Publications by authors named "Hemanth Kumar Kandikattu"

27 Publications

  • Page 1 of 1

Macrophages-induced IL-18-mediated eosinophilia promotes characteristics of pancreatic malignancy.

Life Sci Alliance 2021 Aug 28;4(8). Epub 2021 Jun 28.

Department of Medicine, Tulane Eosinophilic Disorders Centre, Section of Pulmonary Diseases, School of Medicine, Tulane University, New Orleans, LA, USA

Reports indicate that accumulated macrophages in the pancreas are responsible for promoting the pathogenesis of chronic pancreatitis (CP). Recently, macrophage-secreted cytokines have been implicated in promoting pancreatic acinar-to-ductal metaplasia (ADM). This study aims to establish the role of accumulated macrophage-activated NLRP3-IL-18-eosinophil mechanistic pathway in promoting several characteristics of pancreatic malignancy in CP. We report that in a murine model of pancreatic cancer (PC), accumulated macrophages are the source of NLRP3-regulated IL-18, which promotes eosinophilic inflammation-mediated accumulation to periductal mucin and collagen, including the formation of ADM, pancreatic intraepithelial neoplasia (PanINs), and intraductal papillary mucinous neoplasm. Most importantly, we show improved malignant characteristics with reduced levels of oncogenes in an anti-IL-18 neutralized and IL-18 gene deficient murine model of CP. Last, human biopsies validated that NLRP3-IL-18-induced eosinophils accumulate near the ducts, showing PanINs formation in PC. Taken together, we present the evidence on the role of IL-18-induced eosinophilia in the development of PC phenotype like ADM, PanINs, and ductal cell differentiation in inflammation-induced CP.
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http://dx.doi.org/10.26508/lsa.202000979DOI Listing
August 2021

Chronic inflammation promotes epithelial-mesenchymal transition-mediated malignant phenotypes and lung injury in experimentally-induced pancreatitis.

Life Sci 2021 Aug 25;278:119640. Epub 2021 May 25.

Tulane Eosinophilic Disorders Center (TEDC), Section of Pulmonary Diseases, John W. Deming Department of Medicine, Tulane University, New Orleans, LA 70112, USA. Electronic address:

Patients with chronic pancreatitis have an increased risk of pancreatic malignancy, but the mechanisms underlying this relationship are poorly understood. We developed a mouse model of chronic pancreatitis by treatment with a combination of cerulein and azoxymethane. In our model, we show that cerulein and azoxymethane treated mice develop pathological malignant phenotype and associated lung inflammation. We observed chronic pancreatitis-associated induction of proinflammatory cytokines such as interleukin-6, interleukin-15, and granulocyte-macrophage colony-stimulating factor, along with accumulation of macrophages and eosinophilic inflammation. We also observed eosinophils degranulation, pancreatic stellate cell activation-mediated epithelial-to-mesenchymal transition-associated proteins that display a pancreatic malignant phenotype including acinar-to-ductal metaplasia and acinar cell atrophy. We observed highly induced interleukin-15 that has been earlier reported to have a protective role against fibrosis and malignancy; therefore, further evaluated its role in our mouse model of chronic pancreatitis. We observed that introduction of recombinant interleukin-15 has indeed improve chronic pancreatitis-associated epithelial-to-mesenchymal transition-mediated development of a malignant phenotype in the mouse model of chronic pancreatitis. In conclusion, we present evidence that rIL-15 overexpression improves eosinophilic inflammation-induced epithelial-to-mesenchymal transition-mediated progression of pancreatic remodeling associated malignant phenotype and acute lung injury by inducing NKT cells and IFN-γ mediated innate immunity in experimental pancreatitis.
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http://dx.doi.org/10.1016/j.lfs.2021.119640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245354PMC
August 2021

Blood mRNA levels of T cells and IgE receptors are novel non-invasive biomarkers for eosinophilic esophagitis (EoE).

Clin Immunol 2021 06 1;227:108752. Epub 2021 May 1.

John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA. Electronic address:

Eosinophilic esophagitis (EoE) is often misdiagnosed as GERD; therefore, the goal of the current study is to establish a non-invasive diagnostic and monitoring biomarker that differentiated GERD from EoE. Reports indicates that IL-15 responsive iNKT cells and tissue specific IgE have a critical in EoE pathogenesis, not in GERD. Therefore, we tested the hypothesis that the panel of IL-15-responsive T cell and IgE receptors may be novel non-invasive biomarkers for EoE. Accordingly, the receptors of IL-15 responsive T cells (Vα24, Jα18, γδT, αβT) and IgE (FcεRI & FcεRII) were examined. The data indicates that blood mRNA levels of Vα24, Jα18, γδ T, αβ T and FcεRI are significantly reduced in EoE compared to the GERD patients and normal individuals. The ROC curve analysis indicated FcεRII, Jα18 and δ TCR are the positive predictors that discriminate EoE from GERD. Thus, these molecules will be a novel non-invasive diagnostic biomarker for EoE.
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http://dx.doi.org/10.1016/j.clim.2021.108752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215583PMC
June 2021

Eosinophils in the pathogenesis of pancreatic disorders.

Semin Immunopathol 2021 Jun 30;43(3):411-422. Epub 2021 Mar 30.

John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, 70112, USA.

Eosinophils comprise approximately 1-4% of total blood leukocytes that reside in the intestine, bone marrow, mammary gland, and adipose tissues to maintain innate immunity in healthy individuals. Eosinophils have four toxic granules known as major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN), and upon degranulation, these granules promote pathogenesis of inflammatory diseases like allergy, asthma, dermatitis, and gastrointestinal disorders. Additionally, the role of eosinophils is underscored in exocrine disorders including pancreatitis. Chronic pancreatitis (CP) is an inflammatory disorder that occurs due to the alcohol consumption, blockage of the pancreatic duct, and trypsinogen mutation. Eosinophil levels are detected in higher numbers in both CP and pancreatic cancer patients compared with healthy individuals. The mechanistic understanding of chronic inflammation-induced pancreatic malignancy has not yet been reached and requires further exploration. This review provides a comprehensive summary of the epidemiology, pathophysiology, evaluation, and management of eosinophil-associated pancreatic disorders and further summarizes current evidence regarding risk factors, pathophysiology, clinical features, diagnostic evaluation, treatment, and prognosis of eosinophilic pancreatitis (EP) and pancreatic cancer.
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http://dx.doi.org/10.1007/s00281-021-00853-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249347PMC
June 2021

Tacrolimus (FK506) treatment protects allergen-, IL-5- and IL-13-induced mucosal eosinophilia.

Immunology 2021 Jun 28;163(2):220-235. Epub 2021 Feb 28.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA.

Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti-IL-5 and anti-IL-13 treatment have shown some therapeutic promise. Herein, we present evidence that pre- and post-intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec-F eosinophils in Aspergillus-challenged asthma and EoE, CD2-IL-5 induced global eosinophilia, and DOX regulated IL-13-induced asthma. We used flow cytometry and anti-major basic protein (MBP) immunostaining to examine eosinophils in the spleen, bone marrow, BALF, lung, oesophagus and intestine. Additionally, we also performed ELISA and Western blot analyses to show that tacrolimus treatment also reduces the levels of eosinophil-specific cytokines IL-4, IL-5, IL-13 and TGF-β, eosinophil-specific chemokines Eotaxin-1 and Eotaxin-2, and progenitors of target RCAN1 mRNA and protein levels. Additionally, the current investigations also show that the TGF-β-mediated oesophageal and lung fibrosis is also reduced in Aspergillus-challenged, CD2-IL-5 transgenic and DOX-responsive IL-13 mice. Mechanistically, we show that tacrolimus in vitro treatment inhibited bone marrow-derived eosinophil proliferation and viability by promoting eosinophil apoptosis that may be associated with downregulation of RCAN1. Taken together, we provide in vivo and in vitro evidence that tacrolimus ameliorates eosinophil levels and associated pathogenesis in allergen-, IL-5- and IL-13-induced EoE, EG and asthma pathogenesis. Considering tacrolimus side-effects and reactivity to several other drugs, we propose the topical use of tacrolimus for paediatric and low-dose oral for adult patients as a novel therapeutic strategy for the clinical trial to reduce mucosal eosinophilia first in steroid-refractory or elemental diet non-responsive adult EoE, EG and asthma patients.
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http://dx.doi.org/10.1111/imm.13314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114213PMC
June 2021

Experimental Modeling of Eosinophil-Associated Diseases.

Methods Mol Biol 2021 ;2241:275-291

John W. Deming Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center (TEDC), Tulane University School of Medicine, New Orleans, LA, USA.

Eosinophils are an important subtype of leukocytes derived from bone marrow multipotent hematopoietic stem cells and represent about 1% of leukocytes in circulating blood. In homeostatic conditions, eosinophils reside in the intestine to maintain the balance of immune responses by communicating with gut microbes without causing inflammation. However, under the stressed or diseased condition, eosinophils degranulate, releasing their granule-derived cytotoxic proteins that are involved in inflammatory responses. Various eosinophil-associated inflammatory diseases are eosinophilic esophagitis (EoE), eosinophilic gastroenteritis (EG), and eosinophilic colitis (EC), together called EGID, asthma, hypereosinophilic syndrome, and eosinophilic pneumonia (EP). Eosinophil degranulation results in the release of their four toxic proteins [major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN)] which promote disease pathogenesis. Pancreatitis is the inflammatory disease of the pancreas that arises due to blockage of the pancreatic duct, trypsinogen mutation, alcohol consumption, and repeated occurrence of pancreatitis leading to chronic pancreatitis (CP); subsequently some CP patients may also develop pancreatic cancer. The presence of eosinophils is now shown in various case reports with acute, recurrent acute, and chronic pancreatitis and pancreatic cancer indicating the role of eosinophils in the pathogenesis of various pancreatic inflammatory disorders. However, the details of eosinophil accumulation during pancreatic diseases are not well explored and need further attention. Overall, the chapter provides the current understanding of reported eosinophils associated with inflammatory diseases like EGID diseases, asthma, and pancreatic disorders, i.e., acute, chronic pancreatitis, and pancreatic cancer. This knowledge will be helpful for future studies to develop novel treatment options for the eosinophils associated diseases. Therefore, more efforts are needed to perform preclinical and clinical studies in this field for the successful development of eosinophil-targeting treatments for a variety of eosinophil-associated diseases.
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http://dx.doi.org/10.1007/978-1-0716-1095-4_21DOI Listing
March 2021

IL-15 immunotherapy is a viable strategy for COVID-19.

Cytokine Growth Factor Rev 2020 08 6;54:24-31. Epub 2020 Jun 6.

Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, School of Medicine, Tulane University, New Orleans, LA, 70112, USA. Electronic address:

Coronavirus disease 2019 (COVID-19) is a pulmonary inflammatory disease induced by a newly recognized coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection was detected for the first time in the city of Wuhan in China and spread all over the world at the beginning of 2020. Several millions of people have been infected with SARS-CoV-2, and almost 382,867 human deaths worldwide have been reported so far. Notably, there has been no specific, clinically approved vaccine or anti-viral treatment strategy for COVID-19. Herein, we review COVID-19, the viral replication, and its effect on promoting pulmonary fibro-inflammation via immune cell-mediated cytokine storms in humans. Several clinical trials are currently ongoing for anti-viral drugs, vaccines, and neutralizing antibodies against COVID-19. Viral clearance is the result of effective innate and adaptive immune responses. The pivotal role of interleukin (IL)-15 in viral clearance involves maintaining the balance of induced inflammatory cytokines and the homeostatic responses of natural killer and CD8 T cells. This review presents supporting evidence of the impact of IL-15 immunotherapy on COVID-19.
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http://dx.doi.org/10.1016/j.cytogfr.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537239PMC
August 2020

Significance of Interleukin (IL)-15 in IgE associated eosinophilic Esophagitis (EoE).

Int J Basic Clin Immunol 2019 Dec 12;2:1-12. Epub 2019 Sep 12.

Department of Medicine, Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Background And Aim: IgE-mediated immune responses contribute to the pathogenesis of eosinophilic esophagitis (EoE). Interleukin (IL)-4 is a well-established cytokine involved in B cell activation, immunoglobulin (Ig) E production and isotype class switching. Earlier reports indicated that IL-15, B cells and IgE are induced in EoE pathogenesis. Therefore, we hypothesized that induced IL-15 and IgE may have a significant correlation in promoting EoE pathogenesis.

Methods: Accordingly, we performed ELISA, qPCR, flowcytometric and immunostaining analyses to examine IgE, B cells, eosinophils and mast cells in the esophagus of IL-15 overexpressed mice following EoE induction.

Results: Herein, we show that IL-15 overexpressed mice indeed have induced baseline IL-4, B cells, eosinophils, mast cells and IgE levels in the blood and esophagus. Further, we observed that IL-15 overexpressed mice show induction of IgE, and accumulation of degranulated eosinophils and mast cells in allergen-induced experimental EoE. Notably, despite induced blood IgE, esophageal eosinophilia is not induced in intestinal fatty acid binding protein IL-15 overexpressed gene (Fabpi-IL-15) mice. Fabpi-IL-15 transgenic mice showed IgE in the blood and intestine and intestinal eosinophilia, but no esophageal eosinophilia at baseline and comparable eosinophils in the esophagus of saline and allergen challenged Fabpi-IL-15 mice. Similarly, allergen challenged gene-deficient mice show reduced IgE and esophageal eosinophilia in allergen-induced experimental EoE.

Conclusions: Taken together, we for the first time provide direct evidence that tissue-specific IL-15 induced IgE mediated responses, not systemic IgE is critical in promoting EoE pathogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158884PMC
December 2019

Possible novel non-invasive biomarker for inflammation mediated pancreatic malignancy.

Int J Basic Clin Immunol 2020 25;3(1-4):1-8. Epub 2020 Dec 25.

Department of Medicine, Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Objectives: Pancreatic malignancy is a major public health problem worldwide and recent reports indicated that pancreatic cancer will be second most common cause of cancer-related deaths by the end of 2021. The cause of increasing death rate is due to the nonexistence of detection tools to early diagnose, poor prognosis, resistance to chemotherapy and also lack in understanding the mechanism of PDAC pathogenesis. Circulating tumor cells (CTCs) play a major role in metastatic step of intravasation and presence of these cells are strong prognostic marker for the progression of pancreatic malignancy in chronic pancreatitis (CP).

Goal: Identifying the novel CTCs in the chronic inflammation mediated experimental model for the progression of malignancy in CP.

Methods: We have performed flow cytometer and immunofluorescence analyses in the lymphoid and lung samples was performed o detect CTCs in the chronic inflammation induced mouse model CP.

Results: We report that induced SOX9 positive cells were observed in the blood, lymph node and spleen samples of cerulein with azoximethane (AOM) treated mouse model of CP compared to cerulein alone. Further, we provide evidence that early metastasis through the migration and homing of mega merged SOX9 and PDX ductal stem cells (CTCs) in the lungs of cerulein with AOM treated mice. These identified CTCs in experimentally induced malignant pancreatitis may serve as a novel finding to identify a non-invasive biomarker that needs to be examined in the blood of human pancreatic cancer.

Conclusions: Taken together, the presented data of identified mega merged SOX9 and PDX ductal stem cells (CTCs) may serve a non-invasive biomarker for the early detection of pancreatic malignancy and metastasis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204699PMC
December 2020

Synergy of Interleukin (IL)-5 and IL-18 in eosinophil mediated pathogenesis of allergic diseases.

Cytokine Growth Factor Rev 2019 06 10;47:83-98. Epub 2019 May 10.

Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States. Electronic address:

Eosinophils are circulating granulocytes that have pleiotropic effects in response to inflammatory signals in the body. In response to allergens or pathogens, exposure eosinophils are recruited in various organs that execute pathological immune responses. IL-5 plays a key role in the differentiation, development, and survival of eosinophils. Eosinophils are involved in a variety of allergic diseases including asthma, dermatitis and various gastrointestinal disorders (EGID). IL-5 signal transduction involves JAK-STAT-p38MAPK-NFκB activation and executes extracellular matrix remodeling, EMT transition and immune responses in allergic diseases. IL-18 is a classical cytokine also involved in immune responses and has a critical role in inflammasome pathway. We recently identified the IL-18 role in the generation, transformation, and maturation of (CD101CD274) pathogenic eosinophils. In, addition, several other cytokines like IL-2, IL-4, IL-13, IL-21, and IL-33 also contribute in advancing eosinophils associated immune responses in innate and adaptive immunity. This review discusses with a major focus (1) Eosinophils and its constituents, (2) Role of IL-5 and IL-18 in eosinophils development, transformation, maturation, signal transduction of IL-5 and IL-18, (3) The role of eosinophils in allergic disorders and (4) The role of several other associated cytokines in promoting eosinophils mediated allergic diseases.
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http://dx.doi.org/10.1016/j.cytogfr.2019.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781864PMC
June 2019

Intestinal overexpression of IL-18 promotes eosinophils-mediated allergic disorders.

Immunology 2019 06 21;157(2):110-121. Epub 2019 Mar 21.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorder Center, Tulane University School of Medicine, New Orleans, LA, USA.

Baseline eosinophils reside in the gastrointestinal tract; however, in several allergic disorders, excessive eosinophils accumulate in the blood as well in the tissues. Recently, we showed in vitro that interleukin (IL)-18 matures and transforms IL-5-generated eosinophils into the pathogenic eosinophils that are detected in human allergic diseases. To examine the role of local induction of IL-18 in promoting eosinophil-associated intestinal disorders, we generated enterocyte IL-18-overexpressing mice using the rat intestinal fatty acid-binding promoter (Fabpi) and analysed tissue IL-18 overexpression and eosinophilia by performing real-time polymerase chain reaction, Enzyme-Linked Immunosorbent Assay and anti-major basic protein immunostaining. Herein we show that Fabpi-IL-18 mice display highly induced IL-18 mRNA and protein in the jejunum. IL-18 overexpression in enterocytes promotes marked increases of eosinophils in the blood and jejunum. Our analysis shows IL-18 overexpression in the jejunum induces a specific population of CD101 CD274 tissue eosinophils. Additionally, we observed comparable tissue eosinophilia in IL-13-deficient-Fabpi-IL-18 mice, and reduced numbers of tissue eosinophils in eotaxin-deficient-Fabpi-IL-18 and IL-5-deficient-Fabpi-IL-18 mice compared with Fabpi-IL-18 transgenic mice. Notably, jejunum eosinophilia in IL-5-deficient-Fabpi-IL-18 mice is significantly induced compared with wild-type mice, which indicates the direct role of induced IL-18 in the tissue accumulation of eosinophils and mast cells. Furthermore, we also found that overexpression of IL-18 in the intestine promotes eosinophil-associated peanut-induced allergic responses in mice. Taken together, we provide direct in vivo evidence that induced expression of IL-18 in the enterocytes promotes eotaxin-1, IL-5 and IL-13 independent intestinal eosinophilia, which signifies the clinical relevance of induced IL-18 in eosinophil-associated gastrointestinal disorders (EGIDs) to food allergens.
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http://dx.doi.org/10.1111/imm.13051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526631PMC
June 2019

Chemical composition, antioxidant potential, macromolecule damage and neuroprotective activity of .

J Tradit Complement Med 2018 Oct 7;8(4):483-496. Epub 2018 Feb 7.

Biochemistry and Nanosciences Discipline, Defence Food Research Laboratory, Mysuru, India.

Herbal medicines are known to mitigate radical induced cell damage. Hence identification and scientific validation of herbal medicines contribute to better use in Ayurvedic/Unani research. In the present study, we investigated antioxidant and anti-apoptotic properties of (). exhibited antioxidant potential evident by free radical scavenging activities. pretreatment inhibited HO induced macromolecule damage such as plasmid DNA damage and AAPH induced oxidation of bovine serum albumin and lipid peroxidation of rat hepatic tissues. Further to identify the neuroprotective properties of , SHSY5Y cells were treated with HO with or without pretreatment of . The pretreatment at 50 μg/ml dose exhibited 50% cell survival against 100 μM HO challenge for 24 h and it also decreased the lactate dehydrogenase leakage. Further pretreatment restored and regulated the antioxidant and apoptosis markers such as SOD, CAT, p53, and caspase-3 and inhibited, reactive oxygen species generation and depolarization of the mitochondrial membrane. possess a high content of flavonoids and polyphenols and GC-MS and FTIR analysis showed a wide variety of compounds which may contribute to the observed effects.
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http://dx.doi.org/10.1016/j.jtcme.2017.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174265PMC
October 2018

IL-15 regulates fibrosis and inflammation in a mouse model of chronic pancreatitis.

Am J Physiol Gastrointest Liver Physiol 2018 12 13;315(6):G954-G965. Epub 2018 Sep 13.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine , New Orleans, Louisiana.

Pancreatitis is an inflammatory disease characterized by the induction of several proinflammatory cytokines like interleukin (IL)-6, IL-8, IL-1β, and IL-1. Recently, the multifunctional innate cytokine IL-15 has been implicated in the protection of several diseases, including cancer. Tissue fibrosis is one of the major problems in successfully treating chronic pancreatitis pathogenesis. Therefore, we tested the hypothesis that recombinant IL-15 (rIL-15) treatment may induce innate tissue responses and its overexpression will improve the pathogenesis of cerulein-induced chronic pancreatitis, associated remodeling, and fibrosis. We observed atrophy of acinar cells, increased inflammation, and increased deposition of perivascular collagen, the upregulated protein level of transforming growth factor (TGF)-β1, α-smooth muscle actin (α-SMA), and collagen-1 in cerulein-induced chronic pancreatitis in mice. Furthermore, we reported that rIL-15 treatment protects mice from the cerulein-induced chronic pancreatitis pathogenesis, including acinar cell atrophy, and perivascular accumulation of tissue collagen followed by downregulation of profibrotic genes such as TGF-β1, α-SMA, collagen-1, collagen-3, and fibronectin in cerulein-induced chronic pancreatitis in mice. Mechanistically, we show that IL-15-mediated increase of interferon-γ-responsive invariant natural killer T (iNKT) cells in the blood and tissue protects cerulein-induced pancreatic pathogenesis in mice. Of note, a reduction in iNKT cells was also observed in human chronic pancreatitis compared with normal individuals. Taken together, these data suggest that IL-15 treatment may be a novel therapeutic strategy for treating chronic pancreatitis pathogenesis. NEW & NOTEWORTHY Pancreatic fibrosis is a major concern for the successful treatment of chronic pancreatitis and pancreatic cancer. Therefore, restriction in the progression of fibrosis is the promising approach to manage the pancreatitis pathogenesis. Herein, we present in vivo evidences that pharmacological treatment of recombinant interleukin-15 improves remodeling and fibrosis in cerulein-induced chronic pancreatitis in mice. Our observations indicate that interleukin-15 immunotherapy may be a possible and potential strategy for restricting the progression of fibrosis in chronic pancreatitis.
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http://dx.doi.org/10.1152/ajpgi.00139.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336943PMC
December 2018

Nutrition and Nutraceuticals in Neuroinflammatory and Brain Metabolic Stress: Implications for Neurodegenerative Disorders.

CNS Neurol Disord Drug Targets 2018 ;17(9):680-688

Department of Internal Medicine, University of Iowa, Iowa City, 52242, IA, United States.

Background And Objective: A steep rise in the incidences of neurodegenerative disorders could be the combined effect of several non-genetic factors such as increased life expectancy, environmental pollutants, lifestyle, and dietary habits, as population-level genetic change require multiple generations. Emerging evidence suggests that chronic over-nutrition induces brain metabolic stress and neuroinflammation, and are individually known to promote neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Although the association of metabolic disorders such as diabetes, hypertension, dyslipidemia, and atherosclerosis with the dietary habits is well known, neuronal implications of diet and nutritional factors is still in its infancy. Transcriptomics and proteomics-based studies support the view that nutraceuticals target multiple neuroprotective pathways in a slow but effective manner without causing severe adverse effects, and may represent the future of tackling neurodegenerative disorders.

Conclusion: In this article we i) review the diet/dietary supplement connection with brain metabolic stress and neuroinflammation and ii) summarize current knowledge of the effects of nutraceuticals on neurodegenerative disorders.
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http://dx.doi.org/10.2174/1871527317666180625104753DOI Listing
October 2019

Anxiolytic actions of Nardostachys jatamansi via GABA benzodiazepine channel complex mechanism and its biodistribution studies.

Metab Brain Dis 2018 10 22;33(5):1533-1549. Epub 2018 Jun 22.

Department of Pharmaceuticals, Institute of Nuclear Medicine and Allied Sciences, Brigadier Mazumdar Marg, Timar Pur, Delhi, 110054, India.

Nardostachys jatamansi has profound applications against pharmacological interventions and is categorized as a hypno-sedative drug according to Ayurveda. In the present study probable mechanism of anxiolytic action of Nardostachys jatamansi extract (NJE) was studied using behavioral anxiolytic tests (Elevated plus maze, Open field test, Light dark box test, and Vogel's conflict test) in mice. Mice were treated orally with NJE (250 mg/kg) for 3, 7 and 14 days or diazepam (1 mg/kg) followed by behavioral assessment and estimation of monoamine neurotransmitters, GABA, and antioxidant enzymes. Treatment of mice for 7 days caused an increase in time spent in open arms in elevated plus maze, number of line crossings in open field test, increased time spent in lit compartment of light-dark box test, an increase in number of licks made and shocks accepted in Vogel's conflict test, with results comparable to diazepam and this treatment also caused a significant increase in monoamine neurotransmitters and GABA in brain and tissue antioxidant parameters. Co-treatment of NJE with flumazenil (GABA-benzodiazepine antagonist; 0.5 mg/kg i.p) or picrotoxin (GABA gated chloride channel blocker; 1 mg/kg i.p) caused a blockage/antagonised anxiolytic actions of NJE by causing a significant reduction in time spent in open arms of elevated plus maze, an decrease in number of line crossing in open field test and also number of shocks and licks accepted in Vogel's conflict test. Further, NJE was radiolabelled with technetium at their hydroxyl groups following which purity as well as in vivo and in vitro stability of radiolabelled formulations was evaluated. The blood kinetics and in vivo bio-distribution studies were carried out in rabbits and mice respectively. Labeled formulation was found to be stable in vitro (96 to 93% stability) and in vivo (96 to 92% stability). The labeled compound was cleared rapidly from blood (within 24 h) and accumulated majorly in kidneys (11.65 ± 1.33), liver (6.07 ± 0.94), and blood (4.03 ± 0.63) after 1 h. However, a small amount was observed in brain (0.1 ± 0.02) probably because of its inability to cross blood-brain barrier. These results highlight biodistribution pattern of NJE, and also indicated that a 7-day treatment with NJE produced significant anxiolytic effects in mice and also a significant increase in brain monoamine and GABA neurotransmitter levels and suggests that anxiolytic effects of NJE are primarily and plausibly mediated by activating GABAergic receptor complex.
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http://dx.doi.org/10.1007/s11011-018-0261-zDOI Listing
October 2018

Exploring the Potentiality of Novel Rhizospheric Bacterial Strains against the Rice Blast Fungus .

Plant Pathol J 2018 Apr 1;34(2):126-138. Epub 2018 Apr 1.

Department of Seed Science and Technology, UAS, GKVK, Bengaluru, Karnataka 560065, India.

Rice blast caused by is a major disease. In the present study, we aimed to identify and evaluate the novel bacterial isolates from rice rhizosphere for biocontrol of pathogen. Sixty bacterial strains from the rice plant's rhizosphere were tested for their biocontrol activity against under and . Among them, had significant high activity against the pathogen. The least disease severity and highest germination were recorded in seeds treated with UASBR9 (0.96 and 98.00%) compared to untreated control (3.43 and 95.00%, respectively) under condition. These isolates had high activity of enzymes in relation to growth promoting activity upon challenge inoculation of the pathogen. The potential strains were identified based on 16S rRNA gene sequencing and dominance of these particular genes were associated in strains. These strains were also confirmed for the presence of antimicrobial peptide biosynthetic genes viz., (surfactin), (fengycin), (subtilin), and (iturin) related to secondary metabolite production (e.g., AMPs). Overall, the results suggested that application of potential bacterial strains like UASBR9 not only helps in control of the biological suppression of one of the most devastating rice pathogens, but also increases plant growth along with a reduction in application of toxic chemical pesticides.
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http://dx.doi.org/10.5423/PPJ.OA.11.2017.0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880357PMC
April 2018

Immunomodulatory effects of tacrolimus (FK506) for the treatment of allergic diseases.

Int J Cell Biol Physiol 2018 30;1(1-2):5-13. Epub 2018 Dec 30.

Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic DisordersCenter, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans L 70112.

Tacrolimus has been used to prevent allograft rejection and also used in kidney, liver and heart transplantations. Various preclinical and clinical studies demonstrated that Tacrolimus possess immunomodulatory and anti-inflammatory properties. The mechanism of action of Tacrolimus in allergic diseases involves calcineurin inhibition, and downregulation of T-cell reactivity, IgE degranulation, and its actions on mast cells, dendritic cells, basophils, eosinophils and inhibition of transcription of proinflammatory cytokines. Herein we reviewed the Pharmacotherapeutic mechanism of action of Tacrolimus in the prevention of asthma, atopic dermatitis, and allergic conjunctivitis.
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http://dx.doi.org/10.5281/zenodo.2530969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783126PMC
December 2018

TRAF3IP2 mediates high glucose-induced endothelin-1 production as well as endothelin-1-induced inflammation in endothelial cells.

Am J Physiol Heart Circ Physiol 2018 01 29;314(1):H52-H64. Epub 2017 Sep 29.

Dalton Cardiovascular Research Center, University of Missouri , Columbia, Missouri.

Hyperglycemia-induced production of endothelin (ET)-1 is a hallmark of endothelial dysfunction in diabetes. Although the detrimental vascular effects of increased ET-1 are well known, the molecular mechanisms regulating endothelial synthesis of ET-1 in the setting of diabetes remain largely unidentified. Here, we show that adapter molecule TRAF3 interacting protein 2 (TRAF3IP2) mediates high glucose-induced ET-1 production in endothelial cells and ET-1-mediated endothelial cell inflammation. Specifically, we found that high glucose upregulated TRAF3IP2 in human aortic endothelial cells, which subsequently led to activation of JNK and IKKβ. shRNA-mediated silencing of TRAF3IP2, JNK1, or IKKβ abrogated high-glucose-induced ET-converting enzyme 1 expression and ET-1 production. Likewise, overexpression of TRAF3IP2, in the absence of high glucose, led to activation of JNK and IKKβ as well as increased ET-1 production. Furthermore, ET-1 transcriptionally upregulated TRAF3IP2, and this upregulation was prevented by pharmacological inhibition of ET-1 receptor B using BQ-788, or inhibition of NADPH oxidase-derived reactive oxygen species using gp91ds-tat and GKT137831. Notably, we found that knockdown of TRAF3IP2 abolished ET-1-induced proinflammatory and adhesion molecule (IL-1β, TNF-α, monocyte chemoattractant protein 1, ICAM-1, VCAM-1, and E-selectin) expression and monocyte adhesion to endothelial cells. Finally, we report that TRAF3IP2 is upregulated and colocalized with CD31, an endothelial marker, in the aorta of diabetic mice. Collectively, findings from the present study identify endothelial TRAF3IP2 as a potential new therapeutic target to suppress ET-1 production and associated vascular complications in diabetes. NEW & NOTEWORTHY This study provides the first evidence that the adapter molecule TRAF3 interacting protein 2 mediates high glucose-induced production of endothelin-1 by endothelial cells as well as endothelin-1-mediated endothelial cell inflammation. The findings presented herein suggest that TRAF3 interacting protein 2 may be an important therapeutic target in diabetic vasculopathy characterized by excess endothelin-1 production.
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http://dx.doi.org/10.1152/ajpheart.00478.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866390PMC
January 2018

Dipeptidyl peptidase-4 (DPP-4) inhibition with linagliptin reduces western diet-induced myocardial TRAF3IP2 expression, inflammation and fibrosis in female mice.

Cardiovasc Diabetol 2017 05 5;16(1):61. Epub 2017 May 5.

Diabetes and Cardiovascular Center, Department of Medicine, University of Missouri, Columbia, MO, USA.

Background: Diastolic dysfunction (DD), a hallmark of obesity and primary defect in heart failure with preserved ejection fraction, is a predictor of future cardiovascular events. We previously reported that linagliptin, a dipeptidyl peptidase-4 inhibitor, improved DD in Zucker Obese rats, a genetic model of obesity and hypertension. Here we investigated the cardioprotective effects of linagliptin on development of DD in western diet (WD)-fed mice, a clinically relevant model of overnutrition and activation of the renin-angiotensin-aldosterone system.

Methods: Female C56Bl/6 J mice were fed an obesogenic WD high in fat and simple sugars, and supplemented or not with linagliptin for 16 weeks.

Results: WD induced oxidative stress, inflammation, upregulation of Angiotensin II type 1 receptor and mineralocorticoid receptor (MR) expression, interstitial fibrosis, ultrastructural abnormalities and DD. Linagliptin inhibited cardiac DPP-4 activity and prevented molecular impairments and associated functional and structural abnormalities. Further, WD upregulated the expression of TRAF3IP2, a cytoplasmic adapter molecule and a regulator of multiple inflammatory mediators. Linagliptin inhibited its expression, activation of its downstream signaling intermediates NF-κB, AP-1 and p38-MAPK, and induction of multiple inflammatory mediators and growth factors that are known to contribute to development and progression of hypertrophy, fibrosis and contractile dysfunction. Linagliptin also inhibited WD-induced collagens I and III expression. Supporting these in vivo observations, linagliptin inhibited aldosterone-mediated MR-dependent oxidative stress, upregulation of TRAF3IP2, proinflammatory cytokine, and growth factor expression, and collagen induction in cultured primary cardiac fibroblasts. More importantly, linagliptin inhibited aldosterone-induced fibroblast activation and migration.

Conclusions: Together, these in vivo and in vitro results suggest that inhibition of DPP-4 activity by linagliptin reverses WD-induced DD, possibly by targeting TRAF3IP2 expression and its downstream inflammatory signaling.
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http://dx.doi.org/10.1186/s12933-017-0544-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420102PMC
May 2017

Anti-inflammatory and anti-oxidant effects of Cardamom (Elettaria repens (Sonn.) Baill) and its phytochemical analysis by 4D GCXGC TOF-MS.

Biomed Pharmacother 2017 Jul 28;91:191-201. Epub 2017 Apr 28.

Biochemistry and Nanosciences Discipline, Defence Food Research Laboratory, Mysore, India. Electronic address:

Elleteria repens is a large cardamom used in the culinary preparations. In the present study, we have evaluated in vitro antioxidant and free radical scavenging activities E. repens hexane extract (ERH) exhibited DPPH and metal chelating activity with IC values of 464±28.3μg/ml, 199±7.2μg/ml whereas the reducing power and antioxidant activities are found to be 289±14.6 AAE/mg, 468±22.7 GAE/mg. The observed antioxidant activities could be correlated with metabolites such as polyphenol, flavonoid, and terpenoid group of compounds identified in hexane fraction of E. repens by 4D GCXGC TOF-MS. Further ERH was evaluated for its protective properties against macromolecules such as DNA, protein and lipid damage. The extract showed protection against HO induced DNA damage and inhibited AAPH induced protein oxidation and lipid peroxidation. Moreover, ERH administration to rats at 50 and 100mg/kg inhibited carrageenan-induced paw edema, and down-regulated cytokines such as COX-2, IL-6, and TNF-α and inhibited i-NOS mediated NO generation. E. repens also exhibited antioxidant effects by restoring SOD, catalase, GSH levels and inhibited lipid peroxidation in carrageenan challenged rats. Overall, the results suggest that E. repens may be useful in combating inflammation and oxidative stress.
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http://dx.doi.org/10.1016/j.biopha.2017.04.049DOI Listing
July 2017

Chemical composition of Ocimum sanctum by LC-ESI-MS/MS analysis and its protective effects against smoke induced lung and neuronal tissue damage in rats.

Biomed Pharmacother 2017 Jul 20;91:1-12. Epub 2017 Apr 20.

Biochemistry and Nanosciences Discipline, Defence Food Research Laboratory, Mysore, India. Electronic address:

Smoke induced oxidative stress is known to cause various cancers and associated health problems including lung cancer. Herbal extracts have been reported as antioxidant supplements which attenuate free radical induced oxidative damage of tissues, among which Ocimum sanctum has been reported as the elixir of life due to its innumerable health benefits. In the present study, we investigated the protective effect of O. sanctum against cracker smoke induced lung and brain tissue damage. The results of the study demonstrate that O. sanctum regulates the hematological and serum biochemical parameters such as RBC, WBC, blood urea nitrogen and creatinine kinase. O. sanctum supplementation inhibited oxidative stress as analyzed by SOD, CAT enzyme levels and i-NOS, HSP-70 protein expression. O. sanctum administration also regulated neurotransmitter levels, such as serotonin, dopamine, and regulated acetylcholine esterase levels which play a vital role in neuronal function. Further O. sanctum treatment also preserved the morphology of lung and brain tissues of smoke stress induced rats as observed by histopathology and transmission electron microscope analysis. The biodistribution of O. sanctum was showed its accumulation in key tissues such as kidney, liver, lungs and heart. The LC-ESI-MS/MS analysis of O. sanctum showed the presence of polyphenols, flavonoids and fatty acids which might be responsible for the observed anti-stress effects.
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http://dx.doi.org/10.1016/j.biopha.2017.04.011DOI Listing
July 2017

Hypoxia induced cognitive impairment modulating activity of Cyperus rotundus.

Physiol Behav 2017 06 27;175:56-65. Epub 2017 Mar 27.

Biochemistry and Nanosciences Department, Defence Food Research Laboratory, Mysore, India.. Electronic address:

Hypobaric hypoxia leads to decrease in cellular oxygen content which subsequently damages the hippocampus with an increase in brain oxidative stress and impairs the memory of the individual. In the present study, we have evaluated the cognitive impairment modulating activity of total oligomeric flavonoids fraction of Cyperus rotundus (TOF) in Sprague Dawley rats. The rats were trained for memory activity for a period of 7days followed by 7days exposure to 25,000ft. altitude and the spatial reference memory was evaluated. Behavioral analysis of the rats by Morris water maze experiment showed that TOF supplementation enhanced the spatial reference memory activity of the rats exposed to hypobaric hypoxia. The decrease in antioxidant status of the animals exposed to hypoxia was restored with TOF supplementation. The increase in ROS, lipid peroxidation products and protein carbonyls of the hippocampus was significantly decreased in animals with TOF administration. The histological assessment of the pyramidal cells of the hippocampus of hypoxia-exposed animals showed nuclear damage and TOF supplementation prevented nuclear damage. TOF administration suppressed hypoxia-induced increase in serotonin, dopamine, and norepinephrine. GABA and Ach levels were decreased by hypoxia which was prevented by TOF supplementation. The increase in GFAP, HIF-1α and VEGF expression in CA3 region of the hippocampus in hypoxia-exposed rats was decreased in TOF administered rats. Taken together, TOF extract ameliorates hypobaric hypoxia induced memory impairment and neurodegeneration in hippocampus through its anti-stress effects.
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http://dx.doi.org/10.1016/j.physbeh.2017.03.035DOI Listing
June 2017

Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling.

J Biol Chem 2017 02 4;292(6):2345-2358. Epub 2017 Jan 4.

the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri 65211,

Re-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results in nitroxidative stress and a marked inflammatory response in the heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) is an oxidative stress-responsive cytoplasmic adapter molecule that is an upstream regulator of both IκB kinase (IKK) and c-Jun N-terminal kinase (JNK), and an important mediator of autoimmune and inflammatory responses. Here we investigated the role of TRAF3IP2 in ischemia/reperfusion (I/R)-induced nitroxidative stress, inflammation, myocardial dysfunction, injury, and adverse remodeling. Our data show that I/R up-regulates TRAF3IP2 expression in the heart, and its gene deletion, in a conditional cardiomyocyte-specific manner, significantly attenuates I/R-induced nitroxidative stress, IKK/NF-κB and JNK/AP-1 activation, inflammatory cytokine, chemokine, and adhesion molecule expression, immune cell infiltration, myocardial injury, and contractile dysfunction. Furthermore, gene deletion blunts adverse remodeling 12 weeks post-I/R, as evidenced by reduced hypertrophy, fibrosis, and contractile dysfunction. Supporting the genetic approach, an interventional approach using ultrasound-targeted microbubble destruction-mediated delivery of phosphorothioated TRAF3IP2 antisense oligonucleotides into the LV in a clinically relevant time frame significantly inhibits TRAF3IP2 expression and myocardial injury in wild type mice post-I/R. Furthermore, ameliorating myocardial damage by targeting TRAF3IP2 appears to be more effective to inhibiting its downstream signaling intermediates NF-κB and JNK. Therefore, TRAF3IP2 could be a potential therapeutic target in ischemic heart disease.
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http://dx.doi.org/10.1074/jbc.M116.764522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313105PMC
February 2017

Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction.

J Biol Chem 2016 09 27;291(37):19425-36. Epub 2016 Jul 27.

From the Department of Medicine and Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri 65201,

TRAF3IP2 (TRAF3 interacting protein 2; previously known as CIKS or Act1) is a key intermediate in the normal inflammatory response and the pathogenesis of various autoimmune and inflammatory diseases. Induction of TRAF3IP2 activates IκB kinase (IKK)/NF-κB, JNK/AP-1, and c/EBPβ and stimulates the expression of various inflammatory mediators with negative myocardial inotropic effects. To investigate the role of TRAF3IP2 in heart disease, we generated a transgenic mouse model with cardiomyocyte-specific TRAF3IP2 overexpression (TRAF3IP2-Tg). Echocardiography, magnetic resonance imaging, and pressure-volume conductance catheterization revealed impaired cardiac function in 2-month-old male transgenic (Tg) mice as evidenced by decreased ejection fraction, stroke volume, cardiac output, and peak ejection rate. Moreover, the male Tg mice spontaneously developed myocardial hypertrophy (increased heart/body weight ratio, cardiomyocyte cross-sectional area, GATA4 induction, and fetal gene re-expression). Furthermore, TRAF3IP2 overexpression resulted in the activation of IKK/NF-κB, JNK/AP-1, c/EBPβ, and p38 MAPK and induction of proinflammatory cytokines, chemokines, and extracellular matrix proteins in the heart. Although myocardial hypertrophy decreased with age, cardiac fibrosis (increased number of myofibroblasts and enhanced expression and deposition of fibrillar collagens) increased progressively. Despite these adverse changes, TRAF3IP2 overexpression did not result in cell death at any time period. Interestingly, despite increased mRNA expression, TRAF3IP2 protein levels and activation of its downstream signaling intermediates remained unchanged in the hearts of female Tg mice. The female Tg mice also failed to develop myocardial hypertrophy. In summary, these results demonstrate that overexpression of TRAF3IP2 in male mice is sufficient to induce myocardial hypertrophy, cardiac fibrosis, and contractile dysfunction.
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http://dx.doi.org/10.1074/jbc.M116.724138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016681PMC
September 2016

LC-ESI-MS/MS analysis of total oligomeric flavonoid fraction of Cyperus rotundus and its antioxidant, macromolecule damage protective and antihemolytic effects.

Pathophysiology 2015 Dec 28;22(4):165-73. Epub 2015 Jul 28.

Biochemistry and Nanosciences Discipline, Defence Food Research Laboratory, Mysore 570011, Karnataka, India. Electronic address:

In the present investigation, we identified the phytochemical constituents of total oligomeric flavonoid fraction (TOF) of Cyperus rotundus by LC-ESI-MS/MS and also demonstrated its antihemolytic effects against 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) induced hemolysis of rat erythrocytes. Our results of TOF extract exhibited DPPH, metal chelating, ABTS, NO and hydroxyl radical scavenging activities with an IC50 values of 23.72±1.6, 52.45±2.88, 9.8±0.42, 6.5±0.33 and 120±6.83μg/ml respectively, whereas total antioxidant and reducing power activities were 194±12.5μg GAE/mg extract and 145±8.3μg AAE/mg extract. The extract showed potent inhibitory activity against AAPH induced plasmid DNA damage, protein oxidation and lipid peroxidation. The TOF extract mitigates AAPH induced hemolysis and exhibits ∼50% antihemolytic activity. TOF pretreatment also preserved morphology of erythrocytes as observed and measured by light microscope and atomic force microscope analysis. Furthermore, the TOF fraction effectively inhibited AAPH induced LDH release, ROS generation and lipid peroxidation. Taken together, our data demonstrate the antihemolytic activity of C. rotundus against AAPH induced oxidative stress of erythrocytes, and was associated with the decrease in oxidative stress, cellular damage and protection of macromolecules. In conclusion, the effects might be correlated with high content of flavonoids and polyphenols identified in C. rotundus. This suggests the clinical application of TOF fraction of C. rotundus against ROS induced cell death.
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http://dx.doi.org/10.1016/j.pathophys.2015.07.001DOI Listing
December 2015

Neuroprotective effects of hydroalcoholic extract of Ocimum sanctum against H2O2 induced neuronal cell damage in SH-SY5Y cells via its antioxidative defence mechanism.

Neurochem Res 2013 Oct 31;38(10):2190-200. Epub 2013 Aug 31.

Biochemistry and Nanosciences Discipline, Defence Food Research Laboratory, Mysore, India.

Oxidative stress mediates the cell damage in several ailments including neurodegenerative conditions. Ocimum sanctum is widely used in Indian ayurvedic medications to cure various ailments. The present study was carried out to investigate the antioxidant activity and neuroprotective effects of hydroalcoholic extract of O. sanctum (OSE) on hydrogen peroxide (H2O2)-induced oxidative challenge in SH-SY5Y human neuronal cells. The extract exhibited strong antioxidant activity against DPPH, 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radical and hydroxyl radicals with IC50 values of 395 ± 16.2, 241 ± 11.5 and 188.6 ± 12.2 μg/ml respectively, which could be due to high amount of polyphenols and flavonoids. The observed data demonstrates 41.5% cell survival with 100 μM H2O2 challenge for 24 h, which was restored to 73% by pre-treatment with OSE for 2 h. It also decreased the lactate dehydrogenase leakage and preserved the cellular morphology. Similarly OSE inhibited lipid peroxidation, DNA damage, reactive oxygen species generation and depolarization of mitochondrial membrane. The extract restored superoxide dismutase and catalase enzyme/protein levels and further downregulated HSP-70 over-expression. These findings suggest that OSE ameliorates H2O2 induced neuronal damage via its antioxidant defence mechanism and might be used to treat oxidative stress mediated neuronal disorders.
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http://dx.doi.org/10.1007/s11064-013-1128-7DOI Listing
October 2013

Neuroprotective effects of Cyperus rotundus on SIN-1 induced nitric oxide generation and protein nitration: ameliorative effect against apoptosis mediated neuronal cell damage.

Neurotoxicology 2013 Jan 19;34:150-9. Epub 2012 Nov 19.

Biochemistry and Nanosciences Discipline, Defence Food Research Laboratory, Mysore, India.

Nitrosylation of tyrosine (3-nitro tyrosine, 3-NT) has been implicated in the pathophysiology of various disorders particularly neurodegenerative conditions and aging. Cyperus rotundus rhizome is being used as a traditional folk medicine to alleviate a variety of disorders including neuronal stress. The herb has recently found applications in food and confectionary industries also. In current study, we have explored the protective effects of C. rotundus rhizome extract (CRE) through its oxido-nitrosative and anti apoptotic mechanism to attenuate peroxynitrite (ONOO(-)) induced neurotoxicity using human neuroblastoma SH-SY5Y cells. Our results elucidate that pre-treatment of neurons with CRE ameliorates the mitochondrial and plasma membrane damage induced by 500 μM SIN-1 to 80% and 24% as evidenced by MTT and LDH assays. CRE inhibited NO generation by downregulating i-NOS expression. SIN-1 induced depletion of antioxidant enzyme status was also replenished by CRE which was confirmed by immunoblot analysis of SOD and CAT. The CRE pre-treatment efficiently potentiated the SIN-1 induced apoptotic biomarkers such as bcl-2 and caspase-3 which orchestrate the proteolytic damage of the cell. The ONOO(-) induced damage to cellular, nuclear and mitochondrial integrity was also restored by CRE. Furthermore, CRE pre-treatment also regulated the 3-NT formation which shows the potential of plant extract against tyrosine nitration. Taken together, our findings suggest that CRE might be developed as a preventive agent against ONOO(-) induced apoptosis.
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http://dx.doi.org/10.1016/j.neuro.2012.11.002DOI Listing
January 2013
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