Nimbolide abrogates cerulein-induced chronic pancreatitis by modulating β-catenin/Smad in a sirtuin-dependent way

Bansod, Sapana; Saifi, Mohd Aslam; Khurana, Amit; Godugu, Chandraiah

doi:10.1016/j.phrs.2020.104756

Cited by 21 publications

(19 citation statements)

References 49 publications

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“…TGF-β1 binds to its receptors expressed by PSCs and initiates its fibrotic responses through the activation of Smad pathway. In addition, our earlier studies reported that activation of TGF-β/Smad stimulates PSCs activation and consequently results in the progression of the pancreatic fibrosis 18 , 25 . In context with CP, researchers have documented that there is an activation of TGF-β1/Smad signaling in response to the overexpression of DDR1/DDR2 52 , but its role in the regulation of TGF-β1/Smad signaling and PSCs activation in CP has not been explored.…”

Section: Discussionmentioning

confidence: 94%

“…CP is a fibro-inflammatory disease which is majorly associated with abnormal synthesis and deposition of ECM in the pancreas leading to the development of pancreatic fibrosis 18 , 20 , 25 . Although, there are multiple signaling pathways involved in the pathogenesis of CP, activation of collagen-producing PSCs is the foremost event in the progression of pancreatic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Pancreas were fixed in 10% formaldehyde solution and paraffin-embedded pancreatic sections were taken at 5 µm using microtome (Leica, Germany). The pancreatic sections were stained with H & E, picrosirius red (PSR) and Masson’s trichrome (MT) as per previously described protocol 25 . For immunostaining, antigen retrieval was carried out by citrate buffer.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of discoidin domain receptors by imatinib prevented pancreatic fibrosis demonstrated in experimental chronic pancreatitis model

Bansod

Saifi

Godugu

2021

Sci Rep

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Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play significant role in the diseases like inflammation, fibrosis and cancer. Chronic pancreatitis (CP) is a fibro-inflammatory disease in which recurrent pancreatic inflammation leads to pancreatic fibrosis. In the present study, we have investigated the role of DDR1 and DDR2 in CP. The induced expression of DDR1 and DDR2 was observed in primary pancreatic stellate cells (PSCs) and cerulein-induced CP. Subsequently, the protective effects of DDR1/DDR2 inhibitor, imatinib (IMT) were investigated. Pharmacological intervention with IMT effectively downregulated DDR1 and DDR2 expression. Further, IMT treatment reduced pancreatic injury, inflammation, extracellular matrix deposition and PSCs activation along with inhibition of TGF-β1/Smad signaling pathway. Taken together, these results suggest that inhibition of DDR1 and DDR2 controls pancreatic inflammation and fibrosis, which could represent an attractive and promising therapeutic strategy for the treatment of CP.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Inhibition of discoidin domain receptors by imatinib prevented pancreatic fibrosis demonstrated in experimental chronic pancreatitis model

Bansod

Saifi

Godugu

2021

Sci Rep

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“…Pancreas were xed with 10% formaldehyde solution and para n-embedded pancreatic sections were taken at 5 µm. Further, pancreatic sections were stained with H & E, picrosirius red (PSR) and Masson's trichrome (MT) as per previously described protocol [23]. For immunostaining, antigen retrieval was carried out by using citrate buffer.…”

Section: Histopathology and Immunohistochemistry Analysismentioning

confidence: 99%

Inhibition of DDR1 and DDR2 receptors: The Potential Therapeutic Option to Treat Pancreatic Fibrosis Demonstrated in Experimental Chronic Pancreatitis Model

Bansod¹,

Saifi²,

Godugu³

2020

Preprint

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Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play significant role in the diseases like inflammation, fibrosis and cancer. Chronic pancreatitis (CP) is a fibro-inflammatory disease in which recurrent pancreatic inflammation leads to pancreatic fibrosis.Methods: In the present study for the first time, we have investigated the role of DDR1 and DDR2 in cerulein-induced CP. Pancreatic DDR1 and DDR2 expression was examined by immunoblotting and immunostaining analysis. Subsequently, the protective effects of selective DDR1 and DDR2 inhibitor, imatinib (IMT) was investigated in CP mice as a therapeutic intervention.Results: Activated pancreatic stellate cells (PSCs) and CP mice showed significant upregulation of DDR1 and DDR2 expression. Pharmacological intervention with IMT effectively downregulated DDR1 and DDR2 expression. Further, we found that pancreatic injury, inflammation, extracellular matrix (ECM) deposition and PSCs activation were significantly inhibited by IMT. Further, we found a significant inhibition of TGF-β1/Smad signaling pathway by IMT and showed its protective effects against CP and associated fibrosis.Conclusions: Taken together, these results suggest that inhibition of DDR1 and DDR2 controls pancreatic inflammation and fibrosis, which could represent an attractive and promising therapeutic strategy for the treatment of CP.

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“…Recently, natural products have gained popularity for their unrevealed antioxidant and antiinflammatory properties for treating various acute and chronic inflammatory diseases. 12,13 (+) -Borneol is a naturally occurring bicyclic monoterpenoid alcohol-based aromatic flavoring substance of plant Acorus calamus, which possesses different biological effects, such as analgesic and neuroprotective activities. 14,15 Moreover, it is the most commonly used ancient herb in traditional Chinese medicine, which has several clinical applications.…”

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confidence: 99%

Borneol protects against cerulein‐induced oxidative stress and inflammation in acute pancreatitis mice model

Bansod

Chilvery

Saifi

et al. 2020

Environmental Toxicology

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Borneol is a commonly used flavouring substance in traditional Chinese medicine, which possesses several pharmacological activities including analgesic, antiinflammatory, and antioxidant properties. The aim of this study was to investigate the effects of borneol on cerulein‐induced acute pancreatitis (AP) model. Swiss albino mice were pretreated with borneol (100 and 300 mg/kg) daily for 7 days, before six consecutive injections of cerulein (50 μg/kg/hr, intraperitoneally). The protective effect of borneol was studied by biochemical, enzyme linked immunosorbent assay, histological, immunoblotting, and immunohistochemical analysis. Oral administration of borneol significantly attenuated pancreatic damage by reducing amylase, lipase levels and histological changes. Borneol attenuated cerulein‐induced oxidative‐nitrosative stress by decreasing malondialdehyde, nitrite levels, and elevating reduced glutathione levels. Pancreatic inflammation was ameliorated by inhibiting myeloperoxidase activity and pro‐inflammatory cytokine (Interleukins and TNF‐α) levels. Furthermore, borneol administration significantly increased nuclear factor E2‐related factor 2 (Nrf2), superoxide dismutase (SOD1) expression and reduced phospho‐NF‐κB p65 expression. Treatment with borneol significantly inhibited TNF‐α, IL‐1β, IL‐6, and inducible nitric oxide synthase expression in cerulein‐induced AP mouse model. Together, these results indicate that borneol which is currently used as US‐FDA approved food adjuvant has the potential to attenuate cerulein‐induced AP possibly by reducing the oxidative damage and pancreatic inflammation by modulating Nrf2/NF‐κB pathway.

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Nimbolide abrogates cerulein-induced chronic pancreatitis by modulating β-catenin/Smad in a sirtuin-dependent way

Cited by 21 publications

References 49 publications

Inhibition of discoidin domain receptors by imatinib prevented pancreatic fibrosis demonstrated in experimental chronic pancreatitis model

Inhibition of discoidin domain receptors by imatinib prevented pancreatic fibrosis demonstrated in experimental chronic pancreatitis model

Inhibition of DDR1 and DDR2 receptors: The Potential Therapeutic Option to Treat Pancreatic Fibrosis Demonstrated in Experimental Chronic Pancreatitis Model

Borneol protects against cerulein‐induced oxidative stress and inflammation in acute pancreatitis mice model

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