Metabolic disorders are becoming more common in young population due to increased consumption of carbohydrate rich diet, lack of physical activity and stress. Fructose is used as a sweetener in many carbonated beverages and is a known inducer of oxidative stress and hypertension. Up-regulation of the double-stranded RNA-dependent protein kinase (PKR) causes impairment in insulin signaling pathway and metabolic dysfunctions in type 2 diabetes mellitus. In the present study we investigated the role of PKR and associated pathways in high fructose (HF) and streptozotocin (STZ) induced diabetes and whether indirubin-3-hydrazone (IHZ), a novel PKR inhibitor can reverse the HF and STZ induced diabetic impairments in Wistar rats. Diabetes was induced by feeding rats 20% high fructose in drinking water for 6 weeks and by giving a single dose of STZ (35 mg/kg., i.p) at the end of week 5. Glucose and lipid levels were measured by using assay kits. Expression of PKR and its downstream genes were determined by immunohistochemistry, qRT-PCR and western blotting techniques. Histo-pathological studies were performed using H&E staining. Fibrosis was detected in insulin sensitive tissues and organs using Sirius red and Masson’s trichrome staining and apoptosis by TUNEL assay. HF and STZ induced hyperglycemia, fibrosis, oxidative stress, and inflammation in liver, pancreas, skeletal muscle and adipose tissue are mediated via PKR pathway and its downstream effectors, and these effects were attenuated by PKR inhibitor IHZ. Thus, inhibition of PKR can protect insulin sensitive organs and tissues from HF induced diabetic impairments via the inhibition of c-Jun N-terminal kinase (JNK) pathway.
The aim of the study was to investigate the pharmacokinetic parameters of 5-fluorouracil (5FU) and moxifloxacin (MF) after oral administration using layer-by-layer assembled film in enteric coated capsule. The LbL film was prepared by sequential layering of chitosan and sodium alginate polyelectrolytes containing either 5FU or MF. The films were characterized for physical characteristics, drug loading and release behaviour. Pharmacokinetic studies were performed in the rat model for three different drug concentrations after oral administration and compared with intravenous administration. The results showed that the thickness of 10 bilayerd film was 147 ± 11.66 and 212.3 ± 7.19 µm after 5FU and MF loading, respectively. The amount of 5FU and MF loaded was found to be 1.93 ± 0.48 and 4.64 ± 0.33 mg/cm2, respectively. The DSC and PXRD results showed crystalline nature of 5FU and MF after entrapment in LbL film. The LbL film with backing layer provided directional release of 5FU and MF, where 63.81 ± 4.52% and 101.38 ± 5.08%, respectively was released in 24 h. 5FU showed non-linear pharmacokinetics compared with linear pharmacokinetics showed by MF after oral administration. There is a dose dependent increase in Cmax after oral administration of 5FU and MF LbL film. The Tmax was found to be 720 and 840 mins for 5FU and MF after oral administration. The mean residence time and AUC0-t at 45 mg/kg were 871.4 ± 6.45 min and 198.6 ± 5.03 x 103 min. ng/mL and 1267 ± 142.4 min and 1590 ± 55.60 103 min. ng/mL for 5FU and MF, respectively. Biodistribution studies showed significantly (p<0.01) greater disposition of 5FU within colon tissue after administration using oral LbL film. Taken together, colon targeted LbL film can be developed for oral administration of drugs for local and systemic applications.
Background: Metabolic disorders are becoming more common in young population due to increased consumption of carbohydrate rich diet, lack of physical activity and stress. Fructose is used as a sweetener in many carbonated beverages and is a known inducer of oxidative stress and hypertension. Up-regulation of the double-stranded RNA-dependent protein kinase (PKR) causes impairment in insulin signaling pathway and metabolic dysfunctions in type 2 diabetes mellitus. In the present study we investigated the role of PKR and associated pathways in high fructose (HF) and streptozotocin (STZ) induced diabetes and whether indirubin-3-hydrazone (IHZ), a novel PKR inhibitor can reverse the HF and STZ induced diabetic impairments in Wistar rats.Methods: Diabetes was induced by feeding rats 20% high fructose in drinking water for 6 weeks and by giving a single dose of STZ (35mg/kg., i.p) at the end of week 5. Glucose and lipid levels were measured by using assay kits. Expression of PKR and its downstream genes were determined by immunohistochemistry, qRT-PCR and western blotting techniques. Histo-pathological studies were performed using H&E staining. Fibrosis was detected in insulin sensitive tissues and organs using Sirius red and Masson’s trichrome staining and apoptosis by TUNEL assay. Results and Conclusion: HF and STZ induced hyperglycemia, fibrosis, oxidative stress, and inflammation in liver, pancreas, skeletal muscle and adipose tissue are mediated via PKR pathway and its downstream effectors, and these effects were attenuated by PKR inhibitor IHZ. Thus, inhibition of PKR can protect insulin sensitive organs and tissues from HF induced diabetic impairments via the inhibition of c-Jun N-terminal kinase (JNK) pathway.
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