sapana bansod - Academia.edu (original) (raw)
Papers by sapana bansod
Nature communications, Mar 20, 2024
Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma... more Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients. More than 90% of pancreatic ductal adenocarcinoma (PDAC) cases harbor activating mutations in the KRAS (Kristen's rat sarcoma viral oncogene homolog (KRAS) gene 1. KRAS mutant proteins exert their oncogenic functions by engaging multiple downstream signaling cascades, including the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) and PI3K-AKT-mTOR pathways. The MAPK pathway is considered one of the most critical therapeutic targets based on numerous preclinical studies 2. However, MAPK inhibitors, in combination with targeted agents including PI3K inhibitors or chemotherapy, have lacked efficacy in clinical trials and have been shown to have significant
Journal of Clinical Oncology
566 Background: 5-FU-based chemotherapy is the standard of care for patients with advanced pancre... more 566 Background: 5-FU-based chemotherapy is the standard of care for patients with advanced pancreatic cancer progressed on gemcitabine-based therapy. Based on the NAPOLI-1 study, liposomal irinotecan and 5-FU/LV is currently an FDA-approved regimen in this setting with median progression free survival (mPFS) 3.1 months, median overall survival (mOS) 6.1 months and ORR 16%. In pancreatic cancer mouse models, vitamin D was shown to remodel the desmoplastic stroma and when combined with chemotherapy significantly improved animal survival. Methods: We conducted a pilot study in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy treated with 5FU (2,400mg/m2)/LV (400mg/m2)/liposomal irinotecan (70mg/m2) with paricalcitol in two dose level cohorts: paricalcitol 75mcg IV on day 1 weekly (N = 10, dose level 1) or 7mcg/kg IV on day 1 weekly (N = 10, dose level 2). The primary endpoint was the occurrence of grade 3 and 4 toxicities. Dose-limiting toxicities (DLT) ...
Drug Discovery Today
Coronavirus 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-... more Coronavirus 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has had significant impacts worldwide since its emergence in December, 2019. Despite a high recovery rate, there is a growing concern over its residual, long-term effects. However, because of a lack of long-term data, we are still far from establishing a consensus on post-COVID-19 complications. The deposition of excessive extracellular matrix (ECM), known as fibrosis, has been observed in numerous survivors of COVID-19. Given the exceptionally high number of individuals affected, there is an urgent need to address the emergence of fibrosis post-COVID-19. In this review, we discuss the clinical relevance of COVID-19-associated fibrosis, the current status of antifibrotic agents, novel antifibrotic targets, and challenges to its management.
Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kina... more Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play signi cant role in the diseases like in ammation, brosis and cancer. Chronic pancreatitis (CP) is a bro-in ammatory disease in which recurrent pancreatic in ammation leads to pancreatic brosis. Methods: In the present study for the rst 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 signi cant upregulation of DDR1 and DDR2 expression. Pharmacological intervention with IMT effectively downregulated DDR1 and DDR2 expression. Further, we found that pancreatic injury, in ammation, extracellular matrix (ECM) deposition and PSCs activation were signi cantly inhibited by IMT. Further, we found a signi cant inhibition of TGF-β1/Smad signaling pathway by IMT and showed its protective effects against CP and associated brosis. Conclusions: Taken together, these results suggest that inhibition of DDR1 and DDR2 controls pancreatic in ammation and brosis, which could represent an attractive and promising therapeutic strategy for the treatment of CP.
![Research paper thumbnail of Design, synthesis, and biological evaluation of N-(4-substituted)-3-phenylisoxazolo[5,4-d]pyrimidin-4-amine derivatives as apoptosis-inducing cytotoxic agents](https://attachments.academia-assets.com/88831522/thumbnails/1.jpg)
](A library of new 3-phenylisoxazolo[5,4-d]pyrimidines (8-10) was designed based on a scaffold hybr... more A library of new 3-phenylisoxazolo[5,4-d]pyrimidines (8-10) was designed based on a scaffold hybridization technique incorporating the important pharmacophoric features of 4-aminopyrimidine and phenyl isoxazole scaffold which is renowned for its BET inhibition activity. The designed molecules were synthesized and evaluated with the NCI-60 cell line panel. Examination by NCI-60 cell lines at single-dose and the five-dose study showed that compound 10h exhibited promising growth inhibitory effects with GI50 values on various cancer cell lines such as HCT-15 (Colon Cancer)-0.0221 μM, MDA-MB-435 (Melanoma) - 0.0318 μM, SNB-75(CNS Cancer)-0.0263 μM, and MCF7 (Breast Cancer)-0.0372 μM. Further studies to know the mechanism of action of 10h based on the phase-contrast microscopic evaluation, DAPI, acridine orange/ethidium bromide (AO/EB) staining, and annexin V-FITC assays revealed that elevation in the intracellular ROS leads to alteration in mitochondrial membrane potential which in turn...
International Immunopharmacology, 2021
Acute pancreatitis (AP) is a potential gastrointestinal problem most commonly associated with pan... more Acute pancreatitis (AP) is a potential gastrointestinal problem most commonly associated with pancreatic inflammation and acinar cells injury. Nimbolide (NB), isolated from the tree Azadirachta indica, possesses antioxidant and anti-inflammatory effects. Here, we aimed to investigate the pancreatic protective effects of NB in ameliorating cerulein-induced pancreatic inflammation and apoptosis in AP model and evaluate the potential mechanism of action. AP was induced in Swiss albino mice by six-hourly intraperitoneal exposures of cerulein (50 µg/kg/hr) and pre-treatment of NB (0.3 and 1 mg/kg) 7 days prior to the cerulein exposure. Various parameters associated with AP in plasma and pancreatic tissues were evaluated. Severity of AP was effectively ameliorated by NB as shown by reducing pancreatic edema, plasma amylase and lipase levels, MPO levels and in cerulein-induced histological damage. Further, the antioxidant effect of NB was associated with a significant inhibition of oxidative-nitrosative stress in Raw 264.7 cells and cerulein-induced AP mice. Moreover, NB suppressed proinflammatory cytokines, iNOS and nitrotyrosine expression. In addition, NB inhibited NF-κB activation and increased SIRT1 expression in cerulein challenged mice. Furthermore, NB also inhibited pancreatic apoptosis by downregulating cleaved caspase 3 and Bax while upregulating Bcl2 expression in cerulein-treated mice. Inhibition of pancreatic inflammation and apoptosis resulted in attenuation of cerulein-induced AP. These results suggest that NB exerts strong anti-pancreatitis effects against cerulein-induced AP by combating inflammatory and apoptosis signaling via SIRT1 activation.
Scientific Reports, 2021
Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kina... more 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 c...
Cancers, 2021
Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS on... more Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncog...
Phytotherapy Research, 2021
Liver diseases are life‐threatening illnesses and are the major cause of mortality and morbidity ... more Liver diseases are life‐threatening illnesses and are the major cause of mortality and morbidity worldwide. These may include liver fibrosis, liver cirrhosis, and drug‐induced liver toxicity. Liver diseases have a wide prevalence globally and the fifth most common cause of death among all gastrointestinal disorders. Several novel therapeutic approaches have emerged for the therapy of liver diseases that may provide better clinical outcomes with improved safety. The use of phytochemicals for the amelioration of liver diseases has gained considerable popularity. Berberine (BBR), an isoquinoline alkaloid of the protoberberine type, has emerged as a promising molecule for the treatment of gastrointestinal disorders. Accumulating studies have proved the hepatoprotective effects of BBR. BBR has been shown to modulate multiple signaling pathways implicated in the pathogenesis of liver diseases including Akt/FoxO2, PPAR‐γ, Nrf2, insulin, AMPK, mTOR, and epigenetic pathways. In the present review, we have emphasized the important pharmacological activities and mechanisms of BBR in liver diseases. Further, we have reviewed various pharmacokinetic and toxicological barriers of this promising phytoconstituent. Finally, formulation‐based novel approaches are also summarized to overcome the clinical hurdles for BBR.
Phytotherapy Research, 2021
Liver diseases are life‐threatening illnesses and are the major cause of mortality and morbidity ... more Liver diseases are life‐threatening illnesses and are the major cause of mortality and morbidity worldwide. These may include liver fibrosis, liver cirrhosis, and drug‐induced liver toxicity. Liver diseases have a wide prevalence globally and the fifth most common cause of death among all gastrointestinal disorders. Several novel therapeutic approaches have emerged for the therapy of liver diseases that may provide better clinical outcomes with improved safety. The use of phytochemicals for the amelioration of liver diseases has gained considerable popularity. Berberine (BBR), an isoquinoline alkaloid of the protoberberine type, has emerged as a promising molecule for the treatment of gastrointestinal disorders. Accumulating studies have proved the hepatoprotective effects of BBR. BBR has been shown to modulate multiple signaling pathways implicated in the pathogenesis of liver diseases including Akt/FoxO2, PPAR‐γ, Nrf2, insulin, AMPK, mTOR, and epigenetic pathways. In the present review, we have emphasized the important pharmacological activities and mechanisms of BBR in liver diseases. Further, we have reviewed various pharmacokinetic and toxicological barriers of this promising phytoconstituent. Finally, formulation‐based novel approaches are also summarized to overcome the clinical hurdles for BBR.
Environmental Toxicology, 2020
Borneol is a commonly used flavouring substance in traditional Chinese medicine, which possesses ... more 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.
![Research paper thumbnail of Design, synthesis, and biological evaluation of N-(4-substituted)-3-phenylisoxazolo[5,4–d]pyrimidin-4-amine derivatives as apoptosis-inducing cytotoxic agents](https://attachments.academia-assets.com/88831347/thumbnails/1.jpg)
](Bioorganic & Medicinal Chemistry Letters, 2021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pleione, 2019
This paper discusses the brief cross cultural ethnobotany of the Abotani tribes of Arunachal Prad... more This paper discusses the brief cross cultural ethnobotany of the Abotani tribes of Arunachal Pradesh which comprises five different indigenous tribal communities, namely Adi, Apatani, Nyishi, Galo and Tagin residing in Arunachal Pradesh, India. A brief ethnobotanical survey was conducted in Abotani Biocultural Landscape (ABL) in 11 districts of Arunachal Pradesh during the year 2018-2019 with fundamental aims to document significant ethnobotanical plants commonly used among all the 05 Abotani tribes in their local biocultural landscape and to document traditional knowledge and skills related to utilization of ethnobotanical plants resources using semi-structured questionnaire format. The survey have revealed impressive number of 45 species of ethnobotanically significant species frequently harvested and used as local food and medicine security as well as cultural materials among the local residents of 05 major tribes of Abotani cultural group residing in Siang,
Pleione, 2019
Present paper discusses ethnobotany of the economically significant food and medicinal plants use... more Present paper discusses ethnobotany of the economically significant food and medicinal plants used among the Monpa and Nyishi community of West Kameng and Kamle District of Arunachal Pradesh in cross-cultural approaches. The 49 species of both cultivated and wild food and medicinal plants recorded from Monpa and Nyishi biocultural landscape are frequently harvested and used by the local communities as antioxidant food, anti-inflammatory agent and for treatment of various diseases including prevention of cancer and liver cirrhosis which has the potential to be used as nutraceuticals and capable of sustaining the rural economy and livelihood of the rural community.
Pharmacological Research, 2020
abrogates cerulein-induced chronic pancreatitis by modulating -catenin/Smad in a sirtuin-depende... more abrogates cerulein-induced chronic pancreatitis by modulating -catenin/Smad in a sirtuin-dependent way,
Cancer Research
Background: Oncogenic KRAS is present in almost all cases of pancreatic ductal adenocarcinoma (PD... more Background: Oncogenic KRAS is present in almost all cases of pancreatic ductal adenocarcinoma (PDAC). However, targeting KRAS or its canonical signaling cascades, especially the mitogen-activated protein kinase (MAPK) pathway, remains clinically unsuccessful. Targeting ERK kinases has recently emerged as a promising therapeutic strategy and combinatorial strategies should be developed. Aim: Identify adaptive mechanisms to ERK inhibition that can be co-targeted to achieve effective tumor inhibition in multiple patient-derived xenograft (PDX) models. Methods: Reverse-phase protein array (RPPA) was used in early-passage patient-derived cell lines (PDCLs) to identify potential resistance mechanisms. These were confirmed using RNA interference and overexpression in PDAC cell lines and PDCLs. The promising combinations were tested in 30 early-passaged PDAC PDXs. Results: RPPA showed dramatic downregulation of DUSP4 and DUSP6 phosphatases following MEK and ERK inhibition, which coincided w...
International Immunopharmacology
Toxicology and Applied Pharmacology
Journal of Pharmacological and Toxicological Methods
Nature communications, Mar 20, 2024
Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma... more Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients. More than 90% of pancreatic ductal adenocarcinoma (PDAC) cases harbor activating mutations in the KRAS (Kristen's rat sarcoma viral oncogene homolog (KRAS) gene 1. KRAS mutant proteins exert their oncogenic functions by engaging multiple downstream signaling cascades, including the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) and PI3K-AKT-mTOR pathways. The MAPK pathway is considered one of the most critical therapeutic targets based on numerous preclinical studies 2. However, MAPK inhibitors, in combination with targeted agents including PI3K inhibitors or chemotherapy, have lacked efficacy in clinical trials and have been shown to have significant
Journal of Clinical Oncology
566 Background: 5-FU-based chemotherapy is the standard of care for patients with advanced pancre... more 566 Background: 5-FU-based chemotherapy is the standard of care for patients with advanced pancreatic cancer progressed on gemcitabine-based therapy. Based on the NAPOLI-1 study, liposomal irinotecan and 5-FU/LV is currently an FDA-approved regimen in this setting with median progression free survival (mPFS) 3.1 months, median overall survival (mOS) 6.1 months and ORR 16%. In pancreatic cancer mouse models, vitamin D was shown to remodel the desmoplastic stroma and when combined with chemotherapy significantly improved animal survival. Methods: We conducted a pilot study in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy treated with 5FU (2,400mg/m2)/LV (400mg/m2)/liposomal irinotecan (70mg/m2) with paricalcitol in two dose level cohorts: paricalcitol 75mcg IV on day 1 weekly (N = 10, dose level 1) or 7mcg/kg IV on day 1 weekly (N = 10, dose level 2). The primary endpoint was the occurrence of grade 3 and 4 toxicities. Dose-limiting toxicities (DLT) ...
Drug Discovery Today
Coronavirus 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-... more Coronavirus 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has had significant impacts worldwide since its emergence in December, 2019. Despite a high recovery rate, there is a growing concern over its residual, long-term effects. However, because of a lack of long-term data, we are still far from establishing a consensus on post-COVID-19 complications. The deposition of excessive extracellular matrix (ECM), known as fibrosis, has been observed in numerous survivors of COVID-19. Given the exceptionally high number of individuals affected, there is an urgent need to address the emergence of fibrosis post-COVID-19. In this review, we discuss the clinical relevance of COVID-19-associated fibrosis, the current status of antifibrotic agents, novel antifibrotic targets, and challenges to its management.
Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kina... more Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kinases, which play signi cant role in the diseases like in ammation, brosis and cancer. Chronic pancreatitis (CP) is a bro-in ammatory disease in which recurrent pancreatic in ammation leads to pancreatic brosis. Methods: In the present study for the rst 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 signi cant upregulation of DDR1 and DDR2 expression. Pharmacological intervention with IMT effectively downregulated DDR1 and DDR2 expression. Further, we found that pancreatic injury, in ammation, extracellular matrix (ECM) deposition and PSCs activation were signi cantly inhibited by IMT. Further, we found a signi cant inhibition of TGF-β1/Smad signaling pathway by IMT and showed its protective effects against CP and associated brosis. Conclusions: Taken together, these results suggest that inhibition of DDR1 and DDR2 controls pancreatic in ammation and brosis, which could represent an attractive and promising therapeutic strategy for the treatment of CP.
A library of new 3-phenylisoxazolo[5,4-d]pyrimidines (8-10) was designed based on a scaffold hybr... more A library of new 3-phenylisoxazolo[5,4-d]pyrimidines (8-10) was designed based on a scaffold hybridization technique incorporating the important pharmacophoric features of 4-aminopyrimidine and phenyl isoxazole scaffold which is renowned for its BET inhibition activity. The designed molecules were synthesized and evaluated with the NCI-60 cell line panel. Examination by NCI-60 cell lines at single-dose and the five-dose study showed that compound 10h exhibited promising growth inhibitory effects with GI50 values on various cancer cell lines such as HCT-15 (Colon Cancer)-0.0221 μM, MDA-MB-435 (Melanoma) - 0.0318 μM, SNB-75(CNS Cancer)-0.0263 μM, and MCF7 (Breast Cancer)-0.0372 μM. Further studies to know the mechanism of action of 10h based on the phase-contrast microscopic evaluation, DAPI, acridine orange/ethidium bromide (AO/EB) staining, and annexin V-FITC assays revealed that elevation in the intracellular ROS leads to alteration in mitochondrial membrane potential which in turn...
International Immunopharmacology, 2021
Acute pancreatitis (AP) is a potential gastrointestinal problem most commonly associated with pan... more Acute pancreatitis (AP) is a potential gastrointestinal problem most commonly associated with pancreatic inflammation and acinar cells injury. Nimbolide (NB), isolated from the tree Azadirachta indica, possesses antioxidant and anti-inflammatory effects. Here, we aimed to investigate the pancreatic protective effects of NB in ameliorating cerulein-induced pancreatic inflammation and apoptosis in AP model and evaluate the potential mechanism of action. AP was induced in Swiss albino mice by six-hourly intraperitoneal exposures of cerulein (50 µg/kg/hr) and pre-treatment of NB (0.3 and 1 mg/kg) 7 days prior to the cerulein exposure. Various parameters associated with AP in plasma and pancreatic tissues were evaluated. Severity of AP was effectively ameliorated by NB as shown by reducing pancreatic edema, plasma amylase and lipase levels, MPO levels and in cerulein-induced histological damage. Further, the antioxidant effect of NB was associated with a significant inhibition of oxidative-nitrosative stress in Raw 264.7 cells and cerulein-induced AP mice. Moreover, NB suppressed proinflammatory cytokines, iNOS and nitrotyrosine expression. In addition, NB inhibited NF-κB activation and increased SIRT1 expression in cerulein challenged mice. Furthermore, NB also inhibited pancreatic apoptosis by downregulating cleaved caspase 3 and Bax while upregulating Bcl2 expression in cerulein-treated mice. Inhibition of pancreatic inflammation and apoptosis resulted in attenuation of cerulein-induced AP. These results suggest that NB exerts strong anti-pancreatitis effects against cerulein-induced AP by combating inflammatory and apoptosis signaling via SIRT1 activation.
Scientific Reports, 2021
Discoidin domain receptors (DDR1 and DDR2) are the collagen receptors of the family tyrosine kina... more 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 c...
Cancers, 2021
Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS on... more Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncog...
Phytotherapy Research, 2021
Liver diseases are life‐threatening illnesses and are the major cause of mortality and morbidity ... more Liver diseases are life‐threatening illnesses and are the major cause of mortality and morbidity worldwide. These may include liver fibrosis, liver cirrhosis, and drug‐induced liver toxicity. Liver diseases have a wide prevalence globally and the fifth most common cause of death among all gastrointestinal disorders. Several novel therapeutic approaches have emerged for the therapy of liver diseases that may provide better clinical outcomes with improved safety. The use of phytochemicals for the amelioration of liver diseases has gained considerable popularity. Berberine (BBR), an isoquinoline alkaloid of the protoberberine type, has emerged as a promising molecule for the treatment of gastrointestinal disorders. Accumulating studies have proved the hepatoprotective effects of BBR. BBR has been shown to modulate multiple signaling pathways implicated in the pathogenesis of liver diseases including Akt/FoxO2, PPAR‐γ, Nrf2, insulin, AMPK, mTOR, and epigenetic pathways. In the present review, we have emphasized the important pharmacological activities and mechanisms of BBR in liver diseases. Further, we have reviewed various pharmacokinetic and toxicological barriers of this promising phytoconstituent. Finally, formulation‐based novel approaches are also summarized to overcome the clinical hurdles for BBR.
Phytotherapy Research, 2021
Liver diseases are life‐threatening illnesses and are the major cause of mortality and morbidity ... more Liver diseases are life‐threatening illnesses and are the major cause of mortality and morbidity worldwide. These may include liver fibrosis, liver cirrhosis, and drug‐induced liver toxicity. Liver diseases have a wide prevalence globally and the fifth most common cause of death among all gastrointestinal disorders. Several novel therapeutic approaches have emerged for the therapy of liver diseases that may provide better clinical outcomes with improved safety. The use of phytochemicals for the amelioration of liver diseases has gained considerable popularity. Berberine (BBR), an isoquinoline alkaloid of the protoberberine type, has emerged as a promising molecule for the treatment of gastrointestinal disorders. Accumulating studies have proved the hepatoprotective effects of BBR. BBR has been shown to modulate multiple signaling pathways implicated in the pathogenesis of liver diseases including Akt/FoxO2, PPAR‐γ, Nrf2, insulin, AMPK, mTOR, and epigenetic pathways. In the present review, we have emphasized the important pharmacological activities and mechanisms of BBR in liver diseases. Further, we have reviewed various pharmacokinetic and toxicological barriers of this promising phytoconstituent. Finally, formulation‐based novel approaches are also summarized to overcome the clinical hurdles for BBR.
Environmental Toxicology, 2020
Borneol is a commonly used flavouring substance in traditional Chinese medicine, which possesses ... more 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.
Bioorganic & Medicinal Chemistry Letters, 2021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pleione, 2019
This paper discusses the brief cross cultural ethnobotany of the Abotani tribes of Arunachal Prad... more This paper discusses the brief cross cultural ethnobotany of the Abotani tribes of Arunachal Pradesh which comprises five different indigenous tribal communities, namely Adi, Apatani, Nyishi, Galo and Tagin residing in Arunachal Pradesh, India. A brief ethnobotanical survey was conducted in Abotani Biocultural Landscape (ABL) in 11 districts of Arunachal Pradesh during the year 2018-2019 with fundamental aims to document significant ethnobotanical plants commonly used among all the 05 Abotani tribes in their local biocultural landscape and to document traditional knowledge and skills related to utilization of ethnobotanical plants resources using semi-structured questionnaire format. The survey have revealed impressive number of 45 species of ethnobotanically significant species frequently harvested and used as local food and medicine security as well as cultural materials among the local residents of 05 major tribes of Abotani cultural group residing in Siang,
Pleione, 2019
Present paper discusses ethnobotany of the economically significant food and medicinal plants use... more Present paper discusses ethnobotany of the economically significant food and medicinal plants used among the Monpa and Nyishi community of West Kameng and Kamle District of Arunachal Pradesh in cross-cultural approaches. The 49 species of both cultivated and wild food and medicinal plants recorded from Monpa and Nyishi biocultural landscape are frequently harvested and used by the local communities as antioxidant food, anti-inflammatory agent and for treatment of various diseases including prevention of cancer and liver cirrhosis which has the potential to be used as nutraceuticals and capable of sustaining the rural economy and livelihood of the rural community.
Pharmacological Research, 2020
abrogates cerulein-induced chronic pancreatitis by modulating -catenin/Smad in a sirtuin-depende... more abrogates cerulein-induced chronic pancreatitis by modulating -catenin/Smad in a sirtuin-dependent way,
Cancer Research
Background: Oncogenic KRAS is present in almost all cases of pancreatic ductal adenocarcinoma (PD... more Background: Oncogenic KRAS is present in almost all cases of pancreatic ductal adenocarcinoma (PDAC). However, targeting KRAS or its canonical signaling cascades, especially the mitogen-activated protein kinase (MAPK) pathway, remains clinically unsuccessful. Targeting ERK kinases has recently emerged as a promising therapeutic strategy and combinatorial strategies should be developed. Aim: Identify adaptive mechanisms to ERK inhibition that can be co-targeted to achieve effective tumor inhibition in multiple patient-derived xenograft (PDX) models. Methods: Reverse-phase protein array (RPPA) was used in early-passage patient-derived cell lines (PDCLs) to identify potential resistance mechanisms. These were confirmed using RNA interference and overexpression in PDAC cell lines and PDCLs. The promising combinations were tested in 30 early-passaged PDAC PDXs. Results: RPPA showed dramatic downregulation of DUSP4 and DUSP6 phosphatases following MEK and ERK inhibition, which coincided w...
International Immunopharmacology
Toxicology and Applied Pharmacology
Journal of Pharmacological and Toxicological Methods