Apigenin alleviates neuroinflammation in a mouse model of Parkinson's disease.

PURPOSE OF THE STUDY: The aim of this study is to evaluate the effect of apigenin on inflammatory response in brain tissue in Parkinson's mouse model. MATERIALS AND METHODS: Parkinson's disease model was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Sixty 8-10-weeks-old male C57BL/6 mice were randomly divided into four groups control, Parkinson, prophylaxis, and treatment. Control (0.9% NaCl 0.5 ml, 10 days, i.p.), Parkinson (25 mg/kg MPTP, 5 days, i.p.), prophylaxis (50 mg/kg apigenin, 5 days + 25 mg/kg MPTP, 5 days, i.p.), and treatment (25 mg/kg MPTP, 5 days + 50 mg/kg apigenin, 5 days). The expressions and protein levels of tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1ß), IL-6, IL-10, and transforming growth factor-beta (TGF-ß) were determined using immunohistochemistry and enzyme-linked immunosorbent analysis. RESULTS: Apigenin administration attenuated MPTP-induced histopathological changes in brain tissue. Furthermore, apigenin reversed the changes in expressions and concentrations of TNF-α, IL-1ß, IL-6, IL-10, and TGF-ß. CONCLUSION: This study suggests that apigenin could be used as a neuroprotective option to attenuate neuroinflammation in Parkinson's disease.

Nobiletin attenuates inflammation via modulating proinflammatory and antiinflammatory cytokine expressions in an autoimmune encephalomyelitis mouse model.

The aim of this study is to investigate the potential preventive and therapeutic effects of nobiletin by evaluating the expression of cytokines associated with inflammatory reactions in an autoimmune encephalomyelitis mouse model. A total of 60 male C57BL/6 mice aged between 8 and 10 weeks were used. Mice were divided into six groups (n = 10 mice per group): control, EAE, low-prophylaxis, high-prophylaxis, low-treatment and high-treatment. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG) and pertussis toxin. Nobiletin was administered in low (25 mg/kg) and high (50 mg/kg) doses, intraperitoneally. The prophylactic and therapeutic effects of nobiletin on brain tissue and spinal cord were evaluated by expression of interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), interferon gamma (IFNγ), IL-6, IL-10 and transforming growth factor-beta (TGF-ß) using immunohistochemistry and real-time polymerase chain reaction (RT-PCR). Prophylactic and therapeutic use of nobiletin inhibited EAE-induced increase of TNF-α, IL-1ß and IL-6 activities to alleviate inflammatory response in brain and spinal cord. Moreover, nobiletin supplement dramatically increased the IL-10, TGF-ß and IFNγ expressions in prophylaxis and treatment groups compared with the EAE group in the brain and spinal cord. The results obtained from this study show that prophylactic and therapeutic nobiletin modulates expressions of proinflammatory and antiinflammatory cytokines in brain and spinal cord dose-dependent manner in EAE model. These data demonstrates that nobiletin has a potential to attenuate inflammation in EAE mouse model. These experimental findings need to be supported by clinical studies.

The Effect of Di (2-Ethylhexyl) Phthalate on Hair Trace Mineral Levels in Rats.

We studied the effect of di (2-ethylhexyl) phthalate (DEHP) on rat hair deposition of Iron (Fe), Copper (Cu), Manganese (Mn), and Zinc (Zn). Four groups, each of eight of female Wistar rats weighing 250-300 g, were randomly distributed to (1) control (corn oil-based diet), (2) DEHP 20 (20 mg DEHP per kg body weight (bw), (3) DEHP 100 (100mg DEHP kg/bw, and (4) DEHP 500 (500 mg DEHP kg/bw). The diets were fed daily for 14 days by gastric gavage before the rats were sacrificed. Hair content of Fe, Cu, Mn, and Zn was analyzed with atomic absorption spectrophotometry. There were no significant effect of DEHP on hair Fe content. However, hair Cu, Mn, and Zn were increased after DEHP 20 exposure (p<0.001). After administering DEHP 100 and DEHP 500, both Mn and Zn were decreased (p<0.001), respectively. Hair deposition of Cu, Mn, and Zn was affected by DEHP.

Toward Better Understanding of Insulin Therapy by Translation of a PK-PD Model to Visualize Insulin and Glucose Action Profiles.

Insulin replacement therapy is a fundamental treatment for glycemic control for managing diabetes. The engineering of insulin analogues has focused on providing formulations with action profiles that mimic as closely as possible the pattern of physiological insulin secretion that normally occurs in healthy individuals without diabetes. Hence, it may be helpful to practitioners to visualize insulin concentration profiles and associated glucose action profiles. Expanding on a previous analysis that established a pharmacokinetic (PK) model to describe typical profiles of insulin concentration over time following subcutaneous administration of various insulin formulations, the goal of the current analysis was to link the PK model to an integrated glucose-insulin (IGI) systems pharmacology model. After the pharmacokinetic-pharmacodynamic (PK-PD) model was qualified by comparing model predictions with clinical observations, it was used to project insulin (PK) and glucose (PD) profiles of common insulin regimens and dosing scenarios. The application of the PK-PD model to clinical scenarios was further explored by incorporating the impact of several hypothetical factors together, such as changing the timing or frequency of administration in a multiple-dosing regimen over the course of a day, administration of more than 1 insulin formulation, or insulin dosing adjusted for carbohydrates in meals. Visualizations of insulin and glucose profiles for commonly prescribed regimens could be rapidly generated by implementing the linked subcutaneous insulin PK-IGI model using the R statistical program (version 3.4.4) and a contemporary web-based interface, which could enhance clinical education on glycemic control with insulin therapy.

Modeling Pharmacokinetic Profiles of Insulin Regimens to Enhance Understanding of Subcutaneous Insulin Regimens.

Insulin pharmacokinetics following subcutaneous administration were modeled, simulated, and displayed through an interactive and user-friendly interface to illustrate the time course of administered insulins frequently prescribed, providing a simple tool for clinicians through a straightforward visualization of insulin regimens. Pharmacokinetic data of insulin formulations with different onset and duration of action from several clinical studies, including insulin glargine, regular insulin, neutral protamine Hagedorn (NPH), insulin lispro, and premixed preparations of NPH with regular insulin (Mix 70/30), and insulin lispro protamine suspension with insulin lispro (Mix 50/50, Mix 75/25), were used to develop a predictive population pharmacokinetic model of insulins with consideration of factors such as insulin formulation, weight-based dosing, body-weight effect on volume of distribution, and administration time relative to meals, on the insulin time-action profile. The model-predicted insulin profile of each insulin was validated and confirmed to be comparable to observed data via an external validation method. Model-based simulations of clinically relevant insulin-dosing scenarios to cater to specific initial patient and prescribing conditions were then implemented with differential equations using the R statistical program (version 3.2.2). The R package Shiny was subsequently applied to build a web browser interface to execute and visualize the model simulation outputs. The application of insulin pharmacokinetic modeling enabled informative visualization of insulin time-action profiles and provided an efficient and intuitive educational tool to quickly convey and interactively explore many insulin time-action profiles to ease the understanding of insulin formulations in clinical practice.

Therapeutic role of curcumin in oxidative DNA damage caused by formaldehyde.

PURPOSE: Formaldehyde is a common environmental contaminant that causes oxidative DNA damage in cells by increasing the production of reactive oxygen species. The aim of this study was to investigate the amount of 8-hydroxy-deoxyguanosine (8-OhdG), tumor protein 53(TP53), beta-amyloid[Aß(1-42), Aß (1-40)], total antioxidant capacity (TAC) and malondialdehyde (MDA) and the therapeutic role of curcumin in rat cells with oxidative DNA damage caused by formaldehyde. METHOD: The control group was given physiological saline for 15 days (i.p.) and the second group was given 37% formaldehyde (i.p.) at a dose of 9 mg/kg group every other day. The third group was given 9 mg/kg formaldehyde (i.p.) every other day and treated therapeutically with 100 mg/kg curcumin every day by gavage. At the end of the trial period, urine, blood, and brain tissue was collected from the rats. RESULTS: The levels of MDA in sera were increased and the TAC, TP53, and Aß (1-40) levels were reduced in the formaldehyde-treated group with respect to the control group (p<0.005). After treatment with curcumin, the levels of sera MDA were significantly reduced, the TAC, TP53, and Aß (1-40) levels were significantly increased (P < 0.05). The levels of whole brain Aß (1-42) and 8-OhdG were increased in the formaldehyde-treated group and reduced after treatment with curcumin (P < 0.05). Urinary 8-OhdG excretion increased in the formaldehyde-treated group (P < 0.05) and decreased after treatment with curcumin (P > 0.05). CONCLUSIONS: In conclusion, the oxidative stress caused by formaldehyde exposure was reduced with the application of curcumin.

Vitamin levels in lung tissue of rats with bleomycin induced pulmonary fibrosis.

Bleomycin (BLM) is a chemotherapeutic agent against different carcinomas, one dose of which causes dependent pulmonary fibrosis. The present study was taken up in order to measure the retinyl ester, alpha-tocopherol and cholecalciferol (vitamin D(3)) level in lung tissue in the rats following BLM-induced fibrosis. Fourteen rats were randomly divided into two groups as a control and a BLM group. On the day of the experiment, the BLM group rats were instilled with BLM (7.5 mg/kg) and the control group with sterile saline intratracheally. Fourteen days after instillation, rats in each group were sacrificed and the lungs were prepared for histopathological examination and determination of the vitamin levels with a HPLC system. The levels of retinyl ester, alpha-tocopherol and vitamin D(3) in the lungs of the BLM group were determined to be lower than in the controls. There was statistically significant difference for the alpha-tocopherol and vitamin D(3) concentrations compared to the control group (p<0.01, p<0.001), respectively. According to these results in pulmonary fibrosis, vitamins were consumed by the lung tissue and their levels decreased.

[Determination of the status of lipid peroxidation and antioxidants in cattle infected with Dictyocaulus viviparus]. / Dictyocaulus viviparus ile Enfekte Sigirlarda Lipit Peroksidasyon ve Antioksidan Durumunun Saptanmasi.

Endoparasites cause significant economic losses and health problems in domestic animals. In this study, lipid peroxidation and the antioxidant status were investigated in the lung tissue taken from twenty cattle infected with Dictyocaulus viviparus and ten healthy cattle. Malondialdehyde superoxide dismutase, catalase, glutathione, vitamin C and beta-carotene were measured. In comparison to the control group, the concentration of MDA was high (p < 0.001), but the activities of Cu-Zn-SOD and CAT, and the concentration of GSH, vitamin C and beta-carotene were low (Cu-Zn-SOD, CAT, GSH, vitamin C, p < 0.001 and beta-carotene p < 0.05) in the parasite infected group. These results suggested that endoparasitic infection is among the major causes of oxidative stress. Lipid peroxidation was observed and the activities and concentrations of antioxidants systems were decreased in the lungs of cattle infected with Dictyocaulus viviparus.

Lipid peroxidation and antioxidant potential of sheep liver infected naturally with distomatosis.

The aim of this study was to assess the effects of natural distomatosis infections on sheep liver malondialdehyde (MDA) concentration, activities of enzymatic antioxidants (glutathione peroxidase (GPx), superoxide dismutase (Cu, Zn-SOD), catalase (CAT)) and concentrations of non-enzymatic antioxidants (reduced glutathione (GSH), vitamin C, and beta-carotene). Eighteen Akkaraman sheep naturally infected with Fasciola sp and Dicrocoelium dentriticum (D. dentriticum) and ten healthy Akkaraman sheep were included in the study Liver samples for the analysis of MDA, GPx, Cu, Zn-SOD, CAT, GSH, vitamin C, and beta-carotene and blood samples for the measurement of alanine aminotransferase and aspartate aminotransferase were collected immediately after sheep in the two groups were slaughtered. The concentration of MDA and activity of GPx in the group with distomatosis were higher than in the control group (P < 0.001). However, the Cu, Zn-SOD, CAT activities and the GSH, vitamin C concentrations in the infected group were significantly lower than in the control group (P < 0.001). The serum beta-carotene was not found to be statistically different in the two groups (P > 0.05). ALT and AST serum activities of the group with distomatosis were significantly higher in comparison to the control group (P < 0.001). In this study it was demonstrated that lipid peroxidation increased and activities or/and concentrations of antioxidant compounds were significantly changed in the liver of sheep with distomatosis.

Investigation of the effects of alpha-tocopherol on the levels of Fe, Cu, Zn, Mn, and carbonic anhydrase in rats with bleomycin-induced pulmonary fibrosis.

This study was designed to examine the effects of vitamin E on the levels of Zn, Mn, Cu, Fe, and carbonic anhydrase in rats with bleomycininduced pulmonary fibrosis. Twenty-one male Wistar albino rats were randomly divided into three groups: bleomycin alone, bleomycin+vitamin E, and saline alone (control group). The bleomycin group was given 7.5 mg/kg body weight (single dose) bleomycin hydrochloride intratracheally. The bleomycin+vitamin E group was also instilled with bleomycin hydrochloride but received injections of alpha-tocopherol twice a week. The control group was treated with saline alone. Animals were sacrified 14 d after intratracheal instillation of bleomycin. Tissue Zn, Mn, Cu, Fe, and carbonic anhydrase activities were measured in the lung and liver. Lung Cu, Fe, and carbonic anhydrase activity increase in both experimental groups. Zn and Mn levels decreased, except for the Mn level in the bleomycin group. Liver Zn, Mn, and Cu levels decreased in both experimental groups compared to the control group, whereas Fe and carbonic anhydrase activity increased in comparison to the control group. However, the liver tissue Fe level decreased compared to the control group. In the histopathologic assesment of lung sections in the bleomycin+vitamin E group, partial fibrotic lesions were observed, but the histopathologic changes were much less severe compared to the bleomycin-treated group.

[Some biochemical parameters in sheep infected with endoparasites (Fasciola spp., Dicrocoelium dendriticum, hydatid cysts, Trichostrongylidae and Protostrongylidae)]. / Endoparazitli (Fasciola spp., Dicrocoelium dendriticum, kist hidatik, Trichostrongylidae ve Protostrongylidae) koyunlarda bazi biyokimyasal parametreler.

This study was performed in order to investigate the variations of some blood biochemical parameters as well as the levels of Vitamin. B(12) and some macro elements in sheep infected with endoparasites. The blood samples were taken from the sheep that were to be slaughtered in the Van Municipality Slaughterhouse while the stool samples were taken after the slaughtering of the same animals. The postmortem examinations were made to investigate for the presence of Fasciola spp., D. dendriticum and cyst hydatid infections. The stool samples were examined helminthologically using native, sedimentation, flotation and Baermann-Wetzel methods. The control group was composed of animals not showing any internal organ parasites or parasites in the stool examination. Following the macroscopic and the stool examination, the animals found to have the same type of parasites were considered to be the study group. According to the analyses performed on the animals, the levels of total protein (in Trichostrongylidae, hydatid cysts), globulin, amylase, chlorine, and Vit.B(12) were found to be increased significantly, while the levels of albumin, magnesium, and phosphorus were found to be decreased significantly. The other parameters analyzed were not significant statistically between the groups.

Protective effect of alpha-tocopherol on oxidative stress in experimental pulmonary fibrosis in rats.

The study was undertaken to investigate the influence of alpha-tocopherol (vitamin E) on malondialdehyde (MDA) and glutathione (GSH) levels and catalase (CAT) activity in lung of rats with bleomycin-induced pulmonary fibrosis (PF). Fourteen Wistar-albino rats were randomly divided into two groups of seven animals each. The first group was treated intra-tracheally with bleomycin hydrochloride (BM group); the second group was also instilled with BM but received injections of alpha-tocopherol twice a week (BM + E group). The third group was treated in the same manner with saline solution only, acting as controls (C). There were decreases in GSH level and CAT activity while an increase in MDA level in BM group was found compared to the control group (p < 0.05). Vitamin E had a regulator effect on these parameters. After administration of alpha-tocopherol, the increase in GSH level and CAT activity and the decrease in MDA level were seen in BM + E group compared to BM group (p < 0.05). Distinct histopathological changes were found in the BM group compared to the untreated rats. Less severe fibrotic lesions were also observed in the BM + E group. The results show that vitamin E is effective on the prevention of BM-induced PF, as indicated by differences in the lung levels of oxidants and antioxidants.

Effects of alpha-tocopherol on serum trace and major elements in rats with bleomycin-induced pulmonary fibrosis.

The study was undertaken to investigate the influence of alpha-tocopherol on zinc, copper, iron, calcium, magnesium, and potassium concentrations in serum of rats with bleomycin-induced pulmonary fibrosis. Fourteen Wistar albino rats were randomly divided into two groups of seven animals each. The first group was treated intratracheally with bleomycin hydrochloride (BM group); the second group was also instilled with BM but received injections of alpha-tocopherol twice a week (BM+E group). The third group was treated in the same manner with saline solution only, acting as controls (C). The zinc concentrations of the BM and BM+E groups were significantly decreased compared to the controls (p<0.05). The iron concentration of the controls was significantly higher than the other two groups. The magnesium concentration in the controls and the BM+E group was significantly higher than that of the BM group. The serum copper, calcium, and potassium concentrations were not found to be statistically different among the three groups. Distinct histopathologic changes were found in the BM group compared to the untreated rats. Less severe fibrotic lesions were also observed in the BM+E group. The results of this study show that lungs of rats treated with bleomycin were seriously damaged and that vitamin E seemed to counteract some of the damage, as indicated by differences in the serum concentrations of major elements.