Berberine attenuates severity of chronic pancreatitis and fibrosis via AMPK-mediated inhibition of TGF-β1/Smad signaling and M2 polarization

Bansod, Sapana; Doijad, Nandkumar; Godugu, Chandraiah

doi:10.1016/j.taap.2020.115162

Cited by 37 publications

(36 citation statements)

References 55 publications

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“…CP is a bro-in ammatory disease which is majorly associated with excess synthesis and deposition of ECM in the pancreas and leads to the development of pancreatic brosis [17,19,23]. Due to limited treatment options, there is a need to understand the exact pathogenesis and explore therapeutically effective treatment option for CP.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…After 24 h of treatment, cells were fixed with 4% paraformaldehyde and 0.1% Triton X-100 followed by blocking with 3% bovine serum albumin (BSA) for 1 h. The cells were then labeled with primary antibodies against α-SMA, collagen 1a, pSmad2/3, pDDR1, and DDR2 at 4 °C for overnight. Next day, cells were probed with secondary antibody conjugated with rhodamine (1:200 dilution) or fluorescein isothiocyanate (FITC) (1:100 dilution) for 1 h. After washing, cells were mounted with fluoroshield 4′,6-diamidino-2-phenylindole (DAPI) (Sigma-Aldrich, USA) medium and fluorescent signals were captured by confocal laser-scanning microscopy (Leica, Germany) 18 .…”

Section: Methodsmentioning

confidence: 99%

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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“…Malondialdehyde (MDA), nitrite, and GSH contents were measured in pancreatic tissue by following the previously described method 27,28 . Pancreatic tissue samples were homogenized in phosphate buffer and homogenates were used for the estimation of MDA levels and remaining tissue homogenate were centrifuged at 9168 g for 10 minutes at 4°C and the supernatant was used for the estimation of nitrite and GSH content in the pancreas.…”

Section: Methodsmentioning

confidence: 99%

“…Then, supernatant was collected and protein concentrations were estimated by Bicinchoninic acid assay. An equal amount of protein were run on 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred to a nitrocellulose membrane following the standard protocol 28,31 . The primary antibodies, such as NFκB p65 (Catalogue no.‐D14E12, #8242) and p‐NFκB p65 (Catalogue no.‐93H1, #3033) were procured from Cell Signaling Technology, USA, whereas iNOS (Catalogue no.‐N9657) were purchased from Sigma–Aldrich, USA.…”

Section: Methodsmentioning

confidence: 99%

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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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Berberine attenuates severity of chronic pancreatitis and fibrosis via AMPK-mediated inhibition of TGF-β1/Smad signaling and M2 polarization

Cited by 37 publications

References 55 publications

Inhibition of DDR1 and DDR2 receptors: The Potential Therapeutic Option to Treat 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

Inhibition of discoidin domain receptors by imatinib prevented 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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