glucuronosyltransferase (UGT) enzymes such as UGT1A1, UGT1A3, UGT1A7, UGT1A8, and UGT1A9, and sulfation via sulfotransferase (SULT) enzymes including SULT1A1, SULT1A2, SULT1A3, and SULT1B1. These processes produce polar conjugates that facilitate , with the major metabolites being hesperetin-7-glucuronide (predominantly from UGT1A3 and others at the 7-position) and hesperetin-3'-sulfate (primarily from SULT1A1 and SULT1A2 at the 3'-position). The conjugated metabolites are primarily excreted via the , accounting for below 10% of the ingested dose in studies, with the remainder undergoing further microbial in the gut or fecal elimination; overall, urinary represents the main route for absorbed and conjugated forms, while unabsorbed hesperidin contributes to fecal output. Hesperidin exhibits species differences, with more efficient and higher observed in rats compared to humans, attributed to variations in composition and phase II enzyme expression.

Biological Activities

Antioxidant Effects

Hesperidin exhibits potent radical scavenging activity primarily through the donation of hydrogen atoms from its phenolic hydroxyl groups, neutralizing free radicals such as and ABTS in a dose-dependent manner. This mechanism involves the flavonoid's B-ring phenolic structure, which facilitates and stabilizes radical intermediates, thereby preventing oxidative reactions. In vitro studies demonstrate hesperidin's efficacy against radicals, with an value of approximately 117 μM, highlighting its capacity to inhibit (ROS) generation at physiologically relevant concentrations. Beyond direct scavenging, hesperidin modulates endogenous antioxidant enzyme systems by upregulating (), (), and (GSH-Px) activities in various cell types. This enhancement occurs through activation of cellular signaling pathways that boost enzyme expression, thereby amplifying the cell's defense against oxidative damage. For instance, in hepatic cells exposed to oxidative stressors, hesperidin treatment significantly increases and levels, reducing ROS accumulation and maintaining . Hesperidin provides cellular protection by attenuating , a key marker of oxidative injury, particularly in hepatocytes subjected to toxic insults like tert-butyl . This effect is evidenced by dose-dependent reductions in levels and preservation of membrane integrity, underscoring hesperidin's role in safeguarding lipid-rich cellular compartments. Recent investigations up to 2025 have shown hesperidin's protective effects against in models of chronic fatigue syndrome, where it restores antioxidant enzyme balance and mitigates ROS-induced fatigue-like symptoms. In exercise-induced fatigue paradigms, chronic supplementation with hesperidin elevates activity and lowers oxidized levels post-exertion, demonstrating its potential to counteract oxidative burden in prolonged stress conditions.

Anti-inflammatory and Other Effects

Hesperidin exhibits potent anti-inflammatory properties primarily through inhibition of the signaling pathway, which suppresses the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). In experimental models of , including high-fat diet-induced hepatic stress in rats, hesperidin administration significantly reduced NF-κB activation and lowered serum levels of TNF-α and IL-6, thereby mitigating inflammatory responses. These effects are attributed to hesperidin's ability to modulate upstream signaling cascades, preventing the translocation of NF-κB to the nucleus and subsequent gene transcription of inflammatory mediators. In the context of anticancer activity, hesperidin promotes in cells, notably through activation of caspase-3, a key executor in the intrinsic mitochondrial pathway. Treatment of cells with hesperidin leads to upregulation of pro-apoptotic Bax and downregulation of anti-apoptotic , culminating in caspase-3 cleavage and execution of . This mechanism has been observed , where hesperidin depletes and elevates , further sensitizing cells to apoptotic signals without excessive toxicity to normal cells. Hesperidin supports cardiovascular health by enhancing endothelial function and reducing (LDL) oxidation. It stimulates production in endothelial cells via activation of , improving and reducing markers of in models of . Additionally, hesperidin inhibits LDL oxidation by scavenging free radicals and preserving enzymes like paraoxonase-1, thereby lowering oxidized LDL levels in hyperlipidemic conditions. Neuroprotective effects of hesperidin are mediated via its metabolite , which crosses the blood-brain barrier to attenuate amyloid-beta in models. penetrates the , where it inhibits amyloid-beta aggregation and reduces neuroinflammatory responses. In preclinical studies, hesperidin supplementation decreased amyloid-beta levels and improved cognitive outcomes by modulating pathways such as Akt/Nrf2 and enhancing defenses. Recent investigations from 2024 highlight hesperidin's hepatoprotective role against metabolic dysfunction-associated steatotic liver disease through activation of peroxisome proliferator-activated receptor gamma (PPARγ). In mouse models of liver injury, hesperidin upregulated PPARγ expression, reducing inflammation and lipid accumulation while improving hepatic steatosis and fibrosis markers. This PPARγ-mediated mechanism complements its broader anti-inflammatory actions, positioning hesperidin as a promising agent for managing steatotic liver conditions.

Research and Applications

Health Research Findings

Clinical trials and meta-analyses conducted between 2023 and 2025 have demonstrated that hesperidin supplementation at doses of 500–1000 mg/day significantly reduces systolic in individuals with or related cardiometabolic conditions, with effects more pronounced in interventions lasting over 12 weeks. For instance, a 2025 of randomized controlled trials reported a notable decrease in systolic with doses exceeding 500 mg/day, alongside improvements in lipid profiles and inflammatory markers like TNF-α. A 2024 further confirmed these antihypertensive benefits specifically in diabetic patients, attributing the outcomes to hesperidin's vascular effects without altering diastolic pressure. In preclinical studies using animal models of , hesperidin has shown promise in lowering (HbA1c) levels, indicating improved glycemic control. Administration of hesperidin at doses around 100 mg/kg body weight for 30 days in streptozotocin-induced diabetic rats significantly reduced HbA1c levels, comparable to the effects of glibenclamide, while also regulating key carbohydrate-metabolizing enzymes. Similarly, preclinical investigations into hesperidin's role as an adjunct for have highlighted its antiviral potential through ACE2 inhibition; models demonstrated that its metabolite blocks SARS-CoV-2 spike protein binding to ACE2 receptors, while both hesperidin and downregulate ACE2 expression in cells, suggesting a mechanism to limit viral entry. Hesperidin holds (GRAS) status from the U.S. FDA, with no evidence of observed in studies at doses up to 1000 mg/day (the highest evaluated in trials); higher doses such as 5 g/day have not been assessed, though most trials evaluate up to 1000 mg/day without adverse events. assessments confirm a high (NOAEL) of 750 mg/kg body weight per day in rats, with derived no-effect levels (DNEL) at 3.75 mg/kg body weight per day, and only mild gastrointestinal side effects, such as occasional discomfort, reported at higher doses like 500–800 mg/day. No genotoxic, carcinogenic, or has been identified. Despite promising neuroprotective effects in animal models of neurodegeneration, research gaps persist, particularly the scarcity of long-term human trials evaluating hesperidin's efficacy in patients with conditions like Alzheimer's or . Existing human studies are limited to short-term interventions in healthy or mildly impaired populations, showing improvements in and cerebral flow with doses around 500 mg, but lacking robust, patient-specific data on disease progression or optimal dosing. A 2025 integrated analysis combining traditional and predictions underscores hesperidin's efficacy in managing chronic fatigue syndrome, attributing benefits to its , , and neuroprotective properties that may alleviate fatigue symptoms and enhance overall well-being. This review highlights hesperidin's potential as a for CFS, though it calls for additional empirical validation to confirm therapeutic outcomes.

Practical Applications

Hesperidin is widely incorporated into dietary supplements, often as part of bioflavonoid complexes, to support vascular health and circulatory function. Typical dosages range from 300 to 600 mg per day of pure hesperidin, though formulations combining it with may reach up to 1,000 mg daily for conditions like . These supplements are marketed for improving integrity and reducing symptoms of poor circulation, such as leg swelling. In pharmaceuticals, hesperidin serves as a key component in venotonic drugs, notably 500 mg, which contains 10% standardized to hesperidin alongside 90% micronized . This formulation is prescribed for the symptomatic treatment of and hemorrhoidal disease, with recommended dosages of 500 mg twice daily for up to six months to enhance venous tone and reduce inflammation. Clinical use demonstrates its role in accelerating ulcer healing when combined with compression therapy. Within the , hesperidin functions as a natural additive, contributing to the oxidative stability of products like beverages and processed foods derived from by-products. Its application helps extend by scavenging free radicals, aligning with trends toward natural preservatives over synthetic alternatives. Beyond human applications, hesperidin finds use in environmental , particularly in mitigating heavy metal in soil, as evidenced by 2024 studies showing its enhancement of systems and reduction in metal uptake by crops like under cadmium, , , and stress. As a livestock feed additive, it improves growth performance in , such as broilers, by augmenting secretion and intestinal barrier function, leading to better nutrient absorption and reduced heat stress impacts. Supplementation at levels like 200-400 mg/kg in diets enhances oxidative stability and overall animal health. Hesperidin is primarily extracted from citrus waste, such as orange peels, using solvent-based methods like extraction or advanced techniques including ultrasound-assisted and microwave-assisted extraction, which optimize yields from agricultural by-products. Enzymatic combined with can achieve purities up to 93% and yields exceeding 80%, enabling efficient valorization of food industry residues.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Hesperidin
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  3. https://www.mdpi.com/2227-9717/8/5/549
  4. https://www.sciencedirect.com/science/article/pii/S2405844024028937
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  8. https://link.springer.com/article/10.1007/s11101-024-10008-2
  9. https://www.chemspider.com/Chemical-Structure.10176.html
  10. https://www.researchgate.net/figure/Structure-of-hesperidin-narirutin-and-naringin-and-the-aglycones-hesperetin-and_fig3_352679441
  11. https://www.mdpi.com/2076-3417/12/1/29
  12. https://biomedres.us/pdfs/BJSTR.MS.ID.001602.pdf
  13. https://www.sigmaaldrich.com/US/en/product/sigma/h5254
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  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC2664388/
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  18. https://www.mdpi.com/1422-0067/25/9/4822
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