Citrus Flavone Research Articles

Hesperidin Reversed Long-Term N-methyl-N-nitro-N-Nitroguanidine Exposure Induced EMT and Cell Proliferation by Activating Autophagy in Gastric Tissues of Rats.

Gastric cancer is a common malignant tumor worldwide. N-methyl-N-nitro-N-nitroguanidine (MNNG) is one of the most important inducing factors of gastric cancer. Autophagy can affect the occurrence and development of gastric cancer, but the mechanism is not clear. Chemoprevention has been shown to be a rational and very promising approach to the prevention of gastric cancer. Hesperidin is a citrus flavone, an abundant polyphenol in citrus fruits and traditional Chinese medicine. It has an excellent phytochemistry that plays an intervention role in gastric cancer. However, it is unclear whether long-term exposure to MNNG will affect the occurrence of gastric cancer by regulating autophagy and whether hesperidin can play an intervention role in this process. In the present study, we demonstrated that long-term MNNG exposure inhibits autophagy in stomach tissues of rats, promotes the epithelial-mesenchymal transition (EMT) process and cell proliferation and suppresses the activity of the PI3K/AKT pathway. We further found that after rapamycin-activated autophagy, long-term MNNG exposure promoted cell proliferation and EMT were inhibited. In addition, hesperidin promotes autophagy and the activity of the PI3K/AKT pathway, as well as the suppression of proliferation and EMT in the stomach tissues of rats. Our findings indicate that hesperidin reverses MNNG-induced gastric cancer by activating autophagy and the PI3K/AKT pathway, which may provide a new basis for the early prevention and treatment of MNNG-induced gastric cancer.

Effect of the Citrus Flavone Nobiletin on Circadian Rhythms and Metabolic Syndrome.

The importance of the circadian clock in maintaining human health is now widely acknowledged. Dysregulated and dampened clocks may be a common cause of age-related diseases and metabolic syndrome Thus, circadian clocks should be considered as therapeutic targets to mitigate disease symptoms. This review highlights a number of dietary compounds that positively affect the maintenance of the circadian clock. Notably the polymethoxyflavone nobiletin has shown some encouraging results in pre-clinical experiments. Although many more experiments are needed to fully elucidate its exact mechanism of action, it is a promising candidate with potential as a chronotherapeutic agent.

Inhibitory mechanism of tangeretin, a citrus flavone on the sphingosylphosphorylcholine (SPC)-induced vascular smooth muscle contraction

We previously discovered that the SPC/Fyn/Rho-kinase (ROK) pathway mediates the Ca2+-sensitization of coronary arterial smooth muscle (CASM) contraction leading to vasospasm, a major cause of sudden death. Lately, we have been trying to find and develop more natural edible compounds which can treat and/or prevent the SPC-induced abnormal CASM contraction, and finally the first to discover that tangeretin (5,6,7,8,4′-pentamethoxyflavone), a natural compound extracted from citrus plants, can inhibit the SPC-induced CASM contraction both in the pretreatment and posttreatment. In porcine CASM tissues, tangeretin showed remarkable inhibitory effects on the SPC-induced contraction with modest inhibitory effects on the high K+-depolarization-induced Ca2+-dependent contraction, both in pretreatment and posttreatment at the optimal concentrations; Regarding the mechanisms, tangeretin markedly abolished the SPC-induced cell contraction through inhibiting the SPC-induced activation and translocation of Fyn and ROK from the cytoplasm to the cell membrane in cultured CASM cells, resulting in the reduction of phosphorylation of myosin light chain. Taken together, these findings indicate that tangeretin, upon pre- or post-treatment, inhibits the SPC-induced CASM contraction through suppressing the Fyn/ROK signaling pathway, thereby suggesting that tangeretin can be a potential candidate for the treatment and/or prevention of vasospasm.

Citrus Flavone Tangeretin Inhibits CRPC Cell Proliferation by Regulating Cx26, AKT, and AR Signaling.

Prostate cancer (PCa) progression depends on the action of androgen receptors (AR). Therefore, preventing ligand-mediated activation of AR is the first-line treatment strategy for metastatic PCa. Androgen deprivation therapy (ADT) can inhibit ligand binding to AR and alleviate PCa progression initially. However, due to the adaptation of PCa and recovery of AR signaling, castration-resistant prostate cancer (CRPC) eventually develops. Exploring novel dietary compounds that can target AR signaling appears to be a viable alternative therapeutic option for CRPC. In the present study, compounds from the citrus fruits were focused upon, which contain various flavonoid ingredients. Key components contained within orange peel, which is frequently used in traditional Chinese medicine, and downstream targets were first analyzed using network pharmacology approach. Notably, it was found that tangeretin, an active ingredient from orange peel, can significantly inhibit CRPC cell (C4-2 and Du145 cells) proliferation and migration whilst also synergistically increasing the sensitivity of CRPC cells to anti-tumor drugs sorafenib or cisplatin. Tangeretin also significantly reduced AR and AKT expressions in C4-2 cells and signal transducer and activator of transcription 3 expression in the androgen-insensitive cell line Du145. In addition, tangeretin increased the expression of both connexin26 (Cx26) and gap junction function, which may mediate the bystander effects of cisplatin or sorafenib. Taken together, the present study revealed a novel molecular mechanism by which tangeretin may inhibit the proliferation of CRPC cells, by affecting the Cx26/AKT/AR pathway, to synergistically increase the sensitivity of CRPC cells to sorafenib and cisplatin.

Describing a novel chemotherapeutic drug formulated by Diosmin for the treatment of acute lymphoblastic leukemia and diabetes mellitus

IntroductionDiosmin is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features. Acute leukemia is a common type of cancer that is caused in the blood.Material and methodsAlpha amylase activity was determined by a method adapted from the work of Taha et al.ResultsIn this study, we examined its effect on some important enzymes, the IC50 values were 196.07 for Aldose reductase, and 76.40 for alpha amylase. The molecular docking study was performed to assess the binding affinity and biological activities of diosmin in the presence of alpha amylase and aldose reductase. The results of the docking study indicated that diosmin has a remarkable binding affinity to these enzymes with a docking score of -9.768 and -140469 for alpha-amylase and aldose reductase, respectively. Therefore, this compound could be used as a potential inhibitor for these enzymes. In the cellular and molecular part of the recent study, the treated cells with Diosmin were assessed by MTT assay for 48h about the cytotoxicity and anti-human acute lymphoblastic leukemia properties on HL-60, Clone 15 HL-60, HL-60/MX1, and HL-60/MX2 cell lines. The IC50 of Diosmin were 466, 323, 502, and 537 µg/mL against HL-60, Clone 15 HL-60, HL-60/MX1, and HL-60/MX2 cell lines, respectively.ConclusionsThe viability of acute lymphoblastic leukemia cell lines reduced dose-dependently in the presence of Diosmin. It appears that the anti-human acute lymphoblastic leukemia effect of Diosmin is due to their antioxidant effects.

The protective role of Diosmin, Hesperidine combination against heavy metals toxicity in Wistar albino rats: Biochemical, Immunohistochemical and Molecular Studies

The benchmark of this study is to evaluate the antioxidant protective efficiency of Diosmin-Hesperidin combination, a natural citrus flavone of hesperidin derivative on heavy metals intoxication and Oxidative stress-induced damage in Wistar albino rats. Oral doses of diosmin-hesperidin in rats (200 and 100 mg/kg body weight, respectively) for a month (every other day) prior to heavy metals intoxication. Evaluation of the protective and antioxidant effects of the combination of diosmin and hesperidin, various Rt-PCR estimations, biochemical estimations, histopathological alterations as well as comet assay and caspase-3 activity for assessment of apoptosis were performed. Results indicated that heavy metals intoxication-induced decline in the levels of liver tissue P53 gene expression and increase of liver tissues of the apoptotic caspase-3 gene, also induced decline in the levels of liver tissue antioxidant parameters (SOD, GPx, and GSH), increased lipid peroxidation (MDA), DNA damage and apoptosis, these parameters were improved by pre-administration of diosmin+hesperidine. Diosmin+hesperidine dose (200 and100 mg/kg body wt. respectively) restored the p53 and caspase-3 genes near-normal values, antioxidant status to near normal and reduced lipid peroxidation, DNA, and tissue damage. These results were confirmed by histopathological examinations, which showed that pre-administration of diosmin+hesperidine protected the liver of albino rats against heavy metals intoxication-induced damage. Hence, it has been illustrated that diosmin+hesperidine might be an effective antioxidant and protector against heavy metals intoxication-induced damage in rats. Moreover, the diosmin+hesperidine alone pretreated group did not show any biochemical alterations, fold change of P53 or caspase-3 genes or DNA damage indicating the protective nature of the drug.

Citrus flavone tangeretin is a potential insulin sensitizer targeting hepatocytes through suppressing MEK-ERK1/2 pathway

BackgroundTangeretin, a flavonoid derived from citrus peel, showed anti-diabetic effects. However, the role of tangeretin on liver, the organ that act as target of insulin and play the central role in maintaining the blood glucose level control, is still largely unknown. The current study was designed to assess the effect of tangeretin on liver insulin sensitivity in vitro and in vivo. MethodsPrimary hepatocytes and mice were treated with different dose of tangeretin, parameters of insulin sensitivity, such as blood glucose levels, serum insulin levels, glucose tolerate test (GTT), insulin tolerate test (ITT), insulin stimulated IR-AKT pathway were analyzed. ResultsPrimary hepatocytes treated with 10/20 μM tangeretin showed up-regulated insulin signaling pathway as well as the glycogen content, while the glucose output were reduced. Intragastric administration of tangeretin (25/50 mg/kg) also ameliorated the liver insulin sensitivity and improved the glucose homeostasis, both in wild type C57 mice and in db/db mice, a diabetic model. Tangeretin treatment dose-dependently suppressed the MEK-ERK1/2 pathway, while forced activation of p-ERK1/2 reversed the insulin sensitized effect of tangeretin. ConclusionThese results indicated that tangeretin enhanced the liver insulin sensitivity in vitro and in vivo, through suppressing the MEK-ERK1/2 pathway.

Effect of a Combination of Citrus Flavones and Flavanones and Olive Polyphenols for the Reduction of Cardiovascular Disease Risk: An Exploratory Randomized, Double-Blind, Placebo-Controlled Study in Healthy Subjects.

A single-center, randomized, double-blind controlled trial was conducted to assess the efficacy of a food supplement based on a combination of grapefruit, bitter orange, and olive extracts administered for eight weeks (n = 51) versus placebo (n = 45) on reduction of cardiovascular risk in healthy volunteers. Study variables included flow-mediated vasodilation (FMD), blood pressure (BP), lipid profile, thrombotic status, oxidative stress biomarkers, inflammation-related biomarkers, anthropometric variables, quality of life, and physical activity. The per-protocol data set was analyzed. In the active product group, there were statistically significant within-group differences at eight weeks as compared with baseline in FMD, systolic and diastolic BP, total cholesterol, LDL-C, LDL-oxidase, oxidized/reduced glutathione ratio, protein carbonyl, and IL-6. Significant between-group differences in these variables were also found. Significant changes in anthropometric variables and quality of life were not observed in the study groups. Changes in the level of physical activity were not recorded. Treatment with the active product was well tolerated. All these findings, taken together, support a beneficial effect of supplementation with a mixture of grapefruit, bitter orange fruits, and olive leaf extracts on underlying mechanisms that may interact each other to decrease the cardiovascular risk in healthy people.

Protective effect of citrus flavone against acute hypoxia in cultured human intestinal smooth muscle cells and the mechanism

Protective effect of citrus flavone against acute hypoxia in cultured human intestinal smooth muscle cells and the mechanism

Citrus Flavones: An Update on Sources, Biological Functions, and Health Promoting Properties.

Citrus spp. are among the most widespread plants cultivated worldwide and every year millions of tons of fruit, juices, or processed compounds are produced and consumed, representing one of the main sources of nutrients in human diet. Among these, the flavonoids play a key role in providing a wide range of health beneficial effects. Apigenin, diosmetin, luteolin, acacetin, chrysoeriol, and their respective glycosides, that occur in concentrations up to 60 mg/L, are the most common flavones found in Citrus fruits and juices. The unique characteristics of their basic skeleton and the nature and position of the substituents have attracted and stimulated vigorous investigations as a consequence of an enormous biological potential, that manifests itself as (among other properties) antioxidant, anti-inflammatory, antiviral, antimicrobial, and anticancer activities. This review analyzes the biochemical, pharmacological, and biological properties of Citrus flavones, emphasizing their occurrence in Citrus spp. fruits and juices, on their bioavailability, and their ability to modulate signal cascades and key metabolic enzymes both in vitro and in vivo. Electronic databases including PubMed, Scopus, Web of Science, and SciFinder were used to investigate recent published articles on Citrus spp. in terms of components and bioactivity potentials.

Role of Diosmin in protection against the oxidative stress induced damage by gamma-radiation in Wistar albino rats

The benchmark of this study is to evaluate the radio protective efficiency of diosmin, a natural citrus flavone of hesperidin derivative on radiation-induced damage in wistar albino rats. Rats orally administered two diosmin doses (100 and 200 mg/kg body wt.) for a month (every other day) prior to exposure to high gamma radiation single dose (8Gy) or cumulative dose (10Gy). To evaluate the radio protective efficiency of diosmin various biochemical estimations, histopathological alterations as well as comet assay and caspase-3 activity for assessment of apoptosis were performed. Results indicated that radiation-induced decline in the levels of antioxidant parameters (SOD and GSH), increased lipid peroxidation, DNA damage and apoptosis were improved by pre-administration of diosmin. Diosmin dose (200 mg/kg body wt.) restored the antioxidant status to near normal and reduced lipid peroxidation, DNA and tissue damage. These results were confirmed by histopathological examinations, which showed that pre-administration of diosmin protected the liver and kidney of albino rats against gamma-irradiation induced damage. Hence, it has been illustrated that diosmin might be an effective radio protector against radiation-induced damage in rats. Moreover, diosmin alone pretreated group did not show any biochemical alterations or DNA damage indicating the protective nature of the drug.

Naringenin: a potential natural remedy against methotrexate-induced hepatotoxicity in rats

Hepatotoxicity is an adverse side effect of methotrexate (MTX) administration for the treatment of different malignancies, psoriasis, and rheumatoid arthritis (RA). Naringenin (NAR) is a citrus flavone with multiple pharmacological characteristics. In this study, we aimed to investigate the protective effects of NAR on MTX-induced hepatotoxicity in rats. For this purpose, 32 Wistar rats were randomly divided into four experimental groups as group 1 Control, group 2 NAR (50 mg/kg/d, o.p.), group 3 MTX (20 mg/kg/d, i.p.), group 4 NAR + MTX. NAR was administrated for 10 consecutive days and MTX was injected on the ninth day. The results indicated that MTX significantly increased malondialdehyde (MDA), NO, TNF-α, and IL-6 levels in the liver. On the other hand, administration of MTX reduced the GSH content, as well as CAT, SOD, and GPx levels. NAR administration remarkably improved MTX-induced alteration of biochemical biomarkers. Our findings were confirmed by the histopathological examination of the liver. Based on our findings, NAR may inhibit MTX-induced hepatotoxicity through scavenging reactive free radicals and inducing anti-inflammatory effects.

Protective role of diosmin against testosterone propionate-induced prostatic hyperplasia in Wistar rats: Plausible role of oxidative stress and inflammation.

Benign prostatic hyperplasia (BPH) is an important key health concern for aging men. Polyphenolic compounds have been found to possess important roles in the inhibition of numerous ailments that involve reactive oxygen species and inflammation. Diosmin is a citrus flavone that possesses antioxidant, anti-inflammatory, antiproliferative, and anticancer activities, so based on these properties of diosmin, we decided to evaluate its effect on testosterone propionate (TP)-induced BPH. A total of 30 Wistar rats were randomly assigned to five groups having six animals in each. This study was of 28 days in which TP (5 mg kg-1) was administered to induce BPH in the last 10 days of the study. It was found that diosmin at the doses of 20 and 40 mg kg-1 significantly reduced malondialdehyde and xanthine oxidase formation in a dose-dependent manner; however, it replenished catalase, glutathione (GSH), and GSH-dependent enzymes, that is, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase significantly against TP-induced BPH. Further, immunohistochemical study showed that diosmin alleviated inflammatory markers (nuclear factor kappa-light-chain-enhancer of activated B cells, cyclooxygenase-2, and interleukin-6). It was also found that diosmin downregulated the expression of androgen receptor and decreased the prostate-specific antigen concentration dose-dependently, significantly against TP-induced BPH. Diosmin also restored histoarchitecture of the prostate in a dose-dependent manner. Findings from the present study revealed the protective role of diosmin against TP-induced BPH in Wistar rats.

Tangeretin Protects against Ethanol‐Induced Injury in Gastric Mucosa of Rats via its Antioxidants and Anti‐inflammatory Activity

Tangeretin (TG), a polymethoxy citrus flavone, has attracted attention due to its significant antioxidant and anti‐inflammatory activities. It showed valuable pharmacological actions and protected against cancer, diabetic‐, liver‐ and renal‐induced injuries. However, its antiulcer activity has not been investigated.This study aimed to explore the possible protective effects of TG against ethanol‐induced gastric injury in rats. Adult male Wistar rats were used and divided into five groups: Control, TG, EtOH, EtOH+TG and EtOH+ Pantoprazole (PAN). Gastric injury was induced by a single dose of Absolute ethanol (5ml/Kg, p.0).Alcohol administration leads to significant macroscopic, histologic and biochemical gastric injuries. Treatment with TG (100mg/kg p.o.) protected against EtOH‐induced gastric injuries as demonstrated by the decrease in the ulcer and bleeding scores. Tangeretin boosted the antioxidants properties of the gastric mucosa via the inhibition of Malondialdehydes (MDA) and nitric oxides (NO) while improving glutathione (GSH), superoxide dismutase (SOD) and the nuclear factor erythroid 2–related factor 2 (Nrf2). Tangeretin curbed gastric inflammation by decreasing myeloperoxidase (MPO) and tumor necrosis factor‐α (TNF‐α) while increasing the anti‐inflammatory interleukin‐10 (IL‐10). In addition, TG caused the upregulation of the gastric cytoprotective prostaglandin E2 (PGE2). These results were comparable to those produced by PAN; the proton pump inhibitor.These findings reported for the first time the gastroprotective actions of TG in EtOH‐induced gastric injury which were mediated via suppression of inflammation and oxidative stress in addition to enhancing the antioxidant and the cytoprotective defenses.Support or Funding InformationThis work has been financially supported by the research grant# 2017‐A‐PH‐03 from the Deanship of Graduate Studies and Research, Ajman University.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Practical Synthesis of Polymethylated Flavones: Nobiletin and Its Desmethyl Derivatives

We present a practical synthesis of the polymethoxylated citrus flavone nobiletin that is suitable for use on a hundred gram scale. Ready availability of this compound and its derivatives will aid ...

Diosmetin Induces Apoptosis of Acute Myeloid Leukemia Cells.

Acute myeloid leukemia is an aggressive disease with limited and nonselective therapeutic options. This study explored the bioactivity and cell death inducing mechanism of diosmetin, a novel compound identified in a nutraceutical screen to impart selective anti-AML activity. Diosmetin, a citrus flavone, induced apoptosis characterized by increases in caspases 8 and 3/7 and the death inducing cytokine TNFα. In fact, through protein and mRNA expression analysis, activity was shown to be dependent on expression of estrogen receptor (ER) β. Treatment with diosmetin also delayed tumor growth in AML mouse xenografts. In summary, these studies highlight diosmetin as a novel therapeutic that induces apoptosis through estrogen receptor β.

Tangeretin attenuates cisplatin-induced renal injury in rats: Impact on the inflammatory cascade and oxidative perturbations

BackgroundDespite the efficacy of cisplatin as a chemotherapeutic agent against various cancers, its clinical utility is limited by serious adverse reactions including nephrotoxicity. AimThe current study aims to investigate the protective potential of tangeretin, a citrus flavone with marked antioxidant actions, against cisplatin-induced renal injury in rats. MethodsTangeretin was administered at 50 and 100 mg/kg p.o. for 1 week starting one day before cisplatin (7.5 mg/kg i.p.) injection. Likewise, silymarin was administered at 100 mg/kg orally. Renal function tests, histopathology, oxidative stress and inflammatory events were investigated. ResultsTangeretin mitigated the increased levels of serum creatinine, blood urea nitrogen and histopathologic alterations evoked by cisplatin. It alleviated renal oxidative stress due to cisplatin by lowering lipid peroxides, nitric oxide and Nrf2 levels with concomitant enhancement of GSH and GPx. Tangeretin also suppressed the upregulated inflammatory response seen with cisplatin treatment by downregulation of activated NF-κB p65 protein expression together with its downstream effectors e.g., iNOS and TNF-α, with restoration of the anti-inflammatory interleukin IL-10. Additionally, it down-regulated the expression of caspase-3, an apoptotic marker, thus favoring renal cell survival. Importantly, tangeretin enhanced the cytotoxic actions of cisplatin in Hep3B and HCT-116 human cancer cell lines. ConclusionTogether, these findings accentuate the dual benefit of tangeretin: mitigation of renal injury-induced by cisplatin and enhancement of its cytotoxic effects.

Nobiletin: A Citrus Isolate to Make Sepsis Less Sour

Septic shock remains a major concern in critically ill patients. Morbidity, as reflected by cardiovascular instability and sequential organ failure, is high and mortality ranges from 20 to 50 % [1]. Treatment options are scarce and mainly causeoriented and symptomatic. Substantial efforts to control the coordinate but sometimes profuse and potentially lethal sepsis-induced immuno-inflammatory response remained unsuccessful. Indeed, large studies investigating numerous “magic bullets” interfering with sepsis-related immuneinflammatory or coagulation processes failed to show efficacy on relevant outcome parameters [2–4]. Also, the theoretical benefit of blood purification by restoring immune homeostasis through indiscriminate removal of inflammatorymediators could not be confirmed [5]. In this context, the paper of Li et al. is highly welcomed. The authors convincingly demonstrate a protective effect of nobiletin, a citrus flavone present in the peels of tangerine, mandarin and oranges, in murine endotoxic shock [6]. Interestingly, apart from inhibiting the “usual pro-inflammatory suspects” tumor necrosis factor-α and interleukin (IL)-6, the study focuses on two key protagonists within the sepsis cascade: high mobility group box-1 (HMGB-1) protein and nuclear factor kappa B (NF-κB) [6]. HMGB-1 is a late mediator of endotoxin lethality [7] and perfectly fits all criteria for an “alarmin” [8]. Alarmins form the endogenous branch of the larger family of damage-associated molecular patterns (DAMPs) that are released by threatened, injured, or necrotic cells [9]. In the nucleus, HMGB-1 stabilizes nucleosome formation and facilitates transcription factor binding. Outside the cell, it functions as a cytokine with weak direct pro-inflammatory activity [10] but considerable ability for indirect triggering of inflammation [11]. HMGB-1, indeed, acts as a potent chemoattractant for neutrophils, monocytes, macrophages, and dendritic cells and engages, among others, Toll-like, IL-1, and receptors for advanced glycation end-products (RAGE) that sustain or enhance the inflammatory process. Moreover, HMGB-1 and endotoxin synergistically reinforce each other at both receptor level and in activating transcriptional responses [11]. Severe sepsis [12] and acute inflammatory lung injury [13] are associated with lifethreatening out-of-control HMGB-1 responses. Thus, it makes perfect sense that measures for keeping the HMGB-1 release in check may dramatically influence the course of sepsis. Inhibiting HMGB-1 in murine sepsis protected against development of organ injury and reversed lethality [14]. Nosaka et al. recently showed that administration of amonoclonal antibody against HMGB1 suppressed the immuno-inflammatory response and significantly improved severe lung injury and survival in patients affected with H1N1 influenza A virus [15]. HMGB-1 is also effectively cleared by highly adsorptive dialysis membranes such as the acrylonitrile 69 surface-treated filter [16] which is increasingly used for continuous renal replacement therapy (CRRT) in hemodynamically unstable septic patients [17]. Though obviously an attractive and more easily available alternative for counteracting the noxious effects of HMGB1, clinical efficacy and benefit of such CRRT approach has not yet been established. 1 ICU Deparment, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium 2 ICU Deparment, UZ Brussel—VUB University, 101, Laarbeeklaan, 1090 Jette Brussels, Belgium 3 To whom correspondence should be addressed at ICU Deparment, UZ Brussel—VUB University, 101, Laarbeeklaan, 1090 Jette Brussels, Belgium. E-mail: Patrick.Honore@az.vub.ac.be

Efficacy of nobiletin, a citrus flavonoid, in the treatment of the cardiovascular dysfunction of diabetes in rats.

Hyperglycemia induced oxidative stress is a prime factor for cardiovascular dysfunction (CVD) in diabetic patients. In this process matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) play important roles. Nobiletin, a polymethoxy citrus flavone, has potent MMP-2 and MMP-9 inhibitory activity in addition to antioxidant activity. We hypothesized that nobiletin due to its MMP-2 & MMP-9 inhibitory and antioxidant effects may ameliorate the cardiovascular dysfunction of diabetes. Diabetes was induced using streptozotocin (50 mg kg(-1) i.p.) in male wistar rats. Four weeks after the induction of diabetes, the rats were treated with nobiletin (10 mg kg(-1), and 25 mg kg(-1)) for a period of the following four weeks. At the end of eight weeks, hemodynamic parameters were recorded, cardiac hypertrophy was measured, and antioxidant assays, and gelatin zymography for MMP-2 & MMP-9 analysis and histopathology were performed. The vascular reactivity of the aorta was measured by recording the contractile response to phenylephrine and relaxation responses to acetylcholine. Treatment with 25 mg kg(-1) nobiletin ameliorated the hemodynamic parameters, oxidative stress, collagen level, MMP-2 and MMP-9 levels, and vascular reactivity significantly compared with vehicle treated diabetic group. Thus, this study suggests that nobiletin ameliorates the CVD of diabetes by inhibiting oxidative stress, MMP-2 & MMP-9 and can be used as a potential therapeutic approach.

Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions.

Alcohol consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Diosmin (DIO) is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features that underlay its protection against cardiac, hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus, the current study aimed to investigate the potential protective effects of DIO against ethanol-induced gastric injury in rats. Pretreatment with DIO (100 mg/kg p.o.) attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of ulcer index (UI) scores, area of gastric lesions, histopathologic aberrations and leukocyte invasion. These actions were analogous to those exerted by the reference antiulcer sucralfate. DIO suppressed gastric inflammation by curbing of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels along with nuclear factor kappa B (NF-κB) p65 expression. It also augmented the anti-inflammatory interleukin-10 (IL-10) levels. Meanwhile, DIO halted gastric oxidative stress via inhibition of lipid peroxides with concomitant enhancement of glutathione (GSH), glutathione peroxidase (GPx) and the total antioxidant capacity (TAC). With respect to gastric mucosal apoptosis, DIO suppressed caspase-3 activity and cytochrome C (Cyt C) with enhancement of the anti-apoptotic B cell lymphoma-2 (Bcl-2) in favor of cell survival. These favorable actions were associated with upregulation of the gastric cytoprotective prostaglandin E2 (PGE2) and nitric oxide (NO). Together, these findings accentuate the gastroprotective actions of DIO in ethanol gastric injury which were mediated via concerted multi-pronged actions, including suppression of gastric inflammation, oxidative stress and apoptosis besides boosting of the antioxidant and the cytoprotective defenses.