2023-10-05 00:30:03
New meta-analyses added
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We added a few meta-analyses to our database and update the clinical effects accordingly.
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Hesperidin
•Last Updated: October 5, 2023
Hesperidin, found abundantly in orange peels and various citrus fruits, exhibits promising potential in reducing risk factors associated with cardiovascular disease, such as triglycerides and total cholesterol. Additionally, it appears to some have anti-inflammatory properties. While other potential benefits of hesperidin exist, further clinical studies are required to fully understand its range of effects.
Hesperidin is most often used for
Last Updated:October 5, 2023
Hesperidin is a flavanone glycoside (a type of flavonoid) that was isolated from the spongy inner peel of oranges, which is known as the mesocarp.[5]
Hesperidin (Hsd) is prominently found in citrus fruits like oranges, lemons, clementines, mandarins, and grapefruits. The name hesperidin is derived from the word “hesperidium”, a word for a berry with a pulpy, segmented interior and a leathery rind containing aromatic oils.[6][7] Its aglycone (i.e., missing a glycosyl group) form is called hesperetin (Hst).[8]
Trials of the anti-inflammatory properties of hesperidin have yielded mixed results. One meta-analysis found that hesperidin, whether consumed through citrus juice or oral supplements, reduced the pro-inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-4 (IL-4) in a non-dose-dependent manner. However, a second meta-analysis did not replicate these findings for CRP and IL-6, although it did find a significant decreased in levels of the inflammatory marker vascular cell adhesion molecule-1 (VCAM-1). These conflicting outcomes could be attributed to variability in study quality, methodology, and participant characteristics, necessitating further research to validate the anti-inflammatory properties of hesperidin.[9][1]
Additionally, one meta-analysis indicated that hesperidin supplementation led to significant reduction of several cardiovascular disease (CVD) risk factors. These benefits included decreased triglyceride (TG) levels, total cholesterol (TC), low-density lipoprotein (LDL) levels, tumor necrosis factor (TNF-α), and systolic blood pressure (SBP). Notably, these effects were predominantly observed with hesperidin doses exceeding 500 mg per day and were considerably influenced by factors such as the duration of hesperidin treatment (typically more effective when exceeding 6 weeks) and participants’ BMI, age, and overall health status.[10]
Hesperidin also appears to promote blood flow, as demonstrated in one randomized controlled trial (RCT) involving participants with metabolic syndrome who took 500 mg of hesperidin daily for 3 weeks. Hesperidin improved blood flow by 2.5%, as assessed by flow-mediated dilation (FMD).[11] Another study noted an improvement in microcirculation (blood flow in the small vessels) 6 hours after supplementation on a full stomach with either hesperidin capsules or standardized orange juice given for 4 weeks to healthy but overweight men.[12] Despite these results being promising, it is still unclear whether these effects are long-lasting and whether they have an impact on blood pressure.
Furthermore, one RCT evaluated the impact of a synthetic form of hesperidin, hesperidin methyl chalcone (HMC), on muscle damage and pain associated with delayed onset muscle soreness (DOMS) induced by an intense anaerobic exercise protocol. HMC supplementation improved muscle recovery, performance, and postural balance. The group taking HMC also showed increased physical performance (measured by the number of repetitions to failure) and improved muscle soreness during passive quadriceps palpation, although not during activities like walking up and down the stairs.[2]
Studies have not yet reported any side effects associated with hesperidin supplementation. However, it’s important to note that the absence of side effects in research does not definitively rule them out, and further investigation is warranted. One study found that a 500 mg dose of hesperidin methyl chalcone (HMC) did not affect renal and hepatic function markers.[2]
One meta-analysis found that hesperidin supplementation was linked to an increase in body weight, which could potentially be concerning for people with obesity or overweight. However, this effect has not been consistently observed in other studies, and it may be influenced by many factors beyond hesperidin supplementation.[10]
The precise mechanism of action of hesperidin is still unknown. However, a number of studies (mostly animal studies), have highlighted potential pathways through which hesperidin may exert its effects.
Hesperidin may improve lipid metabolism via several potential mechanisms: In rat models, a possible pathway involves inhibiting cholesterol synthesis by downregulating the expression of retinol-binding protein (RBP), heart fatty acid binding protein (H-FAB), and cutaneous fatty acid-binding protein (C-FAB). Animal studies suggest that hesperidin may also inhibit the enzymes 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and acyl coenzyme A: cholesterol acyltransferase (ACAT), which play a role in cholesterol biosynthesis.[10]
Furthermore, clinical studies on G-hesperidin (see FAQ “What are the other forms of hesperidin?”) suggest that it enhances very low density lipoprotein (VLDL) catabolism, leading to reduced TG and LDL levels. G-hesperidin also appeared to work by activating the lipoprotein lipase (LPL), an enzyme responsible for hydrolyzing TG. In vitro studies further suggested that G-hesperidin may suppress excessive liver LDL secretion by decreasing the release of apolipoprotein B (a key LDL component).[10]
Regarding its anti-inflammatory effect, both in vitro and in vivo studies suggest that hesperidin may reduce inflammation by suppressing the expression of inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), along with inflammatory markers (e.g., TNF-α, IL-6), thereby reducing prostaglandin levels.[10]
Additionally, one hypothesis explaining hesperidin’s blood pressure-lowering effect is that it increases nitric oxide (NO) production, which induces vasodilation by relaxing blood vessels smooth muscles, leading to a reduction in blood pressure. Another potential mechanism involves hesperidin reducing levels of the vasoconstrictor angiotensin-2 through inhibition of the angiotensin-converting enzyme.[10] It’s worth noting that these mechanisms remain hypothetical, and require clinical confirmation.
Hesperidin and hesperetin also appear to moderately increase blood flow either by stimulating the production of intracellular hydrogen peroxide, which activates the Src family kinase, a group of enzymes that regulate the production of nitric oxide in blood vessels, or through estrogen signaling, which is also involved in the production of nitric oxide.[11][13]
Note that Hesperidin is also known as:
- hesperitin-7-O-rutinoside
- Hesperitin glycoside
- glucosyl hesperidin
- Vitamin P
- hesperitin
- G-hesperidin
- 3' 5 7-trihydroxy-4'-methoxyflavanone
Hesperidin should not be confused with:
- Hesperitin (its aglycone)
- Eriodictyol (another flavonoid known as Vitamin P)
Most studies tend to use 500 mg or more of supplemental hesperidin, and use the standard form of hesperidin if taking it as a daily preventative.[1]
For the prevention of muscle soreness associated with delayed onset muscle soreness (DOMS), a daily dosage of 500 mg of hesperidin methyl chalcone (HMC) for 3 days prior to intensive anaerobic exercise has shown positive outcomes. HMC concentration typically peaks 1–2 hours after oral administration.[2]
When it comes to food products, the amount of hesperidin contained in orange juice or other citrus peels (e.g., tangerine peel) may vary depending on multiple factors. As a result, establishing a recommended quantity of specific foods containing hesperidin to achieve effects similar to those obtained with oral supplements is challenging. For instance, one study analyzing the composition of citrus juices found hesperidin concentrations ranging from 20–60 mg/100 ml in orange juice, 8–46 mg/100 ml in tangerine juice, 4–41 mg/100 ml in lemon juice, and 2–17 mg/100 ml in grapefruit juice.[3] Sun-dried tangerine peels, used in traditional Chinese medicine, appear to confer such a substantial dose of hesperidin that additional supplementation may not be required. These peels may be made more palatable by blending them into a shake.[4]
Research FeedRead all studies
2023-09-09 00:30:03
Standard FAQ and database update
major
We updated this page's FAQs and database with a bunch of new meta-analyses. Additionally, the material in the "research breakdown" section was merged with our FAQs.
- ^Lorzadeh E, Ramezani-Jolfaie N, Mohammadi M, Khoshbakht Y, Salehi-Abargouei AThe effect of hesperidin supplementation on inflammatory markers in human adults: A systematic review and meta-analysis of randomized controlled clinical trials.Chem Biol Interact.(2019-Jul-01)
- ^Luque MZ, Aguiar AF, da Silva-Araújo AK, Zaninelli TH, Heintz OK, Saraiva-Santos T, Bertozzi MM, Souza NA, Júnior EO, Verri WA, Borghi SMEvaluation of a preemptive intervention regimen with hesperidin methyl chalcone in delayed-onset muscle soreness in young adults: a randomized, double-blinded, and placebo-controlled trial study.Eur J Appl Physiol.(2023-Sep)
- ^Gattuso G, Barreca D, Gargiulli C, Leuzzi U, Caristi CFlavonoid composition of Citrus juicesMolecules.(2007 Aug 3)
- ^Liu EH, Zhao P, Duan L, Zheng GD, Guo L, Yang H, Li PSimultaneous determination of six bioactive flavonoids in Citri Reticulatae Pericarpium by rapid resolution liquid chromatography coupled with triple quadrupole electrospray tandem mass spectrometry.Food Chem.(2013-Dec-15)
- ^Roohbakhsh et al.Molecular mechanisms behind the biological effects of hesperidin and hesperetin for the prevention of cancer and cardiovascular diseasesLife Sciences.(2015-03-01)
- ^Hesperidium: Merriam-Webster Online
- ^Benjamin Caballero, ed.Citrus Fruits - Oranges: Encyclopedia of Food Sciences and Nutrition, Second Edition(2003)
- ^Shams-Rad S, Mohammadi M, Ramezani-Jolfaie N, Zarei S, Mohsenpour M, Salehi-Abargouei AHesperidin supplementation has no effect on blood glucose control: A systematic review and meta-analysis of randomized controlled clinical trials.Br J Clin Pharmacol.(2020-Jan)
- ^Buzdağlı Y, Eyipınar CD, Kacı FN, Tekin AEffects of hesperidin on anti-inflammatory and antioxidant response in healthy people: a meta-analysis and meta-regression.Int J Environ Health Res.(2022-Jun-28)
- ^Khorasanian AS, Fateh ST, Gholami F, Rasaei N, Gerami H, Khayyatzadeh SS, Shiraseb F, Asbaghi OThe effects of hesperidin supplementation on cardiovascular risk factors in adults: a systematic review and dose-response meta-analysis.Front Nutr.(2023)
- ^Rizza S, Muniyappa R, Iantorno M, Kim JA, Chen H, Pullikotil P, Senese N, Tesauro M, Lauro D, Cardillo C, Quon MJCitrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndromeJ Clin Endocrinol Metab.(2011 May)
- ^Morand C, Dubray C, Milenkovic D, Lioger D, Martin JF, Scalbert A, Mazur AHesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteersAm J Clin Nutr.(2011 Jan)
- ^Liu L, Xu DM, Cheng YYDistinct effects of naringenin and hesperetin on nitric oxide production from endothelial cells.J Agric Food Chem.(2008-Feb-13)
- ^Gonçalves TT, Lazaro CM, De Mateo FG, Campos MC, Mezencio JG, Claudino MA, de O Carvalho P, Webb RC, Priviero FBEffects of glucosyl-hesperidin and physical training on body weight, plasma lipids, oxidative status and vascular reactivity of rats fed with high-fat diet.Diabetes Metab Syndr Obes.(2018)
- ^Yang YL, Hsu HT, Wang KH, Han CY, Chen CM, Chen CM, Ko WCHesperetin-7,3'-O-dimethylether selectively inhibits phosphodiesterase 4 and effectively suppresses ovalbumin-induced airway hyperresponsiveness with a high therapeutic ratio.J Biomed Sci.(2011-Nov-11)
- ^Yakabi K, Kurosawa S, Tamai M, Yuzurihara M, Nahata M, Ohno S, Ro S, Kato S, Aoyama T, Sakurada T, Takabayashi H, Hattori TRikkunshito and 5-HT2C receptor antagonist improve cisplatin-induced anorexia via hypothalamic ghrelin interaction.Regul Pept.(2010-Apr-09)
- ^Balakrishnan A, Menon VPEffect of hesperidin on matrix metalloproteinases and antioxidant status during nicotine-induced toxicity.Toxicology.(2007-Sep-05)
- ^Balakrishnan A, Menon VPEffect of hesperidin on nicotine toxicity and histopathological studies.Toxicol Mech Methods.(2007)
- ^Tanaka T, Makita H, Kawabata K, Mori H, Kakumoto M, Satoh K, Hara A, Sumida T, Tanaka T, Ogawa HChemoprevention of azoxymethane-induced rat colon carcinogenesis by the naturally occurring flavonoids, diosmin and hesperidin.Carcinogenesis.(1997-May)
- ^Wei D, Ci X, Chu X, Wei M, Hua S, Deng XHesperidin suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model.Inflammation.(2012-Feb)
- ^Kamisli S, Ciftci O, Kaya K, Cetin A, Kamisli O, Ozcan CHesperidin protects brain and sciatic nerve tissues against cisplatin-induced oxidative, histological and electromyographical side effects in rats.Toxicol Ind Health.(2015-Sep)
- ^Cho YA, Choi DH, Choi JSEffect of hesperidin on the oral pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats.J Pharm Pharmacol.(2009-Jun)
- ^Watanabe M, Matsumoto N, Takeba Y, Kumai T, Tanaka M, Tatsunami S, Takenoshita-Nakaya S, Harimoto Y, Kinoshita Y, Kobayashi SOrange juice and its component, hesperidin, decrease the expression of multidrug resistance-associated protein 2 in rat small intestine and liver.J Biomed Biotechnol.(2011)
- ^Mas-Capdevila A, Teichenne J, Domenech-Coca C, Caimari A, Del Bas JM, Escoté X, Crescenti AEffect of Hesperidin on Cardiovascular Disease Risk Factors: The Role of Intestinal Microbiota on Hesperidin Bioavailability.Nutrients.(2020-May-20)
- ^Jin YR, Han XH, Zhang YH, Lee JJ, Lim Y, Chung JH, Yun YPAntiplatelet activity of hesperetin, a bioflavonoid, is mainly mediated by inhibition of PLC-gamma2 phosphorylation and cyclooxygenase-1 activity.Atherosclerosis.(2007 Sep)
- ^Yu HY, Park SW, Chung IM, Jung YSAnti-platelet effects of yuzu extract and its component.Food Chem Toxicol.(2011 Dec)
- ^Andersen KEHesperidin methyl chalcone - a new cosmetic contact allergen.Contact Dermatitis.(2015 Jun)
- ^Piao YJ, Choi JSEnhanced bioavailability of verapamil after oral administration with hesperidin in rats.Arch Pharm Res.(2008 Apr)
- ^Bajraktari-Sylejmani G, Weiss JPotential Risk of Food-Drug Interactions: Citrus Polymethoxyflavones and Flavanones as Inhibitors of the Organic Anion Transporting Polypeptides (OATP) 1B1, 1B3, and 2B1.Eur J Drug Metab Pharmacokinet.(2020 Dec)
- ^Chen M, Zhou SY, Fabriaga E, Zhang PH, Zhou QFood-drug interactions precipitated by fruit juices other than grapefruit juice: An update review.J Food Drug Anal.(2018 Apr)
- ^Kalliokoski A, Niemi MImpact of OATP transporters on pharmacokinetics.Br J Pharmacol.(2009 Oct)
- ^Lilja JJ, Juntti-Patinen L, Neuvonen PJOrange juice substantially reduces the bioavailability of the beta-adrenergic-blocking agent celiprolol.Clin Pharmacol Ther.(2004 Mar)
- ^Bailey DG, Dresser GK, Leake BF, Kim RBNaringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice.Clin Pharmacol Ther.(2007 Apr)
- ^Uesawa Y, Mohri KHesperidin in orange juice reduces the absorption of celiprolol in rats.Biopharm Drug Dispos.(2008 Apr)
- ^Sridhar V, Surya Sandeep M, Ravindra Babu P, Naveen Babu KEvaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using felodipine and hesperetin in combination in Wistar rats and everted rat gut sacs in vitro.Phytother Res.(2014 May)
- ^Pang CY, Mak JW, Ismail R, Ong CEIn vitro modulatory effects of flavonoids on human cytochrome P450 2C8 (CYP2C8).Naunyn Schmiedebergs Arch Pharmacol.(2012 May)
- ^Quintieri L, Bortolozzo S, Stragliotto S, Moro S, Pavanetto M, Nassi A, Palatini P, Floreani MFlavonoids diosmetin and hesperetin are potent inhibitors of cytochrome P450 2C9-mediated drug metabolism in vitro.Drug Metab Pharmacokinet.(2010)
- ^Lacroix I, Beau AB, Hurault-Delarue C, Bouilhac C, Petiot D, Vayssière C, Vidal S, Montastruc JL, Damase-Michel CFirst epidemiological data for venotonics in pregnancy from the EFEMERIS database.Phlebology.(2016 Jun)
- ^K Buckshee, D Takkar, N AggarwalMicronized flavonoid therapy in internal hemorrhoids of pregnancyInt J Gynaecol Obstet.(1997 May)
- ^Song BJ, Jouni ZE, Ferruzzi MGAssessment of phytochemical content in human milk during different stages of lactation.Nutrition.(2013 Jan)
- ^Edyta Nalewajko-Sieliwoniuk, Marta Hryniewicka, Diana Jankowska, Anatol Kojło, Monika Kamianowska, Marek SzczepańskiDispersive liquid-liquid microextraction coupled to liquid chromatography tandem mass spectrometry for the determination of phenolic compounds in human milkFood Chem.(2020 Oct 15)
- Blood Flow - Hiroko Takumi, Hiroyasu Nakamura, Terumi Simizu, Ryoko Harada, Takashi Kometani, Tomonori Nadamoto, Rie Mukai, Kaeko Murota, Yoshichika Kawai, Junji TeraoBioavailability of orally administered water-dispersible hesperetin and its effect on peripheral vasodilatation in human subjects: implication of endothelial functions of plasma conjugated metabolitesFood Funct.(2012 Apr)
- Blood glucose - Morand C, Dubray C, Milenkovic D, Lioger D, Martin JF, Scalbert A, Mazur AHesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteersAm J Clin Nutr.(2011 Jan)
- Blood glucose - Khorasanian AS, Fateh ST, Gholami F, Rasaei N, Gerami H, Khayyatzadeh SS, Shiraseb F, Asbaghi OThe effects of hesperidin supplementation on cardiovascular risk factors in adults: a systematic review and dose-response meta-analysis.Front Nutr.(2023)
- Low-density lipoprotein (LDL) - Miwa Y, Mitsuzumi H, Sunayama T, Yamada M, Okada K, Kubota M, Chaen H, Mishima Y, Kibata MGlucosyl hesperidin lowers serum triglyceride level in hypertriglyceridemic subjects through the improvement of very low-density lipoprotein metabolic abnormalityJ Nutr Sci Vitaminol (Tokyo).(2005 Dec)
- Low-density lipoprotein (LDL) - Miwa Y, Yamada M, Sunayama T, Mitsuzumi H, Tsuzaki Y, Chaen H, Mishima Y, Kibata MEffects of glucosyl hesperidin on serum lipids in hyperlipidemic subjects: preferential reduction in elevated serum triglyceride levelJ Nutr Sci Vitaminol (Tokyo).(2004 Jun)
- Low-density lipoprotein (LDL) - Demonty I, Lin Y, Zebregs YE, Vermeer MA, van der Knaap HC, Jäkel M, Trautwein EAThe citrus flavonoids hesperidin and naringin do not affect serum cholesterol in moderately hypercholesterolemic men and womenJ Nutr.(2010 Sep)
- C-Reactive Protein (CRP) - Lorzadeh E, Ramezani-Jolfaie N, Mohammadi M, Khoshbakht Y, Salehi-Abargouei AThe effect of hesperidin supplementation on inflammatory markers in human adults: A systematic review and meta-analysis of randomized controlled clinical trials.Chem Biol Interact.(2019-Jul-01)
- C-Reactive Protein (CRP) - Buzdağlı Y, Eyipınar CD, Kacı FN, Tekin AEffects of hesperidin on anti-inflammatory and antioxidant response in healthy people: a meta-analysis and meta-regression.Int J Environ Health Res.(2022-Jun-28)
- Blood glucose - Shams-Rad S, Mohammadi M, Ramezani-Jolfaie N, Zarei S, Mohsenpour M, Salehi-Abargouei AHesperidin supplementation has no effect on blood glucose control: A systematic review and meta-analysis of randomized controlled clinical trials.Br J Clin Pharmacol.(2020-Jan)
- Total cholesterol - Rizza S, Muniyappa R, Iantorno M, Kim JA, Chen H, Pullikotil P, Senese N, Tesauro M, Lauro D, Cardillo C, Quon MJCitrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndromeJ Clin Endocrinol Metab.(2011 May)
- Total cholesterol - Mohammadi M, Ramezani-Jolfaie N, Lorzadeh E, Khoshbakht Y, Salehi-Abargouei AHesperidin, a major flavonoid in orange juice, might not affect lipid profile and blood pressure: A systematic review and meta-analysis of randomized controlled clinical trialsPhytother Res.(2019 Mar)
- Rheumatoid Arthritis Symptoms - Kometani T, Fukuda T, Kakuma T, Kawaguchi K, Tamura W, Kumazawa Y, Nagata KEffects of alpha-glucosylhesperidin, a bioactive food material, on collagen-induced arthritis in mice and rheumatoid arthritis in humansImmunopharmacol Immunotoxicol.(2008)
- Neutrophil Count - Perche O, Vergnaud-Gauduchon J, Morand C, Dubray C, Mazur A, Vasson MPOrange juice and its major polyphenol hesperidin consumption do not induce immunomodulation in healthy well-nourished humansClin Nutr.(2013 Mar 26)