The Potential Hepatoprotective Effect of Vaccinium arctostaphylos L. Fruit Extract in Diabetic Rat.

OBJECTIVE: Vaccinium arctostaphylos has traditionally been employed in Iranian folk medicine to treat diabetes. However, the precise molecular mechanisms underlying its antidiabetic properties remain incompletely understood. The current experiment intended to explore the modulatory effects of V. arctostaphylos fruit ethanolic extract (VAE) on biochemical and molecular events in the livers of diabetic rats. MATERIALS AND METHODS: In this experimental study, male Wistar rats were randomly assigned to four groups: normal control, normal rats with VAE treatment, diabetic control, and diabetic rats with VAE treatment. Following 42 days of treatment, the impact of VAE on diabetes-induced rats was assessed by measuring various serum biochemical parameters, including insulin, free fatty acids (FFA), tumor necrosis factor-α (TNF-α), reactive oxygen species (ROS), and adiponectin levels. The activities of hepatic carbohydrate metabolic enzymes and glycogen content were determined. Additionally, expression levels of selected genes implicated in carbohydrate/lipid metabolism and miR-27b expression were evaluated. H and E-stained liver sections were prepared for light microscopy examination. RESULTS: Treatment with VAE elevated levels of insulin and adiponectin that reduced levels of FFA, ROS, and TNF-α in the serum of diabetic rats. VAE-treated rats exhibited increased activities of hepatic glucokinase (GK), glucose-6-phosphate dehydrogenase (G6PD), and glycogen concentrations, in conjunction with decreased activities of glucose-6-phosphatase (G6Pase) and fructose-1,6-bisphosphatase (FBPase). Furthermore, VAE significantly upregulated the transcription levels of hepatic insulin receptor substrate 1 (Irs1) and glucose transporter 2 (Glut2), while considerably downregulated the expression of peroxisome proliferator-activated receptor gamma (Pparg) and sterol regulatory element-binding protein 1c (Srebp1c). VAE remarkably enhanced the expression of miR27-b in the hepatic tissues of diabetic rats. Abnormal histological signs were dramatically normalized in diabetic rats receiving VAE compared to those in the diabetic control group. CONCLUSION: Our findings underscore the hypoglycemic and hypolipidemic activities of V. arctostaphylos and assist in better comprehension of its antidiabetic properties.

Caucasian Blueberry: Comparative Study of Phenolic Compounds and Neuroprotective and Antioxidant Potential of Vaccinium myrtillus and Vaccinium arctostaphylos Leaves

(1) Background: Two Caucasian blueberries Vaccinium myrtillus L. and Vaccinium arctostaphylos L. are famous berry bushes growing in the Caucasus region and used to treat neurological diseases, but the chemistry and bioactivity of leaf extracts are still poorly studied. (2) Methods: Phenolic compounds of V. myrtillus and V. arctostaphylos leaf extracts were profiled and quantified by HPLC-PDA-ESI-tQ-MS. The neurotropic potential of Vaccinium extracts was studied using the model of middle cerebral artery permanent occlusion to determine cerebral blood flow, the area of the brain tissue necrosis, and antioxidant enzyme activity (including superoxide dismutase, succinate dehydrogenase, and cytochrome C oxidase), as well as the concentration of TBARS. (3) Results: Hydroxycinnamates and flavonoids were identified in the leaves of V. myrtillus and V. arctostaphylos, and the dominant metabolite of both extracts was 5-O-caffeoylquinic acid in the amount of 105-226 mg/g. The studied extracts enhanced the cerebral hemodynamics and decreased the frequency of necrotic and lipooxidative processes in the brain tissue, accompanied by an increase in the activity of antioxidant enzymes. The positive effect of V. arctostaphylos was stronger and exceeded the effectiveness of Ginkgo biloba standardized extract. (4) Conclusion: The leaf extracts of Caucasian blueberries V. myrtillus and V. arctostaphylos as a new source of hydroxycinnamates demonstrated a protective effect of the brain ischemia pathology and can be used as therapeutic agents to treat neurological diseases.

Biogenic and facile synthesis of selenium nanoparticles using Vaccinium arctostaphylos L. fruit extract and anticancer activity against in vitro model of breast cancer.

Biogenic synthesis of selenium nanoparticles (SeNPs) using plant extracts has emerged as a promising alternative approach to traditional chemical synthesis. The current study aims to introduce a safe, low-cost, and green synthesis of SeNPs using fresh fruit extract of Vaccinium arctostaphylos L. The biogenic synthesis of SeNPs was confirmed by different analyses including ultraviolet-visible spectrophotometry, Fourier transform infrared, and energy-dispersive X-ray. Also, the crystalline nature, size, and morphology of the obtained SeNPs were characterized by X-ray diffraction, dynamic light scattering, field emission scanning electron microscopy, and transmission electron microscopy techniques. The SeNPs were successfully synthesized with fruit extract of V. arctostaphylos L. in a regular spherical form and narrow size distribution with suitable zeta-potential values and exhibited appropriate biocompatibility. It revealed that the synthesized SeNPs can significantly inhibit the growth of 4T1 breast cancer cells with an IC50 of ∼84.19 ± 25.96 µg/ml after 72 h treatment. Overall, it can be concluded that the green synthesized SeNPs can be attractive, nontoxic, and eco-friendly candidates for drug delivery or medicinal applications.

The effects of hydroalcoholic extract of Vaccinium arctostaphylos L. on sperm parameters, oxidative injury and apoptotic changes in oxymetholone-induced testicular toxicity in mouse.

Anabolic androgenic steroids (AAS) such as oxymetholone (OM) used for athletic enhancement, but increased free radicals damage and changes in hormonal levels, lead to serious and irreversible organ damage. Vaccinium arctostaphylos(V. arctostaphylos( has been demonstrated to have antioxidant and antiinflammatory effects. The aim of present study was to investigate V. arctostaphylos effect on OM-induced oxidative injury in mouse testis and sperm parameters. In this experimental study, 30 BALB/c mice were divided into five groups, including healthy, positive control(5 mg/kg OM) and three treatment groups (100, 200 and 400 mg/kg of V. arctostaphylos extract + 5 mg/kg OM). At the end of the study, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone levels were measured. Testis stereological and sperm parameters were calculated. Antioxidant status was measured using nitric oxide (NO) and FRAP assay, and malondialdehyde (MDA) levels. Furthermore, the expression of p53, caspase-3, Bax and Bcl-2 was measured. V. arctostaphylos decreased the serum level of testosterone, increased the LH and FSH, and improved the stereological and sperm parameters and down-regulated the p53, caspase-3 and Bax and up-regulated Bcl-2 genes. Furthermore, this dose decreased serum levels of NO and increased testis FRAP and MDA levels in treated groups compared with OM group. V. arctostaphylos extract has protective effects against testicular toxicity caused by OM.

Antihypertensive efficacy and safety of Vaccinium arctostaphylos berry extract in overweight/obese hypertensive patients: A randomized, double-blind and placebo-controlled clinical trial.

OBJECTIVES: To evaluate the antihypertensive efficacy and safety of a standardized Vaccinium arctostaphylos (V. arctostaphylos) berry hydro-alcoholic extract in the overweight/obese hypertensive patients. DESIGN: Randomized placebo-controlled trial. SETTING: Baqiyatallah hospital (Tehran, Iran). INTERVENTIONS: The antihypertensive efficacy and safety of 3-month intake of 400 mg extract capsule three times daily alongside standardized anti-hypertensive regimen in the treatment of 50 patients was compared with the placebo (n = 50). MAIN OUTCOME MEASURES: SBP (systolic blood pressure), DBP (diastolic blood pressure), body mass index, waist circumference, CBC (complete blood count), blood levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase), BUN (blood urea nitrogen) and creatinine. RESULTS: SBP decreased from 152.1 ± 7.7 to 140.5 ± 10.7 in the V. arctostaphylos group and from 152.9 ± 8.1 to 150.8 ± 9.3 in the placebo group (P < 0.001). DBP decreased from 90.3±8 to 82.1±8.8 in the V. arctostaphylos group and from 89.6 ± 7.8 to 87.6 ± 7.9 in the placebo group (P < 0.001). The extract capsule had no significant effect on the other parameters (P > 0.05). Moreover, no drug side effect and adverse interaction with other antihypertensive drugs was observed in the patients. CONCLUSIONS: V. arctostaphylosberry extract improves blood pressure control and has safety and tolerability in the overweight/obese hypertensive patients taking standard antihypertensive drugs.

Effects of standardized hydro-alcoholic extract of Vaccinium arctostaphylos leaf on hypertension and biochemical parameters in hypertensive hyperlipidemic type 2 diabetic patients: a randomized, double-blind and placebo-controlled clinical trial.

OBJECTIVE: To study the blood pressure, lipid and glycemic effects and safety of Vaccinium arctostaphylos leaf in the hypertensive hyperlipidemic type 2 diabetic patients. MATERIALS AND METHODS: The patients took 350 mg standardized plant leaf hydro-alcoholic extract capsule (n=50) or placebo capsule (n=50) three times daily alongside conventional drugs for 2 months. At the baseline and endpoint, systolic and diastolic blood pressures and blood levels of fasting glucose (FG), 2-hr postprandial glucose (2hPPG), glycosylated hemoglobin (HbA1c), total cholesterol (TC), LDL-C, triglyceride, HDL-C, SGOT, SGPT and creatinine were determined in both groups. To evaluate the extract safety, serum SGOT, SGPT and creatinine levels were tested; also, the patients were requested to report any adverse effects. RESULTS: FG, 2hPPG, HbA1c, TC, LDL-C, triglyceride and systolic and diastolic blood pressures were decreased, whereas HDL-C was increased significantly in the extract group compared to those of the placebo group at the endpoint (for all cases, p<0.05). The extract did not significantly influence other parameters and no adverse effects were reported. CONCLUSION: V. arctostaphylos leaf hydro-alcoholic extract as an adjunct to the conventional drugs has additional antihypertensive as well as anti-dyslipidemic and anti-hyperglycemic effects in hypertensive hyperlipidemic type 2 diabetic patients. Besides, the extract lacks hepatic, renal and patient-reported adverse effects.

Investigation of the Antioxidant, α-Glucosidase Inhibitory, Anti-inflammatory, and DNA Protective Properties of Vaccinium arctostaphylos L.

OBJECTIVES: The scope of this study was to investigate the total phenolic, anthocyanin, and flavonoid contents and the biological properties of ethanol extract (EE), methanol extract (ME), and aqueous extract (AE) from Vaccinium arctostaphylos L. MATERIALS AND METHODS: EE, ME, and AE of V. arctostaphylos were prepared. Various biological activities such as total phenolic, anthocyanin, and flavonoid contents, and antioxidant (2,2'-diphenyl-1-picrylhydrazyl ferrous ion-chelating, and ferric reducing antioxidant power assays), α-glucosidase inhibitory, anti-inflammatory, and DNA protective properties of these extracts were studied. RESULTS: EE exhibited the highest total phenolic, anthocyanin, and flavonoid contents with 44.42±1.22 mg gallic acid equivalents/g dry weight, 8.46±0.49 mg/Cyaniding-3-glucoside equivalents/g dry weight, and 9.22±0.92 mg quercetin equivalents/g dry weight, respectively. The antioxidant activities of the extracts followed the order: EE>ME>AE. EE and ME inhibited α-glucosidase enzyme and their IC50 values were 0.301±0.002 mg/mL and 0.477±0.003 mg/mL, respectively. In addition, EE and ME were determined as noncompetitive inhibitors with inhibitory constant (Ki ) values of 0.48±0.02 mg/mL and 0.46±0.01 mg/mL, respectively. EE in 100 and 300 mg/kg doses caused a significant reduction in formalin-induced edema in mice, demonstrating the anti-inflammatory effect of EE. In DNA protective studies, all of the extracts protected supercoiled plasmid pBR322 DNA against damage caused by Fenton's reagents due to their radical scavenging activities. CONCLUSION: Our results demonstrated that EE of V. arctostaphylos L. had strong antioxidant, anti-inflammatory, α-glucosidase inhibitory, and DNA protective effects, suggesting that it might be an effective medical plant to prevent or treat diseases associated with oxidative damage and inflammation.

Modeling of ultrasound-assisted extraction, characterization and in vitro pharmacological potential of polysaccharides from Vaccinium arctostaphylos L.

In the study, Box-Behnken design was used to optimized the operational parameters involved in ultrasound-assisted extraction (UAE) of Vaccinium arctostaphylos polysaccharide (VAP) including ultrasound power, extraction temperature and time and water to raw material ratio. The highest extraction polysaccharide was obtained at 100W, 19.12min, 79.32C and 20 (ml water/g powdered Vaccinium arctostaphylos). Under these condition, total anthocyanin, total phenolic contents and total flavonoid were 10.16mlg/g, 0.43mlg/g and 0.58mlg/g, respectably. Also, structure of polysaccharide was identified by GC-Mass Fourie transform-infrared spectroscopy (FT-IR). Then, we demonstrated that VAPs had significantly scavenging activities against 2,2-diphenyl-1-picrylhydrazyl and hydroxyl radicals in vitro. The effect of degradation of DPPH was increased by increasing the concentration of polysaccharide up to 15mg/ml. The anti-microbial activity of the resulted polysaccharide with highest concentration (15mg/ml) was the following in order of inhibition zone diameter: B. panis (9.89mm)>S. aureus (9.12mm)>Sh. dysenteriae (7.45mm)>E. coli (6.38mm). VAPs can thus be used as anexcellent antioxidant and antimicrobial ingredient in food and medicinal preparations.

Bio-extract-mediated ZnO nanoparticles: microwave-assisted synthesis, characterization and antidiabetic activity evaluation.

Herein, ZnO nanoparticles were synthesized using microwave-assisted method in the presence of Vaccinium arctostaphylos L, fruits extract. The structure, size, morphology and optical properties of the samples were characterized by XRD, SEM, TEM, EDX, FT-IR, UV-vis DRS and TGA analysis. A decrease in crystallite size was observed for the biologically synthesized ZnO compared to the chemically synthesized sample. Furthermore, the existence of organic moieties over the biologically synthesized ZnO NPs was approved using characterizing methods. Then, the alloxan-induced diabetic rats were divided into not treated (diabetic control group), and the groups received: insulin, chemically synthesized ZnO, plant extract, biologically synthesized ZnO with a normal healthy control group. After treatment, fasting blood glucose (FBS), high-density lipoprotein (HDL), total triglyceride (TG), total cholesterol (TC) and insulin were measured. Analysis showed a significant decrease in FBS and increase in HDL levels in all groups under treatment. However, the results for cholesterol reduction were only significant for the group treated by biologically synthesized ZnO. Despite the changes in the triglyceride and insulin levels, the results were not significant. For all the studied parameters, bio-mediated ZnO NPs were found the most effective in treating the alloxan-diabetic rats compared to the other studied treatment agents.

Hepatoprotective effects of Vaccinium arctostaphylos against CCl4-induced acute liver injury in rats.

BACKGROUND: This study was carried out to evaluate the antioxidant and hepatoprotective effects of Vaccinium arctostaphylos (V.a) methanolic extract on carbon tetrachloride (CCl4)-induced acute liver injury in Wistar rats. METHODS: Total phenolic and total flavonoid contents as well as antioxidant activity of V.a were determined. Extracts of V.a at doses of 200 and 400 mg/kg were administered by oral gavage to rats once per day for 7 days and then were given an intraperitoneal injection of 1 mL/kg CCl4 (1:1 in olive oil) for 3 consecutive days. Serum biochemical markers of liver injury, oxidative markers, as well as hydroxyproline (HP) content and histopathology of liver were evaluated. RESULTS: The obtained results showed that V.a had strong antioxidant activity. Treatment of rats with V.a blocked the CCl4-induced elevation of serum markers of liver function and enhanced albumin and total protein levels. The level of hepatic HP content was also reduced by the administration of V.a treatment. Histological examination of the liver section revealed that V.a prevented the occurrence of pathological changes in CCl4-treated rats. CONCLUSIONS: These findings suggested that V.a may be useful in the treatment and prevention of hepatic injury induced by CCl4.

Evaluation of the effect of Vaccinium arctostaphylos L. fruit extract on serum inflammatory biomarkers in adult hyperlipidemic patients: a randomized double-blind placebo-controlled clinical trial.

Atherosclerosis is a chronic inflammatory condition. Many pro-inflammatory factors including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and adhesion molecules including intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) are expressed in atherosclerotic lesions. The plants of genus Vaccinium are rich in anthocyanins with anti-inflammatory effects. This study aimed to evaluate the effects of Vaccinium arctostaphylos fruit extract on the serum level of TNF-α, IL-6, ICAM-1, and VCAM-1 in adult patients with mild hyperlipidemia to detect its possible inhibitory effects on progression of atherosclerosis. In a randomized double-blind placebo-controlled clinical trial, eligible hyperlipidemic patients were randomly and equally divided in to two groups of study drug or placebo control to receive either the Vaccinium extract or placebo capsules, respectively, twice daily for four consecutive weeks. Each drug capsule contained 0.8 mg of anthocyanins. Serum levels of TNF-α, IL-6, ICAM-1, and VCAM-1 were measured before and after the interventions and finally were compared.A total of 8 men and 12 women in drug group as well as 11 men and 9 women in placebo group completed the study (P = 0.527). The use of Vaccinium extract significantly reduced only the IL-6 level (P = 0.037); however, this reduction was not significant compared to placebo (P = 0.062). Consumption of Vaccinium arctostaphylos fruit extract with the dose of 500 mg twice daily did not show any significant effect on serum levels of TNF-α, IL-6, ICAM-1, and VCAM-1 in adult hyperlipidemic patients. However, considering slight decrease in the level of IL-6, ICAM-1, and VCAM-1, the use of higher doses with longer duration might have significant effects on these factors.

Ethnopharmacological knowledge of Shiraz and Fasa in Fars region of Iran for diabetes mellitus.

ETHNOPHARMACOLOGICAL RELEVANCE: This study provides ethnopharmacological knowledge of traditional herbal healers from Shiraz and Fasa in Fars region (Iran) for treatment of diabetes mellitus. MATERIALS AND METHODS: Field surveys were carried out during September 2013-February 2014 in Shiraz and Fasa. The data were collected through structured questionnaire in Persian. All plant species recorded for the treatment of diabetes mellitus were sampled. Samples were identified by a botanist and obtained a voucher specimens number and deposited in the Shiraz School of Pharmacy Herbarium. The information such as scientific name, family, local name, medicinal use(s), parts used and preparation method were provided. Literature review on available data about antidiabetic effect of the addressed plant species was done to highlight gaps in current knowledge and propose the next steps. RESULTS: In total, 50 informants were interviewed. Totally 39 plant species were recommended by herbal healers, of which 28 are native to Iran. The most recommended plants for diabetes were Trigonella foenum-graecam (28 Attars), Securigera securidaca (22 Attars), Vaccinium arctostaphylos (18 Attars). The most abundant families were Fabaceae, Asteraceae, Lamiaceae and Apiaceae. Plant parts used were mainly seeds, flowers, leaves and fruits. The most usual preparation methods were decoction, powder and distillation. Around 44% of all reported plants for diabetes are also in use for obesity management CONCLUSIONS: This study provided ethnopharmacological knowledge from Fars region in Iran for a specific disease and we have introduced important plant species which are recommended by local herbal healers for diabetes mellitus. For 23% of reported plants, clinical studies approved antidiabetic properties and for 61%, animal studies approved antidiabetic activity.

Improved lipid profile in hyperlipidemic patients taking Vaccinium arctostaphylos fruit hydroalcoholic extract: a randomized double-blind placebo-controlled clinical trial.

Dyslipidemia is a common contributory cause of cardiovascular disease. Vaccinium arctostaphylos L. (Caucasian whortleberry) fruit is rich of anthocyanins. Anthocyanins may exert cardioprotective effects by various mechanisms such as favorably modulating dyslipidemia. Therefore, in this randomized double-blind placebo-controlled clinical trial with hyperlipidemic (hypercholesterolemic and/or hypertriglyceridemic) patients aged 20-60 years, the effects of taking a standardized whortleberry fruit hydroalcoholic extract (one 350 mg capsule every 8 h for 2 months) on fasting blood levels of lipids, creatinine and liver enzymes including SGOT and SGPT were evaluated in 40 patients and compared with the placebo group (n = 40). The extract lowered the blood levels of total cholesterol (P < 0.001), triglyceride (P = 0.002) and low-density lipoprotein cholesterol (LDL-C) (P = 0.002), but increased the blood high-density lipoprotein cholesterol (HDL-C) levels (P < 0.001) without any significant effects on the blood levels of SGOT, SGPT and creatinine (P > 0.05) compared with the placebo group at the endpoint. Whortleberry reduced total cholesterol, triglyceride and LDL-C 27.6%, 19.2% and 26.3%, respectively, but increased HDL-C 37.5% compared with baseline. No adverse effects were reported. Short-term treatment with whortleberry fruit appears safe and improves lipid profile in hyperlipidemic patients.

Enzyme Assay Guided Isolation of an α-Amylase Inhibitor Flavonoid from Vaccinium arctostaphylos Leaves.

The management of postprandial hyperglycemia is an important strategy in the control of diabetes mellitus and complications associated with the disease, especially in the diabetes type 2. Therefore, inhibitors of carbohydrate hydrolyzing enzymes can be useful in the treatment of diabetes and medicinal plants can offer an attractive strategy for the purpose. Vaccinium arctostaphylos leaves are considered useful for the treatment of diabetes mellitus in some countries. In our research for antidiabetic compounds from natural sources, we found that the methanol extract of the leaves of V. arctostaphylos displayed a potent inhibitory activity on pancreatic α-amylase activity (IC50 = 0.53 (0.53 - 0.54) mg/mL). The bioassay-guided fractionation of the extract resulted in the isolation of quercetin as an active α-amylase inhibitor. Quercetin showed a dose-dependent inhibitory effect with IC50 value 0.17 (0.16 - 0.17) mM.

The effects of aqueous extract of vaccinium arctostaphylos leaves on blood pressure in renal hypertensive rats.

BACKGROUND: The leaves of Vaccinium arctostaphylos (Qare qat) is advocated for the treatment of hypertension in Iran' folk medicine. The objective of was to examine the possible hypotensive activity of aqueous extract of Vaccinium arctostaphylos leaves in rat model of two-kidney, one-clip hypertension. METHODS: Rats were subjected to sham operation of the placement of Plexiglass clip on left renal arteries. Four weeks later, renal artery clipped rats were given intravenous injection of normal saline or the extract at 10, 25, or 75 mg/kg, and mean blood pressure and heart rate were measured before and 20, 40 and 60 minutes after vehicle or drug administration. RESULTS: Compared to sham group, renal artery clipped groups had a significantly higher mean blood pressure, heart and right kidney weights, lower left kidney weight and significantly indifferent heart rate. Compared to vehicle treatment, the extract at 75 mg/kg, but not at 10 or 25 mg/kg, did reduce the mean blood pressure at 20, 40 and 60 minutes after administration without changing the heart rate. CONCLUSION: The findings showed that at a higher dose the extract did have hypotensive activity without changing the heart rate. The exact hypotensive mechanism remains to be investigated.