Pharmacological evaluation of novel PKR inhibitor indirubin-3-hydrazone in-vitro in cardiac myocytes and in-vivo in wistar rats

Udumula, Mary Priyanka; Bhat, Audesh; Mangali, Sureshbabu; Kalra, Jaspreet; Dhar, Indu; Sriram, D.; Dhar, Animesh

doi:10.1016/j.lfs.2018.07.055

Cited by 9 publications

(8 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apart from imoxin and 2-aminopurine, indirubin-3-oxime, a derivative of indirubin has been reported as novel PKR inhibitor 14 . Previously, our lab reported the effect of a newly synthesized derivative of indirubin, indirubin-3-hydrazone on high glucose induced apoptosis and oxidative stress 15 . However, the effect of PKR inhibitors on insulin resistance in skeletal muscle, liver and the relationship between PKR and pancreatic β-cell mass has not been reported yet.…”

Section: Discussionmentioning

confidence: 99%

“…To develop diabetic animal model, hyperglycemia was induced by feeding rats with 20% high fructose water, followed by induction of late onset of type 2 diabetes by administering low dose of STZ as described previously 15 , 16 . Study animals were divided into four groups.…”

Section: Methodsmentioning

confidence: 99%

“…Group IV (IHZ) rats received IHZ only at the above mentioned dose. IHZ dose was chosen based on the literature and our previous study 15 , 24 .…”

Section: Methodsmentioning

confidence: 99%

“…RNA extraction and qRT-PCR was performed as described previously 15 . The qRT-PCR of 42 cycles was done in the iCycler iQ apparatus (Bio-rad) in triplicates.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, our lab has reported a protective effect of indirubin derivative, indirubin-3-oxime (I3O) against PKR mediated deleterious effects in cardiomyocytes treated with high glucose 14 . Indirubin is the main active ingredient of Dangui Luhui Wan, a Chinese herbal drug and a new indirubin analogue, indirubin-3-hydrazone (IHZ) was recently characterized as a novel PKR inhibitor in cardiac myocytes by our group 15 . In our preliminary studies we found IHZ more potent inhibitor of PKR than I3O (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

High fructose and streptozotocin induced diabetic impairments are mitigated by Indirubin-3-hydrazone via downregulation of PKR pathway in Wistar rats

Udumula

Mangali

Kalra

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Group IV (IHZ) rats received IHZ only at the above mentioned dose. IHZ dose was chosen based on the literature and our previous study 15 , 24 .…”

Section: Methodsmentioning

confidence: 99%

“…RNA extraction and qRT-PCR was performed as described previously 15 . The qRT-PCR of 42 cycles was done in the iCycler iQ apparatus (Bio-rad) in triplicates.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations