Citrus bioflavonoids and liver health -
Male wistar rats g— g , bred in the central animal house of Panjab University Chandigarh, India were used. The animals were housed under standard conditions of light and dark cycle with free access to food Hindustan Lever Products, Kolkata, India and water. The experimental protocols were approved by the Institutional Ethical Committee of Panjab University, Chandigarh.
Chemicals employed in these studies were reagent grade. Carbon tetrachloride E Merck, India was administered subcutaneously in olive oil Hesperidin Sigma chemical USA was suspended in 0.
Animals were divided into following groups, each containing 6—8 animals: Control : These animals received a vehicle for HDN i. CMC by oral route for eight days and on 8 th day, they were administered the subcutaneous injection of olive oil.
Thus we adopted the subcutaneous route of CCl 4 administration as reported in the literature [ 35 ]. c in olive oil. HDN was further continued for 2 more days.
On the 10 th day, animals were sacrificed 2 hr, after the last dose of HDN and blood was collected, by carotid bleeding, in centrifuge tubes. Serum was separated and was used freshly for the assessment of renal and liver function tests.
Both the kidneys and the liver were quickly harvested and immediately stored at °C till further biochemical estimations. Before sacrifice, rats were kept individually in metabolic cages for 24 h to collect urine for estimation of renal function. Serum alanine aminotransferase ALT and serum aspartate aminotransferase AST were estimated by International Federation of Clinical Chemistry [ 36 ] ERBA test kits.
Serum bilirubin was estimated by Diazo method [ 37 ] ERBA test kits. Kidneys and liver were, perfused with ice cold saline 0.
The homogenates were centrifuged at g for 5 minutes at 4°C to separate the nuclear debris. The supernatant so obtained was centrifuged at 10, g for 20 minutes at 4°C to get the post mitochondrial supernatant which was used to assay catalase and superoxide dismutase SOD activity.
The malondialdehyde MDA content, a measure of lipid peroxidation, was assayed in the form of thiobarbituric acid reacting substances TBARS by method of Okhawa et al. The mixture was brought up to 4. After cooling with tap water, 1.
The organic layer was taken out and its absorbance was measured at nm. TBARS were quantified using an extinction coefficient of 1. Tissue protein was estimated using Biuret method of protein assay and the TBARS content expressed as nanomoles per milligram of protein.
Reduced glutathione GSH in the kidneys and liver was assayed by the method of Jollow et al [ 39 ]. Briefly, 1. The samples were kept at 4°C for at least 1 hour and then subjected to centrifugation at g for 15 minutes at 4°C.
The assay mixture contained 0. The yellow colour developed was read immediately at nm on a spectrophotometer. SOD activity was assayed by the method of Kono et al. In the cuvette, 2 ml of above mixture, 0. Catalase activity was assayed by the method of Claiborne et al [ 41 ].
Briefly, the assay mixture consisted of 1. Changes in absorbance were recorded at nm. Catalase activity was calculated in terms of k minutes Results were expressed as mean ± SEM.
The intergroup variation was measured by one way analysis of variance ANOVA followed by Fischer's LSD test. The statistical analysis was done using the Jandel Sigma Stat Statistical Software version 2.
Abraham P, Wilfred G, Cathrine: Oxidative damage to the lipids and proteins pf the lungs, testis and kidney of rats during carbon tetrachloride intoxication. Clin Chim Acta. Article CAS PubMed Google Scholar.
Szymonik-Lesiuk S, Czechowska G, Stryjecka-Zimmer M, Slomka M, Madro A, Celinski K, Wielosz M: Catalase, superoxide dismutase, and glutathione peroxidase activities in various rat tissues after carbon tetrachloride intoxication.
J Hepatobiliary Pancreat Surg. Article PubMed Google Scholar. Guven A, Guven A, Gulmez M: The effect of kefir on the activities of GSH-Px, GST, CAT, GSH and LPO levels in carbon tetrachloride-induced mice tissue. J Vet Med B Infect Dis Vet Public Health.
Ahmad FF, Cowan DL, Sun AY: Detection of free radical formation in various tissues after acute carbon tetrachloride administration in gerbil. Life Sci. Ohta Y, Nishida K, Sasaki E, Kongo M, Ishiguro I: Attenuation of disrupted hepatic active oxygen metabolism with the recovery of acute liver injury in rats intoxicated with carbon tetrachloride.
Res Commun Mol Pathol Pharmacol. CAS PubMed Google Scholar. Ozturk F, Ucar M, Ozturk IC, Vardi N, Batcioglu K: Carbon tetrachloride-induced nephrotoxicity and protective effect of betaine in Sprague-Dawley rats. Perez AJ, Courel M, Sobrado J, Gonzalez L: Acute renal failure after topical application of carbon tetrachloride.
Article Google Scholar. Churchill DN, Finn A, Gault M: Association between hydrocharbon exposure and glomerulonephritis. An araisal of the evidence. Ruprah H, Mant TGK, Flanagan RJ: Acute carbon tetrachloride poisoning in19 pateints: implications for diagnosis and treatment.
Yoshikawa T, Furukawa Y, Murakami M, Takemura S, Kondo M: Effect of viatmin E on D-Galactosamine-induced or carbon tetrachloride-induced hepatotoxicity. Ko KM, Ip SP, Poon MK, Wu SS, Che CT, Ng KH, Kong YC: Effect of a lignan-enriched fructus schisandrae extract on hepatic glutathione status in rats: protection against carbon tetrachloride toxicity.
Planta Med. Garg A, Garg S, Zaneveld LJ, Singla AK: Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res. Jovanovic SV, Steenken S, Tosic M, Marjanovic B, Simic MG: Flavonoids as anti-oxidants.
J Am Chem Soc. Article CAS Google Scholar. Fraga CG, Martino VS, Ferraro GE, Coussio JD, Boveris A: Flavonoids as antioxidants evaluated by in vitro and in situ liver chemiluminescence. Biochem Pharmacol.
Miller NJ, Rice-Evans CA: The relative contribution of ascorbic acid and phenolic antioxidants to the total antioxidant activity of orange and apple fruit juices and balckcurrant drink.
Food Chem. Suarez , Herrera MD, Marhuenda E: In vitro scavenger and antioxidant properites of hesperidin and neohesperidin dihydrochalcone. Recknagel RO: Carbon tetrachloride hepatotoxicity: Status quo and future prospects.
Google Scholar. Recknagel RO, Ghoshal AK: Lipoperoxidation as a vector in carbon tetrachloride hepatotoxicity. Lab Invest. Durk H, Frank H: Carbon tetrachloride metabolism in vivo and exhalation of volatile alkanes: dependence upon oxygen parital pressure.
Mansuy D, Fontecane M, Chottard J: A heme model study of carbon tetrachloride metabolism: mechanism of phosgene and carbon dioxide formation. Biochem Biophys Res Commun.
Pohl L, Schulick R, George J: Reductive oxygenation mechanism of metabolism of carbon tetrachlorideto phosgene by cytochrome P Mol Pharmacol. Pohl L, Schulick R, Highet R, George J: Identification of dichloromethyl carbene as a metabolite of carbon tetrachloride.
Tom WM, Fong D, Woo D, Prasongwatana V, Boyde TR: Microsomal lipid peroxidation and oxidative metabolism in rat liver. Chem Biol Interact. Slater TF: Free-radical mechanisms in tissue injury.
Biochem J. Article PubMed Central CAS PubMed Google Scholar. Recknagel RO, Glende EA, Lowery K: Lipid peroxidation: Biochemisry, measurement and significance in liver cell injury. Toxicology of the Liver. Edited by: Plaa GL and Hewitt W. A kind of citrus juice containing neohesperidin and naringin significantly alleviates subclinical atherosclerosis by reducing lipoprotein content and carotid intima-media thickness within 6 months Increasing data have indicated that obesity is not the necessary factor for cardiovascular events in NAFLD population, but boosts the development of atherosclerotic plaques to a certain extent.
Notably, NAFLD population with dyslipidemia is highly risky for cardiovascular events. The ingredients of PTFC, especially hesperidin and naringin, possess therapeutic efficiency on lipid deposition and adiposity, which dramatically inhibit the formation of atherosclerosis via blocking the secretion and transport of redundant lipid.
Glucose abnormality induced by insulin resistance and beta cell dysfunction is a hallmark of NAFLD, which takes on a great significance in the pathogenesis of CVD 65 , Elevated FFAs released by enlarged adipose mass remarkably restrict the anti-lipid effect of insulin and even lead to insulin resistance, which in turn aggravates dyslipidemia and pathoglycemia Naringin exerts the insulinotropic effect by increasing the expression levels of insulin receptors and adiponectin in adipose tissues Also, naringin attenuates mellitus-mediated steatohepatitis by upregulating the transcription factor PDX-1 that regulates insulin secretion and maintains β-cells mass 69 , and inhibiting hyperglycemia-mediated oxidative stress and pro-inflammatory cytokine secretion Yari et al.
Meanwhile, hesperidin and naringin contribute to glucose uptake by enhancing hepatic glycolysis and glycogen content, and lowering hepatic gluconeogenesis 72 , Neohesperidin suppresses fat accumulation and reduces the size of adipocytes, which further improves oral glucose tolerance and insulin sensitivity A conclusion is drawn that, PTFC, at least in part, plays a positive role in the treatment of CVDs by suppressing vascular senescence, improving lipid profile and maintaining glucose homeostasis for its active ingredients.
Moreover, their activities of controlling persistent inflammatory response and oxidative stress facilitate the prevention of CVD. However, inconsistent results on glucolipid metabolism have been obtained in some randomized controlled trials RCTs.
Motallaei et al. The above phenomenon can be explained by the poor bioavailability of flavonoids in the human body. Since the absorption of flavonoids focuses on the colon, individualized differences in gut microbiota compositions and activities result in varied therapeutic efficiency. Therefore, in addition to early intervention of steatosis to prevent CVD, it is also essential to mediate the intestinal microecology, which can facilitate the absorption of PTFC.
The growth of the primary tumors often do not pose major health threats except for those growing in sensitive and restrictive organs, such as the brain. Transformation into a cell capable of metastasis, acquiring the capabilities to escape the primary tumor, to enter vascular systems, to invade, and to colonize secondary organs, is more of a concern.
Hesperidin is reported to control tumor growth by regulating mitochondria production 76 , arresting cell cycle progression 77 , and inhibiting cell viability via the endoplasmic reticulum stress signaling pathway It also can inhibit the metastatic potential by suppressing metastases growth in vivo and cell migration and invasion in vitro 79 , Existing research indicated that hesperidin contributes to chemotherapy by modulating Smad4 and the activin A signaling in colon cancer 81 , and downregulating Ki expression in breast cancer During the process of diethyl nitrosamine-induced hepatocellular carcinoma, the addition of hesperidin preserves liver tissue integrity, improves liver function 83 , and exerts a hypomethylating effect As the major component in PTFC, naringin is considered an anti-tumor agent and adjuvant in the combination therapy by inducing lysosomal permeabilization and autophagy in gastric cancer It induces mitochondrial and cellular apoptosis in colon cancer via inhibiting NF-κB and endoplasmic reticulum stress Though downregulating MMP-2 and MMP-9 and inactivating the p38 signaling, naringin inhibits angiogenesis and cell invasion in glioblastoma cancer 87 , Due to the anti-tumor capacities of hesperidin and naringin in inhibiting metastatic potential, blocking neovascularization, and strengthening chemical protection, the anti-tumor function of PTFC appears to be consistent and reliable.
Considering some uncertain aspects of cancer treatment, more in vivo and in vitro studies are needed to validate the anti-tumor effect of PTFC. Besides the physical barrier created by intestinal epithelial cells, the symbiotic relationship between intestinal microbiota and host also contributes to the intestinal immunity.
The gut microbiota complements human genome functions based on its wide range of metabolic properties. However, the individualized difference in gut microbiota changes significantly due to diet, antibiotic use, and lifestyle It is found that neohesperidin administration changes the structure of gut microbiota by decreasing the intestinal ratio of Firmicutes to Bacteroidetes and enhances gut barrier integrity by mitigating serum metabolic endotoxemia in obese mice, which is reversed by the antibiotic treatment.
Increasing evidence suggested that the profitable effect of neohesperidin on the obese population is largely dependent on gut microbiota Naringin alleviates atherosclerosis by modulating the abundances of Bifidobacterium , Bacteroidetes , Clostridium , and Eubacterium Fidélix et al.
The immunomodulatory effect of hesperidin on the gut-associated lymphoid tissue is achieved by increasing the proportions of Lactobacillus and Bifidobacterium Furthermore, an increased dose of hesperidin supplementation reduces the risk of CVD by modulating the metabolism of the Bacteroidaceae family Feeding with fecal of neohesperidin-treated mice yielded a considerable inhibition of colon cancer, suggesting that the adjustment of neohesperidin on gut microbiota may be a promising strategy for cancer Notably, knowledge of PTFC compounds as antimicrobial agent is equally attractive.
The current research indicates that hesperidin combining with widely used NaNO2 has synergistic antibacterial activity against Bacillus cereus , Staphylococcus aureus , Escherichia coli , and Pseudomonas aeruginosa 96 , showing the advantages of nutrients as safe natural bio-preservatives to reduce the hazards of overuse of chemical preservatives.
Ciprofloxacin and tetracycline are antibiotics for P. aeruginosa , and the addition of naringin potentiates their efficacies to further manage bacterial infection As for methicillin-resistant S.
aureus that has developed resistance against most of the antibiotics and resulted in life-threatening outbreaks, naringin, hesperidin and neohesperidin are all strongly supported to be the adjuvant antimicrobial agent via the docking interactions Overall, the regulatory effect of its components on raising the proportion of beneficial bacteria implies the improvement of PTFC on chronic diseases may begin from the impact of its components on gut microbiota, and protecting intestinal microecological homeostasis can be the priority of human health.
Based on the efforts on bacteriostasis by its components, the positive effect of PTFC on intestinal immunity has been affirmed again. Regional factors and personal habits lead to individualized differences in the dynamic equilibrium of intestinal microecology, which may be eliminated by the long-term administration of PTFC through regulating the structure of intestinal microbiota or clearing relevant pathological factors.
Most flavonoids are extensively absorbed in the intestine and then transported to the liver for the further metabolization. The metabolites formed in the liver can re-enter enterohepatic circulation through hydrolysis of bile excretion to aglycones via gut microbiota or being directly excreted in urine or feces However, flavonoids are poorly absorbed through the gastrointestinal tract , and great efforts have been made on enhancing the bioavailability of flavonoids by inhibiting relevant enzymes, altering food intakes, and increasing dissolution rate — Xia et al.
Additionally, the low activity of α-rhamnosidase serves as a limiting step for hesperidin degraded by colonic microbiota , Pereira-Caro et al.
They also highlighted that the chronic intake of Bifidobacterium is significantly beneficial to the enhancement of hesperidin bioavailability , suggesting that the long-term intake of PTFC assists the expansion of probiotic communities, also in turn promotes the absorption of PTFC.
Unlike the large difference of hesperidin content in PTFC, plasma concentration of narirutin is significantly lower than that of hesperidin The α-rhamnosidase serves as the catalyst to boost the absorption of naringin via the conversion from rutinoside to glucoside Accordingly, α-rhamnosidase activity is still the critical issue to limit bioavailability.
The commensal intestinal microecology and its substantial gene pool has been validated to significantly regulate the bioavailability and metabolism of nutrients In addition to increasing the activity of α-rhamnosidase, microbiome profiling combined with powerful machine learning algorithms can be employed to select more appropriate biomarkers for flavonoid metabolism from microorganisms, thus enhancing the clinical response and efficacy to PTFC.
A clinical study suggested that the solubility of hesperidin in juice is a vital factor for bioavailability since its excretion and maximal plasma concentration are correlated with the soluble hesperidin concentration in juice, instead of the total hesperidin intake 6 , As a result, encapsuling hesperidin by the nanotechnology is confirmed as a promising strategy to enhance the bioavailability of hesperidin.
Also, a reduced particle size facilitates the interaction with intestinal cells and gut microbiota, thus weakening the demand of α-rhamnosidase hydrolysis Meanwhile, the nanoparticulate systems were employed for the naringin formulations to prevent drug cleavage in the lumen or the gut under harsh pH and enzymatic conditions of gastrointestinal tract, providing a sustained delivery of naringin That is to say, nanotechnology is capable of increasing the encounter area and reducing gastric lysis, which can be extensively used to modulate the release and absorption of bioactive fractions.
As a result, efforts should be made to assess the effects of nanotechnology on the metabolism, bioavailability, and efficacy of PTFC. According to studies on the comparison of various Citrus fruits , the difference of efficacy lies in the total flavonoids content and the main component object.
It is reported that the kind of C. has the relatively stronger anti-inflammation, anti-oxidant and bactericidal effects due to it contains a large amount of naringin and hesperidin , The total flavonoids content is found to increase with maturity stages , so standard planning for the shape, weight and skin luster of C.
before picking may be the new focus associated with the absorption of nutrients. In brief, the effects of lipid-lowering, anti-inflammation, anti-oxidation, anti-cancer, anti-bacterial, and intestinal barrier protection of PTFC were reviewed and novel prospects were put forward in accordance with the findings on its components.
Besides, paying attention to the effects of PTFC on gut microbiota may contribute to the enhancement of therapeutic efficacy, while well-designed experiments and clinical trials are still required to further clarify the specific application of PTFC in clinical practices.
Meanwhile, it is found that the mature stage of raw material affects the total flavonoids content, the manufacturing methods affects PTFC purity, and delivery system and individual intestinal microecology affect the specific bioavailability. Thus, optimization on fruit cultivation system and picking standard, and more elaborate investigations on facilitating their controlled release and actual potency in blood should be further conducted to address the poor bioavailability, as well as effective productive and easier methods to separate and extract PTFC should be explored to improve purity.
To the best of our knowledge, this study has summarized the extraction technology, chemical properties, and biological effects of PTFC, which may boost the development of their biological profiles in human disease treatment.
Of course, studies on pharmacokinetic parameters, toxicity testing, effective dose assessment, and adverse reaction are of significance before PTFC is officially used as a clinical therapeutic agent. SD and PW conducted the data disposal.
XP, LZ, and LQ wrote the manuscript. XJ and WC participated in the discussion. SD, PW, SR, and LS revised and edited the manuscript. All authors have read and agreed to the published version of the manuscript. This work was supported by the Natural Science Foundation of Zhejiang Province LS, No.
LQ22H , National Natural Science Foundation Youth Fund LS, No. We thank the specialists from The First Affiliated Hospital of Zhejiang Chinese Medical University and Zhejiang Chinese Medical University for their support to this work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. PTFC, pure total flavonoids extracted from Citrus maxima Burm. Nair SA, Sr RK, Nair AS, Baby S. Citrus peels prevent cancer. doi: PubMed Abstract CrossRef Full Text Google Scholar.
Ottaviani JI, Heiss C, Spencer JPE, Kelm M, Schroeter H. Recommending flavanols and procyanidins for cardiovascular health: revisited. Mol Aspects Med. Hazafa A, Rehman KU, Jahan N, Jabeen Z. The role of polyphenol flavonoids compounds in the treatment of cancer cells.
Nutr Cancer. Google Scholar. Dinda B, Dinda M, Roy A, Dinda S. Dietary plant flavonoids in prevention of obesity and diabetes. Adv Protein Chem Struct Biol. Jiang J, Shan L, Chen Z, Xu H, Wang J, Liu Y, et al. Evaluation of antioxidant-associated efficacy of flavonoid extracts from a traditional Chinese medicine Hua Ju Hong peels of Citrus grandis L.
J Ethnopharmacol. Aschoff JK, Riedl KM, Cooperstone JL, Högel J, Bosy-Westphal A, Schwartz SJ, et al. Urinary excretion of Citrus flavanones and their major catabolites after consumption of fresh oranges and pasteurized orange juice: a randomized cross-over study.
Mol Nutr Food Res. Bao W, Bowers K, Tobias DK, Olsen SF, Chavarro J, Vaag A, et al. Prepregnancy low-carbohydrate dietary pattern and risk of gestational diabetes mellitus: a prospective cohort study. Am J Clin Nutr. Pereira-Caro G, Polyviou T, Ludwig IA, Nastase AM, Moreno-Rojas JM, Garcia AL, et al.
Bioavailability of orange juice poly phenols: the impact of short-term cessation of training by male endurance athletes. Chen S, Jiang J, Chao G, Hong X, Cao H, Zhang S. Pure total flavonoids from Citrus protect against nonsteroidal anti-inflammatory drug-induced small intestine injury by promoting autophagy in vivo and in vitro.
Front Pharmacol. CrossRef Full Text Google Scholar. Wang TY, Li Q, Bi KS. Bioactive flavonoids in medicinal plants: structure, activity and biological fate.
Asian J Pharm Sci. Najmanová I, Vopršalová M, Saso L, Mladìnka P. The pharmacokinetics of flavanones.
Crit Rev Food Sci Nutr. Lubinska-Szczygeł M, Polkowska Ż, Dymerski T, Gorinstein S. Comparison of the physical and sensory properties of hybrid Citrus fruit Jaffa ® sweetie in relation to the parent fruits. Frydman A, Weisshaus O, Bar-Peled M, Huhman DV, Sumner LW, Marin FR, et al. Citrus fruit bitter flavors: isolation and functional characterization of the gene Cm1,2RhaT encoding a 1,2 rhamnosyltransferase, a key enzyme in the biosynthesis of the bitter flavonoids of Citrus.
Plant J. Zheng YZ, Zhou Y, Liang Q, Chen DF, Guo R. J Mol Model. Xiong Y, Jiang J, Zhang C, Xu C. Preparation Process and Application of Pure Total Flavonoids From Citrus Changshan-Huyou. Patent No CNB. Hangzhou: China National Intellectual Property Administration Zeng H, Xu T, Shi L, Lv L, Li J.
Study on the technology of extracting flavonoids from huyou pomelo peel and comprehensive utilization of residues. J Anhui Agric Sci.
Pham DC, Nguyen HC, Nguyen TL, Ho HL, Trinh TK, Riyaphan J, et al. Optimization of Ultrasound-assisted extraction of flavonoids from Celastrus hindsii leaves using response surface methodology and evaluation of their antioxidant and antitumor activities.
Biomed Res Int. Bagade SB, Patil M. Recent advances in microwave assisted extraction of bioactive compounds from complex herbal samples: a review. Crit Rev Anal Chem. Chaves JO, de Souza MC, da Silva LC, Lachos-Perez D, Torres-Mayanga PC, Machado A, et al. Extraction of flavonoids from natural sources using modern techniques.
Front Chem. Dhanasekaran R, Felsher DW. A tale of two complications of obesity: NASH and hepatocellular carcinoma. Malhotra P, Gill RK, Saksena S, Alrefai WA. Disturbances in cholesterol homeostasis and non-alcoholic fatty liver diseases. Front Med Lausanne. Pierantonelli I, Svegliati-Baroni G.
Nonalcoholic fatty liver disease: basic pathogenetic mechanisms in the progression from NAFLD to NASH. Yang PL, Jiang JP, Li QQ, Wu XM, Chen ZY. Effects of pure total flavonoids from Citrus changshan-huyou on blood lipid metabolism in hyperlipidemic rats.
Zhongguo Zhong Yao Za Zhi. Yachida S, Mizutani S, Shiroma H, Shiba S, Nakajima T, Sakamoto T, et al. Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer.
Nat Med. Moore M, Gill S, Asmis T, Berry S, Burkes R, Zbuk K, et al. Randomized phase II study of modified FOLFOX-6 in combination with ramucirumab or icrucumab as second-line therapy in patients with metastatic colorectal cancer after disease progression on first-line irinotecan-based therapy.
Ann Oncol. Chen ZY, Li JS, Jiang JP, Yan MX, He BH. PubMed Abstract Google Scholar. Jiang J, Yan L, Shi Z, Wang L, Shan L, Efferth T. Hepatoprotective and anti-inflammatory effects of total flavonoids of Qu Zhi Ke peel of Citrus changshan-huyou on non-alcoholic fatty liver disease in rats via modulation of NF-κB and MAPKs.
Li JS, Chen ZY, Jiang JP, He BH. Lee GR. The balance of Th17 versus treg cells in autoimmunity. Int J Mol Sci. Li G, Ding K, Qiao Y, Zhang L, Zheng L, Pan T, et al. Flavonoids regulate inflammation and oxidative stress in cancer.
Dai TY, Wang B, Lin SY, Jiang JP, Wu LQ, Qian WB. Pure total flavonoids from Citrus paradisi Macfad induce leukemia cell apoptosis in vitro.
Chin J Integr Med. Wu L, Zhang X, Lin X, Wang B, Huang C, Qin Y, et al. Inhibition of X-linked inhibitor of apoptosis protein enhances anti-tumor potency of pure total flavonoids on the growth of leukemic cells. Chocolate, tea and wine, as well as some dry beans and seeds, also contain vitamin P.
Flavonoids are a large family of over 5, hydroxylated polyphenolic compounds that carry out key functions in plants, such as attracting pollinating insects, fighting environmental stresses and modulating cell growth. In humans, their bioavailability and biological activities appear to be strongly influenced by their chemical nature.
Bioflavonoids can be broken down into several categories. Although dividing them into categories is not universally agreed upon, one common breakdown includes isoflavones, anthocyanidins , flavans, flavonols, flavones and flavanones.
Some of the best-known flavonoids, like the quercetin found in onions and the genistein found in soy, can be considered subcategories of categories.
Flavonoids also include rutin , citrus flavonoids and hesperidin. In general, the more colorful a food item is, the richer it is in flavonoids. The ability of flavonoids to positively impact the human body in a large variety of ways appears to be related to their ability to regulate cell signaling.
Flavonoids have been shown to exhibit anti-inflammatory, anti-thrombogenic, anti-diabetic, anti-cancer and neuroprotective activities. Rutin is a type of bioflavonoid that may support the walls of your veins and help them work better. A number of studies have shown that flavonoids that come from rutin relieve swelling, aching and pain from varicose veins.
Rutin is found in fruits and fruit rinds especially citrus fruits , buckwheat, and asparagus. Additionally, oligomeric proanthocyanidin complexes OPCs may decrease vein leakage and swelling in the legs.
OPCs are bioflavonoids found in grapeseed and pine bark. Similar flavonoids are also found in cranberry, hawthorn, blueberry and other plants. Studies have shown that bioflavonoids can improve microcirculation , capillary flow and vascular tone, all of which are key in the natural treatment of hemorrhoids.
Bioflavonoid consumption can help you avoid the lengthy and possibly expensive complications of hemorrhoids. Several prospective cohort studies conducted in Europe and the U. have examined the relationship between some measure of dietary flavonoid intake and cardiovascular disease.
A meta-analysis of 14 prospective studies published between and reported that higher intakes in each flavonoid subclass were significantly associated with a reduced risk of cardiovascular issues.
Hepatitis is a a disease characterized by inflammation of the liver. The flavonoid catechin found in high amounts in matcha green tea has been shown in some studies to help people suffering from acute viral hepatitis as well as chronic hepatitis.
A typical amount of catechin used in successful trials is to milligrams three times per day. Bioflavonoids are often recommended along with vitamin C for people who bruise easily. Bioflavonoids help strengthen the capillaries, which makes them helpful for healing bruises.
Flavonoids, especially citrus flavonoids, may also increase the effectiveness of vitamin C. A small, preliminary trial in Germany, conducted by the Department of Dermatology at the Saarland University Hospital and published in the Journal of the American Academy of Dermatology , gave subjects with progressive pigmented purpura a chronic bruising disorder 1, milligrams per day of vitamin C and milligrams per day of the flavonoid rutin.
After four weeks, noticeable bruising was no longer apparent and did not recur in the three-month period after treatment was stopped.
In one study published in Oral Surgery, Oral Medicine, and Oral Pathology , people with herpes infections received either a placebo or milligrams of vitamin C plus milligrams of flavonoids, each taken three to five times per day.
Compared with the placebo, vitamin C and flavonoids reduced the duration of cold sore symptoms by 57 percent. This shows bioflavonoids can naturally treat herpes and cold sores. The bioflavonoid quercetin — found in onion, citrus fruit, pineapple and buckwheat — is commonly used in the treatment of allergies.
Quercetin is a natural antihistamine and an anti-inflammatory that can lower the effects of seasonal allergy symptoms and food allergies, as well as asthma and skin reactions. It can help stabilize the release of histamines from certain immune cells, which results in decreased allergy symptoms like coughs, watery eyes, runny noses, hives and indigestion.
Research published in the Iran Journal of Allergy, Asthma, and Immunology shows that quercetin fights allergies as well as some prescription medications, all with little to no side effects.
Both chronic venous Paleo diet guidelines CVI and heath liver Glucagon hormone and hypoglycemia develop at bioflavonids same time. Alternate-day fasting and oxidative stress and diosmin are healtth for the treatment CVI. There is no information, however, on the effect of these flavonoids in Alternate-day fasting and oxidative stress redox state of fatty liver. We detected free SH-group concentration SHChydrogen-donating ability HDAand natural scavenger capacity were decreased and hepatic malonaldehyde content and dien conjugate DC content in rats with fatty liver were increased compared to the control. After treatment in fatty liver, these parameters except DC significantly improved and approached the control value. Our results indicate that diosmin-hesperidin-containing drug may be a useful agent in improving the antioxidant defensive system in alimentary-induced fatty liver disease. The Alternate-day fasting and oxidative stress and fruit of Citrus bioflavnoids have been healtn raw material for livee traditional Cranberry juice benefits medicine TCM. Pure total Glucagon hormone and hypoglycemia from Citrus maxima Burm. PTFCincluding naringin, hesperidin, narirutin, Leafy greens for salads neohesperidin, have been abd increasing attention for their multiple Alternate-day fasting and oxidative stress efficacies. Based on existing in vitro and in vivo research, this study systematically reviewed the biological functions of PTFC and its components in preventing or treating liver metabolic diseases, cardiovascular diseases, intestinal barrier dysfunction, as well as malignancies. PTFC and its components are capable of regulating glycolipid metabolism, blocking peroxidation and persistent inflammation, inhibiting tumor progression, protecting the integrity of intestinal barrier and positively regulating intestinal microbiota, while the differences in fruit cultivation system, picking standard, manufacturing methods, delivery system and individual intestinal microecology will have impact on the specific therapeutic effect.Citrus bioflavonoids and liver health -
We failed to observe any effect of CCl 4 on renal function. Neither BUN nor serum creatinine levels increased after CCl 4 administration data not shown. Studies by Zimmerman et al [ 29 ] also did not report any rise in BUN levels even after chronic treatment of CCl 4 in nephrectomized rats.
They found an increased frequency of glomerulosclerosis and tubulointerstitial alterations in rats with reduced renal mass on CCl 4 administration thereby indicating nephrotoxicity on long-term CCl 4 administration in rats.
These findings raise the possibility that renal disease in man is related to hydrocarbon solvent exposure and may also be potentiated by concomitant renal disease or impaired renal function. On the contrary, we estimated the renal function just after 48 hrs of CCl 4 challenge. Thus this brief period might not be sufficient to demonstrate any rise in serum BUN and creatinine levels.
Though renal function did not alter after 48 hrs of CCl 4 administration but even this short period of exposure led to a significant oxidative stress in kidneys. Fadhel and coworkers [ 31 ] had also reported increased levels of renal TBARS in rats after CCl 4 exposure which could be improved by black tea extract.
Similar observations were also reported with certain Indian ayurvedic Indian preparations [ 32 ]. HDN treatment has been previously demonstrated to improve GSH levels in liver and kidneys of diabetic rats and a decrease in levels of 8-hydroxydeoxyguanosine 8-OHdG , a marker of DNA fragmentation, in the urine of diabetic rats [ 33 ].
HDN in combination with Diosmin has also been shown to inhibit the reactive oxygen radicals production in Zymosan-stimulated human polymorphonuclear neutrophils [ 34 ].
Thus HDN has been shown to reduce oxidative stress in various in-vivo and in-vitro studies. In conclusion, our study demonstrated that CCl 4 induces a marked oxidative stress in rat liver and kidney, which is amenable to attenuation by HDN.
This protective effect of HDN can be correlated directly to its antioxidant property. Male wistar rats g— g , bred in the central animal house of Panjab University Chandigarh, India were used.
The animals were housed under standard conditions of light and dark cycle with free access to food Hindustan Lever Products, Kolkata, India and water.
The experimental protocols were approved by the Institutional Ethical Committee of Panjab University, Chandigarh. Chemicals employed in these studies were reagent grade.
Carbon tetrachloride E Merck, India was administered subcutaneously in olive oil Hesperidin Sigma chemical USA was suspended in 0. Animals were divided into following groups, each containing 6—8 animals: Control : These animals received a vehicle for HDN i.
CMC by oral route for eight days and on 8 th day, they were administered the subcutaneous injection of olive oil. Thus we adopted the subcutaneous route of CCl 4 administration as reported in the literature [ 35 ]. c in olive oil. HDN was further continued for 2 more days. On the 10 th day, animals were sacrificed 2 hr, after the last dose of HDN and blood was collected, by carotid bleeding, in centrifuge tubes.
Serum was separated and was used freshly for the assessment of renal and liver function tests. Both the kidneys and the liver were quickly harvested and immediately stored at °C till further biochemical estimations. Before sacrifice, rats were kept individually in metabolic cages for 24 h to collect urine for estimation of renal function.
Serum alanine aminotransferase ALT and serum aspartate aminotransferase AST were estimated by International Federation of Clinical Chemistry [ 36 ] ERBA test kits. Serum bilirubin was estimated by Diazo method [ 37 ] ERBA test kits. Kidneys and liver were, perfused with ice cold saline 0.
The homogenates were centrifuged at g for 5 minutes at 4°C to separate the nuclear debris. The supernatant so obtained was centrifuged at 10, g for 20 minutes at 4°C to get the post mitochondrial supernatant which was used to assay catalase and superoxide dismutase SOD activity.
The malondialdehyde MDA content, a measure of lipid peroxidation, was assayed in the form of thiobarbituric acid reacting substances TBARS by method of Okhawa et al. The mixture was brought up to 4. After cooling with tap water, 1.
The organic layer was taken out and its absorbance was measured at nm. TBARS were quantified using an extinction coefficient of 1. Tissue protein was estimated using Biuret method of protein assay and the TBARS content expressed as nanomoles per milligram of protein.
Reduced glutathione GSH in the kidneys and liver was assayed by the method of Jollow et al [ 39 ]. Briefly, 1. The samples were kept at 4°C for at least 1 hour and then subjected to centrifugation at g for 15 minutes at 4°C.
The assay mixture contained 0. The yellow colour developed was read immediately at nm on a spectrophotometer. SOD activity was assayed by the method of Kono et al. In the cuvette, 2 ml of above mixture, 0. Catalase activity was assayed by the method of Claiborne et al [ 41 ].
Briefly, the assay mixture consisted of 1. Changes in absorbance were recorded at nm. Catalase activity was calculated in terms of k minutes Results were expressed as mean ± SEM. The intergroup variation was measured by one way analysis of variance ANOVA followed by Fischer's LSD test.
The statistical analysis was done using the Jandel Sigma Stat Statistical Software version 2. Abraham P, Wilfred G, Cathrine: Oxidative damage to the lipids and proteins pf the lungs, testis and kidney of rats during carbon tetrachloride intoxication.
Clin Chim Acta. Article CAS PubMed Google Scholar. Szymonik-Lesiuk S, Czechowska G, Stryjecka-Zimmer M, Slomka M, Madro A, Celinski K, Wielosz M: Catalase, superoxide dismutase, and glutathione peroxidase activities in various rat tissues after carbon tetrachloride intoxication.
J Hepatobiliary Pancreat Surg. Article PubMed Google Scholar. Guven A, Guven A, Gulmez M: The effect of kefir on the activities of GSH-Px, GST, CAT, GSH and LPO levels in carbon tetrachloride-induced mice tissue. J Vet Med B Infect Dis Vet Public Health.
Ahmad FF, Cowan DL, Sun AY: Detection of free radical formation in various tissues after acute carbon tetrachloride administration in gerbil. Life Sci. Ohta Y, Nishida K, Sasaki E, Kongo M, Ishiguro I: Attenuation of disrupted hepatic active oxygen metabolism with the recovery of acute liver injury in rats intoxicated with carbon tetrachloride.
Res Commun Mol Pathol Pharmacol. CAS PubMed Google Scholar. Ozturk F, Ucar M, Ozturk IC, Vardi N, Batcioglu K: Carbon tetrachloride-induced nephrotoxicity and protective effect of betaine in Sprague-Dawley rats.
Perez AJ, Courel M, Sobrado J, Gonzalez L: Acute renal failure after topical application of carbon tetrachloride. Article Google Scholar. Churchill DN, Finn A, Gault M: Association between hydrocharbon exposure and glomerulonephritis. An araisal of the evidence. Ruprah H, Mant TGK, Flanagan RJ: Acute carbon tetrachloride poisoning in19 pateints: implications for diagnosis and treatment.
Yoshikawa T, Furukawa Y, Murakami M, Takemura S, Kondo M: Effect of viatmin E on D-Galactosamine-induced or carbon tetrachloride-induced hepatotoxicity. Ko KM, Ip SP, Poon MK, Wu SS, Che CT, Ng KH, Kong YC: Effect of a lignan-enriched fructus schisandrae extract on hepatic glutathione status in rats: protection against carbon tetrachloride toxicity.
Planta Med. Garg A, Garg S, Zaneveld LJ, Singla AK: Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res. Jovanovic SV, Steenken S, Tosic M, Marjanovic B, Simic MG: Flavonoids as anti-oxidants.
J Am Chem Soc. Article CAS Google Scholar. Fraga CG, Martino VS, Ferraro GE, Coussio JD, Boveris A: Flavonoids as antioxidants evaluated by in vitro and in situ liver chemiluminescence. Biochem Pharmacol. Miller NJ, Rice-Evans CA: The relative contribution of ascorbic acid and phenolic antioxidants to the total antioxidant activity of orange and apple fruit juices and balckcurrant drink.
Food Chem. Suarez , Herrera MD, Marhuenda E: In vitro scavenger and antioxidant properites of hesperidin and neohesperidin dihydrochalcone. Recknagel RO: Carbon tetrachloride hepatotoxicity: Status quo and future prospects. Google Scholar. Recknagel RO, Ghoshal AK: Lipoperoxidation as a vector in carbon tetrachloride hepatotoxicity.
Lab Invest. Durk H, Frank H: Carbon tetrachloride metabolism in vivo and exhalation of volatile alkanes: dependence upon oxygen parital pressure. Mansuy D, Fontecane M, Chottard J: A heme model study of carbon tetrachloride metabolism: mechanism of phosgene and carbon dioxide formation.
Biochem Biophys Res Commun. Pohl L, Schulick R, George J: Reductive oxygenation mechanism of metabolism of carbon tetrachlorideto phosgene by cytochrome P Mol Pharmacol. Pohl L, Schulick R, Highet R, George J: Identification of dichloromethyl carbene as a metabolite of carbon tetrachloride.
Tom WM, Fong D, Woo D, Prasongwatana V, Boyde TR: Microsomal lipid peroxidation and oxidative metabolism in rat liver. Chem Biol Interact. Slater TF: Free-radical mechanisms in tissue injury.
Biochem J. Article PubMed Central CAS PubMed Google Scholar. Recknagel RO, Glende EA, Lowery K: Lipid peroxidation: Biochemisry, measurement and significance in liver cell injury. Toxicology of the Liver. Edited by: Plaa GL and Hewitt W. ElSisi AE, Earnest DL, Sipes IG: Vitamin A potentiation of carbon tetrachloride hepatotoxicity: role of liver macrophages and active oxygen species.
Toxicol Appl Pharmacol. Hsiao G, Shen MY, Lin KH, Lan MH, Wu LY, Chou DS, Lin CH, Su CH, Sheu JR: Antioxidative and hepatoprotective effects of Antrodia camphorata extract.
J Agric Food Chem. Jeong TC, Kim HJ, Park J, Ha CS, Park JD, Kim S, Roh JK: Protective effects of red ginseng saponins against carbon tetrachloride-induced hepatotoxicity in sprague dawley rats.
Zimmerman SW, Norback DH, Powers K: Carbon tetrachloride nephrotoxicity in rats with reduced renal mass. Arch Pathol Lab Med. Ogawa M, Mori T, Mori Y, Ueda S, Azemoto R, Makino Y, Wakashin Y, Ohto M, Wakashin M, Yoshida H, et al.
Fadhel ZA, Amran S: Effects of black tea extract on carbon tetrachloride-induced lipid peroxidation in liver, kidneys, and testes of rats. Patil S, Kanase A, Varute AT: Effect of hepatoprotective ayurvedic drugs on lipases following CCl4 induced hepatic injury in rats. Indian J Exp Biol. Miyake Y, Yamamoto K, Tsujihara N, Osawa T: Protective effects of lemon flavonoids on oxidative stress in diabetic rats.
Jean T, Bodinier MC: Mediators involved in inflammation: effects of Daflon mg on their release. Mandal AK, Sinha J, Mandal S, Mukhopadhyay S, Das N: Targeting of liposomal flavonoid to liver in combating hepatocellular oxidative damage.
Drug Deliv. IFCC methods for the measurement of catalytic concentrations of enzymes. part 3, IFCC. Method for alanine aminotransferase l-alanine 2 -oxoglutarate aminotransferase, ec 2. Pearlman FC, Lee RT: Detection and measurement of total bilirubin in serum, with use of surfactants as solubilizing agents.
Clin Chem. Ohkawa H, Ohishi N, Yagi K: Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biocem. Jollow D, Mitchell L, Zampaglione N, Gillete J: Bromobenze induced liver necrosis: protective role of glutathione and evidence for 3,4-bromobenzenoxide as the hepatotoxic intermediate.
Kono Y: Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys. Claiborne A: Handbook of Methods for Oxygen Radical Reaserch.
Edited by: Boca Raton FL. Download references. The grants from University Grants commission for conducting the study is gratefully acknowledged. The authors also like to express their thanks to Ms Saraswati Gupta, Senior Technical officer, University Institute of Pharmaceutical sciences Panjab University Chandigarh for her help in conducting the spectrophotometric analysis.
A higher intake of plant-based flavonoid-rich foods is a feature of the Mediterranean dietary pattern. It is recognized that citrus fruits are the main dietary source of flavanones and their concentrations are higher in fruit tissue compared to juice. Tomás-Navarro et al.
found that the main flavanones detected in urine were phase II conjugated derivatives of naringenin and hesperetin after ingesting ml of citrus fruit orange and mandarin.
These findings are relevant, considering that a serving of orange juice ml has 25—65 mg of flavanones as aglycones , and the flesh of orange g has a range of — mg. It is well documented that the bioavailability of poly phenols can be influenced by several factors.
On the other hand, the transformations suffered during gastrointestinal digestion and metabolism phases I and II depend on genetic polymorphisms, sex, age, and the diversity of the colonic microbiota.
Our results showed that higher values of the flavanone score Q4 were associated with lower GGT levels in a dose—response manner. In the same line, a study evaluated the relationship between flavonoid intake and the risk of NAFLD measured by the fatty liver index FLI.
In a cohort study including 17 participants from the National Health and Nutrition Examination Survey — , the authors showed that the lowest intake of flavonoids was associated with higher FLI, C-reactive protein CRP and liver enzyme levels.
Meanwhile, higher flavonoid intake was associated with less likelihood of NAFLD [third tertile vs. In our study, we only evaluated urinary structurally related flavanone phase II metabolites. Being gut microbial metabolites, the T max of the flavanone conjugates is around 5—7 hours post-consumption, therefore longer than that for other structurally related flavonoid metabolites that are usually absorbed in the small intestine and have a T max of 1—2 hours.
Mechanisms underlying the potential hepatoprotective effects of naringenin and hesperetin in humans are still poorly understood. In in vivo and in vitro studies, naringenin and hesperetin metabolites could reduce membrane phospholipid damage, thus preventing lipid peroxidation.
After twelve weeks of intervention, the participants showed significant improvements in body composition, inflammatory markers CRP and fibrinogen , and oxidative status. The strength of the present study is the large sample size of patients with relevant data.
Furthermore, we applied a validated analytical method to accurately identify and measure flavonoid metabolites with authentic standards. Nevertheless, our study has some limitations. First, this study has a cross-sectional design and our findings cannot establish causation.
Second, this Mediterranean cohort was older in age and had MetS. However, it is plausible that plant-based foods have beneficial effects on health outcomes. View PDF Version Previous Article Next Article. DOI: Received 24th September , Accepted 17th November Abstract Background : Dietary flavonoid intake is associated with a reduced risk of some cardiometabolic disorders, attributed in part to their claimed anti-inflammatory activity.
Table 1 Baseline characteristics of participants concerning sociodemographic, clinical and lifestyle features categorized by sex. a p for differences between sexes. b Mediterranean dietary score from 0 to 17 points.
Abbreviations: BMI, body mass index; HOMA-IR, homeostatic model assessment for insulin resistance; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; AISI, aggregate index of systemic inflammation; SII, systemic inflammation index; MET, metabolic equivalent; MedDiet, Mediterranean diet.
Age years Table 2 Concentrations of spot urinary flavonoid metabolites categorized by sex. Results are expressed as mean standard deviation. Table 3 Spearman's correlations rho values between transformed liver enzymes, inflammatory markers and dietary food intake from FFQ.
Markers Watermelon Citrus Onion Total fruit Total vegetables Fruits and vegetables Fruit, vegetables and cereals Data were expressed as Spearman's rho values.
Liver and inflammatory markers were inverse normally transformed. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; AISI, aggregate index of systemic inflammation index; SII, systemic inflammation index.
Table 4 Spearman's correlations rho values between dietary intake of fruits, vegetables and cereals from FFQ data with transformed urinary flavonoid metabolites. Fruits Citrus 0. The model was adjusted for sex, age, smoking status, marital status, educational level, physical activity, sleeping hours, energy intake, intake of vitamins and alcohol consumption.
The p for trend in the analysis was calculated for the association across quartiles. FDR false discovery rate controlling adjustments were conducted by applying the method of Simes. Liver markers were inverse normally transformed. Inflammatory markers were inverse normally transformed.
Adherence to MedDiet b.
Bioflavoniids the biofoavonoids, there has been a growing Citrus bioflavonoids and liver health in dietary Bioflavonoidss due to their likely contribution Green tea extract the health benefits of diets rich in fruits and vegetables. Bioflavonoids, or flavonoids, are a large class of powerful phytochemicals. Not only are bioflavonoids impressive in and of themselves, but they also help maximize the benefits of vitamin C by inhibiting its breakdown in the body. The great thing is that bioflavonoids are often found in many of the top vitamin C foods. What do broccoli, kale, red onions, hot peppers, rutabaga, spinach and watercress have in common? Department of Agriculture flavonoid database, for their high bioflavonoid content.
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