Rutin ameliorates oxidative stress and preserves hepatic and renal functions following exposure to cadmium and ethanol

Context: Rutin (RUT) is an antioxidant flavonoid with well-known metal chelating potentials.

Objective: This study was designed to evaluate the protective effects of RUT against cadmium (Cd)?+?ethanol (EtOH)-induced hepatic and renal toxicity in rats.

Materials and methods: Wistar rats were treated with Cd (50?mg/kg) alone or in combination with EtOH (5?mg/kg) and RUT (25, 50 and 100?mg/kg) for 15?days. After treatment, the liver, kidney and serum were removed for biochemical assays by spectrophotometric methods.

Results: Serum, hepatic and renal malondialdehyde (MDA) levels were highest in the Cd?+?EtOH group and lowest in Cd?+?EtOH animals co-treated with the highest dose of RUT (2.98?±?0.34, 10.08?±?2.32, 4.99?±?1.21 vs. 1.69?±?0.33, 6.13?±?0.28, 3.66?±?1.12?μmol MDA/mg protein, respectively). The serum level of Cd was increased in the Cd?+?EtOH treated animals compared to Cd?+?EtOH animals co-treated with 100?mg/kg RUT (2.54?±?0.08 vs. 1.28?±?0.04?ppm). Furthermore, RUT at the highest dose protected against Cd?+?EtOH-induced elevation of bilirubin and uric acid levels as well as activities of lactate dehydrogenase and γ-glutamyl transferase (62.86?±?2.74 vs. 122.52?±?6.35?µmol/L; 1.77?±?0.35 vs. 3.23?±?0.55?mmol/L; 9.56?±?1.22 vs. 16.21?±?1.64?U/L; 288.92?±?40.12 vs. 159.8?±?18.01?U/L). The histo-pathological changes in the liver and kidney were also reduced in the Cd?+?EtOH animals co-treated with RUT in a dose-dependent manner.

Discussion and conclusion: RUT protected against the combined effects of Cd?+?EtOH on hepatic and renal functions and improved the antioxidant defence system in the blood.     

Prevention of arsenic-mediated reproductive toxicity in adult female rats by high protein diet

Abstract

Context: The detrimental effects of arsenic on female reproductive functions may involve overt oxidative stress. Casein and pea [Pisum sativum Linn. (Fabaceae)] proteins have antioxidant properties.

Objective: To investigate the role of casein- and pea-supplemented high-protein diet (HPD) in utero-ovarian protection from arsenic toxicity.

Materials and methods: Adult female Wistar rats were orally gavaged with vehicle (Gr-I) or arsenic at 3?ppm/rat/d (Gr-II and Gr-III) for 30 consecutive days, when they were maintained on either regular diet containing 18% protein (Gr-I and Gr-II), or HPD containing 27% protein in the form of casein (20%) and pea (7%) (Gr-III). Reproductive functions were evaluated using a battery of biochemical and histological techniques.

Results: As compared to Gr-I, the Gr-II rats suffered from loss of estrous cyclicity, reduction in weight (mg/100?g body weight) of ovary (Gr-I: 54.3?±?4.2 versus Gr-II: 35.8?±?1.6; p?<?0.001) and uterus (Gr-I: 161.7?±?24.6 versus Gr-II: 94.44?±?13.2; p?<?0.05), utero-ovarian degeneration, attenuated ovarian activities (unit/mg tissue/h) of Δ⁵, 3β-hydroxysteroid dehydrogenase (Gr-I: 3.41?±?0.12 versus Gr-II: 2.31?±?0.09; p?<?0.01) and 17β-hydroxysteroid dehydrogenase (Gr-I: 3.82?±?0.57 versus Gr-II: 1.24?±?0.19; p?<?0.001), and decreased serum estradiol level (pg/ml) (Gr-I: 61.5?±?2.06 versus 34.1?±?2.34; p?<?0.001). Ovarian DNA damage was preponderant with blatant generation of malondialdehyde (nM/mg tissue; Gr-I: 15.10?±?2.45 versus Gr-II: 29.51?±?3.44; p?<?0.01) and attenuated superoxide dismutase activity (unit/mg tissue) (Gr-I: 2.18?±?0.19 versus Gr-II: 1.33?±?0.18; p?<?0.05). The Gr-III rats were significantly protected from these ill effects of arsenic.

Discussion and conclusion: HPD, by way of antioxidant properties, may find prospective role in the protection of reproductive damage caused by arsenic.     

Saponin-enriched sea cucumber extracts exhibit an antiobesity effect through inhibition of pancreatic lipase activity and upregulation of LXR-β signaling

Context: Sea cucumbers have been consumed as tonic, food, and nutrition supplements for many years.

Objective: The objective of this study is to investigate the antiobesity and lipid-lowering effects of sea cucumber extracts in in vitro and in vivo models and elucidate the mechanism of action of the extracts on obesity and dyslipidemia.

Materials and methods: The 60% ethanol extracts from the body walls of 10 different sea cucumbers were investigated for the inhibition of pancreatic lipase (PL) activity in vitro. The optimal active extract (SC-3) was further chemically analyzed by LC-MS and UV. And 0.1% and 0.2% of SC-3 was mixed with a high-fat diet to treat C57/BL6 mice for 6 weeks or 2 weeks as preventive and therapeutic study. The body weight, serum, and liver lipid profile in the mice were investigated.

Results: The crude extract of Pearsonothuria graeffei Semper (Holothuriidae) inhibited the PL activity by 36.44% of control at 0.5?μg/mL. SC-3 and echinoside A inhibited PL with an IC₅₀ value at 2.86?μg/mL and 0.76?μM. 0.1% of SC-3 reduced the body weight (23.0?±?0.62 versus 26.3?±?0.76 g), the serum TC (2.46?±?0.04 versus 2.83?±?0.12?mmol/L), TG (0.19?±?0.08 versus 0.40?±?0.03?mmo/L), and LDL-c (0.48?±?0.02 versus 0.51?±?0.02?mmol/L), and liver TC (1.19?±?0.17 versus 1.85?±?0.13?mmol/mg) and TG (6.18?±?0.92 versus 10.87?±?0.97?mmol/mg) contents of the obese C57BL/six mice on a high-fat diet.

Discussion and conclusion: Sea cucumber may be used for developing antiobesity and antihyperlipidemia drugs.     

The effects of triptolide on the pharmacokinetics of sorafenib in rats and its potential mechanism

Context: Combining sorafenib with triptolide could inhibit tumour growth with greater efficacy than single-agent treatment. However, their herb–drug interaction remains unknown.

Objective: This study investigates the herb–drug interaction between triptolide and sorafenib.

Materials and methods: The effects of triptolide (10?mg/kg) on the pharmacokinetics of different doses of sorafenib (20, 50 and 100?mg/kg) in rats, and blood samples were collected within 48?h and evaluated using LC-MS/MS. The effects of triptolide on the absorption and metabolism of sorafenib were also investigated using Caco-2 cell monolayer model and rat liver microsome incubation systems.

Results: The results showed that the C_max (low dose: 72.38?±?8.76 versus 49.15?±?5.46?ng/mL; medium dose: 178.65?±?21.05 versus 109.31?±?14.17?ng/mL; high dose: 332.81?±?29.38 versus 230.86?±?9.68?ng/mL) of sorafenib at different doses increased significantly with the pretreatment of triptolide, and while the oral clearance rate of sorafenib decreased. The t_1/2 of sorafenib increased significant (p?Discussion and conclusions: These results indicated that triptolide could change the pharmacokinetic profiles of sorafenib in rats; these effects might be exerted via decreasing the intrinsic clearance rate of sorafenib in rat liver.     

Anti-endotoxin effects of terpenoids fraction from Hygrophila auriculata in lipopolysaccharide-induced septic shock in rats

Context: Hygrophila auriculata (K. Schum) Heine (Acanthaceae) has been traditionally used for the treatment of various ailments such as inflammation, rheumatism, jaundice and malaria.

Objective: The present study aims to separate terpenoid fraction (TF) from alcohol (70%) extract of the whole plant of Hygrophila auriculata and assess its anti-inflammatory activity.

Materials and methods: HPTLC analysis of TF was performed for the estimation of lupeol. Edema was induced in Wistar albino rats by subplanter injection of 0.1?ml of 1% (w/v) carrageenan into the right hind paw after 1?h of TF administration (100 and 200?mg/kg oral). Septic shock was induced by intraperitoneal administration of LPS (100?μg/kg) in rats and interleukins (IL-1β and IL-6), tumor necrosis factor (TNF-α), superoxide dismutase (SOD), lipid peroxidation (LPO), and nitric oxide (NO) were measured in serum. AutoDock 4.2 was used for molecular docking.

Results: Administration of TF significantly (p?<?0.005) restored the serum levels of cytokines, LPO (7.77?±?0.034 versus 4.59?±?0.059?nmole of TBARS), NO (9.72?±?0.18 versus 4.15?±?0.23?µmol nitrite/mg of wet tissue), and SOD (4.89?±?0.036 versus 7.83?±?0.033?Unit/mg protein) compared with the LPS-challenged rats. Analysis of in silico results revealed that TNF-α is the most appropriate target in eliciting anti-inflammatory activity.

Conclusion: The present findings suggest that TF of Hygrophila auriculata possesses great promise as an anti-inflammatory agent which may be due to its antioxidant effect. Molecular docking results could be exploited for lead optimization and development of suitable treatment of inflammatory disorders.     

Nephroprotective activity of Macrothelypteris oligophlebia rhizomes ethanol extract

Context: Macrothelypteris oligophlebia (Bak.) Ching (Thelypteridaceae) is a Chinese herbal medicine used traditionally for the treatment of diseases such as edema, boils, burns, and roundworms. However, research about the nephroprotective potential of this plant is not available.

Objective: Present study was designed to evaluate the protective effect of ethanol extract of M. oligophlebia rhizomes (EMO) on gentamicin (GM)-induced nephrotoxicity.

Materials and methods: Rats were intraperitoneal (i.p.) injected with GM (100?mg/kg) to induce nephrotoxicity and simultaneously EMO (250 and 500?mg/kg) was orally given to GM-treated rats for 8 days. Blood urea nitrogen (BUN), serum creatinine (Cr), malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were evaluated in renal tissues. Histopathological analysis was used for evaluation of the renal damage.

Results: Administration with GM-induced renal dysfunction in rats. Pre-treatment with EMO (500?mg/kg) significantly decreased the levels of BUN, Cr, MDA and NO (decreased BUN from 12.71?±?1.28 to 7.19?±?0.23 mmol/l, Cr from 39.77?±?5.34 to 19.17?±?0.90 μmol/l, MDA from 5.60?±?0.37 to 2.63?±?0.24 nmol/ml, and NO from 868.17?±?22.67 to 589.51?±?8.83 μmol/ml), and also restored the activities of renal antioxidant enzymes (SOD, CAT, and GSH-Px) (restored SOD from 1.59?±?0.17 to 2.94?±?0.13?U/mg protein, CAT from 3.22?±?0.34 to 10.57?±?0.27?U/mg protein, and GSH-Px from 9.11?±?1.29 to 20.72?±?1.83?U/mg protein).

Discussion and conclusion: Our results suggest that the rhizomes of M. oligophlebia potentially have a protective role in renal tissue against oxidative stress in acute renal failure.     

Plasma and tissue disposition of florfenicol in Escherichia coli lipopolysaccharide-induced endotoxaemic sheep

1.?The purpose of this study was to understand the effects of the acute inflammatory response (AIR) induced by Escherichia coli lipopolysaccharide (LPS) on florfenicol (FFC) and FFC-amine (FFC-a) plasma and tissue concentrations.

2.?Ten Suffolk Down sheep, 60.5?±?4.7?kg, were distributed into two experimental groups: group 1 (LPS) treated with three intravenous doses of 1?μg/kg bw of LPS at 24, 16, and 0.75?h (45?min) before FFC treatment; group 2 (Control) was treated with saline solution (SS) in parallel to group 1. An IM dose of 20?mg FFC/kg was administered at 0.75?h after the last injection of LPS or SS. Blood and tissue samples were taken after FFC administration.

3.?The plasma AUC_0–4?h values of FFC were higher (p?=?0.0313) in sheep treated with LPS (21.8?±?2.0?μg·min/mL) compared with the control group (12.8?±?2.3?μg·min/mL). Lipopolysaccharide injections increased FFC concentrations in kidneys, spleen, and brain. Low levels of plasma FFC-a were observed in control sheep (C_max?=?0.14?±?0.01?μg/mL) with a metabolite ratio (MR) of 4.0?±?0.87%. While in the LPS group, C_max increased slightly (0.25?±?0.01?μg/mL), and MR decreased to 2.8?±?0.17%.

4.?The changes observed in the plasma and tissue concentrations of FFC were attributed to the pathophysiological effects of LPS on renal hemodynamics that modified tissue distribution and reduced elimination of the drug.     

Effects of rosmarinic acid on acetaminophen-induced hepatotoxicity in male Wistar rats

Context: Drug-induced liver injury is a significant worldwide clinical problem. Rosmarinic acid (RA), a natural phenol, has antioxidant effects.

Objective: The effects of RA against acetaminophen (N-acetyl-p-amino-phenol (APAP))-induced oxidative damage and hepatotoxicity in rats were investigated.

Materials and methods: Male Wistar rats were pretreated with RA (10, 50 and 100?mg/kg, i.g.) for one week. On day 7, rats received APAP (500?mg/kg, i.p.). Then aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein, malondialdehyde (MDA), glutathione (GSH), total antioxidant capacity (TAC), glutathione S-transferase (GST), cytochrome CYP450 and histopathological changes were determined.

Results: APAP-induced oxidative stress in liver by a significant increase in the level of MDA (7.6?±?0.21?nmol/mg) as well as a decrease in the contents of TAC (1.75?±?0.14?μmol/g), GSH (1.9?±?0.22?μmol/g) and GST) 3.2?±?0.28?U/mg). RA treatment decreased MDA (4.32?±?0.35?nmol/mg) but increased the contents of TAC (3.51?±?0.34?μmol/g), GSH (3.42?±?0.16?μmol/g) and GST (5.71?±?0.71?μmol/g) in APAP group. RA 100?mg/kg decreased ALT (91.5?±?1.5?U/L), AST (169?±?8.8?U/L) and CYP450 (3?±?0.2?nmol/min/mg) in APAP group. Histologically RA attenuated hepatic damage by decreasing necrosis, inflammation, and haemorrhage in liver sections of APAP group.

Discussion and conclusions: This is the first report that oral administration of RA dose-dependently elicited significant hepatoprotective effects in rats through inhibition of hepatic CYP2E1 activity and lipid peroxidation. RA-protected hepatic GSH and GST reserves and total tissue antioxidant capacity.     

In vitro effects of simultaneous exposure to platinum and cadmium on the activity of antioxidant enzymes and DNA damage and potential protective effects of selenium and zinc

Circulating platinum (Pt) is detectable in the blood of Pt-treated cancer patients for over a decade after the treatment. Prolonged exposure to Pt, in combination with adverse compounds from nutrition and lifestyle, such as cadmium (Cd), could increase the risk from second cancers. The aim of this study was to investigate the effects of simultaneous exposure to Cd- and Pt-compounds on oxidative and DNA damage and the possible protective effects of zinc (Zn) and selenium (Se). The aqueous solutions of PtCl₄, CdCl_2?×_?H₂O, ZnCl₂ and Na₂SeO₃ were added, alone or in combination, to whole blood and isolated erythrocytes to produce the final concentrations of 2000?μg/L of Pt, 8?μg/L of Cd, 100?μg/L of Se, and 1000?μg/L of Zn. The activity of copper, zinc-superoxide dismutase, glutathione peroxidase and glutathione in whole blood was determined after 1?h exposure in in vitro conditions. The induction of DNA strand-breaks in human peripheral blood leukocytes was determined with the alkaline comet assay after 24?h exposure. Exposure to Pt and/or Cd decreased the activities of antioxidant enzymes and elevated DNA damage compared to control. A statistically significant change in the activity of both enzymes and in the induction of DNA strand-breaks was observed in the cells treated with Pt?+?Cd combination, while the addition of Se and/or Zn resulted in partial recovery of these effects. The results indicate that combined exposure to Pt and Cd could disrupt antioxidant protection of the organism and increase DNA damage, whereas Se and Zn could partially ameliorate these harmful effects.     

Mineral pitch stimulates humoral,cellular and innate immune responses in mice

Abstract

Context: Mineral pitch (MP), a traditional medicine, is proposed to boost immunity in conditions that suppress Th1 cytokines such as AIDS/HIV, tuberculosis, leishmaniasis and cancer.

Objective: This study investigates the immunoregulatory mechanisms of MP in innate, humoral and cell-mediated immunity.

Materials and methods: Mice given MP (100, 200, 300 or 400?mg/kg, orally) for 10 consecutive days were immunized intravenously with goat RBC or ovalbumin, and investigated for plaque-forming cells (PFC), hemagglutination titer, hypersensitivity response, lymphocyte proliferation and macrophage function.

Results: MP increased PFC (330.2 versus 182.2/10⁶ splenocytes) in mice immunized with goat RBC and elicited ovalbumin-specific IgG titer at 400?mg/kg. Increase in Th1 immunity was correlated with the increased level of IFN-γ (724 versus 470?pg/ml) and decreased IL-4 (96 versus 178?pg/ml). CD4⁺/CD3⁺ ratio and delayed-type hypersensitivity response also increased to, respectively, 20.62?±?0.59 (versus 16.47?±?0.72) and 1.59?±?0.12 (versus 0.87?±?0.10?mm) in MP-treated mice. MP increased lymphocyte proliferation (11.14?±?0.60 versus 5.81?±?0.40 SI) and macrophage phagocyte response (0.24?±?0.02 versus 0.15?±?0.009), expressed as absorbance at 570?nm, but decreased nitrite production (17.4?±?1.10 versus 24.3?±?1.30?µM/10⁶ cells). We also observed an increased bone marrow cellularity (24.5?±?1.10 versus 17.10?±?0.70 cells/femur) and WBC count (12?667?±?377 versus 9178?±?213 cells/mm³) following MP treatment. There was no sign of toxicity at 400?mg/kg, 1/12th of reported LD₅₀.

Conclusion: MP elicits a dose-dependent Th1 immune response.     

Caffeic acid methyl and ethyl esters exert potential antidiabetic effects on glucose and lipid metabolism in cultured murine insulin-sensitive cells through mechanisms implicating activation of AMPK

Context: Caffeic acid methyl (CAME) and ethyl (CAEE) esters stimulate glucose uptake and AMP-activated protein kinase (AMPK) in C2C12 myocytes (ATCC^® CRL-1772^TM).

Objective: Effects of CAME and CAEE were now assessed on myocyte glucose transporter GLUT4 activity and expression, on hepatic gluconeogenesis and on adipogenesis as well as major underlying signaling pathways.

Materials and methods: GLUT4 protein translocation was studied in L6 GLUT4myc cells, glucose-6-phospatase (G6Pase) in H4IIE hepatocytes and adipogenesis in 3T3-L1 adipocytes. Key modulators were measured using western immunoblot. Cells were treated for 18?h with either CAME or CAEE at various concentrations (12.5–100?μM).

Results: Myocyte glucose uptake rose from 10.1?±?0.5 to 18.7?±?0.8 and 21.9?±?1.0?pmol/min/mg protein in DMSO-, CAME- and CAEE-stimulated cells, respectively, similar to insulin (17.7?±?1.2?pmol/min/mg protein), while GLUT4myc translocation increased significantly by 1.70?±?0.18, by 1.73?±?0.18- and by 1.95?±?0.30-fold (relative to DMSO), following insulin, CAME and CAEE stimulation, respectively. CAME and CAEE suppressed hepatocyte G6Pase by 62.0?±?6.9% and 62.7?±?6.0% with IC₅₀ of 45.93 and 22.64?μM, respectively, comparable to insulin (70.7?±?2.3% inhibition). Finally, CAME and CAEE almost abrogated adipogenesis (83.3?±?7.2% and 97.3?±?3.0% at 100?μM; IC₅₀ of 13.8 and 12.9?μM, respectively). The compounds inhibited adipogenic factors C/EBP-β and PPAR-γ and stimulated AMPK activity in the three cell-lines.

Discussion and conclusions: CAME and CAEE exerted antidiabetic activities in insulin-responsive cells through insulin-independent mechanisms involving AMPK and adipogenic factors.     

Effects of berberine on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its mechanism

Context: Losartan and berberine (BBR) are often simultaneously used for the treatment of senile diabetic nephropathy in clinics. However, the potential herb–drug interaction between losartan and BBR is unknown.

Objective: This study investigates the influence of BBR on the pharmacokinetics of losartan and EXP3174, and investigates the effects of BBR on the metabolic stability of losartan.

Materials and methods: The pharmacokinetic profiles losartan and EXP3174 of orally administered losartan (10?mg/kg) with and without pretreatment with BBR (20?mg/kg) within 24?h were determined in Sprague-Dawley rats. The inhibitory effects of BBR on the metabolic stability of losartan were investigated using rat liver microsomes.

Results: The C_max (1.26?±?0.37 versus 1.96?±?0.45?mg/L) and the AUC_(0–t) (8.25?±?0.89 versus 12.70?±?1.42?mg h/L) of losartan were significantly (p?<?0.05) increased by BBR compared to the control, while the C_max (0.97?±?0.15 versus 0.77?±?0.06?mg/L) of EXP3174 was significantly decreased compared to the control (p?<?0.05). The T_max of losartan was prolonged from 0.41?±?0.12 to 0.52?±?0.18?h, but the difference was not significant. However, the T_max of EXP3174 was decreased significantly (p?<?0.05) from 8.14?±?0.36 to 3.33?±?0.28?h. The metabolic stability of losartan was increased from 37.4 to 59.6?min.

Discussion and conclusion: We infer that BBR might increase the plasma concentration of losartan and decrease the concentration of EXP3174 through inhibiting the activity of CYP3A4 or CYP2C9.     

The comparative pharmacokinetics and gastric toxicity of bezafibrate and ciprofibrate in the rat

1. The comparative gastric toxicology and pharmacokinetics of two phenoxyisobutyrate derivatives have been evaluated in the Fischer rat.

2. After oral administration of single daily doses for 7 days, the plasma elimination half-life for bezafibrate was rapid (t_1/2 of 4–5?h) in comparison to ciprofibrate (t_1/2 of 76?h).

3. The area under the plasma drug concentration versus time curve (AUC) _0–24 (μg±?h/ml± SD) for bezafibrate (dose 125mg/kg per day) was 1553±334, which was less than half the value of 3748±358 achieved by ciprofibrate (10?mg/kg per day) after 7 days.

4. Oral administration of ciprofibrate at 10?mg/kg every 48?h produced similar sustained plasma concentrations to those achieved by bezafibrate 125?mg/kg dosed every 12?h. The AUC0–48 values (μg±h/ml±SD) achieved were 5124±450 for bezafibrate compared to 4207±240 for ciprofibrate.

5. In chronic oral multidose studies with ciprofibrate and bezafibrate, similar gastric toxicity (neuroendocrine cell hyperplasia) occurred in the rat when dose regimens were adjusted to compensate for the pharmacokinetic differences between these two drugs.     

Effects of calcitriol on bone mineral density in patients treated with esomeprazole

Context: Proton pump inhibitor (PPI) increases the risk of decrease in bone mineral density (BMD). However, whether calcitrol improves this situation is unknown.

Objective: The current study investigates the effects of calcitriol on BMD in patients with esomeprazole therapy.

Materials and methods: Three hundred and eighty-six participants with gastrointestinal ulcerations were enrolled and randomly assigned into controlled and supplemented groups. Participants in the controlled group were prescribed esomeprazole (20?mg/qd), while the supplemented group was prescribed esomeprazole (20?mg/qd) and calcitriol (2.5?μg/qd). BMD, serum levels of calcium, carboxy-terminal collagen crosslinks (CTX), and alkaline-phosphatase (ALP) were assessed.

Results: (1) No significant between-group difference of age, gender, smoking, previous glucocorticoid use and hemoglobin level was found; (2) after 10.6?±?0.8?d of PPI therapy, BMD T score in the controlled group was slightly increased compared with initial (?1.25?±?0.08 versus ?1.28?±?0.06, p?=?0.084), while there was no change in the supplemented group (?1.25?±?0.05 versus ?1.26?±?0.03, p?=?0.308); (3) during study termination, calcium level in the supplemented group was slightly higher than the controlled group (2.05?±?0.03?mmol/L versus 2.01?±?0.05?mmol/L, p?=?0.073), while no significant differences of CTX (366.57?±?43.71?pg/mL versus 373.15?±?50.23?pg/mL, p?=?0.036) and ALP were found among these two groups (50.47?±?9.32?U/L versus 52.23?±?10.45?U/L, p?=?0.075).

Conclusion: Patients with gastrointestinal ulcerations with esomeprazole therapy, calcitriol supplement showed no efficacy on BMD changes.     

Effects of glycyrrhizin on the pharmacokinetics of asiatic acid in rats and its potential mechanism

Context: Asiatic acid has been reported to possess a wide range of pharmacological activities.

Objective: This study investigates the effects of glycyrrhizin on the pharmacokinetics of asiatic acid in rats and its potential mechanism.

Materials and methods: The pharmacokinetics of orally administered asiatic acid (20?mg/kg) with or without glycyrrhizin pretreatment (100?mg/kg/day for seven days) were investigated using a LC–MS method. Additionally, the Caco-2 cell transwell model and rat liver microsome incubation systems were used to investigate the potential mechanism of glycyrrhizin’s effects on the pharmacokinetics of asiatic acid.

Results: The results showed that the C_max (221.33?±?21.06 vs. 324.67?±?28.64?ng/mL), AUC_0–inf (496.12?±?109.31 vs. 749.15?±?163.95?μg·h/L) and the t_1/2 (1.21?±?0.27 vs. 2.04?±?0.32?h) of asiatic acid decreased significantly (p?p?Discussion and conclusions: In conclusion, these results indicated that glycyrrhizin could decrease the system exposure of asiatic acid, possibly by inducing the activity of P-gp or CYP450 enzyme.     

Recombinant bovine pancreatic trypsin inhibitor protects the liver from carbon tetrachloride-induced chronic injury in rats

Abstract

Context: Bovine pancreatic trypsin inhibitor (BPTI) has been reported to relieve liver ischemia-reperfusion-induced injury in rats.

Objective: This study was designed to determine whether the recombinant BPTI (rBPTI) can prevent the chronic liver injury induced by CCl₄ in rats.

Materials and methods: Fifty male Wistar rats were divided into five groups. Rats were treated with 40% CCl₄ at a dose of 2?ml/kg body weight twice a week subcutaneously for 12 weeks. In the 8th week, they were administered intraperitoneally with rBPTI (80 MU/kg), BPTI (80 MU/kg) or hepatocyte growth-promoting factor (pHGF; 100?mg/kg) daily for the next 4 weeks.

Results: rBPTI significantly prevented the disruption of liver function of alanine aminotransferase (ALT; 172.7?±?18.16 versus 141.2?±?15.28, p?=?0.003), aspartate aminotransferase (AST; 225.10?±?36.54 versus 170.06?±?27.14, p?=?0.007) and hydroxyproline (Hyp; 1.14?±?0.27 versus 0.62?±?0.17, p?=?0.001). rBPTI significantly decreased the level of thiobarbituric acid reactive substances (TBARS; 1.15?±?0.16 versus 0.87?±?0.15, p?=?0.003) and increased the activities of superoxide dismutase (SOD; 6.07?±?0.95 versus 7.75?±?1.12, p?=?0.007). rBPTI reduced the production of cytokines of IL-1β and TGF-β. The hepatocyte necrosis, fibrosis, fatty degeneration and inflammatory cell infiltration were ameliorated by rBPTI administration.

Conclusion: This study demonstrated that rBPTI exerted a hepatoprotective effect on chronic liver fibrosis induced by CCl₄, which suggests that rBPTI may have the potential application for chronic liver injury induced by drugs metabolism and toxic substances.     

Antidiabetic,antihyperlipidaemic, and antioxidant activity of Syzygium densiflorum fruits in streptozotocin and nicotinamide-induced diabetic rats

Context Syzygium densiflorum Wall. ex Wight & Arn (Myrtaceae) has been traditionally used by local tribes of the Nilgiris, Tamil Nadu, India, for the treatment of diabetes, however, no definitive experimental studies are available.

Objective This study investigates the antidiabetic, antihyperlipidaemic and antioxidant activities of ethanol extract of S. densiflorum (EFSD) fruits in streptozotocin (STZ) and nicotinamide (NA)-induced diabetic rats.

Materials and methods Acute oral toxicity and oral glucose tolerance were assessed in normal rats. The antidiabetic, antihyperlipidaemic and antioxidant activities were investigated in STZ???NA-induced diabetic rats. Diabetic rats were orally administered with glibenclamide (10?mg/kg b.wt), EFSD (200, 400 and 800?mg/kg b.wt) for 28 d. Further, changes in the blood glucose level (BGL), biochemical parameters, antioxidants were observed and histology of pancreas was performed.

Results No toxicity and lethality were observed. Results of the following parameters are represented by treated versus disease control (STZ?+?NA) groups. BGL (161.33?±?22.8 versus 476.17?±?56.58?mg/dl), glycosylated haemoglobin (5.285?±?0.19 versus 8.05?±?0.55%), urea (40.32?±?1.96 versus 75.37?±?2.91?mg/dl), uric acid (1.2?±?0.07 versus 2.16?±?0.05?mg/dl), total cholesterol (89.3?±?5.14 versus 139.7?±?5.95?mg/dl) and triglycerides (79.65?±?2.52 versus 108.9?±?3.61?mg/dl) were significantly decreased, whereas haemoglobin (11.75?±?0.73 versus 7.95?±?0.42?g/dl), high‐density lipoprotein cholesterol (14.2?±?1.11 versus 6.97?±?0.84?mg/dl), total protein (45%) and liver glycogen (87%) were significantly increased in EFSD-treated diabetic group. Significant changes were observed in the enzymatic and non-enzymatic antioxidants in EFSD-treated groups (p?<?0.001). Histopathological examination showed the regeneration of β-cells in Islets of Langerhans.

Conclusion This study confirms the antidiabetic, antihyperlipidaemic and antioxidant activities of S. densiflorum fruits.     

Antiobesity and antihyperglycaemic effects of Adiantum capillus-veneris extracts: in vitro and in vivo evaluations

Context: Adiantum capillus-veneris L. (Adiantaceae) hypocholesterolemic activity is therapeutically praised.

Objectives: Pharmacological modulation of pancreatic triacylglycerol lipase (PL) and α-amylase/α-glucosidase by A. capillus-veneris are evaluated.

Materials and methods: Using positive controls (acarbose, orlistat, guar gum, atorvastatin, glipizide and metformin) as appropriate, crude aqueous extracts (AEs) of A. capillus-veneris aerial parts were tested via a combination of in vitro enzymatic (0.24–100?mg/mL), acute in vivo carbohydrate tolerance tests (125, 250 or 500?mg/kg body weight [b.wt]) and chronic in vivo studies (500?mg/kg b.wt) in high cholesterol diet (HCD) fed Wistar rats.

Results: Like acarbose, A. capillus-veneris as well as chlorogenic acid, with respective IC₅₀ values (mg/mL) of 0.8?±?0.0 and 0.2?±?0.0, were identified as in vitro potent dual inhibitors of α-amylase/α-glucosidase. Unlike guar gum, A. capillus-veneris had no glucose diffusion hindrance capacity. Equivalent to orlistat, A. capillus-veneris and its phytoconstituents inhibited PL in vitro with an ascending order of PL- IC₅₀ values (μg/mL): ferulic acid; 0.48?±?0.06?A. capillus-veneris; 1600?±?100. Incomparable to acarbose or metformin and glipizide, A. capillus-veneris (125, 250 and 500?mg/kg b.wt) lacked antihyperglycaemic efficacies in acute starch- or glucose-evoked postprandial hyperglycaemia increments in normoglycaemic overnight fasting rats. Superior to atorvastatin; A. capillus-veneris exerted significant antiobesity (p?p?Discussion and conclusion: A. capillus-veneris, modulating pancreatic digestive enzymes, may be advocated as a combinatorial diabesity prevention/phytotherapy agent.     

Amelioration of hyperglycaemia and modulation of antioxidant status by Alcea rosea seeds in alloxan-induced diabetic rats

Context: Alcea rosea L. (Malvaceae) has various medicinal uses including anticancer, anti-inflammatory and analgesic properties. However, there is no report on its antidiabetic activity.

Objective: Alcea rosea seed extracts were evaluated for antihyperglycaemic and antioxidative potential in diabetic rats.

Materials and methods: Single intra-peritoneal injection of alloxan (130?mg/kg b.w.) was used for induction of diabetes in Albino Wistar rats. Antihyperglycaemic and antioxidant activities of methanol and aqueous extracts of Alcea rosea seed (100 and 300?mg/kg b.w.), administered orally on daily basis for 15 days, were assessed in vivo for fasting blood glucose level and antioxidant status of liver and pancreas. Metformin was used as a positive control.

Results: Aqueous and methanol extracts (300?mg/kg b.w.) decreased blood glucose level in diabetic rats by 24% and 46%, respectively. Administration of aqueous and methanol extracts at 300?mg/kg b.w. significantly (p?2O₂ decomposed/min/mg of protein), respectively. Similar results were observed for pancreas.

Discussion and conclusions: Antihyperglycaemic and antioxidative potentials of Alcea rosea seeds suggest its usefulness in management of diabetes and its complications. This is the first report on antidiabetic activity of this plant.