Publications by authors named "Anil Mishra"

302 Publications

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

Lamotrigine loaded PLGA nanoparticles intended for direct nose to brain delivery in epilepsy: pharmacokinetic, pharmacodynamic and scintigraphy study.

Artif Cells Nanomed Biotechnol 2021 Dec;49(1):511-522

Department of Pharmaceutical Sciences, Saurashtra University, Rajkot, India.

The present study aimed to investigate the brain targeting efficacy of Lamotrigine (LTG) loaded PLGA nanoparticles (LTG-PNPs) upon intranasal administration. LTG-PNPs were fabricated through the emulsification-solvent evaporation technique and evaluated for % Entrapment efficiency, particle size, release, surface morphology, crystallinity, permeation & thermal behaviour. Biodistribution, gamma scintigraphy, and pharmacodynamic studies were performed in BALB/c mice, New Zealand rabbits, and Wistar rats respectively. LTG-PNPs exhibited % EE 71%; particle size 170.0 nm; Polydispersity index 0.191; zeta potential -16.60 mV. LTG-PNPs exhibited a biphasic release pattern. Biodistribution and gamma scintigraphy studies proved a greater amount of LTG in the brain following intranasal delivery of LTG-PNPs in comparison to LTG-SOL. Pharmacodynamic studies demonstrated delayed seizure onset time with LTG-PNPs in comparison to LTG-SOL. Intranasal administration of LTG-PNPs provided prolonged release, higher bioavailability, and better brain targeting bypassing the BBB. The developed formulation could be administered as a once-a-day formulation that would reduce the dosing frequency; dose; dose-related side effects; cost of the therapy and would be beneficial in the management of epilepsy as compared to the LTG-SOL. However, the proof of concept generated through these studies needs to be further validated in higher animals and human volunteers.
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http://dx.doi.org/10.1080/21691401.2021.1939709DOI Listing
December 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

Virtual screening of quinoline derived library for SARS-COV-2 targeting viral entry and replication.

J Biomol Struct Dyn 2021 May 25:1-30. Epub 2021 May 25.

Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization Brig, Delhi, India.

The COVID-19 pandemic infection has claimed many lives and added to the social, economic, and psychological distress. The contagious disease has quickly spread to almost 218 countries and territories following the regional outbreak in China. As the number of infected populations increases exponentially, there is a pressing demand for anti-COVID drugs and vaccines. Virtual screening provides possible leads while extensively cutting down the time and resources required for ab-initio drug design. We report structure-based virtual screening of a hundred plus library of quinoline drugs with established antiviral, antimalarial, antibiotic or kinase inhibitor activity. In this study, targets having a role in viral entry, viral assembly, and viral replication have been selected. The targets include: 1) RBD of receptor-binding domain spike protein S 2) M Chymotrypsin main protease 3) P Papain protease 4) RNA binding domain of Nucleocapsid Protein, and 5) RNA Dependent RNA polymerase from SARS-COV-2. An in-depth analysis of the interactions and G-score compared to the controls like hydroxyquinoline and remdesivir has been presented. The salient results are (1) higher scoring of antivirals as potential drugs (2) potential of afatinib by scoring as better inhibitor, and (3) biological explanation of the potency of afatinib. Further MD simulations and MM-PBSA calculations showed that afatinib works best to interfere with the the activity of RNA dependent RNA polymerase of SARS-COV-2, thereby inhibiting replication process of single stranded RNA virus. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1913228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171009PMC
May 2021

The Academic Footprint of Women in Transplantation: Leaky Pipeline Persists.

Transplantation 2021 Mar 18. Epub 2021 Mar 18.

1 Department of Surgery, University of Toledo Medical Center, OH, USA 2 Medical College of Wisconsin, WI, USA 3 Schar School of Policy and Government, George Mason University, Fairfax, VA, USA 4 Albany Medical College, NY, USA.

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http://dx.doi.org/10.1097/TP.0000000000003748DOI Listing
March 2021

Synthesis and evaluation of technetium-99m labelled 1-(2-methoxyphenyl)piperazine derivative for single photon emission computed tomography imaging for targeting 5-HT.

Bioorg Chem 2021 Jun 13;111:104972. Epub 2021 May 13.

Department of Chemistry, School of Physical & Decision Sciences (SPDS), Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow 226025, UP, India; Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi 110054, India. Electronic address:

Quantitative changes in expression level of 5HT are somewhere related to common neurological disorders such as anxiety, major depression and schizophrenia. We have designed EDTA conjugated SPECT imaging probe for localization of 5HT receptor in brain. For designing SPECT probe we have employed the concept of bivalent approach and a homodimeric system with desirable pharmacokinetics of 5HT imaging. Tc-EDHT was also evaluated for its stability through serum stability assay and glutathione challenge experiment. Biodistribution study showed the highest accumulation of radioactivity in kidney which depicted the renal mode of excretion from the body. However in brain the uptake of 1.21% ID per gram was observed in initial 5 min of drug administration. On blocking the receptor this percent get decreased to 0.97% ID per gram. The regional distribution in brain was also performed which showed the accumulation of drug in cerebellum, cortex and hippocampus part, which are already known for 5HT expression. Dynamic study in rabbit is also in support of results derived from biodistribution and blood kinetics experiment. These finding suggest that Tc-EDHT holds promising place for further optimization before nuclear medicine applications in different animal species.
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http://dx.doi.org/10.1016/j.bioorg.2021.104972DOI Listing
June 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

Quercetin: a savior of alveolar barrier integrity under hypoxic microenvironment.

Tissue Barriers 2021 04 26;9(2):1883963. Epub 2021 Feb 26.

Hematology Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur Delhi-India.

High altitude pulmonary edema (HAPE) is generally characterized by the loss of alveolar epithelial barrier integrity. The current study was undertaken to assess the noninvasive approaches of HAPE diagnosis and to evaluate the prophylactic potential of quercetin in preventing alveolar junction impairments. Male SD rats fed with quercetin 1 h prior to hypoxia (7,620 m, for 6 h) were selected. PET/CT imaging was performed to visualize the lung uptake of F-FDG in animals under hypoxia. Further, oxidant status, catalase activity, hematological & blood gas parameters were evaluated. Moreover, tight junction (TJ) proteins (ZO-1, JAM-C, Claudin-4, and occludin) expression analysis was accomplished using immune-blotting. The structural differences in lung epithelia were noted by TEM imaging. Quercetin prophylaxis has significantly reduced the FDG uptake in rat lungs under hypoxia. It has also dramatically alleviated the protein oxidation followed by an elevation in catalase activity in the lungs under hypoxia. The TJ protein expression in the lungs has also been restored to normal upon quercetin pre-treatment. Concomitantly, the quercetin preconditioning has elicited the stable blood gas and hematological parameters under hypoxia. The observations from TEM imaging have also implicated the normal lung epithelial structures in the quercetin pretreated animals under hypoxia. Quercetin prophylaxis has significantly restored alveolar epithelium integrity by abating oxidative stress in the lungs under hypoxia.: - Computed Tomography- Fluorodeoxyglucose (F- High Altitude Pulmonary Edema- Hemoglobin- Hematocrit Bicarbonate- Junctional Adhesion Molecule- Killo Becquerel- Partial pressure of arterial oxygen- Partial pressure of arterial carbon di-oxide- Positron Emission Tomography- Red Blood Corpuscles- Sprague Dawley- Tight Junctions- Transmission Electron Microscopy- White Blood Corpuscles- Zona Occludin.
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http://dx.doi.org/10.1080/21688370.2021.1883963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078770PMC
April 2021

Semen quality and total microbial load: An association study in important Indian Goat breeds during different seasons.

Andrologia 2021 May 25;53(4):e13995. Epub 2021 Feb 25.

Bioenergetics and Environmental Sciences Division, ICAR-National Institute of Animal Nutrition and Physiology (ICAR-NIANP), Bengaluru, Karnataka, India.

The invasion of the male urogenital tract by microorganisms, and its subsequent effects on sperm fertilising ability, has not been well discussed in bucks. The present study was conducted to assess the bacterial load in fresh semen of the 2-6 years old bucks. For conducting the experiment, semen ejaculates from 18 bucks (6 from each breed namely Jakhrana, Jamunapari and Barbari) were used. We collected 5 ejaculates from each buck in each season (Summer-April to June, Rainy-July to Sept and Winter-November to January). Semen was collected with the artificial vagina (AV) method, and separate AV was used for each buck every time. The semen collection frequency was once in a week. Immediately after initial evaluation, collected semen samples were transferred to the microbiology laboratory of the institute. Thereafter, the semen samples were subjected to bacteriological examination to assess the microbial load. The results of the current study indicate that the microbial load in the semen was significantly (p < 0.05) higher in the Jamunapari bucks and in aged bucks. Bacteriospermia in different seasons was not significantly varied; however, nonsignificant increase in microbial load during the rainy season was observed. Overall, the average bacterial load in the semen of Jamunapari, Barbari and Jakhrana bucks was found 540.50 ± 55.88 CFU/ml, 391.81 ± 46.33CFU/ml and 388.93 ± 44.71 CFU/ml respectively. No significant difference in bacterial counts in the subsequent ejaculates among bucks was observed. Moreover, correlation analysis revealed that the proportions of motility, viability, plasma membrane integrity and acrosomal integrity were negatively influenced by the increased bacterial contamination of buck semen.
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http://dx.doi.org/10.1111/and.13995DOI Listing
May 2021

Influence of real and synthetic municipal solid waste leachates on consolidation and shear strength behaviour of bentonites.

Environ Sci Pollut Res Int 2021 Jun 16;28(24):30975-30985. Epub 2021 Feb 16.

Department of Civil Engineering, Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India.

For safe disposal of wastes in landfills, compacted bentonite is recommended as bottom liners due to their significant cation exchange (CEC) and swelling capacity, low permeability and large specific surface area (SSA). The present investigation carried out various experimental studies determining the compressibility behaviour and unconfined compressive strength (UCS) of two different compacted bentonites in the presence of municipal solid waste (MSW) and synthetic MSW leachates. Various examinations were conducted determining alterations in consolidation parameters like the coefficient of consolidation (c), time taken for 90% consolidation (t) and compression index (C) with both leachates. The outcomes reveal that C and t values of both bentonites declined; however, c value rose. Results also indicated that under any given consolidation pressure, a lesser void ratio was achieved for leachates. UCS of both bentonites reduced with leachates' interaction yet, lying within the recommended a value higher than 200 kPa. A comparative assessment of the two bentonites displayed that bentonite having higher CEC and swelling capacity, and SSA unveiled more excellent C and t values and a reduction in the UCS. A higher variation in behaviour of bentonites was perceived in the existence of MSW leachate in comparison to synthetic MSW leachate.
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http://dx.doi.org/10.1007/s11356-021-12863-4DOI Listing
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

Synthesis and biological evaluation of modified laminin peptide (NS-KDP) with enhanced affinity for neuronal growth and targeted molecular imaging (SPECT).

Bioorg Chem 2021 02 24;107:104516. Epub 2020 Nov 24.

Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi 110054, India. Electronic address:

An analog of γ1 laminin (RDIAEIIKDI) decapeptide has been used to augment neuronal survival and regeneration after injuries, during aging and other CNS disorder. As a prime synthetic peptide, KDI, is responsible for the neurite outgrowth of human embryonic neurons. In this study, we have designed, modified a KDI derivative and synthesized by replacing isoleucine (I) with Pro (P) amino acid at C-terminal to enhance its potency towards neurite growth. -Cys-Gly-Cys (-CGC) NS motif was also incorporated in the present design for peptide radiolabeling. The modified peptide showed a better binding with the desired 3T1M receptor for neurite growth. The peptide was synthesized using solid phase peptide synthesis and Fmoc-strategy with more than 80% yield. The receptor binding studies of Tc-NS-KDP in Neuro2A cell lines showed K value in 31 nM range and the complex showed appreciable brain uptake in mice. The results on human SH-SY5Y indicate that the unlabeled NS-KDP may perhaps be useful for neurite growth in neurodegenerative disorder.
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http://dx.doi.org/10.1016/j.bioorg.2020.104516DOI Listing
February 2021

Microenvironment Stimulated Bioresponsive Small Molecule Carriers for Radiopharmaceuticals.

ACS Omega 2020 Oct 5;5(41):26297-26306. Epub 2020 Oct 5.

Division of Cyclotron and Radiopharmaceutical Sciences (DCRS), Institute of Nuclear Medicine and Allied Sciences (INMAS), Timarpur, Delhi 110054, India.

The widespread and successful use of radiopharmaceuticals in diagnosis, treatment, and therapeutic monitoring of cancer and other ailments has spawned significant literature. The transition from untargeted to targeted radiopharmaceuticals reflects the various stages of design and development. Targeted radiopharmaceuticals bind to specific biomarkers, get fixed, and highlight the disease site. A new subset of radioprobes, the bioresponsive radiopharmaceuticals, has been developed in recent years. These probes generally benefit from signal enhancement after undergoing molecular changes due to the fluctuations in the environment (pH, redox, or enzymatic activity) at the site of interest. This review presents a comprehensive overview of bioresponsive radioimaging probes covering the basis, application, and scope of development.
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http://dx.doi.org/10.1021/acsomega.0c03601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581084PMC
October 2020

Tryptophan conjugated magnetic nanoparticles for targeting tumors overexpressing indoleamine 2,3 dioxygenase (IDO) and L-type amino acid transporter.

J Mater Sci Mater Med 2020 Oct 9;31(10):87. Epub 2020 Oct 9.

Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Brig. S.K. Mazumdar Marg, Delhi, 110054, India.

Tryptophan is an amino acid required by all life forms for protein synthesis and other important metabolic functions. It is metabolized in the body using the kynurenine pathway which involves the enzyme indoleamine 2,3 dioxygenase (IDO) and its transport is regulated through the L-type amino acid transporters (LAT 1). IDO and LAT 1 are found to be overexpressed in many cancers i.e., ovarian, lung colorectal etc. In this study we have used this specific interaction as the basis for designing diagnostic agent based on iron oxide nanoparticles which can specifically target the IDO/LAT 1 over expressing tumors. We have conjugated tryptophan to the surface of super-paramagnetic nanoparticles chemically using 3-aminopropyltrimethoxysilane as a linker. The synthesized tryptophan conjugated magnetic nano-conjugate has been characterized using FTIR, UV-Vis, TEM for its shape size, charge and NMR and Mass for conjugation. The magnetization studies show decrease in the magnetic behavior after conjugation however the desired super-paramagnetic property is still retained as shown by the signature sigmoidal B-H curve. The nano-conjugate shows minimal cytotoxicity over 24 h as shown by the SRB assay in two cell lines A-549, MCF-7. Using 99mTc labeling the biodistribution and the blood kinetics of the magnetic nano-conjugate was evaluated. The study highlights the suitability of the designed magnetic Nano bioconjugate as a potential bimodal diagnostic agent.
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http://dx.doi.org/10.1007/s10856-020-06438-xDOI Listing
October 2020

Effect of diluent sugars on capacitation status and acrosome reaction of spermatozoa in buck semen at refrigerated temperature.

Trop Anim Health Prod 2020 Nov 11;52(6):3409-3415. Epub 2020 Sep 11.

Animal Biotechnology, AP&R Division, ICAR-Central Institute for Research on Goats, Makhdoom, Farah, Mathura, 281122, India.

Objective: The aim of the study was to explore the possibility of a better sugar suitable for storage of goat semen at refrigerated temperature.

Materials And Method: For this experiment, semen was collected from eight Jakhrana bucks maintained at Jakhrana unit, ICAR-CIRG, at twice a week interval using artificial vagina. Collected semen was preliminary evaluated, and better semen samples were pooled and divided into two parts. One part of the pooled semen was diluted in egg yolk, Tris, citric acid, and fructose diluter, whereas second part was diluted in egg yolk, Tris, citric acid, and glucose diluter. Then semen samples were kept in equilibration chamber for 4 h at 5 °C after proper dilution. Both the semen samples were evaluated for viability, motility, plasma membrane integrity, sperm abnormality, lipid peroxidation, acrosomal integrity, and capacitation status at 0 h, 24 h, 48 h, and 72 h after dilution.

Results: Significantly (P < 0.05) higher motility was observed at 24 h in extender containing glucose as compared with extender containing fructose but motility was decreased at 48 h and 72 h. Number of capacitated sperm increased significantly (P < 0.05) and acrosomal integrity was decreased significantly (P < 0.05) at 72 h in extender containing glucose. The other parameters like viability and plasma membrane integrity were decreased significantly (P < 0.05) at 72 h and lipid peroxidation as well as sperm abnormality increased significantly (P < 0.05) in extender containing glucose.

Conclusion: From this study, it can be concluded that fructose is better diluent sugar for refrigerated storage of buck semen.
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http://dx.doi.org/10.1007/s11250-020-02374-8DOI Listing
November 2020

Ga-Labeled bismacrocyclic methylene phosphonate as potential bone seeking PET radiopharmaceutical.

Bioorg Chem 2020 11 26;104:104185. Epub 2020 Aug 26.

Institute of Nuclear Medicine & Allied Sciences, DRDO, Brig. SK Mazumdar Marg, Delhi 110054, India. Electronic address:

Phosphonates-based agents are well-known bone-seeking radiopharmaceuticals with application in detection and therapy. With higher sensitivity and resolution offered by Positron Emission Tomography (PET), tracers based on this technique are gaining huge attention. Ga-based generator and radiotracers render independence from the on-site cyclotron. We report the development of Ga-labeled DOTA-based bismacrocyclic phosphonate derivative, for bone PET imaging. The synthesis and characterization of Ga- DO3P-AME-DO3P was carried out in > 95% purity. The radiotracer displayed high stability and low binding affinity (<3%) to blood serum. High in vitro binding affinity were observed for synthetic hydroxyapatite, SAOS-2, osteoclast and osteoblast cells. In vivo pharmacokinetics revealed fast washout with biphasic release pattern. The deposition of radiotracer in osseous tissues was high (Bone/Muscle ratio:18), as studied from the biodistribution studies. In vivo PET/CT and biodistribution analyses revealed the ability of Ga-DO3P-AME-DO3P to target and accumulate in bone, thus displaying its potential as a PET bone imaging agent.
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http://dx.doi.org/10.1016/j.bioorg.2020.104185DOI Listing
November 2020

Lanthanide (Ln) complexes of bifunctional chelate: Synthesis, physicochemical study and interaction with human serum albumin (HSA).

Spectrochim Acta A Mol Biomol Spectrosc 2021 Jan 7;244:118808. Epub 2020 Aug 7.

Institute of Nuclear Medicine and Allied Sciences, DRDO, Timarpur, New Delhi, India; Department of Chemistry, Babasaheb Bhimrao Ambedkar University (A Central University), Lucknow, Lucknow, India. Electronic address:

Bifunctional chelate EDTA-bis amide (N,N'-bis (tyramide)ethylenediamine-N,N'-diacetic acid) that has ability to mimic natural amino acids was synthesized and analyzed by various spectroscopic techniques. The physicochemical studies were performed to calculate the various thermodynamic and kinetic parameters for the synthesized poly-amino carboxylate ligand. The two protonation constant (pka's = 3.460 and 6.722) of the prepared ligand and stability constants (log K's = 15.8, 18.1, 16.2, 18.4, 17.5, 18.9, 13.6 and 12.8) of the complexes formed with Ce, Sm, Eu, Gd, Tb, Lu, Zn and Cu were determined by potentiometric titration using 0.1 M MeNOH as non-aqueous base. The formation kinetics of [EuEDTA-TA] and [CeEDTA-TA] was studied and the rate constants were found to be 2.95 × 10-5 s and 4.414 × 10-5 srespectively including the exchange reaction of [EuEDTA-TA] with Zn and Cu spectrophotometrically. The Eu(III) complex of EDTA(TA) gives three emission bands at 480 nm, 540 nm and 610 nm (λ = 270 nm, excitation) which shows efficacy of the ligand as an optical imaging agent. Molecular docking studies with Human Serum Albumin (HSA: PDB 1E78) showed binding pattern with the residues Arg218, Arg222, Lys195 and Lys444 in sub domain II A of site I via hydrogen bond and identifies the ligand-HSA interaction and specific insight for transportation to the target sites. Subsequently, fluorescence spectroscopy was performed at λ = 350 nm binding constant for HSA was 5.847 × 10 M which showed effective quenching effect.
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http://dx.doi.org/10.1016/j.saa.2020.118808DOI Listing
January 2021

The diagnostic performance of 99mTc-methionine single-photon emission tomography in grading glioma preoperatively: a comparison with histopathology and Ki-67 indices.

Nucl Med Commun 2020 Sep;41(9):848-857

Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Science, DRDO, New Delhi.

Objective: To characterize glioma preoperatively using quantitative 99mTc-methionine SPECT and comparison with MR-perfusion/spectroscopy and histopatholgical/Ki-67 scoring.

Methods: Twenty-nine patients (21M: 8F; mean age 42.3 ± 10.5 years) with clinical and radiological suspicion of glioma assessed by 99mTc-MDM/SPECT and ceMRI. Additionally, 12/29 patients underwent dynamic susceptibility contrast-enhanced (DSCE) MRI and magnetic resonance spectroscopy (MRS) examination. Three patients with benign pathologies were recruited as controls. Histopathological tumor analysis was done in all (n = 29) the patients, and the Ki-67 index was evaluated in 20/29 patients. The target-to-nontarget (T/NT) methionine tumor uptake ratios, normalized cerebral blood volume (nCBV) and metabolites [choline/N-acetyl aspartate (Cho/NAA), Cho/creatine (Cr), Cr/NAA and Cr/Cho) ratios were measured in tumor areas.

Results: On histopathological analysis, 26/29 patients had glioma (G IV-13; G III-04; G II-09). The mean T/NT ratio in G-II was significantly lower (2.46 ± 2.3) than in G-III (7.13 ± 2.2) and G-IV (5.16 ± 1.2). However, the mean ratio was highest (15.9 ± 6.8) in meningioma (n=3). The T/NT cutoff ratio of 3.08 provided 100% sensitivity, 87.5% specificity for discriminating high-grade glioma (HGG) from low-grade glioma (LGG) disease. Likewise, the nCBV cutoff of 2.43 offered 100% sensitivity and 80% specificity. Only the Cho/NAA cutoff value of greater than 3.34 provided reasonable sensitivity and specificity of 85.7% and 80.0% respectively for this differentiation. T/NT ratio correlated significantly with nCBV and Cho/NAA, Cho/Cr ratios but not with Ki-67.

Conclusion: Quantitative 99mTc-MDM -SPECT provided high sensitivity and specificity to differentiate HGG versus LGG preoperatively and demonstrated a potential role for the differential diagnosis of glial versus nonglial tumors.
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http://dx.doi.org/10.1097/MNM.0000000000001230DOI Listing
September 2020

Molecular detection of important abortion-causing microorganisms in preputial swab of breeding bucks using PCR-based assays.

Reprod Domest Anim 2020 Nov 6;55(11):1520-1525. Epub 2020 Sep 6.

AP&R Division, ICAR- Central Institute for Research on Goats, Makhdoom, Farah, Mathura, India.

Infectious diseases and aetiological agents related to female reproductive systems were extensively covered compared to its male counterpart. There needs a proper study to bridge this gap, where microflora and infectious agents of both male and female reproductive are mutually intelligible. With this study, we aimed to evaluate the microbial contamination of the preputial cavity and also screened for abortion-causing agents which are zoonotic as well. In goats, such types of abortions are caused by Brucella melitensis, Chlamydophila, Campylobacter and Coxiella etc. One of the major sources of contamination of semen is the preputial cavity, which is exposed to the external environment leading to spread of infection into the female via semen straws or by natural service. In the current study, good quality bucks (n = 32, Barbari = 12, Jamunapari = 10, Jakhrana = 10) which were routinely used for semen collection were screened for their preputial swabs, for the presence of the above pathogens. For detection of Brucella melitensis, OMP31 based TaqMan® probe real-time PCR assay was used, and for Chlamydia, 16srRNA gene based SYBR® green real-time PCR assay was employed for detection of Chlamydophila abortus. While for Campylobacter spp. and Coxiella burnetii, 16srRNA gene based conventional PCR and Trans-PCR were used, respectively. In the current study, of the screened preputial swabs, none of them showed positive for Brucella and Coxiella, but of the screened 32 samples 17 showed positive for Chlamydia (53.13%) and two (6.25%) showed positive for Campylobacter spp. The current study emphasizes on the farms and laboratories which were regularly involved in screening of brucellosis also often overlook the other potential non-brucella pathogens, causing abortions eventually incurring severe economic losses to the goat keepers.
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http://dx.doi.org/10.1111/rda.13801DOI Listing
November 2020

[Tc]-Bis-Methionine-DTPA Single-Photon Emission Computed Tomography Impacting Glioma Management: A Sensitive Indicator for Postsurgical/Chemoradiotherapy Response Assessment.

Cancer Biother Radiopharm 2020 Jul 9. Epub 2020 Jul 9.

Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Science, DRDO, New Delhi, India.

The present study evaluated the prognostic value of [Tc]MDM (bis-methionine-DTPA) follow-up single-photon emission computed tomography (SPECT) imaging for response assessment to chemoradiotherapy in glioma postoperatively. One hundred fourteen glioma patients (80 M:34 F) were followed postoperatively by sequential [Tc]MDM SPECT, dynamic susceptibility contrast-enhanced (DSCE)-MRI, and magnetic resonance spectroscopy (MRS) at baseline, 6, 12, and 22.5 months postchemoradiotherapy. The quantitative imaging results and the clinical outcome were used for response assessment and for the final diagnosis. The quantitative parameter of [Tc]MDM SPECT were also used for survival analysis. A significantly ( = 0.001) lower target to nontarget (T/NT) ratio was observed in responders than in nonresponders. The sensitivity and specificity of [Tc]MDM-SPECT for identifying tumor recurrence from radiation necrosis at a cutoff ratio of 1.90 were estimated at 97.9% and 92%. Whereas, the sensitivity and specificity of DSCE-MRI with the normalized cerebral blood volume (nCBV) cutoff of 3.32 for this differentiation was found to be 84.6% and 93.0%. MRS intensity ratios of Cho/NAA and Cho/Cr provided comparatively lower sensitivity of 81.0% and 85.3% and specificity of 73.0% and 73.7%. T/NT ratios correlated with nCBV ( = 0.775,  < 0.001) and to a moderate extent with Cho/NAA ratios ( = 0.467,  = 0.001). [Tc]MDM SPECT and DSCE-MRI provided comparable results for predicting response assessment to chemoradiotherapy. There was a final diagnosis in 72 patients, of which 47 cases were tumor recurrence and 25 were radiation necrosis. The Kaplan-Meier analysis indicated that patients with T/NT ratio <1.9 showed prolonged survival (53.8 months) as compared (37.2 months) with those who demonstrated T/NT ratio >1.9 ( = 0.0001). Thus, this low-cost SPECT technique in combination with DSCE-MRI can be used accurately for mapping the disease activity, response assessment, and survival in glioma. [Tc]MDM SPECT and DSCE-MRI had the same diagnostic efficacy to detect recurrent/residual tumor and radiation necrosis while MRS was inferior to both the techniques.
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http://dx.doi.org/10.1089/cbr.2020.3696DOI Listing
July 2020

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

Role of folate-conjugated glycol-chitosan nanoparticles in modulating the activated macrophages to ameliorate inflammatory arthritis: in vitro and in vivo activities.

Drug Deliv Transl Res 2020 08;10(4):1057-1075

NanoBiotech Lab, Department of Zoology, Kirori Mal College, University of Delhi, Delhi, 110007, India.

Activated macrophages are the primary targets in rheumatoid arthritis (RA) management. So, we report efficacious, dual-functional Methotrexate (MTX) loaded folate-conjugated pH-responsive glycol-chitosan nanoparticles (MFGCN) prepared by nano-precipitation and zero-order cross-linking reaction for targeting inflamed arthritic tissue. Physical characterization by DLS, SEM and TEM indicated a spherical, smooth morphology with a diameter ~ 300 nm. H NMR and FTIR indicated folic acid conjugation to GC by zero-order cross-linkers. In vitro release kinetics in PBS showed pH-responsive and sustained release behaviour of MFGCN. Enhanced cellular uptake and cytotoxicity of MFGCN in LPS(+)RAW and activated peritoneal macrophages (Mϕ) were observed when compared to LPS(-)RAW cells. MFGCN-induced mitochondrial membrane potential (MMP) perturbations indicated apoptosis. Oxidative stress was evident by significant increase in ROS and RNS, 4 h post incubation with MFGCN. Negligible hemolysis by FGCN and MFGCN on rat RBC's indicated biocompatibility. In vivo biodistribution of MFGCN in adjuvant-induced arthritis (AIA) rats indicated RA targetability. Prolonged blood circulation coupled with higher concentrations of Tc-MFGCN at the arthritic site was observed post 24 h of injection. The gamma scintigraphic image confirmed accumulation of radiolabelled MFGCN in arthritic paw when compared to the non-inflamed paw, confirming the selective uptake of Tc-MFGCN by folate-overexpressing macrophages in the arthritic synovium thereby proving its targeted efficacy and theranostic potential. In AIA rats, MFGCN lowers arthritic signs, improves antioxidant response and decreases pro-inflammatory cytokines, suggesting its potential in targeting activated macrophages of synovium. Graphical abstract.
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http://dx.doi.org/10.1007/s13346-020-00765-wDOI Listing
August 2020

Chronic Pancreatitis and the Development of Pancreatic Cancer.

Endocr Metab Immune Disord Drug Targets 2020 ;20(8):1182-1210

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

Pancreatitis is a fibro-inflammatory disorder of the pancreas that can occur acutely or chronically as a result of the activation of digestive enzymes that damage pancreatic cells, which promotes inflammation. Chronic pancreatitis with persistent fibro-inflammation of the pancreas progresses to pancreatic cancer, which is the fourth leading cause of cancer deaths across the globe. Pancreatic cancer involves cross-talk of inflammatory, proliferative, migratory, and fibrotic mechanisms. In this review, we discuss the role of cytokines in the inflammatory cell storm in pancreatitis and pancreatic cancer and their role in the activation of SDF1α/CXCR4, SOCS3, inflammasome, and NF-κB signaling. The aberrant immune reactions contribute to pathological damage of acinar and ductal cells, and the activation of pancreatic stellate cells to a myofibroblast-like phenotype. We summarize several aspects involved in the promotion of pancreatic cancer by inflammation and include a number of regulatory molecules that inhibit that process.
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http://dx.doi.org/10.2174/1871530320666200423095700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577953PMC
August 2021

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

Eosinophilic pancreatitis: a rare or unexplored disease entity?

Prz Gastroenterol 2020 3;15(1):34-38. Epub 2020 Mar 3.

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

Several case reports show accumulation of eosinophils in pancreatitis patients and term the disease as "eosinophilic pancreatitis (EP)". EP usually presents with a pancreatic tumour and abdominal pain in obstructive jaundice, which is generally not diagnosed until the patient undergoes pancreatic resection. Histologically, EP reveals distinct patterns like diffused, periductal, acinar, and septal inflammatory infiltrates with eosinophils, eosinophilic phlebitis, and localised extreme eosinophilic infiltrates related with pseudocyst formation. EP patients also have elevated serum IgE levels with high eosinophil counts in the pancreas as well as in other organs such as the gastrointestinal tract, which is termed as eosinophilic gastroenteritis. Due to the lack of knowledge based on just a few case reports, it is considered that eosinophilic infiltration is quite rare in the pancreas; therefore, the significance of eosinophils in pancreatitis is not yet established. This review assesses the current understanding of eosinophilic pancreatitis and the important role of eosinophils in promoting pancreatic fibrosis including malignancy.
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http://dx.doi.org/10.5114/pg.2019.90631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089860PMC
March 2020

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

Interleukin (IL)-15 significance in aging associated asthma pathogenesis.

Authors:
Anil Mishra

Int J Cell Biol Physiol 2020 25;3. Epub 2020 Dec 25.

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

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138936PMC
December 2020

Radioprotective efficacy of GSH based peptidomimetic complex of manganese against radiation induced damage: DT(GS)Mn(II).

Free Radic Biol Med 2019 12 21;145:161-174. Epub 2019 Sep 21.

Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi, 110054, India.

The adverse effects of ionizing radiation (IR) on biological tissues are mediated via increased production of reactive oxygen species (ROS) often resulting in life-threatening injuries. The effects of ionizing radiation on cells include the formation of ROS, DNA single-strand breaks, double-strand breaks, and extensive base modifications inducing the complex DNA damage. The capacity to endure the radiation insult lies in the biochemical mechanisms and structural properties in many bacterial species such as Deinococcus radiodurans and Thermococcus radiotolerans. In addition, a mechanistic link has established between the presence and accumulation of short peptides and Mn in the protection of bacteria (Deinococcus radiodurans) from the harmful ionizing radiation. This paradigm has opened up novel avenues of radioprotection in diverse settings and systems for human application. We hereby report a new bifunctional system that comprises of thiol groups in the form of Glutathione (GSH), and manganese to mimic the above system for radioprotection. The present study, therefore, adopts a novel approach to use GSH complexed Mn, and this conjugated system is complying with the prerequisite for radioprotection as seen in the above mechanism. This unique conjugate DT(GS)Mn(II) was evaluated for its efficacy invitro and invivo. Radioprotective efficacy of DT(GS)Mn(II) on NIH/3T3 cells revealed that compound could significantly protect cells against radiation-induced toxicity as compared to the standard compound N-acetyl cysteine. Pre-treatment of DT(GS)Mn(II) increased the survival of mice by 50% compared to radiation alone treatment group. A significant decrease in cytochrome c levels in the group pre-treated with test compound (0.50 ± 0.14) compared to radiation alone group (1.60 ± 0.07) was observed. DT(GS)Mn(II) attenuated radiation induced apoptosis by promoted expression of anti-apoptotic Bcl-2 along with suppression of cyt-c release and augmented cell survival following irradiation. A distinct improvement in villi length was observed in the group treated with DT(GS)Mn(II) with an average of 1546 ± 61 μm versus 763 ± 154 μm for radiation alone group. The present findings suggested DT(GS)Mn(II) is a promising radioprotective agent and exerts it protective effect both invitro and invivo systems by decreasing radiation induced cytotoxicity.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.09.023DOI Listing
December 2019
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