Citrus Bioflavonoid Research Articles

Diosmin attenuates radiation-induced hepatic fibrosis by boosting PPAR-γ expression and hampering miR-17-5p-activated canonical Wnt-β-catenin signaling.

Liver fibrosis is one of the major complications from upper right quadrant radiotherapy. MicroRNA-17-5p (miR-17-5p) is hypothesized to act as a regulator of hepatic stellate cell (HSCs) activation by activation of the canonical Wnt-β-catenin pathway. Diosmin (Dios), a citrus bioflavonoid, is known to possess potent antioxidant, anti-inflammatory, and anti-apoptotic properties. To explore the molecular mechanisms that underlie radiation-induced liver fibrosis, and to evaluate the possible influence of Dios on the miR-17-5p-Wnt-β-catenin signaling axis during fibrogenesis provoked by irradiation (IRR) in rats. Also, the effect of Dios on hepatic peroxisome proliferator activated receptor-γ (PPAR-γ) expression as a regulator for HSC activation was considered. We administered 100 mg·(kg body mass)-1·day-1 (per oral) of Dios were administered to IRR-exposed rats (overall dose of 12 Gy on 6 fractions of 2 Gy each) for 6 successive weeks. Data analysis revealed that Dios treatment mitigated oxidative stress, enhanced antioxidant defenses, alleviated hepatic inflammatory responses, abrogated pro-fibrogenic cytokines, and stimulated PPAR-γ expression. Dios treatment repressed the miR-17-5p activated Wnt-β-catenin signaling induced by IRR. Moreover, Dios treatment restored the normal hepatic architecture and reversed pathological alterations induced by IRR. We hypothesize that the stimulation of PPAR-γ expression and interference with miR-17-5p activated Wnt-β-catenin signaling mediates the antifibrotic properties of Dios.

Assessment of the Potential Role of Hesperidin as an Antioxidant on the Carbon Tetrachloride - Induced Kidney Damage in Rats

Aim of the work-The present work aimed to investigate the ability of Hesperidine (HDN) as an antioxidant to retard development of renal toxicity induced by CCL4 in rat. Hesperidin (HDN), a citrus bioflavonoid, decreases the oxidative stress produced by carbon tetrachloride in rat kidney. Exposure to CCl4 induces acute and chronic renal injuries. The present study was designed to evaluate the protective effect of hesperidin, on rat kidney damaged by CCl4. Material and methods- Animals were divided into five groups pretreated with hesperidin (HDN) (100 and 200 mg/kg orally) for 10 days and then challenged with CCl4 (2 ml/kg/s.c.) of in olive oil subcutaneously. Rats were sacrificed by carotid bleeding under ether anesthesia. Results: The present results showed that the antioxidant properties of hesperidine might be the main factor responsible for its strong protective action on CCl4-induced nephrotoxicity. Conclusion- This study proved that hesperidin has a protective effect on the renal tissue of rat and the degree of improvement varies in intensity according the dose of Hesperidin

Regulation of urinary crystal inhibiting proteins and inflammatory genes by lemon peel extract and formulated citrus bioflavonoids on ethylene glycol induced urolithic rats

The objective of this study is to check the regulation of crystal matrix proteins and inflammatory mediators by citrus bioflavonoids (CB) and Lemon peel (LP) extract in hyperoxaluric rats. The animals were divided into six groups with 6 animals each. Group 1: Control, Group 2: Urolithic (Ethylene glycol (EG)-0.75%); Group 3 & 5: Preventive study (EG + CB (20 mg/kg body weight) and LP (100 mg/kg body weight) extract administration from 0th-7th week) respectively; Group 4 & 6: Curative study (EG + CB and LP extract administration from 4th–7th week) respectively by oral administration. Urinary lithogenic factors (Calcium, oxalate, phosphate and citrate) were normalized in CB & LP supplemented rats, while serum parameters revealed the nephroprotective nature of the intervening agents compared to urolithic rats (p < 0.001). Immunoblotting studies showed significantly increased expression of THP, osteopontin and transferrin in kidneys of urolithic rats (p < 0.001), while preventive and curative study showed near normal expression of these proteins. Expression of NF-κB, TNF-α and IL-6 were raised significantly (p < 0.001), while a very minimal increase in MCP-1 expression was observed in urolithic rats compared to control. Hence, supplementation of CB and LP reduced the crystal promoting factors and provides protection from crystal induced renal damage.

Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer's disease

Background/aims: Deregulation of metal ion homeostasis has been assumed as one of the key factors in the progression of neurodegenerative diseases. Aluminium (Al) has been believed as a major risk factor for the cause and progression of Alzheimer's disease (AD). In our lab, we have previously reported that hesperidin, a citrus bioflavonoid reversed memory loss caused by aluminium intoxication through attenuating acetylcholine esterase activity and the expression of Amyloid β biosynthesis related markers. Al has been reported to cause oxidative stress associated apoptotic neuronal loss in the brain. So in the present study, protective effect of hesperidin against aluminium chloride (AlCl3) induced cognitive impairment, oxidative stress and apoptosis was studied.Methods: Male Wistar rats were divided into control, AlCl3 treated (100 mg/kg., b.w.), AlCl3 and hesperidin (100 mg/kg., b.w.) co-treated and hesperidin alone treated groups. In control and experimental rats, learning and memory impairment were measured by radial arm maze, elevated plus maze and passive avoidance tests. In addition, oxidative stress and expression of pro and anti-apoptotic markers were also evaluated.Results: Intraperitoneal injection of AlCl3 (100 mg/kg., b.w.) for 60 days significantly enhanced the learning and memory deficits, levels of thiobarbituric acid reactive substances and the expression of Bax and diminished the levels of reduced glutathione, activities of enzymatic antioxidants and the expression of B-cell lymphoma-2 (Bcl-2) as compared to control group in the hippocampus, cortex, and cerebellum. Coadministration of hesperidin (100 mg/kg., b.w. oral) for 60 days prevented the cognitive deficits, biochemical anomalies and apoptosis induced by AlCl3 treatment.Conclusion: Results of the present study demonstrated that hesperidin could be a potential therapeutic agent in the treatment of oxidative stress and apoptosis associated neurodegenerative diseases including AD.

Citrus Bioflavonoids Ameliorate Hyperoxaluria Induced Renal Injury and Calcium Oxalate Crystal Deposition in Wistar Rats

Citrus is considered as a medically important plant from ancient times and the bioflavonoids of different variety of citrus fruits were well explored for their biological activities. The study aim was to explore the effect of citrus bioflavonoids (CB) to prevent and cure hyperoxaluria induced urolithiasis. Twenty four Wistar rats were segregated into 4 Groups. Group 1: Control; Group 2: Urolithic (EG-0.75%); Group 3: Preventive study (EG+CB, day 1-50); Group 4: Curative study (EG+CB, day 30-50). Animals received CB orally (20mg/kg body weight) after performing a toxicity study. Urinary risk factors and serum renal function parameters were significantly reduced by CB administration in both preventive and curative study (p<0.001). Hematoxylin & Eosin and von Kossa staining demonstrated that renal protection was offered by CB against EG insult. Immunohistochemical analyses revealed over expression and abnormal localization of THP and NF-κB in urolithic rats, while it was effectively regulated by CB supplementation. CB prevented and significantly controlled lithogenic factors and CaOx deposition in rats. We propose CB as a potential therapy in management of urolithiasis.

Hesperidin, A Citrus Bioflavonoid Reduces the Oxidative Stress in the Skin of Mouse Exposed to Partial Body γ-Radiation

Generation of reactive oxygen species (ROS) is one of the important and early events after exposure to ionizing radiations and this ROS production is responsible for the degenerative changes ensuing irradiation. An attempt has been made to modulate the radiation induced-ROS by hesperidin (hesperitin-7-rhamnoglucoside), a bioflavonoid in the wounded skin of irradiated mouse. The lower half of the animals was shaved and the animals were orally administered or not with 100 mg/kg body weight of hesperidin before exposure to 6 Gy of partial body gamma-radiation. The activities of glutathione peroxidase, superoxide dismutase and glutathione concentration as well as lipid peroxidation were estimated in the skin of mouse at 0, 1.5, 3, 6, 12, 24 and 48 h post-irradiation. Irradiation of mouse to 6 Gy caused a significant depletion in the activities of glutathione peroxidase, superoxide dismutase as well as glutathione concentration. Exposure of mouse to 6 Gy resulted in a significant elevation in lipid peroxidation when compared to the base line levels of lipid peroxidation. Administration of hesperidin before hemi- body exposure to 6 Gy γ-rays significantly raised the activities of glutathione peroxidase, superoxide dismutase and glutathione concentration, whereas hesperidin pretreatment caused a significant reduction in the radiation induced lipid peroxidation. The present study demonstrates that hesperidin pretreatment reduces the radiation induced oxidative stress in the irradiated wounds of mouse and may be useful paradigm to reduce the radiation-induced oxidative stress before or after surgery.

Ability of naringenin, a bioflavonoid, to activate M-type potassium current in motor neuron-like cells and to increase BKCa-channel activity in HEK293T cells transfected with α-hSlo subunit.

BackgroundNaringenin (NGEN) is a citrus bioflavonoid known to have beneficial health properties; however, the ionic mechanism of its actions remains largely unclear. In this study, we attempted to evaluate the possible effects of NGEN on K+ currents in NSC-34 neuronal cells and in HEK293T cells expressing α-hSlo.ResultsNGEN increased M-type K+ current (IK(M)) in a concentration-dependent manner with an EC50 value of 9.8 μM in NSC-34 cells. NGEN shifted the activation curve of IK(M) conductance to the more negative potentials. In cell-attached recordings, NGEN or flupirtine enhanced the activity of M-type K+ (KM) channels with no changes in single-channel amplitude. NGEN (10 μM) had minimal effect on erg-mediated K+ currents. Under cell-attached voltage-clamp recordings, NGEN decreased the frequency of spontaneous action currents and further application of linopirdine can reverse NGEN-induced inhibition of firing. In HEK293T cells expressing α-hSlo, this compound increased the amplitude of Ca2+-activated K+ current (IK(Ca)). Under inside-out recordings, NGEN applied to the intracellular side of the detached patch enhanced the activity of large-conductance Ca2+-activated K+ (BKCa) channels. Moreover, from the study of a modeled neuron, burst firing of simulated action potentials (APs) was reduced in the presence of the increased conductances of both KM and KCa channels. Fast-slow analysis of AP bursting from this model also revealed that as the conductances of both KM and BKCa channels were increased by two-fold, the voltage nullcline was shifted in an upward direction accompanied by the compression of burst trajectory.ConclusionsThe present results demonstrate that activation of both KM and BKCa channels caused by NGEN might combine to influence neuronal activity if similar channels were functionally co-expressed in central neurons in vivo.

Nobiletin Inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and migration and attenuates neointimal hyperplasia in a rat carotid artery injury model.

Preclinical Research The abnormal migration and proliferation of vascular smooth muscle cells (VSMCs) plays a pivotal role in the development of neointimal hyperplasia after vascular injury. Nobiletin, a citrus bioflavonoid, exhibits anti-inflammatory and anti-oxidative activities. The present study evalutaed whether nobiletin could inhibit platelet-derived growth factor (PDGF)-BB- stimulated VSMC proliferation and migration and decrease neointimal hyperplasia in a rat carotid artery injury model. Cultured VSMCs from rat thoracic aortas were treated with nobiletin before being stimulated with 20 ng/ml PDGF-BB, and rats were subjected to carotid artery injury. Nobiletin inhibited PDGF-BB-induced VSMC proliferation and migration, attenuated reactive oxygen species (ROS) production and reduced phosphorylation of ERK1/2 and the expression of nuclear NF-κB p65 in PDGF-BB-stimulated VSMCs. Nobiletin decreased the intima area and the ratio of neointima to media in balloon-injured rat carotid arteries. Serum levels of TNF-α and IL-6 in nobiletin-treated rats were decreased. These results indicated that nobiletin could be a potential protective agent for the prevention and treatment of restenosis after angioplasty.

Protective effects of hesperidin on concanavalin A-induced hepatic injury in mice.

Hesperidin (HDN) is a citrus bioflavonoid, which widely exists in many plants. Previous researches have proved that HDN has several functions such as anti-oxidant, anti-tumor, anti-inflammatory, immune regulation and so on. In the present study, we explored the protective effects of HDN on concanavalin A (Con A)-induced hepatic injury. Acute hepatic injury model was established successfully by intravenous administration of Con A (15 mg/kg) in male C57BL/6 mice, and HDN was pretreated for 10 days before Con A challenge. It was found that the hepatic injury was notably improved in HDN pretreated mice. Furthermore, hepatic oxidative stress and the production of proinflammatory cytokines including TNF-α and IFN-γ were decreased by HDN pretreatment. More importantly, compared with Con A-treated mice, the expression and releasing of HMGB1 and T-cell activation were markedly reduced in HDN pretreated mice. Thus, these results suggest that HDN protects mice from Con A-induced hepatic injury by suppressing hepatocyte oxidative stress, producing cytokines, expressing and releasing HMGB1 and activating T cells.

Protective effects of citrus and rosemary extracts on UV-induced damage in skin cell model and human volunteers

Ultraviolet radiation absorbed by the epidermis is the major cause of various cutaneous disorders, including photoaging and skin cancers. Although topical sunscreens may offer proper skin protection, dietary plant compounds may significantly contribute to lifelong protection of skin health, especially when unconsciously sun UV exposed. A combination of rosemary and citrus bioflavonoids extracts was used to inhibit UV harmful effects on human HaCaT keratinocytes and in human volunteers after oral intake. Survival of HaCaT cells after UVB radiation was higher in treatments using the combination of extracts than in those performed with individual extracts, indicating potential synergic effects. The combination of extracts also decreased UVB-induced intracellular radical oxygen species (ROS) and prevented DNA damage in HaCaT cells by comet assay and decreased chromosomal aberrations in X-irradiated human lymphocytes. The oral daily consumption of 250mg of the combination by human volunteers revealed a significant minimal erythema dose (MED) increase after eight weeks (34%, p<0.05). Stronger protection was achieved after 12weeks (56%, p<0.01). The combination of citrus flavonoids and rosemary polyphenols and diterpenes may be considered as an ingredient for oral photoprotection. Their mechanism of action may deserve further attention.

Hesperidin, a Citrus Bioflavonoid, Ameliorates Genotoxicity-induced by Diazinon in Human Blood Lymphocytes

Hesperidin (Hes), a natural bioflavonoid, is abundant in citrus fruit and has been reported to exert a wide range of pharmacological effects. Diazinon (DZN) can be mutagenic, or capable of inducing genetic damage, in human blood cells. The protective effect of Hes against DZN-induced micronucleus formation, an index of DNA damage, was investigated in human blood lymphocytes. Whole blood samples were collected from 5 volunteers and were incubated with different Hes concentrations for 3 h. The samples were then incubated with 750 µM DZN for 24 h. Subsequently, the blood samples were cultured with a mitogenic stimulant to evaluate micronucleus formation in cytokinesis-blocked binucleated lymphocytes. The incubation of blood samples with DZN induced additional genotoxicity in lymphocytes, and Hes pretreatment significantly reduced the micronucleus frequency (p<0.01-p<0.001). Hes revealed a potent antigenotoxic effect against DZN-induced DNA damage, which may be due to free radical scavenging property. Since hesperidin is a natural compound and is considered safe, it can be used as a supplement to protect people exposed to chemical or environmental hazards.

Changes in anthropometric measurements, body composition, blood pressure, lipid profile, and testosterone in patients participating in a low-energy dietary intervention

ObjectiveThe purpose of this study was to describe changes in anthropometric measurements, body composition, blood pressure, lipid profile, and testosterone following a low–energy-density dietary intervention plus regimented supplementation program. MethodsThe study design was a pre-post intervention design without a control group. Normal participants were recruited from the faculty, staff, students, and community members from a chiropractic college to participate in a 21-day weight loss program. All participants (n = 49; 36 women, 13 men; 31 ± 10.3 years of age) received freshly prepared mostly vegan meals (breakfast, lunch, and dinner) that included 1200 to 1400 daily calories (5020.8 to 5857.6 J) for the women and 1600 to 1800 (6694.4 to 7531.2 J) daily calories for the men. Nutritional supplements containing enzymes that were intended to facilitate digestion, reduce cholesterol levels, increase metabolic rate, and mediate inflammatory processes were consumed 30 minutes before each meal. The regimented supplementation program included once-daily supplementation with a green drink that contained alfalfa, wheatgrass, apple cider vinegar, and fulvic acid throughout the study period. A cleanse supplementation containing magnesium, chia, flaxseed, lemon, camu camu, cat's claw, bentonite clay, tumeric, pau d'arco, chanca piedra, stevia, zeolite clay, slippery elm, garlic, ginger, peppermint, aloe, citrus bioflavonoids, and fulvic acid was added before each meal during week 2. During week 3, the cleanse supplementation was replaced with probiotic and prebiotic supplementation. ResultsMultiple paired t tests detected clinically meaningful reductions in weight (−8.7 ± 5.54 lb) (−3.9 ± 2.5 kg), total cholesterol (−30.0 ± 29.77 mg/dL), and low-density lipoprotein cholesterol (−21.0 ± 25.20 mg/dL) (P < .05). There was a pre-post intervention increase in testosterone for men (111.0 ± 121.13 ng/dL, P < .05). ConclusionsWeight loss and improvements in total cholesterol and low-density lipoprotein cholesterol levels occurred after a low–energy-density dietary intervention plus regimented supplementation program.

Antimetastatic effect of nobiletin through the down-regulation of CXC chemokine receptor type 4 and matrix metallopeptidase-9

Context: Nobiletin is one of the citrus bioflavonoids and can be found in citrus fruits such as lemons, oranges, tangerines, and grapefruits. The most studied properties of nobiletin are its anti-inflammatory and anticancer activities.Objective: The exact mechanisms of how nobiletin inhibits tumor metastasis and invasion are still not fully understood. In this study, we screened various natural compounds to down-modulate the CXC chemokine receptor-4 (CXCR4) and matrix metallopeptidase-9 (MMP-9).Materials and methods: The effect of nobiletin on the constitutive expressions of CXCR4 and MMP-9, MMP-9 enzymatic activity, associated nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) activation, and tumor cell invasion in human breast cancer cells was investigated. CXCR4 and MMP-9 expression were evaluated via reverse transcription polymerase chain reaction (RT-PCR) and western blotting. NF-κB activation was also evaluated by electrophoretic mobility shift assay (EMSA). In addition, the antimetastatic effects of nobiletin were determined by gelatin zymography and invasion assay.Results: Nobiletin down-regulated both the constitutive expressions of CXCR4 and MMP-9 in human breast cancer cells with IC50 values of 32 and 24 µM, respectively. Nobiletin also suppressed MMP-9 enzymatic activity and tumor cell invasion under noncytotoxic concentrations. Neither proteasome inhibition nor lysosomal stabilization had any effect on the nobiletin-induced decrease in CXCR4 expression. A detailed study of the underlying molecular mechanisms revealed that the regulation of the down-regulation of CXCR4 and MMP-9 were at the transcriptional level, as indicated by the down-regulation of mRNA expression and the suppression of the constitutive NF-κB and MAPKs activation.Discussion and conclusion: Our results indicate, for the first time, that nobiletin is a novel blocker of CXCR4 and MMP-9 expressions and thus has the potential to suppress metastasis of breast cancer.

Antidepressant-like behavioral, neurochemical and neuroendocrine effects of naringenin in the mouse repeated tail suspension test

Our previous study demonstrated that the citrus bioflavonoid naringenin ameliorated behavioral alterations via the central serotonergic and noradrenergic systems in the tail suspension test (TST) induced mice. To better understand its pharmacological activity, mice were submitted to three 6min-TSTs one week apart (Day 1: test, Day 7: retest 1, Day 14: retest 2) followed by hippocampal glucocorticoid receptor (GR), monoamine neurotransmitters and serum corticosterone measurement. The results suggested that repeated TST detected the gradual increase in the efficacy of naringenin over time, additionally 1-day (20 mg/kg), 7-day (10, 20 mg/kg) and 14-day (5, 10, 20 mg/kg) naringenin treatment markedly decreased the immobility time. Moreover, administration of naringenin for 14 days (20 mg/kg) increased hippocampal serotonin (5-HT), norepinephrine (NE) and GR levels, and reduced serum corticosterone levels in mice exposed to the repeated TST. Overall, the present study indicated that the re-exposure would facilitate the detection of the anti-immobility effects of antidepressant drugs in the mouse TST, and clearly demonstrated that the antidepressant-like effect of naringenin may be mediated by an interaction with neuroendocrine and neurochemical systems.

Pharmacological evaluation of the anti-inflammatory activity of a citrus bioflavonoid, hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice.

Pretreatment of rats with hesperidin (50 and 100 mg kg-1, s.c.) reduced the paw oedema induced by carrageenan by 47 and 63%, respectively, within 5 h. The effect was equivalent to that produced by indomethacin (10 mg kg-1, p.o.), although unrelated to the administered dose, particularly at high doses. At 100 mg kg-1 hesperidin decreased the rat paw oedema induced by dextran by 33%, without influencing the histamine-induced paw oedema. Hesperidin also inhibited pleurisy induced by carrageenan, reducing the volume of exudate and the number of migrating leucocytes by 48 and 34%, respectively, of control values. Equal doses of duartin and claussequinone were ineffective in all the above tests. Pretreatment of mice with hesperidin (100 mg kg-1, s.c.) reduced acetic acid-induced abdominal constriction by 50%, but did not affect the tail flick response. Hyperthermia induced by yeast in rats was slightly reduced by hesperidin. No lesions of the gastric mucosae were detected in rats pretreated with hesperidin. The results indicate that hesperidin obtained from citrus cultures may present a potential therapeutical use as a mild anti-inflammatory agent, being also useful as a precursor of new flavonoids endowed with such activity.

Efeito de acibenzolar-S-metil, mananoligossacarídeo e bioflavonóides cítricos no controle da mancha-aquosa e no crescimento do meloeiro

Foi estudado o efeito de acibenzolar-S-metil (ASM), mananoligossacarideos (MOS) e bioflavonoides citricos (BFC) no controle da mancha-aquosa causada por Acidovorax citrulli em meloeiros tipo Amarelo (hibrido AF4945) e tipo Pele de Sapo (hibrido Nilo), em diferentes epocas de aplicacao (10 e 15 dias apos a emergencia das plântulas) e dosagens (ASM 25; 50 e 75 mg i.a. L-1; MOS 0,5; 1,0 e 1,5 p.c. L-1; BFC 2; 3 e 4 mL p.c. L-1); e tambem no crescimento da planta em solo com ou sem suplementacao de NPK. A melhor epoca para aplicacao dos indutores foi dez dias apos a emergencia das plântulas. Considerando os dois genotipos, ASM (50 mg i.a. L-1) e BFC (3 mL p.c. L-1) elevaram o periodo de incubacao em ate 13 e 8 dias e reduziram a incidencia da mancha-aquosa em 88 e 60%; o indice de doenca em 96 e 88%; e a area abaixo da curva de progresso da doenca em 94 e 74%, respectivamente. No entanto, independente do nivel de NPK no solo, ASM e BFC reduziram a altura, biomassa fresca e seca da parte aerea das plantas de meloeiro em ate 24; 41 e 34%, respectivamente.

Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism

Maternal immune activation (MIA) can affect fetal brain development and thus behavior of young and adult offspring. Reports have shown that increased Interleukin-6 (IL-6) in the maternal serum plays a key role in altering fetal brain development, and may impair social behaviors in the offspring. Interestingly, these effects could be attenuated by blocking IL-6. The current study investigated the effects of luteolin, a citrus bioflavonoid, and its structural analog, diosmin, on IL-6 induced JAK2/STAT3 (Janus tyrosine kinase-2/signal transducer and activator of transcription-3) phosphorylation and signaling as well as behavioral phenotypes of MIA offspring. Luteolin and diosmin inhibited neuronal JAK2/STAT3 phosphorylation both in vitro and in vivo following IL-6 challenge as well as significantly diminishing behavioral deficits in social interaction. Importantly, our results showed that diosmin (10 mg/kg day) was able to block the STAT3 signal pathway; significantly opposing MIA-induced abnormal behavior and neuropathological abnormalities in MIA/adult offspring. Diosmin's molecular inhibition of JAK2/STAT3 pathway may underlie the attenuation of abnormal social interaction in IL-6/MIA adult offspring.

Dietary Hesperidin Exerts Hypoglycemic and Hypolipidemic Effects in Streptozotocin-Induced Marginal Type 1 Diabetic Rats

Citrus bioflavonoids may offer some protection against the early stage of diabetes mellitus and the development of complications. We investigated the effect of hesperidin on blood glucose levels, hepatic glucose-regulating enzyme activities, serum insulin and adiponectin levels, serum and hepatic lipid levels, and parameters of bone loss in streptozotocin (STZ)-induced marginal type 1 diabetic rats. Weanling male rats were randomly assigned to experimental 3 groups: a control (C) group, a STZ induced marginal type 1 diabetes (S) group, and a diabetes and hesperidin group, and fed their respective diets for 4 weeks. STZ injection increased blood glucose in rats, but the increase was marginal. Serum and hepatic lipids, serum adiponectin and insulin levels were significantly changed by STZ injection. Dietary hesperidin (10 g/kg diet) decreased blood glucose by altering the activity of glucose-regulating enzymes, and normalized the lipids and adiponectin levels, but did not change bone parameters in the marginal type 1 diabetic rats. Hesperidin showed both hypoglycemic and hypolipidemic effects but did not affect bone tissue and bone metabolic makers in STZ-injected marginal diabetic weanling rats without any body weight loss due to STZ injection.

Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer's disease beta-amyloid production.

Glycogen synthase kinase 3 (GSK-3) dysregulation is implicated in the two Alzheimer's disease (AD) pathological hallmarks: β-amyloid plaques and neurofibrillary tangles. GSK-3 inhibitors may abrogate AD pathology by inhibiting amyloidogenic γ-secretase cleavage of amyloid precursor protein (APP). Here, we report that the citrus bioflavonoid luteolin reduces amyloid-β (Aβ) peptide generation in both human ‘Swedish’ mutant APP transgene-bearing neuron-like cells and primary neurons. We also find that luteolin induces changes consistent with GSK-3 inhibition that (i) decrease amyloidogenic γ-secretase APP processing, and (ii) promote presenilin-1 (PS1) carboxyl-terminal fragment (CTF) phosphorylation. Importantly, we find GSK-3α activity is essential for both PS1 CTF phosphorylation and PS1-APP interaction. As validation of these findings in vivo, we find that luteolin, when applied to the Tg2576 mouse model of AD, decreases soluble Aβ levels, reduces GSK-3 activity, and disrupts PS1-APP association. In addition, we find that Tg2576 mice treated with diosmin, a glycoside of a flavonoid structurally similar to luteolin, display significantly reduced Aβ pathology. We suggest that GSK-3 inhibition is a viable therapeutic approach for AD by impacting PS1 phosphorylation-dependent regulation of amyloidogenesis.

Comparison of the Total Oxyradical Scavenging Capacity and Oxygen Radical Absorbance Capacity Antioxidant Assays

Epidemiological studies have shown that phytochemicals in fruits and vegetables may decrease the incidence of cancer. The antioxidant activity of phytochemicals may be partially responsible for the reduced cancer risk. In this study, the antioxidant activity of several phytochemicals was compared using two different antioxidant assays: the oxygen radical absorbance capacity (ORAC) assay, which measures the decrease in fluorescence decay caused by antioxidants, and the total oxyradical scavenging capacity (TOSC) assay, which measures the decrease in ethylene production caused by antioxidants. TOSC and ORAC values were measured for 11 different phytochemicals, and values were expressed as micromol of Trolox equivalents/mg. As expected, a correlation was seen between the TOSC values and the ORAC values (R2 = 0.60). Quercitin, maritime pine bark extract (Pycnogenol, Horphag Research Ltd., Geneva, Switzerland), grape skin extract, and green tea polyphenols had the highest overall antioxidant activity of the 11 phytochemicals measured. Lemon fruit and citrus bioflavonoids had the lowest overall antioxidant activity. Rutin and alpha-lipoic acid had low ORAC values but high TOSC values when compared to the other phytochemicals. The correlation between the in vitro TOSC and ORAC antioxidant assays suggests that both assays may be useful in identifying phytochemicals with high antioxidant activity.